A Phase Ib Study of Intravenous Copper Loading With Oral Disulfiram in Metastatic, Castration Resistant Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine the safety and optimal dosing of intravenous copper chloride and disulfiram in men with metastatic castrate-resistant prostate cancer (CRPC). Eligible men will have neuroendocrine prostate cancer (NEPC), adenocarcinoma CRPC with non-liver/peritoneal metastases (lymph nodes, bone, or lung) or adenocarcinoma CRPC with liver and/or peritoneal metastases. Subjects will receive three doses of intravenous copper chloride and take disulfiram and oral copper gluconate until disease progression (up to two years). Subjects will also undergo a PET scan with radioactive copper 64 to measure the levels of copper in their tumor. The central hypotheses of this project are that (a) copper chloride and disulfiram are safe to give together and that (b) the combination of disulfiram with copper will have efficacy for both mCRPC and NEPC.

Official Title
-----------------
A Phase Ib Study of Intravenous Copper Loading With Oral Disulfiram in Metastatic, Castration Resistant Prostate Cancer

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Copper
* Drug: Disulfiram
* Drug: Copper gluconate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years Karnofsky performance status ≥ 70 Life expectancy of ≥ 12 weeks as determined by treating investigator Adequate laboratory parameters Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 80 x 109/L, Hb>9 g/dL AST/SGOT and ALT/SGPT ≤ 2.5 x Institutional Upper Limit of Normal (ULN) Serum bilirubin ≤ 1.5 x Institutional ULN Serum creatinine ≤ 1.5 x Institutional ULN or 24-hour clearance ≥ 50 mL/min Histologically confirmed diagnosis of prostate cancer. Histologic variants of prostate cancer, including neuroendocrine features and small cell carcinoma of the prostate are included.If neuroendocrine prostate cancer is not biopsy proven, clinical evidence of neuroendocrine prostate cancer is acceptable for stratification into group A. Radiographic evidence of metastatic disease. Ongoing ADT using an LHRH agonist (e.g. leuprolide, goserelin) or antagonist (e.g. degarelix) must continue on therapy unless prior bilateral orchiectomy has been performed. OR Screening serum testosterone must be <50 ng/dl. Evidence of disease progression on ADT as evidenced by one of the following: 2 consecutive PSA levels 50% or greater above the PSA nadir achieved on ADT and separated at least 1 week apart, OR CT or MRI based evidence of disease progression (soft tissue, nodal or visceral disease progression) according to PCWG3 criteria or RECIST 1.1 criteria, or at least 1 new bone scan lesion as compared to the most immediate prior radiologic studies, OR Absolute rise in PSA of 2.0ng/mL or greater, minimum 2 consecutive rising PSA levels with an interval of ≥ 1 week between each PSA level A minimum of 2 weeks elapsed off of antiandrogen therapy prior to registration (i.e. flutamide, nilutamide, and bicalutamide) without evidence of an anti-androgen withdrawal response. An anti-androgen withdrawal response is a PSA level at 2 weeks (or more) off of anti-androgen equal or higher than PSA level when anti-androgen therapy stopped. For subjects in Groups B or C, previous use of at least one androgen pathway inhibitor (either abiraterone acetate or enzalutamide) for metastatic CRPC For subjects in Group A with NEPC, previous use of at least one platinum-containing chemotherapy regimen. A minimum of 2 weeks off of enzalutamide or abiraterone if applicable, prior to registration. A minimum of 4 weeks from prior chemotherapy, including but not limited to, docetaxel, cabazitaxel, mitoxantrone, carboplatinum, cisplatin, or estramustine; if applicable, prior to registration. A minimum of 4 weeks from any major surgery prior to registration. Ability to swallow, retain, and absorb oral medication. Ability to understand and the willingness to sign a written informed consent document. Willingness to abstain from alcohol or any alcohol-containing fluids for the duration of the study. Exclusion Criteria: Subjects who meet any of the following criteria will be excluded from the study: Symptomatic subjects who accept treatment with approved palliative or life-prolonging systemic therapies, including docetaxel and cabazitaxel chemotherapy. (Note: subjects who refuse chemotherapy or are not symptomatic or in immediate need for standard systemic therapies may be included.) Known history of Wilson's disease or a copper deficiency. Uncontrolled hypertension (systolic BP >160 mmHg or diastolic BP > 95 mmHg) or other medical condition that could jeopardize the assessment of toxicity on study. Active or symptomatic viral hepatitis or chronic liver disease. Known history of Hepatitis B Virus (HBV) or Hepatitis C (HCV) infection. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of < 50% at baseline. Symptomatic atrial fibrillation or other cardiac arrhythmia for which the therapy is not stable or requiring changes in therapy within 1 month of treatment initiation. Atrial fibrillation or other cardiac arrhythmia which is clinically stable on stable therapy is allowed. Corrected QT interval calculated by the Bazett formula (QTcB) >480 msec. Other malignancy, except non-melanoma skin cancer, with a ≥ 30% probability of death within 24 months. Administration of an investigational therapeutic within 30 days of Cycle 1, Day 1. Any condition which, in the opinion of the investigator, would preclude participation in this trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neuroendocrine prostate cancer (NEPC)<br>Subjects with neuroendocrine prostate cancer (NEPC) Copper will be administered intravenously at a dose of 1, 3, 5, or 7 mg on cycle 1 days 1, 8, 15. Disulfiram will administered orally at a dose of 80 mg three times a day starting on cycle 1 day 2. Copper gluconate will be administered orally at a dose of 1.5 mg three times a day starting on cycle 1 day 16. | Drug: Copper<br>* 1 mg, 3 mg, 5 mg or 7 mg intravenously on cycle 1 day 1, 8 and 15<br>* Other names: Copper chloride;Drug: Disulfiram<br>* 80 mg three times a day Source of disulfiram: Cantex Pharmaceuticals<br>* Other names: Anatabuse;Drug: Copper gluconate<br>* 1.5 mg three times a day Source of copper gluconate: Cantex Pharmaceuticals<br>|
| Experimental: Adenocarcinoma CRPC with non-liver/peritoneal metastases<br>Subjects with adenocarcinoma CRPC with non-liver/peritoneal metastases (lymph nodes, bone, or lung) Copper will be administered intravenously at a dose of 1, 3, 5, or 7 mg on cycle 1 days 1, 8, 15. Disulfiram will administered orally at a dose of 80 mg three times a day starting on cycle 1 day 2. Copper gluconate will be administered orally at a dose of 1.5 mg three times a day starting on cycle 1 day 16. | Drug: Copper<br>* 1 mg, 3 mg, 5 mg or 7 mg intravenously on cycle 1 day 1, 8 and 15<br>* Other names: Copper chloride;Drug: Disulfiram<br>* 80 mg three times a day Source of disulfiram: Cantex Pharmaceuticals<br>* Other names: Anatabuse;Drug: Copper gluconate<br>* 1.5 mg three times a day Source of copper gluconate: Cantex Pharmaceuticals<br>|
| Experimental: Adenocarcinoma CRPC with liver and/or peritoneal mets<br>Subjects with adenocarcinoma CRPC with liver and/or peritoneal metastases Copper will be administered intravenously at a dose of 1, 3, 5, or 7 mg on cycle 1 days 1, 8, 15. Disulfiram will administered orally at a dose of 80 mg three times a day starting on cycle 1 day 2. Copper gluconate will be administered orally at a dose of 1.5 mg three times a day starting on cycle 1 day 16. | Drug: Copper<br>* 1 mg, 3 mg, 5 mg or 7 mg intravenously on cycle 1 day 1, 8 and 15<br>* Other names: Copper chloride;Drug: Disulfiram<br>* 80 mg three times a day Source of disulfiram: Cantex Pharmaceuticals<br>* Other names: Anatabuse;Drug: Copper gluconate<br>* 1.5 mg three times a day Source of copper gluconate: Cantex Pharmaceuticals<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events | Safety (NCI CTC v4.0) and tolerability of IV CuCl2 and DSF in men with mCRPC | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median radiographic progression free survival (PFS) | Radiographic PFS based on PCWG3 criteria or based on the onset of a skeletal related event. Imaging obtained every 12 weeks. | Every 12 weeks, up to 2 years | 
| Amount of 64-Copper uptake by the tumor | 64-Copper PET imaging | Baseline | 
| Change in PSA | PSA response | Every 4 weeks, up to 2 years | 
| Time to PSA nadir | Time to PSA nadir | Every 4 weeks, up to 2 years | 
| Time to PSA progression | Time to PSA progression | Every 4 weeks, up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
metastatic castrate-resistant prostate cancer (mCRPC), neuroendocrine prostate cancer (NEPC), adenocarcinoma castrate-resistant prostate cancer (CRPC), Copper, Disulfiram