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

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ClinicalTrials.gov Identifier: NCT02963051
Recruitment Status : Recruiting
First Posted : November 15, 2016
Last Update Posted : June 6, 2018
Sponsor:
Collaborators:
Give 1 For Dad Campaign
The V Foundation for Cancer Research
Peter Michael Foundation
Cantex Pharmaceuticals
Information provided by (Responsible Party):
Daniel George, MD, Duke University

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.

Condition or disease Intervention/treatment Phase
Prostate Cancer Drug: Copper Drug: Disulfiram Drug: Copper gluconate Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib Study of Intravenous Copper Loading With Oral Disulfiram in Metastatic, Castration Resistant Prostate Cancer
Actual Study Start Date : July 11, 2017
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer
Drug Information available for: Disulfiram

Arm Intervention/treatment
Experimental: Neuroendocrine prostate cancer (NEPC)

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
1 mg, 3 mg, 5 mg or 7 mg intravenously on cycle 1 day 1, 8 and 15
Other Name: Copper chloride

Drug: Disulfiram

80 mg three times a day

Source of disulfiram: Cantex Pharmaceuticals

Other Name: Anatabuse

Drug: Copper gluconate

1.5 mg three times a day

Source of copper gluconate: Cantex Pharmaceuticals


Experimental: Adenocarcinoma CRPC with non-liver/peritoneal metastases

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
1 mg, 3 mg, 5 mg or 7 mg intravenously on cycle 1 day 1, 8 and 15
Other Name: Copper chloride

Drug: Disulfiram

80 mg three times a day

Source of disulfiram: Cantex Pharmaceuticals

Other Name: Anatabuse

Drug: Copper gluconate

1.5 mg three times a day

Source of copper gluconate: Cantex Pharmaceuticals


Experimental: Adenocarcinoma CRPC with liver and/or peritoneal mets

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
1 mg, 3 mg, 5 mg or 7 mg intravenously on cycle 1 day 1, 8 and 15
Other Name: Copper chloride

Drug: Disulfiram

80 mg three times a day

Source of disulfiram: Cantex Pharmaceuticals

Other Name: Anatabuse

Drug: Copper gluconate

1.5 mg three times a day

Source of copper gluconate: Cantex Pharmaceuticals





Primary Outcome Measures :
  1. Number of adverse events [ Time Frame: Up to 2 years ]
    Safety (NCI CTC v4.0) and tolerability of IV CuCl2 and DSF in men with mCRPC


Secondary Outcome Measures :
  1. Median radiographic progression free survival (PFS) [ Time Frame: Every 12 weeks, up to 2 years ]
    Radiographic PFS based on PCWG3 criteria or based on the onset of a skeletal related event. Imaging obtained every 12 weeks.

  2. Amount of 64-Copper uptake by the tumor [ Time Frame: Baseline ]
    64-Copper PET imaging

  3. Change in PSA [ Time Frame: Every 4 weeks, up to 2 years ]
    PSA response

  4. Time to PSA nadir [ Time Frame: Every 4 weeks, up to 2 years ]
    Time to PSA nadir

  5. Time to PSA progression [ Time Frame: Every 4 weeks, up to 2 years ]
    Time to PSA progression



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years
  2. Karnofsky performance status ≥ 70
  3. Life expectancy of ≥ 12 weeks as determined by treating investigator
  4. 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
  5. 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.
  6. Radiographic evidence of metastatic disease.
  7. 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.
  8. 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
  9. 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.
  10. For subjects in Groups B or C, previous use of at least one androgen pathway inhibitor (either abiraterone acetate or enzalutamide) for metastatic CRPC
  11. For subjects in Group A with NEPC, previous use of at least one platinum-containing chemotherapy regimen.
  12. A minimum of 2 weeks off of enzalutamide or abiraterone if applicable, prior to registration.
  13. 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.
  14. A minimum of 4 weeks from any major surgery prior to registration.
  15. Ability to swallow, retain, and absorb oral medication.
  16. Ability to understand and the willingness to sign a written informed consent document.
  17. 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:

  1. 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.)
  2. Known history of Wilson's disease or a copper deficiency.
  3. Uncontrolled hypertension (systolic BP >160 mmHg or diastolic BP > 95 mmHg) or other medical condition that could jeopardize the assessment of toxicity on study.
  4. Active or symptomatic viral hepatitis or chronic liver disease.
  5. Known history of Hepatitis B Virus (HBV) or Hepatitis C (HCV) infection.
  6. 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.
  7. 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.
  8. Corrected QT interval calculated by the Bazett formula (QTcB) >480 msec.
  9. Other malignancy, except non-melanoma skin cancer, with a ≥ 30% probability of death within 24 months.
  10. Administration of an investigational therapeutic within 30 days of Cycle 1, Day 1.
  11. Any condition which, in the opinion of the investigator, would preclude participation in this trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02963051


Contacts
Contact: Julia Rasmussen, MS, RN, BSN 919-681-1030 julia.rasmussen@duke.edu

Locations
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Julia Rasmussen, MS, RN, BSN    919-681-1030    julia.rasmussen@duke.edu   
Sponsors and Collaborators
Daniel George, MD
Give 1 For Dad Campaign
The V Foundation for Cancer Research
Peter Michael Foundation
Cantex Pharmaceuticals
Investigators
Principal Investigator: Daniel George, MD Duke University

Responsible Party: Daniel George, MD, Professor of Medicine, Duke University
ClinicalTrials.gov Identifier: NCT02963051     History of Changes
Other Study ID Numbers: Pro00071007
First Posted: November 15, 2016    Key Record Dates
Last Update Posted: June 6, 2018
Last Verified: June 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Daniel George, MD, Duke University:
metastatic castrate-resistant prostate cancer (mCRPC)
neuroendocrine prostate cancer (NEPC)
adenocarcinoma castrate-resistant prostate cancer (CRPC)
Copper
Disulfiram

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Copper
Disulfiram
Trace Elements
Micronutrients
Growth Substances
Physiological Effects of Drugs
Alcohol Deterrents
Acetaldehyde Dehydrogenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action