64Cu-SAR-BBN and 67CU SAR-BBN for Identification and Treatment of Gastrin Releasing Peptide Receptor (GRPR)-Expressing Metastatic Castrate Resistant Prostate Cancer in Patients Who Are Ineligible for Therapy With 177Lu-PSMA-617 (COMBAT)

Study Overview
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Brief Summary
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The aim for this study is to determine the safety and efficacy of 67Cu-SAR-BBN in participants with Gastrin Releasing Peptide Receptor (GRPR)-expressing metastatic castrate resistant prostate cancer in patients who are ineligible for therapy with 177Lu-PSMA-617.

Official Title
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A Phase I/IIa Theranostic Study of 64Cu-SAR-BBN and 67Cu-SAR-BBN for Identification and Treatment of GRPR-expressing Metastatic Castrate Resistant Prostate Cancer in Patients Who Are Ineligible for Therapy With 177Lu-PSMA-617

Conditions
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Prostatic Neoplasms, Castration-Resistant

Intervention / Treatment
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* Drug: 64Cu-SAR-BBN
* Drug: 67Cu-SAR-BBN


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent; ≥18 years of age; Eastern Cooperative Oncology Group performance status of 0 to 2; Life expectancy >6 months; Histological, pathological, and/or cytological confirmation of Prostate cancer (PCa); ≥1 Metastatic lesion that is present at screening computed tomography (CT), magnetic resonance imaging (MRI), or bone scan imaging obtained <28 days prior to enrollment into the study; Positive 64Cu-SAR-BBN positron emission tomography (PET)/CT scan, where 64Cu-SAR-BBN uptake (standardized uptake value [SUV] max) of at least 1 known lesion is positive (higher than that of the liver) and all lesions on anatomical imaging larger in short axis than size criteria are also positive [size criteria: organs ≥ 1 cm, lymph nodes ≥ 2.5 cm, bones (soft tissue component ≥ 1 cm] on the 1 hour PET/CT scan; Castrate level of serum/plasma testosterone (<50 ng/dL or <1.7 nmol/L); Have progressive metastatic castration-resistant prostate cancer (mCRPC) despite prior androgen deprivation therapy (ADT) and at least either enzalutamide and/or abiraterone (or other such androgen receptor pathway inhibitors). Documented progressive mCRPC will be based on at least 1 of the following criteria: Serum/plasma prostate specific antigen (PSA) progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal value for study enrollment is 2.0 ng/mL; Soft-tissue progression defined as a ≥20% increase in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since the last treatment directed at the metastatic cancer has started (not including hormonal therapy) or the appearance of 1 or more new lesions; Progression of bone disease: evaluable disease or new bone lesions(s) by bone scan. Participants must be ineligible for 177Lu-PSMA-617 therapy based on the following criterion:Uptake of 68Ga-PSMA-11 or 18F-DCFPyL in all lesions is negative (equal to or lower than that of liver parenchyma), or any one lesion larger than the size criteria is negative [size criteria: organs ≥1 cm, lymph nodes ≥2.5 cm, bones(soft tissue component) ≥1 cm]. Participants must have recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapies (prior chemotherapy, radiation, immunotherapy, etc.); Participants must have adequate organ function: Bone marrow reserve: White blood cell (WBC) count ≥2.5 x 109/L (2.5 x 109/L is equivalent to 2.5 x 103/μL and 2.5 x K/μL and 2.5 x 103/cc and 2500/μL) OR Absolute neutrophil count (ANC) ≥1.5 x 109 /L (1.5 x 109 /L is equivalent to 1.5 x 103 /μL and 1.5 x K/μL and 1.5 x 103 /cc and 1500/μL); Platelets ≥100 x 109 /L (100 x 109 /L is equivalent to 100 x 103 /μL and 100 x K/μL and 100 x 103 /cc and 100,000/μL); Hemoglobin ≥9 g/dL (5.59 mmol/L); Total bilirubin ≤1.5 x the institutional upper limit of normal (ULN). For participants with known Gilbert's Syndrome ≤3 x ULN is permitted; Alanine aminotransferase or aspartate aminotransferase ≤3.0 x ULN OR ≤5.0 x ULN for participants with liver metastases; Estimated glomerular filtration rate (eGFR) ≥50 mL/min For participants who are human immunodeficiency virus infected: Participant must be healthy and have a low risk of Acquired Immune Deficiency Syndrome related outcomes in the opinion of the Investigator; For participants who have partners of childbearing potential: Partner and/or participant must use a method of birth control with adequate barrier protection. Exclusion Criteria: Major surgery within 12 weeks prior to enrollment into the study; Symptomatic Brain metastasis; Histologic diagnosis of small cell prostate cancer; Prior history of leukemia or Myelodysplastic Syndrome; Diagnosis of Deep Vein Thrombosis or Pulmonary Embolism within 4 weeks prior to enrollment into the study; Unmanageable urinary tract obstruction; Evidence of progressive lesion(s) on MRI and/or CT (according to Response Evaluation Criteria in Solid Tumors V1.1) that is Gastrin-releasing peptide receptor (GRPR) negative on the 1 hour 64Cu-SAR-BBN PET/CT scan as determined at screening; Previous treatment with a systemic radionuclide, including 177Lu, Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Actinium-225, Iodine-131 within 6 months or in case of Radium-223 within 3 months of treatment initiation (Day 0) without prior approval of the medical monitor; Previous treatment with any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or biological therapy [including monoclonal antibodies]) within 4 weeks prior to treatment on study with the exception of Luteinizing Hormone Releasing Hormone, any other androgen deprivation therapy (ADT) (if ADT is discontinued prior to enrolment, 14 days must elapse after abiraterone discontinuation and 28 days after enzalutamide before participant can be enrolled) or low dose corticosteroids; Previous treatment with any investigational agents within 4 weeks prior enrollment into the study; Known hypersensitivity to the components of the investigational products or its analogues; Transfusion for the sole purpose of making a participant eligible for study inclusion; Spinal metastasis with symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression; Concurrent serious medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation; Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease free for more than 3 years are eligible, as are participants with adequately treated non-melanoma skin cancer, superficial bladder cancer; Any condition or personal situation that would pose an unacceptable radiation safety risk (as per institution guidelines, state and/or national regulations) to the participant or carer at the time of release following the completion of therapy (e.g. uncontrolled urinary incontinence, high dependency care); Participants in whom it is known that external beam radiation therapy is scheduled after enrollment into the study; Participants with corrected QT interval (QTc) > 470 msec; Participants with persistent acute and/or chronic pancreatitis.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This study is to be conducted in 2 phases, a dose escalation phase and a cohort expansion phase
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 67Cu-SAR-BBN<br>In the dose escalation phase: 64Cu-SAR-BBN: Patients will receive up to 2 administrations of 200MBq 67Cu-SAR-BBN: Cohorts 1 - 3: Single administration (dose will be determined based on cohort allocation). Cohort 4: 2 administrations at the recommended dose (determined by cohorts 1-3). In the cohort expansion phase: Patients will receive up to 3 administrations of 200MBq of 64Cu-SAR-BBN and 2 administrations at the recommended dose level of 67Cu-SAR-BBN, determined through the dose escalation. Additional administrations: (up to a maximum total of 4) may be offered to those participants, in either the dose escalation or cohort expansion, with radiological non-progression. | Drug: 64Cu-SAR-BBN<br>* 64Cu-SAR-BBN<br>Drug: 67Cu-SAR-BBN<br>* 67Cu-SAR-BBN<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) or maximum feasible dose (MFD) of a single dose of 67Cu-SAR-BBN | MTD as determined by cohort observations of dose limiting toxicities or MFD determined by the activity of the dose to be administered, when the MTD has not been reached. | Up to 8 weeks | 
| Recommended dose of two doses of 67Cu-SAR-BBN | Recommended dose as determined by cohort observations of dose limiting toxicities | Up to 14 weeks | 
| Efficacy of 67Cu-SAR-BBN in terms of Prostate Specific Antigen (PSA) response | Proportion of participants with ≥50% decline in PSA | Up to 5 years | 
| Efficacy of 67Cu-SAR-BBN in terms of radiographic response | Efficacy will be assessed via the overall response rate according to RECIST V1.1 for soft tissue disease and according to PCWG3 for bone lesions | Up to 5 years | 
| Incidence of dose limiting toxicities [Safety and tolerability] of 67Cu-SAR-BBN | Incidence of dose limiting toxicities following a single administration of 67Cu-SAR-BBN | Up to 8 weeks | 
| Incidence of dose limiting toxicities [Safety and tolerability] of 67Cu-SAR-BBN | Incidence of dose limiting toxicities following repeated administrations of 67Cu-SAR-BBN | Up to 14 weeks | 
| Incidence of 67Cu-SAR-BBN treatment-emergent adverse events [Safety and tolerability] | Adverse Events will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 5, following single or repeated administrations of 67Cu-SAR-BBN | Up to 12 months | 
| Incidence of 67Cu-SAR-BBN adverse event of special interest [Safety and tolerability] | Protocol defined adverse event of special interest following single or repeated administrations of 67Cu-SAR-BBN | Up to 5 years | 
| Safety and tolerability of 67Cu-SAR-BBN: Number of Participants with changes from baseline in vital signs | Change from baseline in vital signs following single or repeated administrations of 67Cu-SAR-BBN | Up to 24 weeks | 
| Safety and tolerability of 67Cu-SAR-BBN: Number of Participants with changes from baseline in electrocardiogram (ECG) parameters | Change from baseline in ECG parameters following single or repeated administrations 67Cu-SAR-BBN | Up to 24 weeks | 
| Safety and tolerability of 67Cu-SAR-BBN: Number of Participants with changes from baseline in laboratory results | Change from baseline in laboratory results following single or repeated administrations 67Cu-SAR-BBN | Up to 52 weeks | 
| Incidence of 64Cu-SAR-BBN treatment-emergent adverse events [Safety and tolerability] | Adverse Events will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 5, following single or repeated administrations of 64Cu-SAR-BBN | Up to 12 months |