Datasets:

mi-rei

/

LLaMA_Pretraining_Data

like 0

NCT01872208

Failed

A Pilot Study for Evaluation of the Safety and Efficacy of Humacyte's Human Acellular Vascular Graft as an Above-Knee Femoro-Popliteal Bypass Graft in Patients With Peripheral Arterial Disease

Humacyte, Inc.

The purpose of this study is to assess the safety and efficacy of a novel, tissue-engineered vascular prosthesis, the Human Acellular Vessel (HAV). The HAV is intended as an alternative to synthetic materials and to autologous grafts in the creation of an above-knee femoro-popliteal bypass graft in patients with peripheral arterial disease.

The HAV is a sterile, non-pyrogenic, acellular tubular graft composed of human collagens and other natural extra-cellular matrix proteins. Upon implantation, it is anticipated (based on pre-clinical studies) that the collagen-based matrix comprising the graft will be infiltrated with host cells and re-modeled by the host. This will result in a vascular structure more similar to the histological composition of the native vascular tissue that may improve graft longevity and be less likely to become infected.

ALLOCATION: N/A; INTERVENTION MODEL: Single Group Assignment; PRIMARY PURPOSE: Treatment; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Change in HAV characteristics; TIME_FRAME: From day 5 to month 24 after HAV implantation.; DESCRIPTION: The incidence of aneurysm formation, anastomotic bleeding or rupture, graft infection and irritation/inflammation/infection at the implantation site will be assessed by Doppler ultrasound and tabulated.; > SECONDARY OUTCOME 1: MEASURE: Change from baseline in Panel Reactive Antibody (PRA); TIME_FRAME: From baseline to week 26 after HAV implantation.; DESCRIPTION: Assess changes in the Panel Reactive Antibody response over 6 months after graft implantation.; >; SECONDARY OUTCOME 2: MEASURE: Development of IgG antibodies; TIME_FRAME: From baseline to week 26 after HAV implantation.; DESCRIPTION: Determine whether IgG antibodies to the extracellular matrix material are formed in response to implantation of the HAVG over the 6 months after implantation.; >; SECONDARY OUTCOME 3: MEASURE: HAV patency rates; TIME_FRAME: At months 6, 12, 18 after HAV implantation.; DESCRIPTION: To determine the patency rates of the graft (primary, primary assisted and secondary).; >; SECONDARY OUTCOME 4: MEASURE: Graft interventions; TIME_FRAME: At days 5, 15, weeks 6, 12, 16, months 12, 18, 24 after HAV implantation.; DESCRIPTION: Determine the rates of interventions needed to maintain / restore patency in the graft.; >; SECONDARY OUTCOME 5: MEASURE: Effect of graft implantation on PAD symptoms; TIME_FRAME: From baseline to weeks 6, 12, 26, months 12, 18, 24 after HAV implantation.; DESCRIPTION: Assessment of any effect of graft implantation on claudication, rest pain and ischemic ulcers.; >; SECONDARY OUTCOME 6: MEASURE: Effect of graft on ankle-brachial index (ABI); TIME_FRAME: From baseline to weeks 6, 12, 26, months 12, 18, 24 after HAV implantation.; DESCRIPTION: Assessment of any effect of the graft on ankle-brachial index (ABI).; >;

ARM GROUP 1: <LABEL: Human Acellular Vessel (HAV); GROUP TYPE: Experimental; DESCRIPTION: HAV implantation to study participants.; >;

INTERVENTION 1: <TYPE: Biological; NAME: HAV implantation; DESCRIPTION: Patients will be implanted with a Human Acellular Vessel (HAV) as an above-knee femoro-popliteal bypass graft using standard vascular surgical techniques., >;

Inclusion Criteria: - Patients with symptomatic peripheral arterial disease who require above knee femoro-popliteal bypass surgery - Claudication distance of 200 m or less or rest pain or critical limb ischemia - Preoperative angiography or angio-CT shows superficial femoral artery occlusion of >10 cm AND graft length required ≤ 30 cm. This imaging may have been conducted up to 3 months prior to study entry provided that the patient's symptoms have remained stable since that time - Preoperative imaging shows at least two below knee vessels patent to the ankle with good runoff - Femoral artery occlusion is not considered suitable for endovascular treatment - Autologous vein grafts are not suitable or feasible e.g. because of severe venous disease or prior use of leg veins for other bypass surgery or there is a clinical need to preserve those veins for future bypass surgery in the coronary or peripheral circulation - Aged 18 to 80 years old, inclusive - Hemoglobin ≥ 10 g/dL and platelet count ≥ 100,000/mm3 prior to Day 1 - Other hematological and biochemical parameters within a range considered acceptable for the administration of general anesthesia prior to Day 1 - Adequate liver function, defined as serum bilirubin ≤ 1.5 mg/dL; GGT, AST, ALT, and alkaline phosphatase ≤ 2x upper limit of normal or INR ≤ 1.5 prior to Day 1. - Able to communicate meaningfully with investigative staff, competent to give written informed consent, and able to comply with entire study procedures - Able and willing to give informed consent - Life expectancy of at least 2 years Exclusion Criteria: - History or evidence of severe cardiac disease (NYHA Functional Class III or IV), myocardial infarction within six months prior to study entry (Day 1), ventricular tachyarrhythmias requiring continuing treatment, or unstable angina - Acute injury or active infection (including positive cultures of pathogenic bacteria) in the limb receiving the graft - Stroke within six (6) months prior to study entry (Day 1) - Treatment with any investigational drug or device within 60 days prior to study entry (Day 1) - Women of child bearing potential - Active diagnosis of cancer within the previous year - Immunodeficiency including AIDS / HIV - Documented hypercoagulable state or history of 2 or more DVTs or other spontaneous intravascular thrombotic events - Bleeding diathesis - Ongoing treatment with vitamin K antagonists or direct thrombin inhibitors or factor Xa inhibitors (e.g. dabigatran, apixaban or rivaroxaban) - Previous arterial bypass surgery (autologous vein or synthetic graft) in the operative limb - Previous angioplasty with stenting in the operative limb unless the graft anastomoses can be made at least 1cm distant from the site of the stent - Stenosis of >50% of the external iliac artery unless it is planned to treat this stenosis with angioplasty with or without stenting prior to, or at the time of, graft implantation - Distal graft anastomosis likely to be below the knee - Active autoimmune disease - symptomatic or requiring ongoing drug therapy - Active local or systemic infection (WBC > 15,000/mm3) - Known serious allergy to aspirin or penicillin - Any other condition which in the judgment of the investigator would preclude adequate evaluation of the safety and efficacy of the HAVG - Previous enrollment in this study - Employees of the sponsor or patients who are employees or relatives of the investigator

NCT02887859

Failed

A Phase 2 Study for the Evaluation of Safety and Efficacy of Humacyte's Human Acellular Vessel for Use as a Vascular Prosthesis for Femoro-Popliteal Bypass in Patients With Peripheral Arterial Disease

Humacyte, Inc.

This study will evaluate how well Humacyte's Human Acellular Vessel (HAV) works when surgically implanted into a leg to improve blood flow in patients with peripheral arterial disease (PAD). This study will also evaluate how safe it is to use the HAV in this manner.

This is a prospective, open label, single treatment arm, multicenter phase 2 study to evaluate the safety and efficacy of the HAV in patients with PAD undergoing femoro-popliteal bypass surgery. The primary objective of this study is to evaluate the safety and tolerability of the HAV in these patients and to determine the patency of the Humacyte HAV at 12 months post-implantation. The secondary objectives of this study are to further assess safety in terms of PRA response, and to determine the rates of HAV interventions required to keep the HAV patent. There is no formal hypothesis testing planned; the study involves only a single, open-label treatment group.

ALLOCATION: N/A; INTERVENTION MODEL: Single Group Assignment; PRIMARY PURPOSE: Treatment; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Number of Participants With Aneurysm Formation, Anastomotic Bleeding or Spontaneous Rupture, HAV Infection, HAV Removal, and Significant Inflammation at the HAV Implantation Site; TIME_FRAME: 12 months; > SECONDARY OUTCOME 1: MEASURE: Number of Participants With a Change in Panel Reactive Antibodies (PRA) From Baseline; TIME_FRAME: 12 months; >; SECONDARY OUTCOME 2: MEASURE: Changes From Baseline in Hematology Parameters - Hemoglobin; TIME_FRAME: 12 months; >; SECONDARY OUTCOME 3: MEASURE: Changes From Baseline in Coagulation Parameters - International Normalized Ratio (INR); TIME_FRAME: 12 months; >; SECONDARY OUTCOME 4: MEASURE: Changes From Baseline in Clinical Chemistry Parameters - Sodium, Potassium; TIME_FRAME: 12 months; >; SECONDARY OUTCOME 5: MEASURE: Number of Participants With HAV Interventions; TIME_FRAME: 12 months; DESCRIPTION: e.g., angioplasty, thrombectomy, surgical revision; >; SECONDARY OUTCOME 6: MEASURE: Mean Vascular Quality of Life Questionnaire (VascuQoL) Score (1-7) for Patients With PAD Symptoms; TIME_FRAME: 12 months; DESCRIPTION: scoring per Vascular Quality of Life Questionnaire (VascuQoL) Likert scale: 7, there is 1 (the worst) to 7 (the best possible); >; SECONDARY OUTCOME 7: MEASURE: Ankle Brachial Index (ABI); TIME_FRAME: 12 months; DESCRIPTION: Normal: 1.0 - 1.4 Borderline: 0.9 - 1.0 Mild PAD (peripheral artery disease): 0.8 - 0.9 Moderate PAD: 0.4 - 0.7 Severe PAD: < 0.4; >; SECONDARY OUTCOME 8: MEASURE: Six Minute Walk Test - Duration; TIME_FRAME: 12 months; >; SECONDARY OUTCOME 9: MEASURE: Microscopic Evidence of HAV Remodeling (Host Cells Within HAV); TIME_FRAME: 12 months; >; SECONDARY OUTCOME 10: MEASURE: Changes From Baseline in Hematology Parameters - Hematocrit; TIME_FRAME: 12 months; >; SECONDARY OUTCOME 11: MEASURE: Changes From Baseline in Hematology Parameters - Lymphocytes, Monocyte, Eosinophil, Basophil, White Blood Cell, and Neutrophil Counts; TIME_FRAME: 12 months; >; SECONDARY OUTCOME 12: MEASURE: Changes From Baseline in Coagulation Parameters - Activated Partial Thromboplastin Time; TIME_FRAME: 12 months; >; SECONDARY OUTCOME 13: MEASURE: Changes From Baseline in Clinical Chemistry Parameters - Calcium, BUN, Bilirubin, Creatinine, Glucose; TIME_FRAME: 12 months; >; SECONDARY OUTCOME 14: MEASURE: Changes From Baseline in Clinical Chemistry Parameters - Albumin; TIME_FRAME: 12 months; >; SECONDARY OUTCOME 15: MEASURE: Six Minute Walk Test - Distance; TIME_FRAME: 12 months; >;

ARM GROUP 1: <LABEL: HAV Treatment; GROUP TYPE: Experimental; DESCRIPTION: Human Acellular Vessel (HAV); >;

INTERVENTION 1: <TYPE: Biological; NAME: Human Acellular Vessel (HAV); DESCRIPTION: Patients will be implanted with a Human Acellular Vessel (HAV) as a femoro-popliteal bypass conduit using standard vascular surgical techniques, >;

Inclusion Criteria: 1. Patients with disabling symptomatic peripheral arterial disease 1. Rutherford stage 4 or 5 who require femoro-popliteal bypass surgery or 2. Rutherford stage 3 with severe claudication (less than 50 yards AND causing severe impairment of ability to work or undertake social activities) 2. Ankle - brachial index ≤ 0.6 in the study leg 3. Patient has failed adequate medical therapy which included 1. Exercise program 2. Smoking cessation therapy 3. Control of diabetes, hypertension and dyslipidemias 4. Antiplatelet therapy 4. Preoperative angiography or CT angiography shows superficial femoral artery occlusion AND required Humacyte Human Acellular Vessel (HAV) length of ≤ 38cm. This imaging may have been conducted up to 6 months prior to study entry provided that the patient's symptoms have remained stable since that time 5. Preoperative imaging shows at least one below knee vessel patent to the ankle with good runoff 6. Proximal HAV anastomosis is expected to be to the common femoral artery below the inguinal ligament or to the superficial femoral artery 7. Distal anastomosis is expected to be to the popliteal artery above the knee 8. Femoral artery occlusion is not considered suitable for endovascular treatment; e.g. long segment chronic total occlusion, previous failed stent or stent graft in the superficial femoral artery, previous failed endovascular treatment where the lesion could not be crossed 9. Autologous vein graft is not feasible in the judgment of the treating surgeon; e.g. because all suitable veins have been used previously for coronary or peripheral bypass, or pre-operative vein mapping shows inadequate length or quality of vein to complete the planned bypass 10. Aged 18 to 85 years old, inclusive 11. Hemoglobin ≥ 10g/dL and platelet count ≥ 100,000/mm3 at screening 12. Other hematological and biochemical parameters within a range considered acceptable for the administration of general anesthesia at screening 13. Adequate liver function, defined as serum bilirubin ≤ 1.5 mg/dL; and INR ≤ 1.5 at screening 14. Able to communicate meaningfully with investigative staff, competent to give written informed consent, and able to comply with entire study procedures 15. Life expectancy of at least 1 year Exclusion Criteria: 1. Leg at high risk of amputation (SVS WIfI stage 4) 2. Recent clinically significant trauma to the leg receiving the HAV 3. Severe active infection (SVS foot infection grade 3) in the leg receiving the HAV 4. Distal anastomosis planned to a below knee artery 5. History or evidence of severe cardiac disease (NYHA Functional Class III or IV), myocardial infarction within six months prior to study entry (Day 1), ventricular tachyarrhythmias requiring continuing treatment, or unstable angina 6. Stroke within six (6) months prior to study entry (Day 1) 7. Chronic renal disease such that multiple administrations of contrast agents may pose an increased risk of nephrotoxicity (eGFR<45mL/min) 8. Uncontrolled diabetes (HbA1c >10% at screening) 9. Treatment with any investigational drug or device within 60 days prior to study entry (Day 1) 10. Cancer that is being actively treated with a cytotoxic agent 11. AIDS / HIV infection 12. Documented hypercoagulable state or history as defined as either: 1. a biochemical diagnosis (e.g. Factor V Leiden, Protein C deficiency, etc.) - OR - 2. a clinical history of thrombophilia as diagnosed by 2 or more spontaneous intravascular thrombotic events (e.g. DVT, PE, etc.) within the previous 5 years 13. Spontaneous or unexplained bleeding diathesis clinically documented within the last 5 years or a biochemical diagnosis (e.g. von Willebrand disease, etc.). 14. Ongoing treatment with vitamin K antagonists or oral direct thrombin inhibitors or factor Xa inhibitors (e.g. dabigatran, apixaban or rivaroxaban ) 15. Previous arterial bypass surgery (autologous vein or synthetic graft) in the operative leg 16. Stenosis of >50% of the inflow aortoiliac system ipsilateral to the index leg. Any such stenosis must be corrected with angioplasty with or without stenting prior to, or at the time of, HAV implantation 17. Active autoimmune disease - symptomatic or requiring ongoing drug therapy 18. Active local or systemic infection (WBC > 15,000/mm3) 19. Known serious allergy to aspirin 20. Any other condition which in the judgment of the investigator would preclude adequate evaluation of the safety and efficacy of the Humacyte Human Acellular Vessel (HAV) 21. Previous exposure to HAV 22. Employees of the sponsor or patients who are employees or relatives of the investigator 23. Pregnant women or women planning to become pregnant (Women of child bearing potential, WOCBP, must use adequate contraception [hormonal or barrier method of birth control; abstinence] for the duration of study participation; WOCBP defined as not sterile or not > 1 year postmenopausal.)

NCT03005418

Failed

A Phase 2/3 Study for the Evaluation of Safety and Efficacy of Humacyte's Human Acellular Vessel for Vascular Replacement or Reconstruction in Patients With Life or Limb-threatening Vascular Trauma

Humacyte, Inc.

This study evaluates the use of the Human Acellular Vessel (HAV) in adults with vascular trauma below the neck who are undergoing vascular reconstructive surgery. There will be a torso cohort and a limb cohort. All subjects will be implanted with a HAV as an interposition vessel or bypass using standard vascular surgical techniques. There is no control arm.

This is a prospective, multicenter, multi cohort, non-randomized phase 2 study in up to 40 adult patients with life or limb threatening vascular trauma which requires surgical repair. There will be a limb cohort and a torso cohort. The limb cohort will include patients who require repair of a vessel contained to the upper or lower extremity. The torso cohort includes patients who require repair of vessels within the thorax (excluding the heart), abdomen, and retroperitoneum. Subjects will be implanted with a Humacyte Human Acellular Vessel (HAV) as an interposition vessel or bypass using standard vascular surgical techniques. There is no control arm. The active study duration for each study participant will be 36 months from HAV implantation or until HAV failure/ removal/ death if earlier. Follow up after month 12 will involve the capture of information on assessments performed at "standard of care" routine clinic visits or by telephone follow up with the patient or his/her physician with physical exam and ultrasound at month 24 and month 36 The total expected duration of the clinical study is 61 months (24 months of enrollment and 36 months of follow up).

ALLOCATION: N/A; INTERVENTION MODEL: Single Group Assignment; PRIMARY PURPOSE: Treatment; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: HAV primary patency; TIME_FRAME: 30 days; DESCRIPTION: Primary patency is defined as 'the interval from the time of access placement until any intervention designed to maintain or reestablish patency, access thrombosis or the measurement of patency', i.e., patent without interventions; > SECONDARY OUTCOME 1: MEASURE: Limb viability (avoidance of amputation; limb cohort only); TIME_FRAME: 36 months; >; SECONDARY OUTCOME 2: MEASURE: HAV primary patency; TIME_FRAME: 36 months; DESCRIPTION: Primary patency is defined as 'the interval from the time of access placement until any intervention designed to maintain or reestablish patency, access thrombosis or the measurement of patency', i.e., patent without interventions; >; SECONDARY OUTCOME 3: MEASURE: HAV primary assisted patency; TIME_FRAME: 36 months; DESCRIPTION: Primary assisted patency is defined as 'the interval from the time of access placement until access thrombosis or the time of measurement of patency, including intervening manipulations (surgical or endovascular interventions) designed to maintain the functionality of patent access' i.e., patent without an intervention to clear a thrombus; >; SECONDARY OUTCOME 4: MEASURE: HAV secondary patency; TIME_FRAME: 36 months; DESCRIPTION: Secondary patency is defined as 'the interval from the time of access placement until access abandonment', i.e., patent with or without interventions; >; SECONDARY OUTCOME 5: MEASURE: Rate of HAV interventions; TIME_FRAME: 36 months; >; SECONDARY OUTCOME 6: MEASURE: Patient survival; TIME_FRAME: 36 months; >; SECONDARY OUTCOME 7: MEASURE: HAV remodeling as shown by histopathology of any clinical explants; TIME_FRAME: 36 months; >; SECONDARY OUTCOME 8: MEASURE: Frequency of anastomotic bleeding or spontaneous rupture; TIME_FRAME: 36 months; >; SECONDARY OUTCOME 9: MEASURE: Frequency of HAV infection; TIME_FRAME: 36 months; >; SECONDARY OUTCOME 10: MEASURE: Frequency of HAV thrombosis; TIME_FRAME: 36 months; >; SECONDARY OUTCOME 11: MEASURE: Frequency of HAV pseudoaneursym formation; TIME_FRAME: 36 months; >; SECONDARY OUTCOME 12: MEASURE: Frequency of HAV aneursym formation; TIME_FRAME: 36 months; >; SECONDARY OUTCOME 13: MEASURE: Frequency of HAV of hemodynamically significant stenosis (>70% by duplex ultrasound criteria); TIME_FRAME: 36 months; >; SECONDARY OUTCOME 14: MEASURE: Frequency of HAV removal; TIME_FRAME: 36 months; >;

ARM GROUP 1: <LABEL: Human Acellular Vessel (HAV); GROUP TYPE: Experimental; DESCRIPTION: Patients with life or limb threatening traumatic injury to an arterial vessel in the limb or torso, other than the heart, will be implanted with the Humacyte Human Acellular Vessel (HAV) as an interposition vessel or bypass using standard vascular surgical techniques.; >;

INTERVENTION 1: <TYPE: Biological; NAME: Human Acellular Vessel (HAV); DESCRIPTION: The investigational medicinal product (IMP) - the Human Acellular Vessel (HAV) is a sterile acellular tubular graft composed of human collagen types I and III and other extracellular matrix proteins, including fibronectin and vitronectin which can be used for arterial bypass or reconstruction in patients with life or limb threatening vascular trauma. The vessel is 6 mm in diameter and approximately 42 cm in length. The product is supplied on a silicone mandrel immersed in sterile phosphate buffered saline in a sealed and labeled plastic container. The Humacyte HAV is implanted using standard vascular surgical techniques similar to placement of predicate peripheral vascular prostheses., >;

Inclusion Criteria: 1. Patients with life or limb threatening traumatic injury to an arterial vessel in the limb or torso, other than the heart, which requires replacement or reconstruction 2. Preoperative imaging or clinical examination indicates the damaged vessel has a defect length of ≤ 38cm and is appropriately size matched to the 6mm Human Acellular Vessel (HAV) per the judgment of the treating surgeon taking into account vasoconstriction and situational inflow and outflow considerations. 3. Autologous vein graft is either not feasible in the judgment of the treating surgeon (e.g. because of lack of availability of suitable conduit, presence of severe venous insufficiency) or is not desirable because of the urgency of revascularization 4. Aged 18 to 85 years old, inclusive 5. Able to communicate meaningfully with investigative staff, and able to comply with entire study procedures. If the patient is unconscious, then information from a reliable witness indicates that the patient would normally be able to comply with study procedures 6. Patient or relative is able, willing and competent to give informed consent 7. Life expectancy of at least 1 year Exclusion Criteria: 1. Mangled Extremity Severity Score (MESS) of ≥ 7 2. Limb at high risk of amputation despite vascular reconstruction (e.g., because of crush injury) 3. Catastrophic injuries that make survival unlikely (e.g. Abbreviated Injury Scale (AIS) > 5 or Injury Severity Score (ISS) >60) 4. HAV may not be used for coronary artery repair 5. Known pregnant women 6. Known medical condition which would preclude long term antiplatelet therapy after resolution of acute injuries 7. Any other condition which in the judgment of the investigator would preclude adequate evaluation of the safety and efficacy of the HAV 8. Previous exposure to HAV 9. Known participation in any investigational study within the last 30 days 10. Employees of the sponsor or patients who are employees or relatives of the investigator

NCT04111445

Failed

First-in-human (FIH), Open-Label, Phase I (Dose Escalation) Study of ADG116 in Patients With Advanced/Metastatic Solid Tumors

Adagene Inc

This is a FIH, open-label, Phase I dose-escalation study of ADG116 in subjects with advanced/metastatic solid tumors. Study drug, ADG116, is an anti -CTLA-4 fully human monoclonal antibody that specifically binds to human CTLA-4. ADG 116 administered intravenously (IV) over a period of 60-90 minutes. The study planned to treated 42 patients.

ALLOCATION: N/A; INTERVENTION MODEL: Sequential Assignment; PRIMARY PURPOSE: Treatment; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Number of participants experiencing dose-limiting toxicities; TIME_FRAME: From first dose of ADG116 (Week 1 Day 1) until 30days after the last ADG116 injection (up to 2 years); >

ARM GROUP 1: <LABEL: ADG116; GROUP TYPE: Experimental; >;

INTERVENTION 1: <TYPE: Drug; NAME: ADG116; DESCRIPTION: IV infusion at Day 1 of each cycle, >;

Inclusion Criteria - Male or female, 18-75 years of age at the time of consent. - Provide written informed consent. - Subjects with advanced and/or metastatic histologically or cytologically confirmed solid tumor who have not responded or progressed after standard therapies or for whom no further standard therapy exists or standard therapy is not available - Patients who are refractory or relapsed to prior anti-CTLA4 checkpoint inhibitors will also be recruited if they meet all eligibility criteria. - Eastern Cooperative Oncology Group (ECOG) performance status < 2. - Adequate organ and bone marrow function - Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within the 7 days prior to study Exclusion Criteria: - Pregnant or nursing females. - Treatment with any investigational drug within 4 weeks prior to the first dose of study drug - Grade ≥ 3 immune-related adverse events (irAE) or irAE that lead to discontinuation of prior immunotherapy. Untreated or uncontrolled central nervous system (CNS) tumors or metastases - Any active autoimmune disease or documented history of autoimmune disease. - Infection of human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) - Subjects requiring systemic treatment with corticosteroids or other immunosuppressive medications within 21 days before the planned first dose of study drug. - Current or prior history of pneumonitis, hepatitis, nephritis, colitis or thyroiditis. Peripheral neuropathy ≥ Grade 2. - History of clinically significant cardiac disease. - Uncontrolled current illness.

NCT04501276

Failed

A Phase 1b/2, Open-Label, Dose Escalation and Expansion Study of ADG116, ADG116 Combined With Toripalimab (Anti-PD-1 Antibody), ADG116 Combined With ADG106 (Anti-CD137 Antibody) in Patients With Advanced/Metastatic Solid Tumors

Adagene Inc

This is a Phase 1, open-label, dose escalation study in patients with advanced/metastatic solid tumors. Study drug, ADG116, is an anti -CTLA-4 fully human monoclonal antibody that specifically binds to human CTLA-4. ADG106, a fully human ligand-blocking agonistic anti-CD137 IgG4 mAb, is expected to enhance the activity of activated T cells. The enhanced antitumor efficacy results observed from the preclinical studies of ADG116 in combination with ADG106 or anti-PD-1 provided further support to explore such combinations in clinical settings for better patient responses.

ALLOCATION: Non-Randomized; INTERVENTION MODEL: Sequential Assignment; PRIMARY PURPOSE: Treatment; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Number of participants experiencing dose-limiting toxicities escalating dose levels in adults with advanced / metastatic solid tumors; TIME_FRAME: From first dose of ADG116 (Week 1 Day 1) until 21 days; > SECONDARY OUTCOME 1: MEASURE: Area under the time concentration curve (AUC) from time zero to infinity (AUC0-inf); TIME_FRAME: From first dose (Cycle 1 Day 1, ) until the last dose (up to 2 years); >; SECONDARY OUTCOME 2: MEASURE: Maximum (peak) plasma concentration (Cmax); TIME_FRAME: From first dose (Cycle 1 Day 1,) until the last dose (up to 2 years); >; SECONDARY OUTCOME 3: MEASURE: Time to maximum (peak) plasma concentration (Tmax); TIME_FRAME: From first dose (Cycle 1 Day 1,) until the last dose (up to 2 years); >; SECONDARY OUTCOME 4: MEASURE: Trough plasma concentration (Ctrough); TIME_FRAME: From first dose (Cycle 1 Day 1,) until the last dose (up to 2 years); >; SECONDARY OUTCOME 5: MEASURE: Incidence of ADAs; TIME_FRAME: From first dose (Cycle 1 Day 1,) until the last dose (up to 2 years); >; SECONDARY OUTCOME 6: MEASURE: Preliminary evidence of antitumor activity as characterized by objective response rate (ORR), disease control rate (DCR), duration of response (DOR), duration of stable disease, progression free survival (PFS), and overall survival (OS).; TIME_FRAME: From first dose of ADG116 (Week 1 Day 1) to 28 days post last dose; >;

ARM GROUP 1: <LABEL: Part A : Dose escalation of ADG116 monotherapy; GROUP TYPE: Experimental; >; ARM GROUP 2: <LABEL: Part B : Dose escalation of ADG116 combined with anti PD1 drug; GROUP TYPE: Experimental; >; ARM GROUP 3: <LABEL: Part C : Dose escalation of ADG116 combined with ADG106; GROUP TYPE: Experimental; >;

INTERVENTION 1: <TYPE: Drug; NAME: ADG116; DESCRIPTION: For monotherapy ADG116 (Part A), ADG116 will be administered IV over 60 90 minutes until disease progression, intolerable toxicities, or withdrawal of consent, or up to 2 years., >; INTERVENTION 2: <TYPE: Drug; NAME: ADG106; DESCRIPTION: For the ADG116-ADG106 combination regimen, ADG116 and ADG106 will be administered until disease progression, intolerable toxicities, or withdrawal of consent, or up to 2 years., >; INTERVENTION 3: <TYPE: Drug; NAME: anti PD1 drug; DESCRIPTION: For the ADG116-anti PD1 combination regimen, ADG116 and anti PD1 will be administered until disease progression, intolerable toxicities, or withdrawal of consent, or up to 2 years., >;

Inclusion Criteria: Patients must meet all of the following inclusion criteria to be eligible for participation in this study: 1. ≥ 18 years of age at the time of informed consent. 2. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 3. Patients with advanced or metastatic solid tumors, who have progressed after all standard therapies, or for whom no further standard therapy exists. 4. At least 1 measurable lesion at baseline according to the definition of RECIST v1.1. 5. Adequate organ function. Exclusion Criteria: • Patients who meet any of the following criteria cannot be enrolled: 1. Pregnant or breastfeeding females. 2. Childbearing potential who does not agree to the use of contraception during the treatment period.. 3. Treatment with any investigational drug within washout period. 4. Grade ≥ 3 immune-related AEs (irAEs) or irAE that lead to discontinuation of prior immunotherapy. 5. Central nervous system disease involvement 6. History or risk of autoimmune disease. 7. History of life-threatening hypersensitivity or known to be allergic to protein drugs or recombinant proteins or any ingredients contained in the ADG116 drug formulation. 8. Patients requiring systemic treatment with corticosteroids 9. Patients receiving granulocyte colony stimulating factor (G-CSF), within 14 days prior to the first dose of the study drug. 10. Any uncontrolled active infections requiring systemic antimicrobial treatment (viral, bacterial, or other), or uncontrolled or poorly controlled, asthma, chronic obstructive pulmonary disease (COPD). 11. Major surgery within 4 weeks prior to the first dose of the study drug. 12. Has had an allogeneic tissue/solid organ transplant.

NCT04645069

Failed

A First-in-Human (FIH), Open-Label, Phase 1/2 Dose Escalation and Expansion Study of ADG126, ADG126 in Combination With Anti PD1 Antibody, and ADG126 in Combination With ADG106 in Patients With Advanced/Metastatic Solid Tumors

Adagene Inc

ADG126, ADG126 in Combination with anti-PD1 antibody, and ADG126 in Combination with ADG106 in Patients with Advanced/Metastatic Solid Tumors .

ADG126 is a novel anti-CTLA-4 fully human IgG1 antibody prodrug that is modified with Adagene Safebody technology to control the activation of anti-CTLA4 activity.ADG106 is a fully human ligand-blocking, agonistic anti-CD137 IgG4 mAb which is expected to enhance the activity of activated T cells. The enhanced antitumor efficacy results observed from the preclinical studies of ADG126 in combination with ADG106 or anti-PD-1 provided further support to explore such combinations in clinical settings for better patient responses.

ALLOCATION: Non-Randomized; INTERVENTION MODEL: Sequential Assignment; PRIMARY PURPOSE: Treatment; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Number of participants experiencing dose-limiting toxicities escalating dose levels in adults with advanced / metastatic solid tumors; TIME_FRAME: From first dose of ADG126 (Week 1 Day 1) until 21 days; > SECONDARY OUTCOME 1: MEASURE: Antidrug antibodies (ADAs); TIME_FRAME: From first dose (Cycle 1 Day 1, ) until the last dose (up to 2 years); >; SECONDARY OUTCOME 2: MEASURE: Area under the time concentration curve (AUC) from time zero to infinity (AUC0-inf); TIME_FRAME: From first dose (Cycle 1 Day 1, ) until the last dose (up to 2 years); >; SECONDARY OUTCOME 3: MEASURE: Maximum (peak) plasma concentration (Cmax); TIME_FRAME: From first dose (Cycle 1 Day 1, ) until the last dose (up to 2 years); >; SECONDARY OUTCOME 4: MEASURE: Time to maximum (peak) plasma concentration (Tmax); TIME_FRAME: From first dose (Cycle 1 Day 1, ) until the last dose (up to 2 years); >; SECONDARY OUTCOME 5: MEASURE: Trough plasma concentration (Ctrough); TIME_FRAME: From first dose (Cycle 1 Day 1, ) until the last dose (up to 2 years); >;

ARM GROUP 1: <LABEL: ADG126 mono dose escalation; GROUP TYPE: Experimental; DESCRIPTION: ADG126 monotherapy dose escalation will be traditional 3+3 cohort design.; >; ARM GROUP 2: <LABEL: ADG126 mono dose expansion; GROUP TYPE: Experimental; DESCRIPTION: Monotherapy dose expansion is designed to evaluate the preliminary antitumor activity of ADG126 at RP2D or the doses approved by the SRC.; >; ARM GROUP 3: <LABEL: ADG126-anti PD1 drug dose escalation; GROUP TYPE: Experimental; DESCRIPTION: Combination therapy will commence at a dose level lower than the cleared dose from the monotherapy dose escalation arms and approved by the SRC.; >; ARM GROUP 4: <LABEL: ADG126-anti PD1 drug dose expansion; GROUP TYPE: Experimental; DESCRIPTION: Combination therapy expansion will commence at RP2D or the dose approved by the SRC.; >; ARM GROUP 5: <LABEL: ADG126-ADG106 dose escalation; GROUP TYPE: Experimental; DESCRIPTION: Combination therapy will commence at a dose level lower than the cleared dose from the monotherapy dose escalation arms and approved by the SRC.; >; ARM GROUP 6: <LABEL: ADG126-ADG106 dose expansion; GROUP TYPE: Experimental; DESCRIPTION: Combination therapy expansion will commence at RP2D or the dose approved by the SRC.; >;

INTERVENTION 1: <TYPE: Biological; NAME: ADG126 Mono; DESCRIPTION: ADG126 will be administered as an IV infusion over 30-60 minutes ± 15 minutes., >; INTERVENTION 2: <TYPE: Biological; NAME: ADG126-anti PD1; DESCRIPTION: ADG126-toripalimab combination regimen will receive of toripalimab 15 to 30 minutes after the end of the ADG126 infusion, >; INTERVENTION 3: <TYPE: Biological; NAME: ADG126-ADG106; DESCRIPTION: ADG126-ADG106 combination regimen will be receive of ADG106 15 to 30 minutes after the end of the ADG126 infusion, >;

Inclusion criteria 1. Adults ≥18 years of age. 2. ECOG performance status 0 or 1. 3. Estimated life expectancy of more than 12 weeks . 4. Patients with advanced or metastatic solid tumors, confirmed by histologically or pathologically documented, who have progressed after all standard therapies, or for whom no further standard therapy exists. 5. At least 1 measurable lesion at baseline according to the definition of RECIST v1.1. 6. Adequate organ function. 7. Meets the additional tumor type requirements as specified in Protocol. Exclusion Criteria: 1. Treatment with any investigational drug within washout period. 2. Major trauma or major surgery within 4 weeks prior to first dose of study drug(s) 3. History of significant immune-mediated AE. 4. Central nervous system (CNS) disease involvement. 5. Prior organ allograft transplantations or allogeneic peripheral blood stem cell (PBSC)/bone marrow (BM) transplantation 6. Clinically significant cardiac disease. 7. Evidence of active uncontrolled viral, bacterial, or systemic fungal infection. 8. Patients who received: 1. A COVID-19 vaccine within 7 days of Cycle 1 Day 1. 2. Live vaccines or live-attenuated vaccines within 28 days prior to Cycle 1 Day 1. 9. Known active infection of HBV/BCV/HIV. 10. Patients requiring systemic treatment with corticosteroids or other immunosuppressive medications (>10 mg/day prednisone or equivalent). 11. Second primary malignancy not in remission for greater than 3 years. 12. History(within the last 5 years) or risk of autoimmune disease. 13. Pregnant or breastfeeding females. 14. Childbearing potential who does not agree to the use of contraception during the treatment period.

NCT04678648

Failed

A Phase Ia/Ib, Open Label, Multi-center, Non-randomized Dose Escalation and Dose Expansion Study of RSC-1255 in Patients With Advanced Solid Tumor Malignancies

RasCal Therapeutics, Inc.

RSC-101 is a Phase 1a/1b clinical trial of RSC-1255 in adult study participants with advanced solid tumor malignancies who are intolerant of existing therapies known to provide clinical benefit, have disease that has progressed after standard therapy, or have previously failed other therapies. The study has two phases. The purpose of Phase 1a (Dose Escalation) is to confirm the appropriate treatment dose and Phase 1b (Dose Expansion) is to characterize the safety and efficacy of RSC-1255.

RSC-1255 is an orally bioavailable, small-molecule direct pan-mutant and wild-type RAS inhibitor. RSC-101 is a Phase 1a/1b, open-label, multi-center, non-randomized, Dose Escalation and Dose Expansion study in participants with advanced solid tumor malignancies. Study enrollment is approximately 134 participants. All participants receive oral RSC-1255, twice daily as monotherapy. Following Phase 1a (Dose Escalation) to identify the Maximum Tolerated Dose and Recommended Dose for use in Phase 1b, additional participants are enrolled in the Phase 1b (Dose Expansion) to further characterize the safety, pharmacology, and the clinical efficacy of RSC-1255.

ALLOCATION: N/A; INTERVENTION MODEL: Sequential Assignment; PRIMARY PURPOSE: Treatment; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Maximum Tolerated Dose (MTD) for RSC-1255 as monotherapy; TIME_FRAME: Approximately 12 months; DESCRIPTION: The number and type of dose-limiting toxicities (DLTs) as defined in the protocol that occur during the first 28 days of treatment and all maximum grade of all maximum grade of all treatment-related events using CTCAE V5.0 will be used to identify a safe and tolerable dose.; > SECONDARY OUTCOME 1: MEASURE: Adverse event profile of RSC-1255; TIME_FRAME: Approximately 24 months; DESCRIPTION: Toxicities will be graded according to CTCAE V5.0.; >; SECONDARY OUTCOME 2: MEASURE: Overall Survival (OS); TIME_FRAME: Approximately 24 months; DESCRIPTION: Overall Survival will be assessed using RECIST V1.1.; >;

ARM GROUP 1: <LABEL: RSC-1255 Treatment; GROUP TYPE: Experimental; DESCRIPTION: Single Arm Study. All study participants receive RSC-1255.; >;

INTERVENTION 1: <TYPE: Drug; NAME: RSC-1255 Dose Escalation; DESCRIPTION: Phase 1a will enroll 24-34 participants to identify the dose limiting toxicity (DLT), recommended Phase 1b dose, and the safety and tolerability of RSC-1255. RSC-1255 is administered orally twice daily, without food. Each cycle is 21 days., >; INTERVENTION 2: <TYPE: Drug; NAME: RSC-1255 Dose Expansion; DESCRIPTION: Phase 1b will enroll 48-104 participants to further characterize the safety, pharmacology, and clinical efficacy of RSC-1255. RSC-1255 is administered orally twice daily, without food. Each cycle is 21 days., >;

Inclusion Criteria (Key Factors): 1. Has pathologically confirmed advanced or metastatic malignancy characterized by one or more of the following: - Participant is intolerant of existing therapy(ies) known to provide clinical benefit for their condition - Malignancy is refractory to existing therapy(ies) known to potentially provide clinical benefit - Malignancy has progressed on standard therapy 2. Has evaluable or measurable tumor(s) in dose-escalation by standard radiological and/or laboratory assessments as applicable to their malignancy. 3. Has adequate performance status (PS): Eastern Co-operative Oncology Group (ECOG). 4. Is age ≥ 18 years. Exclusion Criteria (Key Factors): 1. Participants receiving cancer therapy at the time of enrollment. 2. Any clinically significant disease or condition affecting a major organ system. 3. Significant cardiovascular disease or electrocardiogram (ECG) abnormalities. 4. Known Gilbert's disease. 5. Has had a previous (within 2 years) or has a current malignancy other than the target cancer.

NCT02187627

Completed

Evaluation of [11C]RO6924963, [11C]RO6931643, and [18F]RO6958948 as Tracers for Tau Imaging With Positron Emission Tomography in Healthy Control Subjects and Subjects With Alzheimer's Disease

Hoffmann-La Roche

This study is designed to obtain basic information on three PET imaging tracers developed to detect tau pathology in the brain. In this study, healthy control participants and participants with AD will be studied. Information collected will include brain and plasma kinetics, tissue distribution (in the brain), radiation dosimetry, and test-retest variability of the signal in the brain. The study will consist of Part 1, Part 2A, and Part 2B. During Part 1, imaging data will be assessed on an ongoing basis and based on data, one tracer will be prioritized over the other two tracers. The tracer selected will be further investigated in Part 2A and Part 2B.

ALLOCATION: Non-Randomized; INTERVENTION MODEL: Parallel Assignment; PRIMARY PURPOSE: Basic Science; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Part 1: Standard Uptake Value (SUV), as Assessed by Tau PET Brain Scan; TIME_FRAME: Day 1 up to Day 14; > SECONDARY OUTCOME 1: MEASURE: Part 2A: Absolute Percentage Difference Between Test and Retest of SUVR; TIME_FRAME: Days 1, 28; >; SECONDARY OUTCOME 2: MEASURE: Part 2A: Absolute Percentage Difference Between Test and Retest of VT; TIME_FRAME: Days 1, 28; >; SECONDARY OUTCOME 3: MEASURE: Part 2B: Effective dose (ED), as Assessed by Whole Body PET Scan; TIME_FRAME: From the time of tracer injection on Day 1 up to 120 minutes post injection; >; SECONDARY OUTCOME 4: MEASURE: Part 2A: Absolute Percentage Difference Between Test and Retest of SUV; TIME_FRAME: Days 1, 28; >; SECONDARY OUTCOME 5: MEASURE: Percentage of Participants With Adverse Events (AEs); TIME_FRAME: Part 1: Day 1 up to Day 28, Part 2a: Day 1 up to Day 42, Part 2b: Day 1 up to Day 15; >;

ARM GROUP 1: <LABEL: Part 1: Tracer Selection; GROUP TYPE: Experimental; DESCRIPTION: Participants will receive a single dose of one tracer on one occasion and a single dose of a different tracer after 7 to 14 days and will be followed for 7 to 14 days for safety. At the end of Part 1, one tracer with the best performance will be selected for further study in Part 2.; >; ARM GROUP 2: <LABEL: Part 2A: Test-Retest; GROUP TYPE: Experimental; DESCRIPTION: Participants will receive a single dose of selected tracer from Part 1 on one occasion and then same tracer will be administered after 6 weeks. Participants will be followed for 7 to 14 days after last PET tracer administration for safety.; >; ARM GROUP 3: <LABEL: Part 2B: Dosimetry; GROUP TYPE: Experimental; DESCRIPTION: Participants will receive a single dose of selected tracer from Part 1 and will be followed for 7 to 14 days for evaluation of radiation dosimetry.; >;

INTERVENTION 1: <TYPE: Drug; NAME: [11C]RO6924963; DESCRIPTION: Radiolabeled low molecular weight compound, administered as single intravenous injection. The mass dose of [11C]RO6924963 injected will be </=10 micrograms (mcg), injection volume </=20 milliliters (mL). Target injected activity for [11C]RO6924963 will be 370-740 megabecquerel (MBq) [10-20 millicurie (mCi)]., >; INTERVENTION 2: <TYPE: Drug; NAME: [11C]RO6931643; DESCRIPTION: Radiolabeled low molecular weight compound, administered as single intravenous injection. The mass dose of [11C]RO6931643 injected will be </=10 mcg, injection volume </=20 mL. Target injected activity for [11C]RO6931643 will be 370-740 MBq (10-20 mCi)., >; INTERVENTION 3: <TYPE: Drug; NAME: [18F]RO6958948; DESCRIPTION: Radiolabeled low molecular weight compound, administered as single intravenous injection. The mass dose of [18F]RO6958948 injected will be </=10 mcg, injection volume </=20 mL. Target injected activity for [18F]RO6958948 will be 185-370 MBq (5-10 mCi). The final activity of [18F] RO6958948 will be adjusted up to 10 mCi per scan to allow sufficient counts by end of 200 minutes post radiotracer injection., >;

Inclusion Criteria: Inclusion Criteria for All Participants - Agreement to use highly effective contraception measures - If participants are on any concomitant medication, the indication and dosage of these medicines should be stable for at least 4 weeks prior to study start with the expectation that no relevant changes in use or dose will occur throughout the study - Body mass index (BMI) between 18 and 32 kilograms per square meter (kg/m^2) - Weight less than or equal to (</=) 300 pounds (lb) Inclusion Criteria for Healthy Control Participants - Healthy "young" control participants aged 25-40 years or healthy "elderly" control participants aged greater than or equal to (>/=) 50 years - Normal cognitive function, including a normal Mini Mental State Examination (MMSE) score as judged by the investigator - Healthy control participants who participate in Part 2B: must be less than (<) 195 centimeter (cm) (6 feet, 5 inches) tall in order to accommodate the whole body scanning Inclusion Criteria for Participants with a Diagnosis of Probable AD - Diagnosis of probable AD, according to the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria - Participants aged >/= 50 years - A study partner able to accompany the participant to all visits and answer questions about the participant - MMSE score between 16 and 26, inclusive Exclusion Criteria: Exclusion Criteria for All Participants - History or presence of a neurological diagnosis other than AD that may influence the outcome or analysis of the scan results; examples include but are not limited to stroke, traumatic brain injury, space occupying lesions, non-Alzheimer's tauopathies, and Parkinson's disease - Participants with a medical history that includes known autosomal dominant AD mutations in amyloid precursor protein (APP) or presenilin (PS1, PS2) or mutations in genes that cause other types of autosomal dominant familial dementia - History or presence of any clinically relevant hematological, hepatic, respiratory, cardiovascular, renal, metabolic, endocrine, or central nervous system disease or other medical conditions that are not well controlled, may put the participant at risk, could interfere with the objectives of the study, or make the participant unsuitable for participation in the study for any other reason in the opinion of the principal investigator - Clinically relevant pathological findings in physical examination, electrocardiogram, or laboratory values at the screening assessment that could interfere with the objectives of the study - Known history of clinically significant infectious disease including acquired immunodeficiency syndrome (AIDS) or serological indication of acute/chronic hepatitis B or C or human immunodeficiency virus infection - Pregnancy or lactation - Unsuitable veins for repeated venipuncture - Current symptoms of allergy and/or severe allergy to drugs in medical history - Alcohol consumption that averages >3 drinks daily or regular smoker (>10 cigarettes, >3 pipefuls, or >3 cigars per day) - Coffee (or tea) consumption >10 cups per day or methylxanthine-containing drinks >1.5 liters per day (L/day) - Have received an investigational medication within the last 3 months or 5 times (x) the elimination half-life, whichever is longer, prior to Day 1 (i.e., enrollment) Exclusion Criteria Related to Trial Procedures - Presence of pacemakers; aneurysm clips; artificial heart valves; ear implants; foreign metal objects in the eyes, skin, or body, or any other circumstance (e.g. claustrophobia) that would contraindicate a magnetic resonance imaging (MRI) scan - For participants of Part 1 and Part 2A, any contraindications to arterial cannulation Exclusion Criterion for Participants with Probable Alzheimer's Disease - Has received treatment that targeted amyloid-beta or tau within the last 24 months

NCT00606424

Completed

An Exploratory, Open Label, Single Center Study of [F-18]HX4

Siemens Molecular Imaging

[F-18]HX4 is being developed as a diagnostic radiopharmaceutical for PET imaging. This trial is looking at the safety of [F-18]HX4. The Sponsor is seeking to determine if [F-18]HX4 may serve as a clinically useful hypoxia marker in diagnostic imaging, allowing the rational application of hypoxia related therapies to those patients most likely to benefit from them. Tumor hypoxia, a situation where tumor cells have been deprived of oxygen, caused cancer cells to become more resistant to the effects of radiotherapy and chemotherapy. A non-invasive study characterizing tumor hypoxia would facilitate the development of targeted therapies. The population to be studied consists of a total of ten (10) adult subjects, including, four normal volunteers and six cancer subjects, the latter with a confirmed diagnosis of head and neck cancer, as defined by the protocol eligibility criteria. The objectives of this exploratory study are to: - Gain information on bio-distribution of [F-18]HX4, and to evaluate the PET images of [F-18]HX4 for resolution, signal to background ratio for both intermediate levels of oxygenation, and at extreme levels hypoxia - Use this eIND in order to obtain the necessary information to file an IND application with the FDA. The information collected under this exploratory study will not be used for diagnostic purposes, to assess the subject's response to therapy, or for clinical management of the subject. - Begin collection of baseline imaging data - Collect [F-18]HX4 metabolism data - Gain information to improve study design and the conduct of future trials This investigation will be conducted as an exploratory, open-label, non-randomized, uncontrolled, single center, safety study. The trial is expected to begin subject enrollment in early January 2008 and end subject participation in June 2008. The duration of an individual subject's participation includes a screening visit, followed by participation in the actual study starting with the day of dosing with imaging sessions lasting several hours, concluding with a next day safety follow-up visit. Individual doses of [F-18]HX4 shall not exceed 20 mCi. The IP will be administered through a previously placed suitably sized angiocatheter or a butterfly needle. Prior to injection, qualified site personnel will assay the dose. After IP administration several PET imaging series will be acquired. Also, in order to assess major organ function and electrolyte levels, a metabolites analysis will be performed for this study from predose to 90 minutes postdose. In order to determine the quantity of [F-18]HX4 and labeled metabolites excreted by the kidney,urine will be collected and pooled at the designated intervals after administration of the investigational product. This excretion data will provide supportive information for calculating human dosimetry estimates from PET imaging biodistribution data collected in human subjects. For cancer subjects, a tissue biopsy will have been taken or be scheduled to be performed. The biopsy sample will be examined for hypoxic biomarker(s) using immunohistochemistry methods.

ALLOCATION: Non-Randomized; INTERVENTION MODEL: Single Group Assignment; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Safety will be the outcome demonstrated in this clinical trial through analyses of adverse events in subjects who receive study drug.; TIME_FRAME: 24 hours; >

INTERVENTION 1: <TYPE: Drug; NAME: 20 mCi dose for a 50 kg individual of [F-18]HX4; DESCRIPTION: All subjects, normal volunteers and cancer subjects will receive HX4 administered through a previously placed suitably sized angiocatheter or a butterfly needle. Prior to injection, qualified site personnel will assay the dose in the dose calibrator and document the activity of the dose and time of assay. After injection, the line will be flushed with saline (approximately 10 mL)., >;

Inclusion Criteria: Normal Volunteers - Subject may be male or female and of any race / ethnicity - Subject is > 18 years old at the time of investigational product administration - Subject or subject's legally acceptable representative provides written informed consent - Subject is capable of complying with study procedures - Subject is capable of communicating with study personnel Cancer Subjects - Subject may be male or female and of any race / ethnicity - Subject is > 18 years old at the time of investigational product administration - Subject or subject's legally acceptable representative provides written informed consent - Subject is capable of complying with study procedures - Subject is capable of communicating with study personnel - Subject must have histologically confirmed stage III, or IV squamous cell carcinoma of the head and neck whose primary origin was from the oral cavity, oropharynx, hypopharynx, or larynx. Carcinoma must be staged using the American Joint Committee on Cancer (AJCC) staging criteria version 6. Adequate tumor must be amenable to biopsy via outpatient methods - According to the Karnofsky Performance Status Scale, the subject has a value of ≥ 60% at time of screening - Subject is scheduled for a clinical FDG PET scan either within 48 hours prior to (with no intervention in between the two scans), or within 48 hours after the investigational [F-18]HX4 PET scan - Subject must have normal organ and renal function as defined: - total bilirubin within normal institutional limits - AST(SGOT)/ALT(SGPT) less than or equal to 2.5 x institutional upper limit of normal - creatinine within normal institutional limits - BUN within normal institutional limits Exclusion Criteria: Normal Volunteers - Subject is younger than 18 years old at the time of investigational product administration - Female subject is pregnant or nursing--Serum pregnancy test must be negative; test must be completed within 24 hours of dosing or female subject must be either surgically sterilized or post- menopausal, defined as at least one year without menses as reported by the subject - Subject is unable to remain still for duration of imaging procedure (~40 mins) - Subject has previously received [F-18]HX4 at any time, or has been involved in an investigative, radioactive research procedure within the past year - Subject has any other condition or personal circumstance that, in the judgment of the investigator, might interfere with the collection of complete good quality data - Subject has a history of significant prescription or non-prescription drug, or alcohol abuse, including but not limited to marijuana, cocaine, heroin or derivatives. Cancer Subjects - Subject is younger than 18 years old at the time of investigational product administration - Female subject is pregnant or has a positive serum pregnancy test - Subject is unable to remain still for duration of imaging procedure - Subject has a history of significant renal disease - Subject has previously received [F-18]HX4 at any time, or any other investigational product in the past thirty days. - Subject has been involved in an investigative, radioactive research procedure within the past year - Inadequate tumor sites or volume to allow for biopsy - Subject has any other condition or personal circumstance that, in the judgment of the investigator, might interfere with the collection of complete and good quality data - Subject has a history of significant prescription or non-prescription drug, or alcohol abuse, including but not limited to marijuana, cocaine, heroin or derivatives

NCT01213030

Completed

Clinical Evaluation of the New Hypoxia Imaging Agent HX4

Siemens Molecular Imaging

Positron Emission Tomography (PET) with fluorine-18 fluoromisonidazole (FMISO) has been used for several years as a non invasive imaging technique to study tumor hypoxia. Several experimental and clinical studies have indicated that FMISO uptake of tissues is correlated with tissue oxygen tension and that FMSO PET allows non-invasive differentiation between hypoxic and normoxic tumors. Currently, FMISO-PET represents the best characterized and validated noninvasive hypoxia imaging technique. Nevertheless, clinical studies have also shown the limitations of FMISO PET. Accumulation of FMISO in hypoxic tumors is relatively low, resulting in a low contrast between hypoxic tumors and surrounding normal tissues. In addition, imaging needs to be started relatively late after tracer injection (about 3 hours post-injection), when a significant percentage of the fluorine-18 label has already decayed and the count statistics of the PET images are relatively low. Because of these limitations, FMISO PET is still only used at a few research centers, despite high clinical interest in hypoxia imaging.

Objective of the study The aim of this study is to: - evaluate a hypoxia imaging agent, HX4, in patients with solitary tumors (i.e., locally advanced head and neck cancer) - gain information on bio-distribution of [F-18]HX4 - compare the PET images of [F-18] FMISO to [F-18]HX4 for resolution, signal to background ratio, and tumor/blood ratio

ALLOCATION: Non-Randomized; INTERVENTION MODEL: Crossover Assignment; PRIMARY PURPOSE: Diagnostic; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Efficacy of a hypoxia imaging agent, HX4, in patients with solitary tumors (i.e., locally advanced head and neck cancer); TIME_FRAME: 6 months; > SECONDARY OUTCOME 1: MEASURE: Resolution, signal to background ratio, and tumor/blood ratio of PET images with [F-18] FMISO and [F-18]HX4; TIME_FRAME: 6 months; >;

ARM GROUP 1: <LABEL: 10 mCi HX4; GROUP TYPE: Active Comparator; DESCRIPTION: Patient will be injected with [F-18] FMISO; >; ARM GROUP 2: <LABEL: 10 mCi FMISO; GROUP TYPE: Active Comparator; DESCRIPTION: Patient will be injected with [F-18] HX4; >;

INTERVENTION 1: <TYPE: Drug; NAME: [F-18] FMISO; DESCRIPTION: 10 mCi [F18] HX4 and 10 mCi [F-18] FMISO within 7 days of each other regardless of sequence, >; INTERVENTION 2: <TYPE: Drug; NAME: [F-18] HX4; DESCRIPTION: 10 mCi [F18] HX4 and 10 mCi [F-18] FMISO within 7 days of each other regardless of sequence, >;

Inclusion Criteria: - Patient may be male or female and of any race / ethnicity - Patient is > 18 years old at the time of investigational product administration - Patient or patient's legally acceptable representative provides written informed consent - Patient is capable of complying with study procedures - Patient is capable of communicating with study personnel - Patient must have histologically confirmed stage III, or IV squamous cell carcinoma of the head and neck whose primary origin was from the oral cavity, oropharynx, hypopharynx, or larynx. - According to the Karnofsky Performance Status Scale, the patient has a value of ≥ 60% at time of screening - Patient must have normal organ and renal function as defined: - total bilirubin within normal institutional limits - AST(SGOT)/ALT(SGPT) less than or equal to 2.5 x institutional upper limits of normal - creatinine within normal institutional limits - BUN within normal institutional limits - PT and PTT < 2.0 x institutional upper limits of normal Exclusion Criteria: - Patient is younger than 18 years old at the time of investigational product administration - Female patient is pregnant or has a positive serum pregnancy test - Patient is unable to remain still for duration of imaging procedure - Patient has a history of significant renal disease - Patient has previously received [F-18]HX4 at any time, or any other investigational product in the past thirty days. - Patient has been involved in an investigative, radioactive research procedure within the past year - Inadequate tumor sites or volume to allow for biopsy - Patient has any other condition or personal circumstance that, in the judgment of the investigator, might interfere with the collection of complete and good quality data

NCT01075399

Completed

A Pilot, Phase II , Open Label, Nonrandomized, Multi- Center Study of [F 18]HX4 Positron Emission Tomography (PET) to Detect Hypoxia in Tumors

Siemens Molecular Imaging

This pilot phase II study is designed as a test and retest study to investigate [F 18]HX4 as a reliable non-invasive PET imaging marker for detection of tumor hypoxia regions and to establish a threshold for [F 18]HX4 uptake in the tumor. The study will evaluate the relationship between hypoxia biomarkers (HIF1α and CA-IX) by immunohistochemistry (IHC) and tumor uptake of [F 18]HX4 by PET imaging.

A Pilot Phase II Study The primary objectives for this study are: - To test the reproducibility of [F-18] HX-4 uptake in tumors by imaging the same patient on sequential days in a test-retest protocol - To test and confirm the relationship between hypoxia in tumors measured by hypoxia related biomarkers (HIF1α and CA-IX) with immunohistochemistry (IHC) and regional [F-18 HX-4] uptake in tumors with PET/CT. The secondary objectives for this study are: - To continue safety evaluation by the collection of safety data from all patients - To establish the threshold for hypoxia uptake in [F- 18]HX4 PET imaging - To collect data to test [F-18]HX4 PET imaging as a predictor of response in a subgroup of patients receiving treatment - To gain experience with [F-18]HX4 PET/CT in order to improve the study design to conduct future studies Design: An open label, non-randomized, uncontrolled, single group assignment, pilot efficacy study Procedures: Informed consent, collection of demographic information, medical history, blood labs, physical examination, vital signs, ECGs, two or three sets of [F-18]HX4 dosing and imaging scans including two pretreatment, and one mid-treatment if [F-18]HX4 tumor/background ratio ≥ 1.3 from pre-treatment scans, one pre-treatment [F-18]FDG, one mid-treatment if [F- 18]HX4 tumor/background ratio ≥1.3 from pre-treatment scans, concomitant medication collection, adverse event monitoring, and assessment of tumor response to treatment Patients: Approximately forty (40) patients who have diagnosis confirmed by histopathological examination of tumor tissue from head/neck, lung, liver, rectal or cervical cancers and will receive chemotherapy, radiation therapy or chemoradiotherapy. This allows for approximately 30 evaluable patients to complete this study at approximately six sites.

ALLOCATION: N/A; INTERVENTION MODEL: Single Group Assignment; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Reproducibility of [F18]HX4 PET Imaging in Measuring Hypoxia in Tumors; TIME_FRAME: Time between 1st and 2nd scan was 1 to 6 days; DESCRIPTION: Primary tumor uptake of [F 18]HX4 was measured on PET images by onsite radiologist or nuclear medicine physician for 1st and 2nd PET scans. Values measured were: SUV (Standard Uptake Value), SUV Max (Maximum standard uptake value), SUV Mean (Mean standard uptake value), and T/B ratio (Tumor to background ratio). Pearson's correlation coefficient was calculated for each of the parameter.; >

ARM GROUP 1: <LABEL: [F 18]HX4; GROUP TYPE: Experimental; DESCRIPTION: [F18]HX4, 10 mCi, is administered in a single intravenous bolus injection, followed by a saline flush.; >;

INTERVENTION 1: <TYPE: Drug; NAME: [F 18]HX4; DESCRIPTION: Approximately forty (40) patients who have diagnosis confirmed by histopathological examination of tumor tissue from head/neck, lung, liver, rectal or cervical cancers and will receive chemotherapy, radiation therapy or chemoradiotherapy, will be imaged under PET/CT with [F 18]HX4, >;

Inclusion Criteria: - Patient is >18 years and male or female of any race / ethnicity - Patient or patient's legally acceptable representative provides written informed consent and is willing to comply with protocol procedures - Patient must have histopathologically confirmed head/neck, lung, liver, rectal or cervical cancer with tumor size ≥ 3cm - Patient has tumor tissue samples available before treatment for future immunohistochemistry biomarker tests (HIF1alpha and CA-IX) - Patient is scheduled to have or already had a clinical [F 18]FDG PET/CT scan recommended to be within 14 days of the first pre-treatment [F 18]HX4 PET/CT scan and have no treatment intervention in between these two scans - Patient is scheduled or is intended to be scheduled to receive chemotherapy, radiation or chemoradiotherapy treatment(s) after the pre-treatment [F 18]HX4 PET/CT and [F 18]FDG PET/CT scans for his/her cancer care - Patient must have hepatic and renal functions as defined by laboratory results within the following ranges: - Total bilirubin within 2 times institutional upper limit of normal - AST (SGOT) and ALT (SGPT) ≤ 2.5 times institutional upper limits of normal - Serum creatinine ≤ 2.5 times institutional limit of normal - BUN within 2 times institutional upper limit of normal Exclusion Criteria: - Patient is not capable of complying with study procedures - Female patient is pregnant or nursing o Exclude the possibility of pregnancy by one of the following: - Confirming in medical history that the patient is post-menopausal for a minimum of one year, or surgically sterile - Confirming the patient is using one of the following methods of birth control for a minimum of one month prior to entry into this study: IUD, oral contraceptives, Depo-Provera, or Norplant - Confirming a negative urine dipstick test taken the morning of but before receiving [F 18]HX4 - Patient has been involved in an investigative, radioactive research procedure within 7 days and during the study participation period - Patient has any other condition or personal circumstance that, in the judgment of the investigator, might interfere with the collection of complete data

NCT01347281

Completed

Non Invasive Imaging of [18F]HX4 With Positron-Emission-Tomography (PET) in Head and Neck Cancer.

Maastricht Radiation Oncology

The aim of this study is to (i) Determine if tumor hypoxia can be accurately visualised with [18F] HX4 PET imaging in head and neck tumors (ii) correlate the [18F] HX4 PET images with blood and tissue markers and (iii) investigate the quality and optimal timing of [18F] HX4 PET imaging (iv) compare [18F] HX4 PET uptake with [18F] FDG PET uptake before and after treatment.

Tumor hypoxia is the situation where tumor cells are or have been deprived of oxygen. Hypoxic tumor cells are usually more resistant to radiotherapy and chemotherapy and more likely to develop metastasis. In head and neck cancer, tumor hypoxia is known to be an important prognostic factor for long term survival. [18F]HX4 is being developed as a diagnostic radiopharmaceutical for PET imaging to find a marker for hypoxia that can be used in standard clinical practice. Current hypoxia tracers lack reliable image quality and kinetics. Because of the short half life and clearance, we expect that [18F]HX4 will have a higher tumor to background ratio than current nitro-imidazole hypoxia markers such as [18F]-misonidazole. The clinical use of a reliable, non-invasive and easy to use hypoxia imaging agent could allow selection of patients most likely to benefit from hypoxia modifying therapies. Included are eligible patients with head and neck squamous cell carcinoma (T2, T3, T4, any N, M0) with tumor diameter ≥ 2,5 cm of the oral cavity, oropharynx, hypopharynx or larynx, planned to be treated with curative primary radiation treatment (+/- concurrent chemotherapy). Before treatment a standard planning [18F]FDG PET-CT will be performed, a blood sample is drawn and baseline [18F]HX4 PET scans will be performed. 18F-HX4 scans will be repeated after radiotherapy treatment with 20 +/- 4 Gy (approximately two weeks). Three months after the end of treatment a [18F]FDG PET scan will be performed.

ALLOCATION: N/A; INTERVENTION MODEL: Single Group Assignment; PRIMARY PURPOSE: Diagnostic; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Visualisation of tumor hypoxia with [18F] HX4 PET imaging; TIME_FRAME: 2 years; DESCRIPTION: Visualisation of tumor hypoxia with [18F] HX4 PET imaging; > SECONDARY OUTCOME 1: MEASURE: Observe spatial and temporal stability of [18F] HX4 PET images; TIME_FRAME: 2 years; >; SECONDARY OUTCOME 2: MEASURE: Correlation of [18F] HX4 with local tumor recurrence and survivalG PET; TIME_FRAME: 2 years; >; SECONDARY OUTCOME 3: MEASURE: Image quality of [18F] HX4-PET at different time points; TIME_FRAME: 2 years; >; SECONDARY OUTCOME 4: MEASURE: Kinetic analysis of HX4; TIME_FRAME: 2 years; >; SECONDARY OUTCOME 5: MEASURE: Correlation of hypoxia imaging with blood hypoxia markers; TIME_FRAME: 2 years; >; SECONDARY OUTCOME 6: MEASURE: Correlation of hypoxia imaging with tumor tissue biomarkers; TIME_FRAME: 2 years; >; SECONDARY OUTCOME 7: MEASURE: Spatial correlation of [18F] HX4-PET with [18F] FDG PET pre-treatment; TIME_FRAME: 2 years; >; SECONDARY OUTCOME 8: MEASURE: Spatial correlation of [18F] HX4-PET with [18F] FDG PET three months after treatment; TIME_FRAME: 2 years; >;

ARM GROUP 1: <LABEL: [18F]HX4 PET; GROUP TYPE: Experimental; DESCRIPTION: Injection of [18F]HX4; >;

INTERVENTION 1: <TYPE: Procedure; NAME: Injection of [18F]HX4; DESCRIPTION: Injection of [18F]HX4 before treatment (baseline) and after radiotherapy with 20 +/-4 Gy: [18F]HX4 PET scans; 444 MBq (12 mCi) [18F]HX4 administrated via a bolus IV injection. Image acquisition: static scan at 240 min p.i. Venous blood sampling: before injection of [18F]HX4 (blood hypoxia markers) Follow-up (3 months after treatment): [18F]FDG PET in treatment position, >;

Inclusion Criteria: - Histological or cytological confirmed HNSSC of the oral cavity, oropharynx, hypopharynx, larynx, T2-T3-T4, any N, M0 - Tumor diameter ≥ 2,5 cm - WHO performance status 0 to 2 - Scheduled for primary curative (concurrent chemo-) radiotherapy - No previous surgery to the head and neck - No previous radiation to the head and neck - Adequate renal function (calculated creatinine clearance at least 60 ml/min). - The patient is willing and capable to comply with study procedures - 18 years or older - Have given written informed consent before patient registration Exclusion Criteria: - No recent (< 3 months) myocardial infarction - No Uncontrolled infectious disease - Not pregnant or breast feeding and willing to take adequate contraceptive measures during the study

NCT03239561

Completed

Phase 0 Exploratory Study of [18F]MNI-1020 (Also Known as [18F]JNJ-64326067) as an Imaging Marker for Tau Protein in the Brain of Subjects With Alzheimer's Disease Compared to Healthy Subjects

Janssen Research & Development, LLC

The primary objectives of this study are to characterize [18F]molecular neuroimaging (MNI)-1020, a positron emission tomography (PET) radioligand for imaging tau pathology, to visually and quantitatively assess and compare brain uptake and pharmacokinetics of [18F]MNI-1020 in participants with probable Alzheimer's disease (AD) and compare with age matched healthy participants, to evaluate the safety of a single injection of [18F]MNI-1020 and to compare the distribution of tau (using [18F]MNI-1020) and amyloid beta (using florbetapir) in participants with probable AD.

ALLOCATION: N/A; INTERVENTION MODEL: Single Group Assignment; PRIMARY PURPOSE: Diagnostic; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Standardized Uptake Value Ratio (SUVR) of [18F]MNI-1020; TIME_FRAME: Up to 180 minutes after tracer injection on Day 1; DESCRIPTION: Tracer uptake will be expressed in Standardized Uptake Value Ratio (SUVR). Regions used for tracer uptake quantitation will include cortical regions (frontal cortex, posterior cingulate, lateral temporal cortex, parietal cortex, occipital cortex, mesial temporal cortex, inferior temporal cortex, hippocampus, and anterior cingulate). Subcortical regions (basal ganglia, substantia nigra, choroid plexus) will be used for detection of possible off-target binding. Regions predicted to be free of tau pathology will be used as reference (cerebellum and pons). SUVR will be calculated as SUV target/SUV reference region (e.g., cerebellar gray).; >

ARM GROUP 1: <LABEL: [18F]MNI-1020; GROUP TYPE: Experimental; DESCRIPTION: Participants will receive a single intravenous bolus injection of [18F]MNI-1020 at a dose of not more than 10 millicurie (mCi), with a maximum mass dose of 10 microgram (mcg) and maximum volume of 10 milliliter (mL) at imaging visit.; >;

INTERVENTION 1: <TYPE: Drug; NAME: [18F]MNI-1020; DESCRIPTION: Participants will receive a single intravenous bolus injection of [18F]MNI-1020 at a dose of not more than 10 millicurie (mCi), with a maximum mass dose of 10 microgram (mcg) and maximum volume of 10 milliliter (mL) at imaging visit., >;

Inclusion Criteria: All Participants - Female participants must be documented by medical records or physician's note to be either surgically sterile (by means of hysterectomy, bilateral oophorectomy, or tubal ligation) or post-menopausal for at least 1 year. Male participants and their partners of childbearing potential must commit to the use of two methods of contraception, one of which is a barrier method for male participants for the study duration - Male participants must not donate sperm during the study and for 3 months after completion Healthy Participants - Males and females aged greater than or equal 50 years. Healthy with no clinically relevant finding on physical examination at screening and upon reporting for the [18F]molecular neuroimaging (MNI)-1020 imaging visit - Have screening [18F]florbetapir positron emission tomography (PET) imaging demonstrating no significant amyloid binding based on qualitative analysis (visual read) Alzheimer Disease - Have screening [18F]florbetapir or prior amyloid (in the last 12 months) PET imaging demonstrating amyloid binding based on qualitative (visual read) Exclusion Criteria: All Participants - Prior participation in other research protocols or clinical care in the last year in addition to the radiation exposure expected from participation in this clinical study, such that radiation exposure exceeds the effective dose of 50 millisievert (mSv), which would be above the acceptable annual limit established by the United States Federal Guidelines - Unsuitable veins for repeated venipuncture - Magnetic resonance imaging exclusion criteria include: evidence of cerebrovascular disease (more than two lacunar infarcts, any territorial infarct greater than 1 centimeter 3, or deep white matter abnormality corresponding to an overall Fazekas scale of 3 with at least one confluent hyperintense lesion on the FLAIR sequence that is greater than or equal to 20 millimeter (mm) in any dimension), infectious disease, space-occupying lesions, normal pressure hydrocephalus or any other abnormalities associated with central nervous system disease - Implants such as implanted cardiac pacemakers or defibrillators, insulin pumps, cochlear implants, metallic ocular foreign body, implanted neural stimulators, central nervous system aneurysm clips and other medical implants that have not been certified for MRI, or history of claustrophobia in Magnetic Resonance Imaging (MRI) Alzheimer Disease - Has received treatment that targeted amyloid beta or tau within the last 3 months

NCT03073395

Failed

Preliminary Investigation of Uptake in PSMA Expressing Cancer, Biodistribution and Excretion of the Novel Radio Tracer [68Ga]P16-093 by PET/CT

Five Eleven Pharma, Inc.

An phase I study to evaluate the uptake of [68Ga]P16-093 in known or suspected metastatic prostate or renal cancer to establish the feasibility of using [68Ga]P16-093 to image PSMA expressing cancer. Measurement of the whole body biodistribution of [68Ga]P16-093 in prostate cancer patients post primary curative-intent treatment with stable PSA to generate human radiation dosimetry data.

ALLOCATION: Non-Randomized; INTERVENTION MODEL: Parallel Assignment; PRIMARY PURPOSE: Diagnostic; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Uptake of [68Ga]P16-093 in metastatic prostate and renal cancer; TIME_FRAME: 0.5 - 3 hours after injection; DESCRIPTION: Standard uptake value (SUV) of [68Ga]P16-093 in apparent lesions detected by PET/CT.; >

ARM GROUP 1: <LABEL: Dynamic group; GROUP TYPE: Experimental; DESCRIPTION: Dynamic imaging of suspected metastatic lesions with the investigation drug [68Ga]P16-093 in patients with a history of histologically confirmed cancer.; >; ARM GROUP 2: <LABEL: Biodistribution group; GROUP TYPE: Experimental; DESCRIPTION: Whole body imaging to determine human dosimetry of the investigational drug [68Ga]P16-093; >;

INTERVENTION 1: <TYPE: Drug; NAME: [68Ga]P16-093; DESCRIPTION: Imaging by Positron Emission Tomography after iv injection of [68Ga]P16-093, >;

DYNAMIC GROUP: Inclusion Criteria: 1. Participants will be male ≥ 18 years of age 2. History of histologically confirmed cancer that meets criteria for either a) or b) 1. Prostate cancer with known or suspected recurrent or metastatic disease based on clinical imaging (e.g. CT, bone scan, MRI, ultrasound, FDG PET/CT, FACBC PET/CT) within 12 months of screening. If subject is post curative-intent local treatment (e.g. radical prostatectomy, local radiotherapy, brachytherapy) they must have had no intervening change in cancer treatment. OR 2. Renal Cell cancer with known or suspected metastatic disease based on clinical imaging (e.g. CT, bone scan, MRI, ultrasound, FDG PET/CT) 3. Participants must be informed of the investigational nature of this study and be willing to provide written informed consent and participate in this study in accordance with institutional and federal guidelines prior to study-specific procedures. Exclusion Criteria: 1. Estimated creatinine clearance (eGFR) < 30 mL/min (calculated from serum creatinine result within 30 days of screening) 2. Chemotherapy or radiation therapy within 2 weeks of screening 3. Inability to tolerate imaging procedures in the opinion of an investigator or treating physician 4. Any current medical condition, illness, or disorder as assessed by medical record review and/or self-reported that is considered by a physician investigator to be a condition that could compromise participant safety or successful completion of the study BIODISTRIBUTION GROUP: Inclusion Criteria: 1. Participants will be male ≥ 18 years of age 2. History of prostate cancer that is post curative-intent local treatment (e.g. radical prostatectomy, local radiotherapy, brachytherapy) with clinical PSA levels that meet one of the following criteria 1. Post-Prostatectomy (with or without adjuvant RT): PSA level that is < 0.2 ng/mL measured over at least 2 consecutive tests OR 2. Post-Radiotherapy: PSA level that has not risen from nadir measured over at least 2 consecutive tests 3. If clinical imaging (e.g. bone scan, CT, MRI, ultrasound, PET/CT) has been done within 3 months of screening as part of standard clinical surveillance it must be negative or equivocal for sites of recurrent or metastatic disease (clinical imaging is not required for enrollment) 4. Participants must be informed of the investigational nature of this study and be willing to provide written informed consent and participate in this study in accordance with institutional and federal guidelines prior to study-specific procedures. Exclusion Criteria: 1. Estimated creatinine clearance (eGFR) < 30 mL/min (calculated from serum creatinine result within 30 days of screening) 2. Androgen deprivation therapy (ADT) within 3 months prior to screening 3. Chemotherapy or radiation therapy within 2 weeks of screening 4. Inability to tolerate imaging procedures in the opinion of an investigator or treating physician 5. Any current medical condition, illness, or disorder as assessed by medical record review and/or self-reported that is considered by a physician investigator to be a condition that could compromise participant safety or successful completion of the study

NCT04315246

Failed

A Phase I/II Trial of Intracerebroventricular 177Lu DTPA Omburtamab Radioimmunotherapy for Leptomeningeal Metastasis From Solid Tumors

Y-mAbs Therapeutics

Adults with leptomeningeal metastasis from solid tumors will be treated with 177Lu-DTPA-omburtamab, which is a radioactive labelling of a murine monoclonal antibody targeting B7-H3.

Part 1 is a dose-escalation phase with a 3+3 sequential-group design in which patients will receive a dosimetry dose followed by maximum of five 5-week cycles of treatment doses of intracerebroventricular 177Lu-DTPA-omburtamab. Part 2 is a cohort-expansion phase in which patients will receive a treatment at the recommended dose determined in Part 1, until confirmed LM progression, unacceptable toxicity, or for maximum of 5 cycles, whichever comes first; however, the total number of cycles will be determined based upon data from Part 1 (e.g., the dosimetry data) to minimize the risk of radiation necrosis and decreased neurological function End of treatment will take place within 5 weeks after the last cycle and thereafter the patients will be enter the follow-up period. The patients will be followed for up until one year after first dose (Part 1) and 2 years after first dose (Part 2).

ALLOCATION: N/A; INTERVENTION MODEL: Single Group Assignment; DESCRIPTION: Patients will receive up to five cycles of intracerebroventricular 177Lu-DTPA-omburtamab. Safety and efficacy will be investigated during treatment and follow-up period.; PRIMARY PURPOSE: Treatment; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Incidence of adverse events (AEs) and serious adverse events (SAEs); TIME_FRAME: 1 year; DESCRIPTION: Safety will be evaluated by the incidence of AEs and SAEs graded according to CTCAE version 5.0. The maximum tolerated dose and the recommended phase 2 dose (RP2D) will be determined in Part 1; > SECONDARY OUTCOME 1: MEASURE: Maximum radioactivity count of lutetium-177 in blood; TIME_FRAME: 2 weeks; DESCRIPTION: The time for maximum absorbed radiation dose; >; SECONDARY OUTCOME 2: MEASURE: Elimination half-life of lutetium-177 radioactivity in blood; TIME_FRAME: 2 weeks; DESCRIPTION: The time for eliminating half of the radioactivity in blood; >; SECONDARY OUTCOME 3: MEASURE: Absorbed radiation dose of lutetium-177 in blood and cerebrospinal fluid (CSF); TIME_FRAME: 2 weeks; DESCRIPTION: Time-activity curves of radioactivity measurements in blood and CSF will be modeled to deliver absorbed doses in blood and CSF; >; SECONDARY OUTCOME 4: MEASURE: Dosimetry analysis of lutetium-177; TIME_FRAME: 2 weeks; DESCRIPTION: Whole-body dosimetry by gamma camera scans and single-photon emission computed tomography (SPECT); >; SECONDARY OUTCOME 5: MEASURE: Maximum Plasma Concentration [Cmax] in CSF; TIME_FRAME: 7 weeks; DESCRIPTION: Concentration of 177Lu-DTPA-omburtamab in CSF; >; SECONDARY OUTCOME 6: MEASURE: Maximum Plasma Concentration [Cmax] in serum; TIME_FRAME: 7 weeks; DESCRIPTION: Concentration of 177Lu-DTPA-omburtamab in serum; >; SECONDARY OUTCOME 7: MEASURE: Elimination Half Life in CSF; TIME_FRAME: 7 weeks; DESCRIPTION: Concentration of 177Lu-DTPA-omburtamab in CSF; >; SECONDARY OUTCOME 8: MEASURE: Elimination Half Life in serum; TIME_FRAME: 7 weeks; DESCRIPTION: Concentration of 177Lu-DTPA-omburtamab in serum; >; SECONDARY OUTCOME 9: MEASURE: Response; TIME_FRAME: 2 years; DESCRIPTION: Objective response rate (ORR) will be defined as the proportion of all evaluable patients achieving a response as the best overall response at the time of assessment; >; SECONDARY OUTCOME 10: MEASURE: Investigator-assessed Duration of Response (DoR); TIME_FRAME: 2 years; DESCRIPTION: DoR is defined as the time from first response to LM progression; >; SECONDARY OUTCOME 11: MEASURE: Progression-free Survival (PFS); TIME_FRAME: 2 years; DESCRIPTION: PFS is defined as the time from first treatment to date of LM progression or death from any cause, whichever comes first; >; SECONDARY OUTCOME 12: MEASURE: Overall Survival (OS); TIME_FRAME: 2 years; DESCRIPTION: OS is defined as the time from first treatment to date of death; >;

ARM GROUP 1: <LABEL: 177Lu-DTPA-omburtamab; GROUP TYPE: Experimental; DESCRIPTION: Intracerebroventricular administration of 177Lu-DTPA-omburtamab for up to five cycles.; >;

INTERVENTION 1: <TYPE: Biological; NAME: radiolabeled DPTA-omburtamab; DESCRIPTION: Biological, radiolabeled DPTA-omburtamab, >;

Inclusion Criteria: - Primary ductal or lobular breast cancer, non-small cell lung cancer, or malignant melanoma - Type I or Type II LM with a "confirmed" or "probable" diagnosis according to EANO-ESMO guidelines 2017 - Life expectancy more than 2 months, as judged by the Investigator - ECOG Performance status 0, 1, or 2 - Acceptable hematological status and liver and kidney function - Written informed consent obtained in accordance with local regulations - Presence of an intracerebroventricular access device before first dosing Exclusion Criteria: - Obstructive or symptomatic communicating hydrocephalus - Progressive systemic (extra-leptomeningeal) disease - Uncontrolled life-threatening infection - Ventriculo-peritoneal shunts without programmable valves. Ventriculo-atrial or ventriculo-pleural shunts - Received craniospinal irradiation (for intraparenchymal or dural metastases) or intrathecal cytotoxic anti-cancer therapy less than 3 weeks prior to first dose of 177Lu-DTPA-omburtamab - Severe non-hematologic organ toxicity; specifically, any renal, cardiac, hepatic, pulmonary, or gastrointestinal system toxicity Grade 3 or above prior to enrolment - Grade 4 nervous system disorder. Hearing loss or stable neurological deficits due to brain tumor are allowed - Unacceptable coagulation function prior to first dosing defined as INR Grade 2 or above - Female of childbearing potential, who are pregnant, breast-feeding, intend to become pregnant, or are not using highly effective contraceptive methods or male who is not using highly effective contraceptive method - Other significant disease or condition that in the investigator's opinion would exclude the patient from the trial. - Smallest diameter of treated or untreated nodular or linear leptomeningeal metastasis >0.5 cm on MRI (Part 2 only)

NCT04167618

Failed

A Phase I/II Dose-escalation and Expansion Cohort Trial of Intracerebroventricular Radioimmunotherapy Using 177Lu-DTPA-Omburtamab in Pediatric and Adolescent Patients With Recurrent or Refractory Medulloblastoma

Y-mAbs Therapeutics

Children and adolescents diagnosed with medullablastoma and with recurrent or refractory to frontline therapy will be treated with 177Lu-DTPA-omburtamab, which is a radioactive labelling of a murine monoclonal antibody targeting B7-H3.

Part 1 is a dose-escalation phase with a 3+3 sequential-group design in which patients will receive a dosimetry dose followed by maximum of two 5-week cycles of treatment doses of intracerebroventricular 177Lu-DTPA-omburtamab. Part 2 is a cohort-expansion phase in which patients will receive a maximum of five 5-week cycles of intracerebroventricular 177Lu-DTPA-omburtamab at the recommended dose determined in Part 1. End of treatment will take place within 5 weeks after the last cycle and thereafter the patients will be enter the follow-up period. The patients will be followed for up to 2 years after last dose.

ALLOCATION: N/A; INTERVENTION MODEL: Single Group Assignment; DESCRIPTION: Patients will receive up to two cycles in Part 1 and up to five cycles in Part 2 of intracerebroventricular 177Lu-DTPA-omburtamab. Safety and efficacy will be investigated during treatment and follow-up period.; PRIMARY PURPOSE: Treatment; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Dose Limiting Toxicities (DLTs) Part 1; TIME_FRAME: Days 1 through 35 in cycle 1; DESCRIPTION: Summary of DLTs in DLT evaluable subjects.; >

ARM GROUP 1: <LABEL: 177Lu-DTPA-omburtamab; GROUP TYPE: Experimental; DESCRIPTION: Intracerebroventricular administration of 177Lu-DTPA-omburtamab for up to two cycles (Part 1) and up to five cycles (Part 2).; >;

INTERVENTION 1: <TYPE: Drug; NAME: 177Lu-DTPA-omburtamab; DESCRIPTION: Biological, radiolabeled DPTA-omburtamab, >;

Inclusion Criteria: - Histologically confirmed diagnosis of medulloblastoma. - SHH, Group 3, or Group 4 according to World Health Organisation (WHO) 2016 classification. - Recurrent (maximum of 2 recurrences for Part 1 and 1 recurrence for Part 2) or refractory to frontline therapy. Prior frontline or second line therapy may involve surgery, craniospinal irradiation, stereotactic radiosurgery, and multi-agent chemotherapy regimens. - Have refractory disease, focal or multifocal recurrent disease, or pure leptomeningeal disease. Cytological or radiographic remission is allowed; however, not simultaneously. - Performance status score of 50 to 100 on Lansky (less than 16 years) or Karnofsky (16 years or older) scales. - Life expectancy of at least 3 months, as judged by the Investigator. - Acceptable hematological status and liver and kidney function. Exclusion Criteria: - Obstructive or symptomatic communicating hydrocephalus as determined by Ommaya patency/cerebrospinal fluid (CSF) flow study. - Residual disease (nodular or linear) measuring > 15 mm in the smallest diameter. - Ventriculoperitoneal shunts without programmable valves. Ventriculo-atrial or ventriculo-pleural shunts. - Grade 4 nervous system disorder. Stable neurological deficits (due to brain tumor or surgery) or hearing loss are allowed. - Uncontrolled life-threatening infection. - Received radiation therapy less than 3 weeks prior to the screening visit. - Received systemic or intrathecal cytotoxic chemotherapy or intrathecal immunotherapy (corticosteroids not included) less than 3 weeks prior to the screening visit. - Received any prior anti-B7-H3 treatment. - Non-hematologic organ toxicity Grade 3 or above; specifically, any renal, cardiac, hepatic, pulmonary, and gastrointestinal system toxicity. - Other significant disease or condition that in the investigator's opinion would exclude the patient from the trial.

NCT03571204

Failed

An Exploratory Study of Combination Therapy With 3BNC117 and 10-1074 in HIV-Infected Individuals

National Institute of Allergy and Infectious Diseases (NIAID)

Background: Human immunodeficiency virus (HIV) affects the immune system. The main function of the immune system is protect you from infections and other diseases such as cancer. HIV attacks and cripples the immune system making people more susceptible to a variety of infections and cancers. Currently, the standard treatment for HIV infection is a daily administration of anti-HIV drugs. These drugs are called combination antiretroviral therapy (ART). ART is very effective at suppressing HIV, but does not cure HIV infection. ART must be taken continuously for life to be effective. ART can stop being effective if not taken correctly and can cause permanent side effects. Researchers want to see if two new products can control HIV infection without the use of ART. The products are the antibodies 3BNC117 and 10-1074. Objective: To see if 3BNC117 and 10-1074 are safe and can control HIV levels in the blood of people who are not taking ART or people who stop taking their ART during the study. . Eligibility: Adults ages 18-65 with HIV who are: - on ART and willing to stop treatment for at least 28 weeks - OR not taking ART with low levels of HIV in the blood Design: Participants will be screened with a physical exam, medical history, and blood, heart, and urine tests. Participants will get the 2 study products or salt water (placebo). A thin tube will be placed in an arm vein. Each product will be given directly into the vein for about 1 hour. To help collect blood cells to study in the laboratory, participants may have a procedure known as leukapheresis in which blood will be removed through a needle in the arm. Some of the white blood cells will be separated from the blood and used for research studies to see how 3BNC117 and 10-1074 effects HIV and the immune system. The rest of the blood will be returned to the person through another needle in the arm. Participants will have 18 study visits over 28 weeks. They will repeat some screening tests. They may have leukapheresis again. At 8 study visits, participants will get the study products or placebo. All participants will be followed for at least 24 weeks after their last dose of the study infusions. Participants who are in the Group that stops ART will be monitored closely to make sure the levels of virus in their blood do not go to high. If at any time during this the study a person develops HIV-related symptoms, or if the viral levels go up to high levels for more than 4 weeks, ART will be restarted and no further infusions of 3BNC117 and 10-1074 will be given. ...

Recent advances in antibody cloning technologies have led to the discovery of a number of highly potent and HIV-specific broadly neutralizing monoclonal antibodies (bNAbs) from B cells of HIV-infected individuals. It has been shown that certain bNAbs can prevent acquisition of the virus, suppress viral replication, delay and/or prevent plasma viral rebound following treatment interruption in Simian Immunodeficiency virus (SIV)-infected animals and block cell-to-cell transmission of laboratory-adapted HIV in vitro. In light of these encouraging outcomes, a number of clinical trials have been conducted in recent years in order to explore the feasibility of achieving sustained virologic suppression using a single bNAb in HIV-infected individuals following analytical treatment interruption (ATI). Despite the fact that repeated administration of a single bNAb was safe and well-tolerated, the vast majority of study subjects experienced plasma viral rebound following ATI, clearly demonstrating that successful passive immunotherapy will require different approach, including the use of a combination of 2 or more bNAbs to achieve extended periods of virologic suppression. Given a major emphasis on current HIV research lies in the possibility of achieving ART-free virologic remission, it is of great interest to investigate whether a combination of potent HIV- specific bNAbs, such as 3BNC117 and 10-1074, can prevent plasma viral rebound in infected individuals upon discontinuation of ART or suppress viral replication in subjects who are not taking ART.

ALLOCATION: Randomized; INTERVENTION MODEL: Single Group Assignment; PRIMARY PURPOSE: Treatment; MASKING: Triple (Participant, Care Provider, Investigator);

PRIMARY OUTCOME: <MEASURE: Participants With Grade 3 or Higher Adverse Events; TIME_FRAME: 29 months; DESCRIPTION: Participants with grade 3 or higher adverse events (AE), including serious adverse advents. AE severity was graded according to the Division of Aids Table for Grading the Severity of Adult and Pediatric Adverse Events Version 2.1, July, 2017; > SECONDARY OUTCOME 1: MEASURE: Participants Who Experienced Rebound of Plasma Viremia; TIME_FRAME: 28 weeks; DESCRIPTION: Difference between the treatment and placebo arms in the number of participants who experienced rebound of plasma viremia and met criteria to restart ART prior to study week 28.; >; SECONDARY OUTCOME 2: MEASURE: Participants Who Achieved Suppression of Viremia; TIME_FRAME: 28 weeks; DESCRIPTION: Participants who achieved suppression of viremia to <40 copies/ml by study week 28; >;

ARM GROUP 1: <LABEL: Group 1: ART prior to 3BNC117 + 10-1074 in HIV-1 subject; GROUP TYPE: Active Comparator; DESCRIPTION: Subjects who began anti-retroviral therapy (ART) during primary HIV-1 infection within 12 weeks of diagnosis. ART was stopped after study day 3 and were given 3BNC117 and 10-1074 intravenously. Both 3BNC117 and 10-1074 were administered at 30 mg/kg dose level in separate bags of 250 mL normal saline in sequential administration. Subjects received 8 infusions of 3BNC117 and 10-1074 at weeks 0, 2, 4, 8, 12, 16, 20, and 24. The total duration of therapy was 24 weeks.; >; ARM GROUP 2: <LABEL: Group 1: ART prior to placebo treatment in HIV-1 subject; GROUP TYPE: Placebo Comparator; DESCRIPTION: Subjects who began anti-retroviral therapy (ART) during primary HIV-1 infection within 12 weeks of diagnosis. ART was stopped after study day 3 and were given normal saline intravenously. Subjects received two separate bags of 250 mL normal saline in sequential administration. Subjects received 8 infusions at weeks 0, 2, 4, 8, 12, 16, 20, and 24. The total duration of therapy was 24 weeks.; >; ARM GROUP 3: <LABEL: Group 2: 3BNC117 + 10-1074 in HIV-1 subject; GROUP TYPE: Experimental; DESCRIPTION: Subjects who were not on anti-retroviral therapy (ART) during primary HIV-1 infection within the past 2 years. Subjects were given 3BNC117 and 10-1074 intravenously. Both 3BNC117 and 10-1074 were administered at 30 mg/kg dose level in separate bags of 250 mL normal saline in sequential administration. Subjects received 8 infusions of 3BNC117 and 10-1074 at weeks 0, 2, 4, 8, 12, 16, 20, and 24. The total duration of therapy was 24 weeks.; >;

INTERVENTION 1: <TYPE: Biological; NAME: 3BNC117 and 10-1074; DESCRIPTION: Both 3BNC117 and 10-1074 administered intravenously at 30 mg/kg dose level in 250 ml normal saline for 8 infusions at weeks 0, 2, 4, 8, 12, 16, 20, and 24. The two antibodies will be mixed in separate bags of saline for sequential administration., >; INTERVENTION 2: <TYPE: Biological; NAME: Placebo; DESCRIPTION: Placebo is two separate bags of 250 ml normal saline administered intravenously for 8 infusions at weeks 0, 2, 4, 8, 12, 16, 20, and 24. The two separate bags of placebo are administered sequentially., >;

- INCLUSION CRITERIA: General Inclusion Criteria for both Groups: 1. Age 18-65 years old. 2. HIV-1 infection and clinically stable. 3. General good health and has an identified primary health care provider for medical management of HIV infection and is willing to maintain a relationship with a primary health care provider for medical management of HIV infection while participating in the study. 4. Cluster of differentiation 4 (CD4)+ T cell count >450 cells/mm(3) at screening. 5. Laboratory values within pre-defined limits at screening: 1. Absolute neutrophil count >1,000/mm(3). 2. Hemoglobin levels >10.0 g/dL for men and >9.0 g/dL for women. 3. Platelet count >100,000/mm(3). 4. Estimated or a measured glomerular filtration rate >60 mL/min/1.73m(2) as determined by the National Institutes of Health (NIH) Clinical Center laboratory. 5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels of <2.5 times upper limit of normal (ULN), direct bilirubin within the normal range for the NIH Clinical Center laboratory. 6. Willingness to have samples stored for future research. Inclusion criteria specific for Group 1: 7. Institution of ART within 12 weeks of being diagnosed with primary HIV-1 infection 8. Primary HIV-1 infection is defined as meeting at least one of the following criteria: 1. Detectable plasma HIV-1 RNA levels of >2000 copies/mL with a negative result from an HIV-1 enzyme immunoassays (EIA), or 2. Positive result from an HIV-1 EIA with a negative or indeterminate result from an HIV-1 western blot or another confirmatory antibody test that subsequently evolves to a confirmed positive result, or 3. Negative result from an HIV-1 EIA within the past 4 months and HIV-1 RNA levels of >400,000 copies/mL, in the setting of a potential exposure to HIV-1. 4. Negative result from an HIV-1 EIA within 6 months prior to a positive result from an HIV-1 EIA and an HIV-1 western blot or another confirmatory antibody test. 5. Presence of low level of HIV antibodies as determined by having a positive EIA or a positive Western blot with a non-reactive detuned EIA according to a serologic testing algorithm for recent infection. 9. Documentation of continuous ART treatment with suppression of plasma viral level below the limit of detection for greater than or equal to 1 years. Individuals with blips (i.e., detectable viral levels on ART) prior to screening may be included provided they satisfy the following criteria: 1. The blips are <400 copies/mL, and 2. Succeeding viral levels return to levels below the limit of detection on subsequent testing. 10. Willingness to undergo ATI 11. Willingness for both male and female subjects to agree to use barrier protection methods or abstinence during the ATI phase of the study to decrease the risk of HIV transmission. Inclusion criteria specific for Group 2: 12. No ART within 24 months of screening. 13. HIV plasma viremia between 200 and 5,000 copies/mL at screening AND at least two documented viral level greater than or equal to 200 copies/mL in the 12 months prior to screening. At the screening visit, subjects considering enrollment in Group 2 will be advised that current guidelines recommend treatment of all individuals with HIV infection regardless of viral levels and CD4 counts. Reproductive Risks Contraception: The effects of 3BNC117 and 10-1074 on the developing human fetus are unknown. For this reason, men and women of childbearing potential must agree to use adequate pregnancy prevention. This includes the use an effective method of contraception (i.e. condom with spermicide, diaphragm with spermicide, hormone-eluting intrauterine device (IUD), hormone-based contraceptive with condom) for the study duration. Subjects should also agree to use a male or female condom while off ART. Pregnancy prevention must be practiced continuously for the duration of study participation. Females of childbearing-age must have a negative pregnancy test result prior to receiving each infusion of 3BNC117/10-1074. During the course of the study, if a female subject, or the partner of a male subject suspects or in fact becomes pregnant, the effected subject should inform the study staff immediately, as well as the woman s primary care physician. EXCLUSION CRITERIA: 1. Chronic hepatitis B, as evidenced by a positive test for hepatitis B surface antigen (HBsAg), or chronic hepatitis C virus (HCV) infection, as evidenced by a positive test for HCV RNA. Subjects with a positive test for HCV antibody and a negative test for HCV RNA are eligible. 2. HIV immunotherapy or vaccine(s) received within 1 year prior to screening. 3. Any licensed or experimental non-HIV vaccination (e.g., hepatitis B, influenza, pneumococcal polysaccharide) received within 2 weeks prior to study enrollment. 4. Receipt of other investigational study agent within 28 days of enrollment. 5. Any active malignancy that may require systemic chemotherapy or radiation therapy. 6. Systemic immunosuppressive medications received within 3 months prior to enrollment (Not excluded: [1] corticosteroid nasal spray or inhaler; [2] topical corticosteroids for mild, uncomplicated dermatitis; or [3] oral/parenteral corticosteroids administered for non-chronic conditions not expected to recur [length of therapy less than or equal to10 days, with completion in greater than or equal to 30 days prior to enrollment]). 7. History or other clinical evidence of: 1. Significant or unstable cardiac or cerebrovascular disease (e.g., angina, congestive heart failure, recent stroke or myocardial infarction). 2. Severe illness, malignancy, immunodeficiency other than HIV, or any other condition that, in the opinion of the investigator, would make the subject unsuitable for the study. 8. Active drug or alcohol use or any other pattern of behavior that, in the opinion of the investigator, would interfere with adherence to study requirements. 9. Pregnancy or breast-feeding at time of screening. 10. Documented multiclass antiretroviral drug resistance that, in the judgment of the investigator, would pose a risk of virologic failure should additional mutations develop during the study (Group 1 only). Co-enrollment Guidelines: Co-enrollment in other trials is restricted to observational studies or those evaluating the use of a licensed medication and is subject to approval of the principal investigator (PI).

NCT03831945

Failed

An Exploratory Study of Combination Therapy With VRC-HIVMAB060-00-AB (VRC01) and 10-1074 in HIVInfected Individuals Undergoing Sequential Treatment Interruptions

National Institute of Allergy and Infectious Diseases (NIAID)

Background: A daily drug combination can keep human immunodeficiency virus (HIV) levels low for a long time. But if this combination antiretroviral therapy (ART) stops, HIV levels go back up. People can also develop resistance or permanent side effects. Researchers want to see if 2 new drugs can help control HIV when a person is not on ART. Objective: To see if VRC01 and 10-1074 are safe and control HIV when a person is not on ART. Eligibility: Adults 18-65 with HIV Design: All participants must agree to practice safer sex. Those who can get pregnant will have a pregnancy test every visit. Participants will be screened with: Physical exam Medicine review Blood and urine tests Some participants may need to change their HIV medicine for a brief period of time during the study. A few weeks later, participants will repeat screening tests and stop taking their HIV medicines. Interruption phase 1: Participants will have blood tests every 2 weeks, and repeat screening tests every 4 weeks. Treatment phase: Once their HIV reaches a certain level in the blood, participants will get the 2 study drugs or a salt water placebo. They will not know which they get. Each substance will be given through a thin tube in an arm vein for about 1 hour. Participants will restart their HIV medicines and repeat screening tests every 4 weeks. Interruption phase 2: Once the level of HIV in the blood becomes undetectable for 3 months, participants will again stop taking their HIV medicines and have blood tests every 2 weeks to monitor the level of HIV in the blood. Participants will restart their medicines by week 24. They will start sooner if they have certain symptoms or blood levels of HIV become too high. They will repeat most screening tests 3 times over 24 weeks.

Recent advances in antibody cloning technologies have led to the development of a number of highly potent and human immunodeficiency virus (HIV)-specific broadly neutralizing monoclonal antibodies (bNAbs) from B cells of HIV-infected individuals. It has been shown that certain bNAbs can prevent acquisition of the virus, suppress viral replication, delay and/or prevent plasma viral rebound following treatment interruption in simian/human immunodeficiency virus (SHIV)-infected animals. Preliminary data from clinical trials indicates that bNAbs may delay plasma viral rebound following interruption of antiretroviral therapy (ART) and block cell-to-cell transmission of laboratory-adapted HIV in vitro. In the above studies, suppression of plasma viremia was dependent on maintaining neutralizing serum levels of bNAbs via repeated intravenous (IV) infusions. A recent pre-clinical study in an acute SHIV-macaque model suggests a limited course of passive immunotherapy with two bNAbs (10-1074 and 3BNC117) given shortly after infection, can result in prolonged suppression of plasma viremia that is not dependent on the continuous presence of the bNAbs18. Based on CD8+ T cell depletion studies, it appears that the prolonged suppression of plasma viremia observed in these animals resulted from the induction of potent antiviral CD8+ T cell immunity by the short course bNAb treatment. The mechanism by which bNAb therapy could induce such a response is unclear but could involve the early formation of unique bNAb-SHIV immune complexes that subsequently induce an effective and durable T cell response to the virus. In light of these encouraging preclinical outcomes, it is of considerable interest to investigate whether treatment with a single infusion of two bNAbs (VRC01 and 10-1074) which target different epitopes of HIV gp120 (CD4 binding site and V3 glycan, respectively), during transient plasma viremia can induce long-lasting anti-HIV immunity capable of controlling plasma viremia in the absence of ART.

ALLOCATION: Randomized; INTERVENTION MODEL: Single Group Assignment; PRIMARY PURPOSE: Treatment; MASKING: Double (Participant, Investigator);

PRIMARY OUTCOME: <MEASURE: Days From Start of the Second Treatment Interruption Until the Subject Meets Criteria to Restart ART; TIME_FRAME: From start of second Analytical Treatment Interruption (ATI) until up to 16 weeks; DESCRIPTION: Number of days from start of the second analytical treatment interruption (ATI) until the subject meets criteria to restart Antiretroviral Therapy (ART) before Week 16 [a confirmed >30% decline in baseline CD4+ T Cell count or an absolute CD4+ T Cell count in the setting of detectable HIV viremia (>40 copies/mL); a sustained (>4weeks) HIV RNA level of > 1000 copies/mL, or any HIV related symptoms or pregnancy.]; > SECONDARY OUTCOME 1: MEASURE: Percent of Participants With Grade 3 or Higher Related Adverse Events; TIME_FRAME: From the start of the initial infusion through follow-up phase week 24; DESCRIPTION: Percent of participants with grade 3 or higher adverse events, including serious adverse events, that were probably or definitely related to study agent; >;

ARM GROUP 1: <LABEL: Single infusion of VRC01 and 10-1074; GROUP TYPE: Active Comparator; DESCRIPTION: Single infusion of 40 mg/kg VRC-HIVMAB060-00-AB (VRC01) in 100 mL of saline and 30 mg/kg of 10-1074 in 250 mL of saline when viral load is >/= 200 copies/mL in HIV-infected individuals undergoing antiretroviral treatment interruption.; >; ARM GROUP 2: <LABEL: Single infusion of Normal Saline; GROUP TYPE: Placebo Comparator; DESCRIPTION: Single infusion of 100 mL and 250 mL of normal saline when viral load is >/= 200 copies/mL in HIV-infected individuals undergoing antiretroviral treatment interruption.; >;

INTERVENTION 1: <TYPE: Biological; NAME: VRC-HIVMAB060-00-AB (VRC01); DESCRIPTION: VRC01 is a broadly neutralizing human mAb targeted against the HIV-1CD4 binding site. As single intravenous infusion of VRC01(40 mg/kg) plus10-1074 (30mg/kg) or placebo will be administered after the first analytical treatment interruption phase once the subject's plasma viremia is > or = 200 copies/mL., >; INTERVENTION 2: <TYPE: Biological; NAME: 10-1074; DESCRIPTION: 10-1074 is a recombinant, fully human mAb of the IgG1 lambda isotype that specifically binds to the base of the V3 loop within HIV-1 envelope gp-120. A single intravenous infusion of VRC01 (40 mg/kg) plus 10-1074 (30 mg/kg) or placebo will be administered after the first analytical treatment interruption phase once the subject's plasma viremia is > or = 200 copies/mL., >; INTERVENTION 3: <TYPE: Biological; NAME: Normal Saline Placebo; DESCRIPTION: 2 sequential infusions of normal saline placebo in matching volumes to antibody infusions will be administered after the first analytical treatment interruption phase once the subject's plasma viremia is > or = 200 copies/mL., >;

- INCLUSION CRITERIA: 1. 18-65 years of age. 2. HIV-1 infection and clinically stable. 3. General good health and has an identified primary health care provider for medical management of HIV infection and is willing to maintain a relationship with a primary health care provider for medical management of HIV infection while participating in the study. 4. CD4+ T cell count >450 cells/mm(3) at screening. 5. Documentation of continuous ART treatment with suppression of plasma viral level below the lower limit of quantification (LLOQ) for the assay used for greater than or equal to 2 years. Individuals with blips (i.e., detectable viral levels on ART) prior to screening may be included provided they satisfy the following criteria: 1. The blips are <400 copies/mL, and 2. Succeeding viral levels return to levels below the limit of detection on subsequent testing. 6. Laboratory values within pre-defined limits at screening: 1. Absolute neutrophil count >1,000/mm(3). 2. Hemoglobin levels >10.0 g/dL for men and >9.0 g/dL for women. 3. Platelet count >100,000/mm(3). 4. Estimated or a measured glomerular filtration rate >60 mL/min/1.73 m(2) as determined by the NIH Clinical Center (CC) laboratory. 5. Aspartate aminotransferase (AST) and alanine transaminase (ALT) levels of <2.5 times upper limit of normal (ULN), direct bilirubin within the normal range for the NIH CC laboratory. 7. Willingness to have samples stored for future research. 8. Willingness to undergo analytical treatment interruption (ATI) 9. Willingness for both male and female subjects to agree to use barrier protection methods or abstinence during the ATI phase of the study to decrease the risk of HIV transmission. Reproductive Risks Contraception: The effects of VRC01 and 10-1074 on the developing human fetus are unknown. For this reason, men and women of childbearing potential must agree to use adequate pregnancy prevention. This includes the use an effective method of contraception (i.e. condom with spermicide, diaphragm with spermicide, hormone-eluting intrauterine device (IUD), hormone-based contraceptive with condom) for the study duration. Subjects should also agree to use a male or female condom while off ART. Pregnancy prevention must be practiced continuously for the duration of study participation. Females of childbearing-age must have a negative pregnancy test result prior to receiving the infusions of VRC01 and 10-1074/placebo. During the course of the study, if a female subject, or the partner of a male subject suspects or in fact becomes pregnant, the affected subject should inform the study staff immediately, as well as the woman s primary care physician. EXCLUSION CRITERIA: 1. Chronic hepatitis B, as evidenced by a positive test for hepatitis B surface antigen (HBsAg), or chronic hepatitis C virus (HCV) infection, as evidenced by a positive test for HCV RNA. Subjects with a positive test for HCV antibody and a negative test for HCV RNA are eligible. 2. HIV immunotherapy or HIV vaccine(s) received within 1 year prior to screening. 3. Any prior history of receiving 10-1074 or VRC01. 4. Any licensed or experimental non-HIV vaccination (e.g., hepatitis B, influenza, pneumococcal polysaccharide) received within 2 weeks prior to study enrollment. 5. Receipt of other investigational study agent within 28 days of enrollment. 6. Any active malignancy that may require systemic chemotherapy or radiation therapy. 7. Systemic immunosuppressive medications received within 3 months prior to enrollment (Exceptions: [1] corticosteroid nasal spray or inhaler; [2] topical corticosteroids for mild, uncomplicated dermatitis; or [3] oral/parenteral corticosteroids administered for non-chronic conditions not expected to recur [length of therapy less than or equal to 10 days, with completion in greater than or equal to 30 days prior to enrollment]). 8. History or other clinical evidence of: 1. Significant or unstable cardiac or cerebrovascular disease (e.g., angina, congestive heart failure, recent stroke or myocardial infarction). 2. Severe illness, malignancy, immunodeficiency other than HIV, or any other condition that, in the opinion of the investigator, would make the subject unsuitable for the study. 9. Active drug or alcohol use or any other pattern of behavior that, in the opinion of the investigator, would interfere with adherence to study requirements. 10. Pregnancy or breast-feeding at time of screening. 11. Documented multiclass antiretroviral drug resistance that, in the judgment of the investigator, would pose a risk of virologic failure should additional mutations develop during the study.

NCT02754687

Failed

Single Dose, Dose-Ranging Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics Study of 11-β Methyl Nortestosterone Dodecylcarbonate (11β-MNTDC) in Healthy Men

Health Decisions

The long term objective is to develop a new male hormone 11-β Methyl Nortestosterone Dodecylcarbonate (11β-MNTDC) as a male hormonal contraceptive.

This is a Phase I multicenter, double-blind, single dose, dose-ranging study, in healthy men followed on an inpatient basis to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics of 11β-methyl nortestosterone dodecylcarbonate (11β-MNTDC). This single dose, dose-ranging study of 4 escalating doses will be conducted in two centers. Initially, 12 men will be enrolled in total, 6 men at each center, with a goal of having a minimum of 12 healthy male subjects completing this study (10 active drugs and 2 placebos) both in the fed and fasting states at each dose. Each of the 4 doses of 11β-MNTDC will be administered first fasting and then fed. Each of the doses of 11β-MNTDC will be administered about 28 days apart +/- 14 days with the time interval between the fasting and fed dosing will be approximately 7 days (-2/+9 days) and a 7 to 14 day washout will occur before dose escalation.

ALLOCATION: Randomized; INTERVENTION MODEL: Parallel Assignment; PRIMARY PURPOSE: Treatment; MASKING: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);

PRIMARY OUTCOME: <MEASURE: Safety and tolerability of single dose oral administration of up to 4 escalating doses of 11-β methyl nortestosterone dodecylcarbonate (11β-MNTDC) as measured by adverse events; TIME_FRAME: 12-20 weeks; DESCRIPTION: As by adverse events; > SECONDARY OUTCOME 1: MEASURE: Pharmacokinetics of 11β-MNTDC after 4 escalating oral doses of 11β-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose using area under the curve (AUC); TIME_FRAME: 112 days; DESCRIPTION: 11β-MNTDC PK levels at various time points through the 112 days of treatment using AUC; >; SECONDARY OUTCOME 2: MEASURE: Pharmacokinetics of 11β-MNTDC after 4 escalating oral doses of 11β-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose using maximum concentration (Cmax); TIME_FRAME: 112 days; DESCRIPTION: 11β-MNTDC PK levels at various time points through the 112 days of treatment using Cmax; >; SECONDARY OUTCOME 3: MEASURE: Pharmacokinetics of 11β-MNTDC after 4 escalating oral doses of 11β-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose using Time to Reach Maximum Concentration (Tmax); TIME_FRAME: 112 days; DESCRIPTION: 11β-MNTDC PK levels at various time points through the 112 days of treatment using Tmax; >; SECONDARY OUTCOME 4: MEASURE: Pharmacodynamics of 11β-MNTDC after 4 escalating oral doses of 11β-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by Luteinizing Hormone (LH); TIME_FRAME: 112 days; DESCRIPTION: 11β-MNTDC PD levels at various time points through the 112 days of treatment; >; SECONDARY OUTCOME 5: MEASURE: Pharmacodynamics of 11β-MNTDC after 4 escalating oral doses of 11β-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by Follicle Stimulating Hormone (FSH); TIME_FRAME: 112 days; DESCRIPTION: 11β-MNTDC PD levels at various time points through the 112 days of treatment; >; SECONDARY OUTCOME 6: MEASURE: Pharmacodynamics of 11β-MNTDC after 4 escalating oral doses of 11β-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by Testosterone (T); TIME_FRAME: 112 days; DESCRIPTION: 11β-MNTDC PD levels at various time points through the 112 days of treatment; >; SECONDARY OUTCOME 7: MEASURE: Pharmacodynamics of 11β-MNTDC after 4 escalating oral doses of 11β-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by free Testosterone (free T); TIME_FRAME: 112 days; DESCRIPTION: 11β-MNTDC PD levels at various time points through the 112 days of treatment; >; SECONDARY OUTCOME 8: MEASURE: Pharmacodynamics of 11β-MNTDC after 4 escalating oral doses of 11β-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by Dihydrotestosterone (DHT); TIME_FRAME: 112 days; DESCRIPTION: 11β-MNTDC PD levels at various time points through the 112 days of treatment; >; SECONDARY OUTCOME 9: MEASURE: Pharmacodynamics of 11β-MNTDC after 4 escalating oral doses of 11β-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by estradiol (E2); TIME_FRAME: 112 days; DESCRIPTION: 11β-MNTDC PD levels at various time points through the 112 days of treatment; >; SECONDARY OUTCOME 10: MEASURE: Pharmacodynamics of 11β-MNTDC after 4 escalating oral doses of 11β-MNTDC administered in a fast and fed cycle lasting approximately 28 days for each dose as measured by Sex Hormone Binding Globulin (SHBG); TIME_FRAME: 112 days; DESCRIPTION: 11β-MNTDC PD levels at various time points through the 112 days of treatment; >; SECONDARY OUTCOME 11: MEASURE: Effect of food on the pharmacokinetics of orally administered 11β-MNTDC using Average Concentration (Cavg); TIME_FRAME: 112 days; DESCRIPTION: Comparison of pharmacokinetic measures among the single dose periods and comparison of PK parameters in the fed and fasting states will be performed with mixed model repeated measures analysis of variance (ANOVA). Evidence of lack of food effect will be concluded if ANOVA-estimated PK parameters (Cavg) after food are within 80 to 125% of those obtained at the fasting state.; >; SECONDARY OUTCOME 12: MEASURE: Effect of food on the pharmacokinetics of orally administered 11β-MNTDC using the area under the curve from 0-24 hours (AUC 0-24h); TIME_FRAME: 112 days; DESCRIPTION: Comparison of pharmacokinetic measures among the single dose periods and comparison of PK parameters in the fed and fasting states will be performed with mixed model repeated measures analysis of variance (ANOVA). Evidence of lack of food effect will be concluded if ANOVA-estimated PK parameters (AUC0-24h) after food are within 80 to 125% of those obtained at the fasting state.; >; SECONDARY OUTCOME 13: MEASURE: Effect of food on the pharmacokinetics of orally administered 11β-MNTDC using maximum concentration (Cmax); TIME_FRAME: 112 days; DESCRIPTION: Comparison of pharmacokinetic measures among the single dose periods and comparison of PK parameters in the fed and fasting states will be performed with mixed model repeated measures analysis of variance (ANOVA). Evidence of lack of food effect will be concluded if ANOVA-estimated PK parameters (Cmax) after food are within 80 to 125% of those obtained at the fasting state.; >;

ARM GROUP 1: <LABEL: Placebo; GROUP TYPE: Placebo Comparator; DESCRIPTION: Placebo; >; ARM GROUP 2: <LABEL: 11βmethyl nortestosterone dodecylcarbonate; GROUP TYPE: Experimental; DESCRIPTION: 11β-MNTDC in doses of 100 mg, 200 mg, 400 mg, and 800 mg; >;

INTERVENTION 1: <TYPE: Drug; NAME: Placebo; DESCRIPTION: Placebo with capsules that look like the 11β-MNTDC capsules but with no active ingredients, >; INTERVENTION 2: <TYPE: Drug; NAME: 11βmethyl nortestosterone dodecylcarbonate; DESCRIPTION: Escalating doses of 100, 200, 400, and 800 mg 11β-MNTDC, >;

Inclusion Criteria: 1. Male volunteers in good health as confirmed by physical examination, medical history, and clinical laboratory tests of blood and urine at the time of screening. 2. 18 to 50 years of age (inclusive). 3. BMI ≤ 33 calculated as weight in kg/ (height in m2). 4. No history of hormonal therapy use in the last three months prior to the first screening visit. 5. Subject agrees to use a recognized effective method of contraception with any female partner (i.e. at a minimum, use barrier plus and additional method of contraception) during the course of the study treatment and recovery phase. 6. Subjects will refrain from donating blood or plasma during the study period. 7. Subjects will be advised to refrain/abstain from alcoholic beverages and grapefruit juice during the study period. 8. Subjects will not use cannabis or any recreational drugs at least 2 weeks before completing screening and during the study. 9. In the opinion of the investigator, subject is able to comply with the protocol, understand and sign an informed consent and HIPAA form. 10. Does not meet any of the exclusion criteria. Exclusion Criteria: 1. Men participating in another clinical trial involving an investigational drug within the last 30 days prior to the first screening visit. 2. Men not living in the catchment area of the clinic or within a reasonable distance from the study site. 3. Clinically significant abnormal physical and laboratory findings at screening. 4. Elevated PSA (levels ≥ 2.5 ng/mL), according to local laboratory normal values. 5. Abnormal serum chemistry values, according to local laboratory reference ranges that indicate liver or kidney dysfunction or that may be considered clinically significant except for: an upper limit for fasting bilirubin less than 2 mg/dL, upper limit for cholesterol less than 221 mg/dL, or upper limit for fasting triglycerides less than 201 mg/dL. 6. Use of androgens within 2 months before first screening visit. 7. Ongoing use of body building nutritional supplements. 8. Systolic BP > 135 mm Hg and Diastolic blood pressure BP > 85 and mm Hg; ((BP) Blood pressure will be taken 3 times at 5 - minute intervals and the mean of all measurements be considered). 9. Clinically significant abnormal EKG or a QTc interval of > 450 msec. 10. History of hypertension, including hypertension controlled with treatment. 11. Benign or malignant liver tumors; active liver disease. 12. History of breast carcinoma. 13. Known history of androgen deficiency due to hypothalamic-pituitary or testicular disease. 14. Known history of cardiovascular, renal, hepatic or prostatic disease or significant psychiatric illness. 15. Positive serology for active Hepatitis (not immunization-related serology) or HIV at screening visit. 16. A serious systemic disease such as diabetes mellitus or obesity (body weight greater than BMI >33 kg/m2 as above). 17. History of known, untreated sleep apnea. 18. Known or suspected alcoholism or drug abuse that may affect metabolism/transformation of steroid hormones or study treatment compliance. 19. Partner is known to be pregnant. 20. Men desiring fertility within the first 24 weeks of study participation. 21. Men participating in competitive sports where drug screening for prohibited substances (including anabolic steroids) is routine will be advised of the relative and temporary hazards that participating in this study may have for their sporting status.

NCT03298373

Failed

28-Day Repeat-Dose, Dose Escalation Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics Study of 11-β Methyl Nortestosterone Dodecylcarbonate (11β-MNTDC) in Healthy Men

Health Decisions

This is a Phase I multicenter, double-blind, repeat dose, dose-escalating study, in healthy men to evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of 11-β Methyl Nortestosterone Dodecylcarbonate (11β-MNTDC).

This repeat dose, dose-ranging study will be conducted at two centers: the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and the University of Washington. Two doses of 11β-MNTDC (200 mg and 400 mg) were selected for a dose-escalating 28-day repeat dose study. Twenty subjects will complete this study at each of the 11β-MNTDC (15 on 11β-MNTDC and 5 on placebo) yielding a total of 40 completed subjects (30 on 11β-MNTDC and 10 on placebo) across both sites. Safety will be assessed in subjects receiving the lower dosage before additional men receive the higher dose for 28 days. In addition to safety and tolerability, suppression of serum T, calculated free T, E2, gonadotropins (LH & FSH), and SHBG will also be assessed as secondary pharmacodynamic (PD) endpoints. The 24-hour detailed PK of 11β-MNTDC will be assessed on Days 1 and 28. Trough levels of 11β-MNTDC will be obtained throughout the 28-day treatment period, at 48 and 72 hours (Days 30 and 31) after the last dose and at the End of Study visit (between Days 70-76).

ALLOCATION: Randomized; INTERVENTION MODEL: Parallel Assignment; PRIMARY PURPOSE: Other; MASKING: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);

PRIMARY OUTCOME: <MEASURE: Incidence of treatment emergent adverse events (safety and tolerability) of repeated daily oral dosing of 11β-MNTDC.; TIME_FRAME: 28 days; > SECONDARY OUTCOME 1: MEASURE: Pharmacokinetics of 11β-MNTDC using AUC (0-24).; TIME_FRAME: 28 days; >; SECONDARY OUTCOME 2: MEASURE: Pharmacodynamics of 11β-MNTDC by assessing the suppression of serum Testosterone (T) using mean values at each visit.; TIME_FRAME: 28 days; >; SECONDARY OUTCOME 3: MEASURE: Pharmacodynamics of 11β-MNTDC by assessing the suppression of Estradiol (E2) using mean values at each visit.; TIME_FRAME: 28 days; >; SECONDARY OUTCOME 4: MEASURE: Pharmacodynamics of 11β-MNTDC by assessing the suppression of Follicle Stimulating Hormone (FSH) using mean values at each visit.; TIME_FRAME: 28 days; >; SECONDARY OUTCOME 5: MEASURE: Pharmacodynamics of 11β-MNTDC by assessing the suppression of Luteinizing Hormone (LH) using mean values at each visit; TIME_FRAME: 28 days; >; SECONDARY OUTCOME 6: MEASURE: Pharmacodynamics of 11β-MNTDC by assessing the suppression of Sex Hormone Binding Globulin (SHBG) using mean values at each visit.; TIME_FRAME: 28 days; >; SECONDARY OUTCOME 7: MEASURE: Changes from baseline in sexual function (safety and tolerability) with 11β-MNTDC after 28 days of dosing using the psychosexual daily questionnaire.; TIME_FRAME: 28 days; >; SECONDARY OUTCOME 8: MEASURE: Changes from baseline in mood (safety and tolerability) with 11β-MNTDC after 28 days of dosing using the Patient Health Questionnaire-9.; TIME_FRAME: 28 days; >;

ARM GROUP 1: <LABEL: Placebo; GROUP TYPE: Placebo Comparator; DESCRIPTION: Placebo capsules that look like the 11β-MNTDC capsules but with no active ingredients.; >; ARM GROUP 2: <LABEL: 11β-MNTDC; GROUP TYPE: Experimental; DESCRIPTION: 11β-MNTDC capsules administered orally (200 mg or 400 mg).; >;

INTERVENTION 1: <TYPE: Drug; NAME: Placebo; DESCRIPTION: Placebo capsules that look like the 11β-MNTDC capsules but with no active ingredients., >; INTERVENTION 2: <TYPE: Drug; NAME: 11β-methyl-nortestosterone-dodecylcarbonate; DESCRIPTION: 11β-MNTDC doses in castor oil/benzyl benzoate capsules (100 mg each) administered in 200 mg or 400 mg doses orally., >;

Inclusion Criteria: Men who meet all the following criteria are eligible for enrollment in the trial: 1. Male volunteers in good health as confirmed by physical examination, medical history, and clinical laboratory tests of blood and urine at the time of screening. 2. 18 to 50 years of age (inclusive) at the time of the enrollment visit. 3. BMI ≤ 33 calculated as weight in kg/ (height in m2). 4. No history of hormonal therapy use in the three months prior to the first screening visit. 5. Subject agrees to use a recognized effective method of contraception with any female partner during the course of the study. 6. Subjects agrees to refrain from donating blood or plasma during the study period and from participating in other investigational drug studies. 7. Subjects agrees to refrain from excessive alcohol consumption during the study period. (No more than 15 drinks per week and no alcohol consumption within 24 hours of a study visit.) 8. Subjects agrees to refrain from significant changes in their current exercise regimen during the drug exposure period. 9. No known or suspected current alcohol dependence syndrome, chronic marijuana use, or any illicit drug use that may affect metabolism/transformation of steroid hormones and study treatment compliance. 10. In the opinion of the investigator, subject can comply with the protocol, understand and sign an informed consent and HIPAA form. Exclusion Criteria: Men who meet any of the following criteria are NOT eligible for enrollment in the trial: 1. Men participating in another clinical trial involving an investigational drug within 30 days prior to the first screening visit. 2. Men not living in the catchment area of the clinic or within a reasonable distance from the study site. 3. Clinically significant abnormal physical or laboratory findings at screening. 4. Elevated PSA (levels ≥ 2.5 ng/mL) at screening, per local laboratory normal values. 5. Abnormal serum chemistry values at screening, per local laboratory reference ranges that indicate liver or kidney dysfunction or that may be considered clinically significant. In addition, the following upper limits will be observed: fasting bilirubin less than 2 mg/dL, cholesterol less than 221 mg/dL, and fasting triglycerides less than 201 mg/dL. 6. Abnormal semen analyses or abnormal semen concentration as defined by the WHO semen manual. 7. Use of androgens within 3 months before the first screening visit except for long acting, intramuscular testosterone undecanoate which will require a wash out period of 6 months prior to randomization. 8. Ongoing use of body building substances including nutritional supplements. 9. Systolic BP > 135 mm Hg and Diastolic blood pressure BP > 85 and mm Hg; Blood pressure (BP) will be taken 3 times at 5 - minute intervals and the mean of all measurements be used to determine eligibility. 10. Clinically significant abnormal EKG or a QTc interval of > 450 msec. 11. PHQ-9 score of 15 or above. 12. History of hypertension, including hypertension controlled with medication. 13. Known history of primary testicular disease or disorders of the hypothalamic-pituitary axis. 14. Benign or malignant liver tumors, active liver disease or known non-alchoholic fatty liver disease (NAFLD) 15. History of breast carcinoma. 16. Known history of androgen deficiency due to hypothalamic-pituitary or testicular disease. 17. Known history of cardiovascular, renal, hepatic or prostatic disease or significant psychiatric illness. 18. Positive serology for active Hepatitis (not immunization-related serology) or HIV at screening visit. 19. A serious systemic disease such as diabetes mellitus. 20. History of known, untreated sleep apnea. 21. Partner is known to be pregnant. 22. Men desiring fertility within the first 24 weeks of study participation. 23. Men participating in competitive sports where drug screening for prohibited substances (including anabolic steroids) is routine. Exclusion is due to the potential of testing positive for androgens that may occur from their study participation coupled with the unknown efficacy (i.e. duration of positive testing) of a single dose. 24. Subjects taking anticonvulsants. 25. Subjects taking recombinant human growth factor (HGH). 26. Subjects with a hematocrit greater than 55%. 27. Previous participation in this clinical trial or any trials of 11-Beta MNTDC. 28. Any site staff member with delegated study responsibilities or a family member of a site staff member with delegated study responsibilities.

NCT03291080

Completed

Relative Bioavailability and Comparative Pharmacokinetics of 13-CRA Oral Liquid and Extracted Capsule Formulations: a Randomised, Open Label, Multi-dose, Cross-over Clinical Trial in Patients Requiring Treatment Cycles of 13-CRA.

Nova Laboratories Limited

An open label, randomised, multiple dose, cross-over relative bioavailability and pharmacokinetics trial of a novel oral liquid and capsule formulations of 13-CRA administered to patients from 0 months - < 21 years.

All patients requiring at least two cycles of 13-CRA therapy will be eligible for recruitment into the trial. 13-CRA will be prescribed to patients according to local treatment protocols at each clinical site. The dose administered will be 200mg/m2/day for both test and reference product. Patients with a body weight of ≤12kg will receive a dose of 160 mg/m2/day. The pharmacokinetics of 13-CRA liquid (test product) and extracted from capsule (reference product) will be evaluated over two months. Prior to the initiation of 13-CRA treatment as part of the trial, patients will be randomised to receive either liquid or capsule formulation in "My-CRA month 1". The patients will then cross-over to the alternative formulation in "My-CRA month 2". The patients on the trial who require further treatment will revert to standard therapy i.e. 13-CRA extracted from capsules according to local practice.

ALLOCATION: Randomized; INTERVENTION MODEL: Crossover Assignment; PRIMARY PURPOSE: Other; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Relative Bioavailability; TIME_FRAME: On day 1 and 14 of treatment; DESCRIPTION: Relative bioavailability (Area under the curve) of 13-CRA administered as oral liquid (test) and extracted capsule (reference) formulations.; > SECONDARY OUTCOME 1: MEASURE: Maximum Plasma Concentration (Cmax); TIME_FRAME: On day 1 and 14 of treatment; DESCRIPTION: Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation; >; SECONDARY OUTCOME 2: MEASURE: Time to Maximum Concentration (Tmax); TIME_FRAME: On day 1 and 14 of treatment; DESCRIPTION: Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation; >; SECONDARY OUTCOME 3: MEASURE: Area Under Plasma Concentration Time Curve (AUC) Metabolite; TIME_FRAME: On day 1 and 14 of treatment; DESCRIPTION: Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation- metabolite 4-oxo-13-cisRA; >; SECONDARY OUTCOME 4: MEASURE: Cmax (ng/mL)- Metabolite; TIME_FRAME: On day 1 and 14 of treatment; DESCRIPTION: Pharmacokinetic parameter for metabolite 4-oxo-13-cisRA PK; >; SECONDARY OUTCOME 5: MEASURE: T Max of Metabolite; TIME_FRAME: On day 1 and 14 of treatment; DESCRIPTION: T max for metabolite -4-oxo-13-cisRA PK; >;

ARM GROUP 1: <LABEL: Liquid; GROUP TYPE: Experimental; DESCRIPTION: Oral liquid formulation of 13-Cis Retinoic Acid - test product.; >; ARM GROUP 2: <LABEL: Capsule; GROUP TYPE: Experimental; DESCRIPTION: Isotretinoin capsules (13-CRA extracted per standard of care)- reference product.; >;

INTERVENTION 1: <TYPE: Drug; NAME: Liquid 13-Cis Retinoic Acid; DESCRIPTION: Liquid 13-Cis Retinoic Acid, >; INTERVENTION 2: <TYPE: Drug; NAME: Extracted capsules 13-CRA; DESCRIPTION: Extracted capsules 13-CRA, >;

Inclusion Criteria: 1. Male or female aged from 0 years to < 21 years of age. 2. Patient with high risk neuroblastoma, or unresectable, unfavourable histology intermediate risk neuroblastoma the latter age ≥ 18 months at diagnosis 3. Patient who is scheduled to receive at least two treatment cycles of 13-CRA. 4. Patient who cannot swallow 13-CRA capsules (i.e. requires extraction of 13-CRA from the capsules). 5. Negative pregnancy test for females of child-bearing potential before initiation of treatment, and sexually active patients and partners agreeing to undertake adequate contraceptive measures (see section 4.5). 6. Provision of a single or double lumen central venous catheter for sampling (i.e. already in place). 7. Parent(s)/legal guardian able and willing to provide written informed consent for the patient to take part in the trial. 8. Where applicable, the patient should assent to undergo blood sampling for pharmacokinetic purposes and to allow physiological measurements to be made. Exclusion Criteria: 1. Any clinically significant medical condition or abnormality, which, in the opinion of the investigator, might compromise the safety of the patient or which might interfere with the trial. 2. Diagnosis of high-risk neuroblastoma (HRNBL) which is currently being treated on the SIOPEN HRNBL trial (patients who have exited this trial will be eligible). 3. Known allergy to 13-CRA or any of the excipients. 4. Inadequate contraception measures in females of childbearing age. 5. Receiving concomitant treatment with tetracyclines. Prior to each cycle: 1. Total bilirubin ≤ 1.5 x normal, and (SGPT) ALT ≤ 5 x normal. Veno-occlusive disease if present, should be stable or improving. 2. Skin toxicity no greater than CTCAE Grade 1(10) 3. Serum triglycerides <5.65mmol/L. 4. No haematuria and / or proteinuria on urinalysis. 5. Serum calcium ≤ 2.9mmol/L. 6. Serum creatinine based on age / gender as follows: Age Maximum Serum Creatinine µmol/L Male Female 1 month to < 6 months 35 35 6 months to < 1 year 44 44 1 to < 2 years 53 53 2 to < 6 years 70 70 6 to < 10 years 88 88 10 to < 13 years 106 106 13 to < 16 years 132 124 ≥ 16 years 150 124 7. Patients with a seizure disorder must be well controlled and taking anticonvulsants. CNS toxicity < grade 2 (CTCAE). Withdrawal Criteria: 1. Positive pregnancy test - pregnancy testing will be undertaken before treatment commences and routinely before each course of treatment in females of childbearing potential. If a patient is found to be pregnant during the trial, the next course of treatment will not be given until the pregnancy has been discussed with the treating clinician, and the patient will be withdrawn from the trial whether or not treatment is continued. 2. Request of the patient, for any reason. 3. Discretion of the investigator.

NCT03490838

Failed

A Phase 1/2 Open-label, Multi-center, Dose-escalation Study of Safety, Tolerability, Pharmacokinetics, Dosimetry, and Response to Repeat Dosing of 177Lu-PSMA-R2 Radio-ligand Therapy in Patients With Prostate Specific Membrane Antigen (PSMA) Positive (68Ga-PSMA-R2) Progressive Metastatic Castration-resistant Prostate Cancer, Following Previous Systemic Treatment

Advanced Accelerator Applications

This Phase 1/2 study is intended to investigate the safety, tolerability, and radiation dosimetry of 177Lu-PSMA-R2 and further assess preliminary efficacy data in patients with metastatic castration-resistant prostate cancer (mCRPC). The Phase 1 portion of the study will determine the recommended dose of 177Lu-PSMA-R2 for radio-ligand therapy (RLT) of mCRPC, and the Phase 2 portion will expand into approximately 60 patients documenting the preliminary activity (anti-tumor response) of repeated treatments administered, continuing safety assessments and collecting QoL data.

Recruitment for PROter A206T-G01-001 (NCT03490838) was halted in Phase I by sponsor decision. Phase II expansion portion of the study was never initiated. Importantly, this recruitment halt was not a consequence of any safety concern. Ongoing patients at the time of recruitment halt continued per protocol and completed the 1 year safety follow-up prior to early study termination. The primary objective of the Phase I portion of the study to assess the safety and tolerability of 177Lu-PSMA-R2 and to assess Dose Limiting Toxicities (DLTs) and determine the maximum tolerated dose (MTD) (if reached) and the recommended Phase II dose was not reached due to early recruitment halt.

ALLOCATION: Non-Randomized; INTERVENTION MODEL: Sequential Assignment; PRIMARY PURPOSE: Treatment; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Phase I: Incidence of dose limiting toxicities (DLTs) during first cycle of study treatment.; TIME_FRAME: Up to 8 weeks after the first 177Lu-PSMA-R2 dose; DESCRIPTION: A dose-limiting toxicity (DLT) is defined as any toxicity not attributable to the disease or disease-related processes under investigation, the time window for DLT assessment period is Cycle 1. To be considered a DLT, it must be related to the IP (attributions: possible, probable, and definite) while fulfilling one of the following criteria as per the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0.; > SECONDARY OUTCOME 1: MEASURE: Phase I and II: Treatment Emergent Adverse Event (TEAE) rate; TIME_FRAME: From randomization till 30 days safety follow-up, assessed up to 4 years (estimated final OS analysis); DESCRIPTION: The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.; >; SECONDARY OUTCOME 2: MEASURE: Phase I and II: Objective Response Rate (ORR); TIME_FRAME: From date of randomization assessed up to 4 years (estimated final OS analysis); DESCRIPTION: ORR is defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) per RECIST 1.1.; >; SECONDARY OUTCOME 3: MEASURE: Phase I and II: Duration of Response (DoR); TIME_FRAME: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 4 years (estimated final OS analysis); DESCRIPTION: Duration of Response (DoR) according to RECIST v1.1 is defined as the time that measurement criteria are met for objective response (CR/PR) (whichever status is recorded first) until the first date of progression or death is documented.; >; SECONDARY OUTCOME 4: MEASURE: Phase I and II: Prostate-Specific Antigen (PSA) response rate 30; TIME_FRAME: Week 13 (12 weeks after the first 177Lu-PSMA-R2 injection); DESCRIPTION: PSA response rate 30 is defined as the proportion of participants who have a greater or equal 30% in PSA from Baseline that is confirmed by a second PSA measurement 4 weeks later, as per Prostate Cancer Working Group 3 (PCWG3) criteria.; >; SECONDARY OUTCOME 5: MEASURE: Phase I: Prostate-Specific Antigen (PSA) response rate 50; TIME_FRAME: Week 13 (12 weeks after the first 177Lu-PSMA-R2 injection); DESCRIPTION: PSA response rate 50 is defined as the proportion of participants who have a greater or equal 50% in PSA from Baseline that is confirmed by a second PSA measurement 4 weeks later, as per Prostate Cancer Working Group 3 (PCWG3) criteria.; >; SECONDARY OUTCOME 6: MEASURE: Phase I: 177Lu-PSMA-R2 plasma concentration; TIME_FRAME: Days 1 through 8 post-treatment; >; SECONDARY OUTCOME 7: MEASURE: Phase I: Maximum plasma concentration (Cmax) of 177Lu-PSMA-R2; TIME_FRAME: Day 1 (before the start of infusion, at the mid-point, and just before the end of infusion, then at post infusion at approximately 5, 15, 30 minutes, 1, 2, 4, 6, 8, 24, 40 (+/- 4 hours), 48 hours), Day 4 (+2 days) and Day 8 post end of infusion; DESCRIPTION: Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.; >; SECONDARY OUTCOME 8: MEASURE: Phase I: Minimum plasma concentration (Cmin) of 177Lu-PSMA-R2; TIME_FRAME: Day 1 (before the start of infusion, at the mid-point, and just before the end of infusion, then at post infusion at approximately 5, 15, 30 minutes, 1, 2, 4, 6, 8, 24, 40 (+/- 4 hours), 48 hours), Day 4 (+2 days) and Day 8 post end of infusion; DESCRIPTION: Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmin will be listed and summarized using descriptive statistics.; >; SECONDARY OUTCOME 9: MEASURE: Phase I: Area under the plasma concentration-time curve (AUC) of 177Lu-PSMA-R2; TIME_FRAME: Day 1 (before the start of infusion, at the mid-point, and just before the end of infusion, then at post infusion at approximately 5, 15, 30 minutes, 1, 2, 4, 6, 8, 24, 40 (+/- 4 hours), 48 hours), Day 4 (+2 days) and Day 8 post end of infusion; DESCRIPTION: Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUC will be listed and summarized using descriptive statistics.; >; SECONDARY OUTCOME 10: MEASURE: Phase I: Dosimetry; TIME_FRAME: Days 1 through 8 post-treatment; DESCRIPTION: Radiation (Gy, Gy/MBq) update by critical organs and metastatic lesions; >; SECONDARY OUTCOME 11: MEASURE: Phase I and II: Patient Reported Outcomes (PRO) of Mouth Dryness using Xerostomia Questionnaire; TIME_FRAME: Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first; DESCRIPTION: The Xerostomia questionnaire is a questionnaire used to describe mouth dryness and its effects on daily life. It consists of 8 questions with each question score ranging from 0 ("never"/"none") to 10 ("worst"). The sum of the 8 scores produces a total score (score range from 0-80). A low score corresponds to a good quality of life while a high score means a poor quality of life due to the dry mouth.; >; SECONDARY OUTCOME 12: MEASURE: Phase I and II: Patient Reported Outcomes (PRO) of Eye Dryness using Xerophthalmia Questionnaire; TIME_FRAME: Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first; DESCRIPTION: The Xerophthalmia questionnaire is a questionnaire used to describe eye dryness and its effects on daily life. It consists of 3 questions. The first 2 questions scores range from 1 ("never") to 4 ("constantly") and the last question is a Yes/No question about previous dry eye diagnosis. The sum of the scores of the first 2 questions produces a total score (score range from 2-8). A low score corresponds to a good quality of life while a high score means a poor quality of life due to the dry eye.; >; SECONDARY OUTCOME 13: MEASURE: Phase I and II: Brief Pain Inventory-short Form (PBI-SF); TIME_FRAME: Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first; DESCRIPTION: The BPI-SF is a publicly available instrument to assess the pain and includes severity and interference scores. BPI-SF is an 11-item self report questionnaire that is designed to assess the severity and impact of pain on daily functions of a participant. Pain severity score is a mean value for BPI-SF questions 3, 4, 5 and 6 (questions inquiring about the extent of pain, where the extent is ranked from 0 [no pain] to 10 [pain as bad as you can imagine]). Pain severity progression is defined as an increase in score of 30% or greater from baseline without decrease in analgesic use.; >; SECONDARY OUTCOME 14: MEASURE: Phase II: Disease Control Rate (DCR); TIME_FRAME: From date of randomization till 30 days safety fup, assessed up to 4 years (estimated final OS analysis); DESCRIPTION: DCR is defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) per RECIST 1.1.; >; SECONDARY OUTCOME 15: MEASURE: Phase II: Radiographic Progression Free Survival (rPFS); TIME_FRAME: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 4 years (estimated final OS analysis); DESCRIPTION: rPFS is defined as the time to radiographic progression by PCWG3-modified RECIST v1.1 or death.; >; SECONDARY OUTCOME 16: MEASURE: Phase II: Overall Survival (OS); TIME_FRAME: From date of randomization until date of death from any cause, assessed up to 4 years (estimated final OS analysis); DESCRIPTION: OS is defined as the time to death for any cause.; >; SECONDARY OUTCOME 17: MEASURE: Phase II: Time to Prostate Specific Antigen (PSA) progression; TIME_FRAME: From date of randomization until date of death from any cause, assessed up to 4 years (estimated final OS analysis); DESCRIPTION: PSA progression is defined as the time from the date of first dose of 177Lu-PSMA-R2 injection to the first date that a >= 25% increase in PSA and an absolute increase of 2 ng/mL or more from the nadir was documented and confirmed by a second consecutive value obtained 3 or more weeks later.; >; SECONDARY OUTCOME 18: MEASURE: Phase II: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Score; TIME_FRAME: Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first; DESCRIPTION: The EORTC QLQ-C30 contains 30 questions assessed by the participant. There are 9 multiple-item scales: 5 scales that assess aspects of functioning (physical, role functioning, cognitive, emotional, and social); 3 symptom scales (Fatigue, Pain, and Nausea and Vomiting); and a global health status/Quality of Life (QOL) scale. There are 5 single-item measures assessing additional symptoms (i.e., dyspnea, loss of appetite, insomnia, constipation, and diarrhea) and a single item concerning perceived financial impact of the disease. All but two questions have 4 point scales ranging from "Not at all" to "Very much." The two questions concerning global health status/ QOL have 7 point scales with ratings ranging from "Very poor" to "Excellent." For each of the 14 domains, final scores are transformed such that they range from 0-100, where higher scores indicate improvement.; >; SECONDARY OUTCOME 19: MEASURE: Phase II: Change from Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Prostate Module (EORTC QLQ-PR25) Score; TIME_FRAME: Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first; DESCRIPTION: The EORTC QLQ-PR25 is a prostate cancer module for the assessment of health-related quality of life (HRQoL). It consists of 25 questions distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Questions use a 4 point scale (1 'Not at all' to 4 'Very much'). All raw domain scores are linearly transformed to a 0-100 scale, with higher scores reflecting either more symptoms (urinary, bowel, hormonal treatment-related symptoms) or higher levels of activity or functioning (sexual).; >;

ARM GROUP 1: <LABEL: Phase I: Dose Escalation Cohort 1; GROUP TYPE: Experimental; DESCRIPTION: 3.70 GBq (100 mCi) x 3 times; >; ARM GROUP 2: <LABEL: Phase I: Dose Escalation Cohort 2; GROUP TYPE: Experimental; DESCRIPTION: 7.40 GBq (200 mCi) up to 4 times; >; ARM GROUP 3: <LABEL: Phase I: Dose Escalation Cohort 3; GROUP TYPE: Experimental; DESCRIPTION: 11.1 GBq (300 mCi) up to 4 times; >; ARM GROUP 4: <LABEL: Phase I: Dose Escalation Cohort 4; GROUP TYPE: Experimental; DESCRIPTION: 14.8 GBq (400 mCi) up to 4 times; >; ARM GROUP 5: <LABEL: Phase I: Dose Escalation Cohort 5; GROUP TYPE: Experimental; DESCRIPTION: 18.5 GBq (500 mCi) up to 4 times; >; ARM GROUP 6: <LABEL: Phase I: Dose Escalation Cohort 6; GROUP TYPE: Experimental; DESCRIPTION: 18.5 GBq (500 mCi) up to 3 times; >;

INTERVENTION 1: <TYPE: Drug; NAME: 177Lu-PSMA-R2; DESCRIPTION: radio-ligand therapy, >;

Inclusion Criteria: - Male patients, 18 years of age or older - Signed and dated written ICF by the patient or legally acceptable representative prior to any study-specific procedures - Histologically confirmed adenocarcinoma of the prostate - Serum testosterone levels < 50 ng/dL after surgical or continued chemical castration - Metastatic disease documented by CT/MRI or bone scan (not older than 28 days at enrollment) revealing at least one metastatic lymph-node, visceral metastasis and/or bone metastasis - Positive 68Ga-PSMA-R2 PET/CT scan for central eligibility assessment. Patients who receive 68Ga-PSMA-R2 as part of separate clinical protocol are eligible (must meet all study eligibility criteria) - Documented progressive mCRPC on or after the last systemic treatment administered for the advanced disease including metastatic disease. Disease progression defined as increasing serum PSA (per PCWG3), radiological progression or ≥ 2 new bone lesions. - Must have received prior systemic treatment for mCRPC including CYP17 inhibitors and/or androgen-pathway inhibitors (i.e. abiraterone and/or enzalutamide when available) and one and no more than one line of chemotherapy for the advanced disease (unless ineligible (unfit) to receive chemotherapy). - At least 28 days elapsed between last anti-cancer treatment administration and the initiation of study treatment (except for Luteinizing Hormone-releasing Hormone [LHRH] or Gonadotropin-releasing Hormone [GnRH]), or resolution of all previous treatment related toxicities to CTCAE version 5.0 grade of ≤ 1 (except for chemotherapy induced alopecia and grade 2 peripheral neuropathy or grade 2 urinary frequency which are allowed). Prior major surgery must be at least 12 weeks prior to study entry. - Eastern cooperative oncology group (ECOG) performance status of 0-2 with a life expectancy ≥ 6 months - Adequate bone marrow reserve and organ function as demonstrated by complete blood count, and biochemistry in blood and urine at baseline 1. Platelet count of >100 x10e9/L 2. White blood cell (WBC) count > 3,000/mL 3. Neutrophil count > 1,500/mL 4. Hemoglobin ≥ 10 g/dL 5. Serum creatinine < 1.5 x upper limit normal (ULN) or estimated glomerular filtration rate (GFR) > 50 mL/min based upon Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Patients with estimated GFR between 50 - 60 mL/min at baseline will require a 99mTc-DTPA GFR test and only patients with non-obstructive pathology will be included in the study. 6. Total bilirubin < 3 x ULN (except if confirmed history of Gilbert's disease) 7. Baseline serum albumin > 30 g/L 8. Aspartate aminotransferase (AST) < 3 times the ULN - For male patients with partners of childbearing potential, agreement to use barrier contraceptive method (condom) and to continue its use for 6 months from receiving the last dose of IP Exclusion Criteria: - Pathological finding consistent with small cell, neuroendocrine carcinoma of the prostate or any other histology different than adenocarcinoma. - Diffuse bone-marrow involvement (i.e. "superscan" defined as bone scintigraphy in which there is excessive skeletal radioisotope uptake [>20 bone lesions] in relation to soft tissues along with absent or faint activity in the genitourinary tract due to diffuse bone/ bone marrow metastases) - Prior exposure to radioligand therapy radioisotope therapy (e.g. 89Sr), systemic radiotherapy or 223Ra-therapy. - Current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, any level of urinary obstruction requiring indwelling/condom catheters - Spinal cord compression or brain metastases - Uncontrolled pain that results in patient's lack of compliance with the imaging procedures - Uncontrolled cardiovascular history, defined as: - Congestive heart failure (New York Heart Association [NYHA] II, III, IV) - Mean resting corrected QT interval (QTc) >450 millisecond (msec), obtained from 3 ECGs recordings, using the screening clinic ECG machine-derived QTc value. - Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250 msec). - Any factor increasing the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives, or any concomitant medication known to prolong the QT interval. - Other known co-existing malignancies except non-melanoma skin cancer or low grade superficial bladder cancer unless definitively treated and proven no evidence of recurrence for 5 years. - History of deep vein thrombosis and/or pulmonary embolism within 4 weeks of enrollment. - Known incompatibility to CT or PET scans. - Any evidence of severe or uncontrolled systemic or psychiatric diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol - Active infection including human immunodeficiency virus (HIV) and untreated hepatitis B, and hepatitis C. Screening for chronic conditions is not required. - Patients who have received any investigational treatment agent within the last 28 days. - Known allergies, hypersensitivity, or intolerance to the IP or its excipients - Known history of myelodysplastic syndrome/leukemia at any time - Patient is unlikely to comply with study procedures, restrictions and requirements and judged by the Investigator that the patient is not suitable for participation in the study.

NCT03490032

Completed

A Phase 1/2 Open-label, Multi-center, Safety and Tolerability Study of a Single Dose of 68Ga-PSMA-R2 in Patients With Biochemical Relapse (BR) and Metastatic Prostate Cancer (mPCa)

Advanced Accelerator Applications

This was an open-label, multicenter, single dose, Phase I/II study to evaluate the safety and tolerability of a single administration of 3 mega Becquerel (MBq)/kg, but not less than 150 MBq and not more than 250 MBq, of 68^Ga-PSMA-R2 in adult male patients with biochemical relapse (BR) and metastatic prostate cancer (mPCa).

This study consisted of 2 parts. - During the first part (Phase I) of the study, 6 subjects with biochemically recurrent prostate cancer (PCa) received the investigational product (IP) and remained at the site for approximately 6 hours post-administration in order to assess the PK, biodistribution versus time, and dosimetry for critical organs. Subjects received a single dose of 3 MBq/kg, (>=150 and =<250 MBq), of 68^Ga-PSMA-R2 intravenously. Serial blood and urine samples were collected for PK characterization and dosimetry and whole-body PET/CT were acquired at selected time points (0 to 4 hours) to determine organ and tumor absorbed doses. Safety assessments were conducted after IP administration on Day 1, and during follow-up on Days 7 and 28. - In the second part of the study (Phase II), 2 groups of 12 subjects were enrolled (subjects with PCa in biochemical recurrence [PCa-BR], and subjects with prostate cancer in the metastatic stage [mPCa]). Based on the preliminary data analysis from the Phase I part of the study provided sufficient dosimetry data, all subjects underwent the whole body PET/CT imaging optimized for time (up to 2 time points) according to the data analysis from the Phase I part of the study. This study was comprised of 4 clinical visits and conducted in 3 study periods: screening, administration/imaging, and safety follow-up period.

ALLOCATION: Non-Randomized; INTERVENTION MODEL: Sequential Assignment; DESCRIPTION: Phase I: characterize PK and dosimetry Phase II: diagnostic potential in 2 groups Prostate Cancer in biochemical relapse, and Metastatic Prostate Cancer; PRIMARY PURPOSE: Diagnostic; MASKING: None (Open Label);

PRIMARY OUTCOME: <MEASURE: Number of Participants With Treatment Emergent Adverse Events; TIME_FRAME: dosing through 28 days post-dose; DESCRIPTION: Treatment-emergent adverse events (TEAEs) were collected from first dosing (single administration, Day 1) up to last follow-up visit or until the event has resolved to baseline grade or better or the event was assessed stable by the investigator or the patient was lost to follow-up or withdrew consent. The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.; > SECONDARY OUTCOME 1: MEASURE: Phase I: Decay Corrected Tissue Time-activity Curves (TACs) From 68Ga-PSMA-R2 PET/CT Images in Normal Organs; TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1 (20-30 min post-injection, 1 hour, 2 hours and 3-4 hours post-injection); DESCRIPTION: PET/CT scans were performed at approximately 20 to 30 min and at 1, 2, 3 to 4 hours postinjection. Time activity curves (TACs) for various organs (Brain, Heart Wall, Kidney, Lacrimal Gland, Liver, Lungs, Salivary Gland, Spleen and Thyroid) were produced as decay-corrected tissue of injected activity (mSv/MBq) per organ. Only descriptive analysis performed.; >; SECONDARY OUTCOME 2: MEASURE: Phase I: Urinary Excretion of [68Ga]-PSMA-R2; TIME_FRAME: 0 to 6 hours post-dose; DESCRIPTION: Urine samples were collected (up to 6 hours after dosing) for activity-based pharmacokinetics characterization. The apparent systemic clearance for the analyte in urine (Cl) was summarized with descriptive statistics.; >; SECONDARY OUTCOME 3: MEASURE: Phase I: Half-life of 68Ga-PSMA-R2 in Blood; TIME_FRAME: 0 to 6 hours post-dose; DESCRIPTION: Serial blood samples were collected (up to 6 hours after dosing) for activity-based pharmacokinetics characterization. The half-life (T^1/2) for the analyte in blood was summarized with descriptive statistics.; >; SECONDARY OUTCOME 4: MEASURE: Phase I: Non-decay Corrected Tissue Time-activity Curves (TACs) From 68Ga-PSMA-R2 PET/CT Images in Normal Organs; TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1 (20-30 min post-injection, 1 hour, 2 hours and 3-4 hours post-injection); DESCRIPTION: PET/CT scans were performed at approximately 20 to 30 min and at 1, 2, 3 to 4 hours postinjection. Time activity curves (TACs) for the various organs were produced as non-decay-corrected fraction of injected activity (mSv/MBq) per organ. Only descriptive analysis performed.; >; SECONDARY OUTCOME 5: MEASURE: Phase I: Residence Times in Normal Organs; TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1; DESCRIPTION: Residence times of radiation in normal organs were summarized with descriptive statistics.; >; SECONDARY OUTCOME 6: MEASURE: Phase I: Absorbed Dose of 68Ga-PSMA-R2; TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1; DESCRIPTION: Absorbed radiation dose of 68Ga-PSMA-R2 in target organs were summarized with descriptive statistics.; >; SECONDARY OUTCOME 7: MEASURE: Phase I: Whole-body Dose of 68Ga-PSMA-R2; TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1; DESCRIPTION: The whole-body dose of 68Ga-PSMA-R2 was summarized with descriptive statistics.; >; SECONDARY OUTCOME 8: MEASURE: Phase I: Effective Dose of 68Ga-PSMA-R2; TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1; DESCRIPTION: The effective dose of 68Ga-PSMA-R2 was summarized with descriptive statistics.; >; SECONDARY OUTCOME 9: MEASURE: Standard Uptake Value (SUV) Mean and Max in Lesions Detected by PET Scans by Timepoint; TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection); DESCRIPTION: Targeting properties of 68Ga-PSMA-R2 were evaluated by semi-quantitatively assessing radiotracer uptake at lesion level, identified via PET/CT imaging (4 scans). The SUVmean and SUVmax (g/mL) of each lesion were calculated and reported by lesion location with summary statistics at all imaging time points.; >; SECONDARY OUTCOME 10: MEASURE: Tumor to Background Ratio (TBR) of Lesions Detected by PET Scans by Timepoint; TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection); DESCRIPTION: Targeting properties of 68Ga-PSMA-R2 were evaluated by semi-quantitatively assessing radiotracer uptake at lesion level, identified via PET/CT imaging (4 scans). The lesion Tumor to Background Ratio (TBR) was defined as SUVmax(lesion) / SUVmean(gluteal or thigh) was calculated and reported by lesion location with summary statistics at all imaging time points.; >; SECONDARY OUTCOME 11: MEASURE: Standard Uptake Value (SUV) Mean and Max in Lesions Detected by PET Scans and Also Detected by Conventional Scans by Timepoint; TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection); DESCRIPTION: Targeting properties of 68Ga-PSMA-R2 were evaluated by semi-quantitatively assessing radiotracer uptake at lesion level, identified via PET/CT imaging (4 scans). The SUVmean and SUVmax (g/mL) of each lesion were calculated and reported by lesion location with summary statistics at all imaging time points.; >; SECONDARY OUTCOME 12: MEASURE: Tumor to Background Ratio (TBR) of Lesions Detected by PET Scans and Also Detected by Conventional Scans by Timepoint; TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection); DESCRIPTION: Targeting properties of 68Ga-PSMA-R2 were evaluated by semi-quantitatively assessing radiotracer uptake at lesion level, identified via PET/CT imaging (4 scans). The lesion Tumor to Background Ratio (TBR) was defined as SUVmax(lesion) / SUVmean(gluteal or thigh) was calculated and reported by lesion location with summary statistics at all imaging time points.; >; SECONDARY OUTCOME 13: MEASURE: Standard Uptake Value (SUV) Mean and Max in Lesions Detected by PET Scans and Not Detected by Conventional Scans by Timepoint; TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection); DESCRIPTION: Targeting properties of 68Ga-PSMA-R2 were evaluated by semi-quantitatively assessing radiotracer uptake at lesion level, identified via PET/CT imaging (4 scans). The SUVmean and SUVmax (g/mL) of each lesion were calculated and reported by lesion location with summary statistics at all imaging time points.; >; SECONDARY OUTCOME 14: MEASURE: Tumor to Background Ratio (TBR) of Lesions Detected by PET Scans and Not Detected by Conventional Scans by Timepoint; TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection); DESCRIPTION: Targeting properties of 68Ga-PSMA-R2 were evaluated by semi-quantitatively assessing radiotracer uptake at lesion level, identified via PET/CT imaging (4 scans). The lesion Tumor to Background Ratio (TBR) was defined as SUVmax(lesion) / SUVmean(gluteal or thigh) was calculated and reported by lesion location with summary statistics at all imaging time points.; >; SECONDARY OUTCOME 15: MEASURE: Patient Level Agreement of 68Ga-PSMA-R2 PET Imaging Relative to Conventional Techniques in Prostate Cancer Patients; TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour, 2 hours post-injection); DESCRIPTION: The subject-level positive percent agreement, negative percent agreement, and overall percent agreement was calculated based on the number of subjects with at least 1 positive lesion detected by conventional scan or at least 1 positive lesion detected by PET scan. These percent agreements were calculated as follows: Positive percent agreement: a/(a+c) × 100 Negative percent agreement: d/(b+d) × 100 Overall percent agreement: (a+d)/(a+b+c+d) × 100 Where: a = number of subjects with at least 1 positive lesion detected by conventional scan and at least 1 positive lesion detected by PET scan b = number of subjects with at least 1 positive lesion detected by PET scan that was not correlated with conventional scan c = number of subjects with at least 1 positive lesion detected by conventional scan that was not correlated with PET scan d = number of subjects with no lesions detected by conventional scan or PET scan.; >; SECONDARY OUTCOME 16: MEASURE: Burden of Tumor Lesions Measured by 68Ga-PSMA-R2 PET (1hr) Scan Compared With Standard Imaging Modality, by Location (Overall); TIME_FRAME: 68Ga-PSMA-R2 PET imaging acquired at Day 1 (1 hour post-injection); DESCRIPTION: The differences of number of positive lesions, number of positive lesions detected by PET scan and/or conventional scan and the location of positive lesions were summarized with descriptive statistics.; >;

ARM GROUP 1: <LABEL: Biochemically Recurrent Prostate Cancer (PCa-BR) (Phase I); GROUP TYPE: Experimental; DESCRIPTION: All eligible participants received recommended dose of [68Ga]-PSMA-R2 of 3 Mega Becquerel (MBq)/Kg (+/- 10%) [but not more than 250 and not less than 150 MBq].; >; ARM GROUP 2: <LABEL: Biochemically Recurrent Prostate Cancer (PCa-BR) (Phase II); GROUP TYPE: Experimental; DESCRIPTION: All eligible participants received recommended dose of [68Ga]-PSMA-R2 of 3 Mega Becquerel (MBq)/Kg (+/- 10%) [but not more than 250 and not less than 150 MBq].; >; ARM GROUP 3: <LABEL: Metastatic Prostate Cancer (mPCa) (Phase II); GROUP TYPE: Experimental; DESCRIPTION: All eligible participants received recommended dose of [68Ga]-PSMA-R2 of 3 Mega Becquerel (MBq)/Kg (+/- 10%) [but not more than 250 and not less than 150 MBq].; >;

INTERVENTION 1: <TYPE: Drug; NAME: [68Ga]-PSMA-R2; DESCRIPTION: radio-labelled PSMA ligand, >;

Inclusion Criteria: 1. Males 18 years or older. 2. Signed and dated written informed consent by the subject prior to any study-specific procedures. 3. Histologically confirmed adenocarcinoma of the prostate, defined as follows: 1. Biochemical recurrence: defined as PSA is ≥0.2 ng/mL after radical prostatectomy or PSA nadir plus 2 ng/mL after radiation therapy with corresponding CT/MRI or bone scan revealing absence of local recurrence or metastatic lesions. OR 2. Metastatic disease: defined as both, castration-sensitive or castration-resistant mPCa (presence of at least 1 metastatic lymph node, visceral metastasis and/or bone metastasis). 3. At least 2 weeks must have elapsed between last anticancer treatment administration and the administration of the imaging product, 68Ga-PSMA-R2. 4. Prior major surgery must be at least 12 weeks prior to study entry. 5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, with a life expectancy ≥6 months. 6. Adequate bone marrow reserve and organ function as demonstrated by complete blood count, and biochemistry in blood and urine at Screening: 1. Hemoglobin (Hb): >8 g/dL 2. Platelet count of >50.000/mm3 7. Serum creatinine <1.5*upper limit normal (ULN) or estimated glomerular filtration rate (eGFR) >50 mL/min based upon The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 8. For male subjects with partners of childbearing potential, agreement to use barrier contraceptive method (condom) and to continue its use for 28 days after IP administration. Exclusion Criteria: 1. Pathological finding consistent with small cell, neuroendocrine carcinoma of the prostate or any other histologies different than adenocarcinoma. 2. Administered a radioisotope =<10 physical half-lives prior to the day of PET/CT. 3. Current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, or need of indwelling/condom catheters. 4. Uncontrolled pain or incompatibility that results in subject's lack of compliance with imaging procedures. 5. Other known coexisting malignancies except non-melanoma skin or low grade superficial bladder cancer unless definitively treated and proven no evidence of recurrence for 5 years. 6. Subject with known incompatibility to CT scans. 7. Any evidence of severe or uncontrolled systemic or psychiatric diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the subject to participate in the study or which would jeopardize compliance with the protocol, or active infection including human immunodeficiency virus (HIV) and untreated hepatitis B, hepatitis C. Screening for chronic conditions was not required. 8. Subjects who have received any investigational agent within the last 28 days were excluded from participation in this study. 9. Any acute toxicity due to prior chemotherapy and/or radiotherapy that has not resolved according to the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Studies. 10. Known allergy, hypersensitivity, or intolerance to the IP or its excipients. 11. Subject unlikely to comply with study procedures, restrictions and requirements and judged by the investigator to be unsuitable for study participation.

NCT02048358

Failed

Randomized, Double-blind, Placebo- and Active Comparator- Controlled Crossover Study in Healthy Male Subjects and an Open Label Study in Healthy Subjects and MS Patients to Assess the Safety, Pharmacokinetics and Pharmacodynamics of 2B3-201

BBB-Therapeutics B.V.

In this first in human study the aim is to assess the safety, pharmacokinetics and pharmacodynamics of 2B3-201 in a randomized, first in human, double-blind, placebo- and active comparator- controlled 3-way crossover study in 18 healthy male subjects (part 1). Furthermore, the findings obtained from part 1 will be extended and confirmed in a subsequent parallel open label study in 18 healthy male and 12 MS patients and an open label study with methylprednisolone as comparator in 12 female volunteers (part 2).

PRIMARY OUTCOME: <MEASURE: Number of subjects with adverse events as a measure of safety and tolerability of 2B3-201; TIME_FRAME: 3 weeks; DESCRIPTION: Safety and tolerability of 2B3-201, in comparison to free methylprednisolone hemisuccinate and placebo and the safety and tolerability of 2B3-201amongst the different study populations: healthy male and female subjects and MS patients, additionally the safety and tolerability of 2B3-201 with hydroxypropyl β-cyclodextrin added to the infusion bag will be assessed in healthy male subjects; > SECONDARY OUTCOME 1: MEASURE: Measure changes in central nervous system (CNS) functioning after intravenous administration of 2B3-201 by using the Neurocart test battery; TIME_FRAME: 3 weeks; DESCRIPTION: Neurocart test battery (Pharmaco-EEG, Maze learning, Visual verbal Learning test, Stroop test, Adaptive tracking, VAS Bond & Lader and VAS Bowdle, Eye movements, LSEQ sleep questionnaire) as a measure of pharmacodynamic effects of 2B3-201 on CNS functioning in comparison to free methylprednisolone hemisuccinate and placebo;; >; SECONDARY OUTCOME 2: MEASURE: Changes in levels of Hypothalamic-pituitary-adrenal (HPA) axis hormones as a measure of pharmacodynamic effects of 2B3-201 in comparison to free methylprednisolone hemisuccinate and placebo;; TIME_FRAME: 3 weeks; >; SECONDARY OUTCOME 3: MEASURE: Changes in levels of fasting blood glucose as a measure of pharmacodynamic effects of 2B3-201 in comparison to free methylprednisolone hemisuccinate and placebo;; TIME_FRAME: 3 weeks; >; SECONDARY OUTCOME 4: MEASURE: Changes in levels of osteocalcin concentrations as a measure of pharmacodynamic effects of 2B3-201 in comparison to free methylprednisolone hemisuccinate and placebo;; TIME_FRAME: 3 weeks; >; SECONDARY OUTCOME 5: MEASURE: Changes in levels of lymphocyte count as a measure of pharmacodynamic effects of 2B3-201 in comparison to free methylprednisolone hemisuccinate and placebo;; TIME_FRAME: 3 weeks; >; SECONDARY OUTCOME 6: MEASURE: Changes in levels of complement factors during infusion as a measure of pharmacodynamic effects of 2B3-201 in comparison to free methylprednisolone hemisuccinate and placebo;; TIME_FRAME: 3 weeks; >;

ARM GROUP 1: <LABEL: 2B3-201 150mg; GROUP TYPE: Experimental; DESCRIPTION: 2B3-201 150mg, once, IV infusion in 1000ml 5% dextrose/ Methylprednisolone hemisuccinate 1000mg, once, IV infusion in 1000ml 5% dextrose/ Placebo, once, IV infusion 1000ml 5% dextrose; >; ARM GROUP 2: <LABEL: 2B3-201 300mg; GROUP TYPE: Experimental; DESCRIPTION: 2B3-201 300mg, once, IV infusion in 1500ml 5% dextrose/ Methylprednisolone hemisuccinate 300mg, once, IV infusion in 1500ml 5% dextrose/ Placebo, once, IV infusion 1500ml 5% dextrose; >; ARM GROUP 3: <LABEL: 2B3-201 450mg; GROUP TYPE: Experimental; DESCRIPTION: 2B3-201 450mg, once, IV infusion in 2500ml 5% dextrose/ Methylprednisolone hemisuccinate 1000mg, once, IV infusion in 2500ml 5% dextrose/ Placebo, once, IV infusion 2500ml 5% dextrose; >; ARM GROUP 4: <LABEL: 450mg 2B3-201; GROUP TYPE: Experimental; DESCRIPTION: 2B3-201 450mg, once, IV infusion in 2500ml 5% dextrose; >; ARM GROUP 5: <LABEL: 300mg 2B3-201; GROUP TYPE: Experimental; DESCRIPTION: 2B3-201 300mg, once, IV infusion in 1500ml 5% dextrose; >; ARM GROUP 6: <LABEL: 2B3-201 450mg male volunteers; GROUP TYPE: Experimental; DESCRIPTION: 2B3-201 450mg, once, IV infusion in 1500ml 5% dextrose; >; ARM GROUP 7: <LABEL: 2B3-201 300mg or 450mg female volunteers; GROUP TYPE: Experimental; DESCRIPTION: 2B3-201 300mg or 450mg, once, IV infusion in 1500 or 2500ml 5% dextrose/ Methylprednisolone hemisuccinate 1000mg, once, IV infusion in 1500 or 2500ml 5% dextrose; >; ARM GROUP 8: <LABEL: Relapsing MS patients; 2B3-201 450 mg; GROUP TYPE: Experimental; DESCRIPTION: 2B3-201 450mg, once, IV infusion in 2500ml 5% dextrose; >; ARM GROUP 9: <LABEL: Relapsing MS patients; 2B3-201 dose tbd; GROUP TYPE: Experimental; DESCRIPTION: 2B3-201 (dose to be determined), once, IV infusion in 5% dextrose; >;

INTERVENTION 1: <TYPE: Drug; NAME: 2B3-201; >; INTERVENTION 2: <TYPE: Drug; NAME: Placebo; >; INTERVENTION 3: <TYPE: Drug; NAME: Methylprednisolone hemisuccinate; >;

Inclusion Criteria: Healthy subjects - Healthy male or female subjects, 18 to 45 years of age, inclusive. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, hematology, blood chemistry, and urinalysis. - Body mass index (BMI) between 18 and 30 kg/m2, inclusive, and with a minimum weight of 50 kg. - Able to participate and willing to give written informed consent and to comply with the study restrictions. Relapsing MS patients - Age: 18 to 65 years, both men and women. - Patients with relapsing multiple sclerosis (RMS), defined as below, with an acute exacerbation, who in the opinion of the treating physician should undergo a 3 - 5 day course of high dose methylprednisolone; - Patients with Relapsing Remitting Multiple Sclerosis (RRMS). - Patients with Secondary Progressive Multiple Sclerosis (SPMS) and - Patients with clinically isolated syndromes (CIS) who show dissemination of lesions in time (DIT) and space (DIS) on MRI scans according to the 2010 McDonald criteria. - Able to participate and willing to comply with the study restrictions. Understands and signs the written informed consent prior to any of the testing under this protocol, including screening tests and evaluations that are not considered part of the subject's routine care. Exclusion Criteria: Healthy volunteers: - Any subject who is pregnant or breastfeeding. A urine pregnancy test should be performed in female subjects of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) prior to the start of the study treatment. - For female subjects of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) and male subjects who are not surgically sterile or with female partners of childbearing potential: absence of effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel) will be a contraindication. - Not willing to use double-barrier contraception, for the duration of the study and for 3 months after the last dose. - Positive test for drugs of abuse at screening or pre-dose. - History of alcohol consumption exceeding 2 standard drinks per day on average (1 standard drink = 10 grams of alcohol) within 3 months of screening. Alcohol consumption will be prohibited during study confinement and at least 48 hours before screening, before dosing, and before each scheduled visit. - History or symptoms of any significant disease including (but not limited to), neurological, psychiatric, endocrine, cardiovascular, respiratory, gastrointestinal, hepatic, or renal disorder. - Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening. - Systolic blood pressure (SBP) greater than 140 mm Hg or less than 90 mm Hg, and diastolic blood pressure (DBP) greater than 90 mm Hg or less than 50 mm Hg. - Use of any medications (prescription or over-the-counter [OTC]), vitamin, mineral, herbal, and dietary supplements within 21 days of study drug administration. Exceptions are paracetamol (up to 4 g/day). - Use of CYP3A4-inhibiting drugs, including quinine containing drinks (bitter lemon and tonic water) is prohibited within 21 days of study drug administration - Subject has used grapefruit, grapefruit juice, grapefruit-containing products, Seville oranges, or pomelo-containing products, within 14 days prior to day -1. - Clinically significant abnormalities, as judged by the investigator, in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis). In the case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for healthy subjects. - Participation in an investigational drug or device study within 3 months prior to screening. - Donation of blood over 500 mL within three months prior to screening. - Concomitant disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the subject in this study. - Smoker of more than 10 cigarettes per day prior to screening or who use tobacco products equivalent to more than 10 cigarettes per day. - Clinically significant abnormal ECG, as judged by the Investigator. - Current infection or inflammation study within 1 month prior to screening - Recent vaccinations study within 3 months prior to screening. - Positive Mantoux test of 5 mm or more. - Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any drug, or multiple drug allergies (non-active hay fever is acceptable). - Unwillingness or inability to comply with the study protocol for any other reason. RMS patients: - Previous acute exacerbations, and/or corticosteroid treatment or ACTH < 1 month before present exacerbation, - Hypersensitivity to methylprednisolone. - Prior use of immunosuppressive treatments / disease-modifying drugs (DMDs) other than interferon-beta, glatiramer acetate, fingolimod, dimethylfumarate or teriflunomide within 12 months of the index episode. Shorter periods may be allowed at the discretion of the PI and after approval from the sponsor. Subjects may continue their current therapy with interferons, glatiramer acetate, fingolimod, or teriflunomide throughout the course of the study. - Non-steroidal anti-inflammatory agents, including salicylic acid, should be avoided during the administration of the steroid therapy. If absolutely necessary they are permitted for subjects to treat interferon side effects, when the patient is not responding to acetaminophen/paracetamol. - Current or recent (within 30 days of first study treatment) treatment with any other investigational drug or participation in any other investigational study - Evidence of psychiatric illness - History of any significant cardiac, gastrointestinal, hepatic, pulmonary, renal or active immunosuppressive disease. - Immune deficiency or any other medical conditions that would preclude corticosteroid therapy. - Any patient who is pregnant or breastfeeding. A urine pregnancy test should be performed in female subjects of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) prior to the start of the study treatment. - For female subjects of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) and male subjects who are not surgically sterile or with female partners of childbearing potential: absence of effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel) will be a contraindication. - Physical examination results or laboratory findings that may interfere with the planned treatment, affect patient compliance or place the patient at a high risk of treatment-related complications. - Known hypersensitivity to any of the cyclodextrin or any excipients in 2B3-201 (e.g. PEG, Cholesterol, HSPC or GSH).