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Study of Recurrent Prostate Cancer With Rising Prostate Specific Antigen (PSA)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Michael A. Carducci, MD, Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT01118741
First received: April 29, 2010
Last updated: May 15, 2014
Last verified: May 2014
  Purpose

disulfiram is a DNA methyltransferase inhibitor that may provide benefit for patients with prostate cancer by restoring tumor suppressor genes.


Condition Intervention
Prostate Cancer
Drug: Disulfiram

Study Type: Interventional
Study Design: Endpoint Classification: Bio-availability Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multi-institutional Translational Clinical Trial of Disulfiram in Men With Recurrent Prostate Cancer as Evident by a Rising PSA

Resource links provided by NLM:


Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:
  • Proportion of Subjects With a Demethylation Response at Each Dose Level [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    For both of the doses explored (i.e. disulfiram 250 mg PO daily and 500 mg PO daily) the proportion of subjects with a demethylation response was computed. A demethylation response was defined as a >=10% decrease from baseline in global 5-methyl cytosine content as assessed from peripheral blood mononuclear cells.


Secondary Outcome Measures:
  • Clinical Response [ Time Frame: After 6 months ] [ Designated as safety issue: Yes ]
    To assess the clinical response measured by prostate specific antigen (PSA) progression at 6 months after treatment with the defined dose of disulfiram in prostate cancer (PCa) patients with evidence of biochemical relapse after local therapy


Enrollment: 19
Study Start Date: May 2010
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Disulfiram
    Cohort 1: 250mg PO daily for 28 days Cohort 2: 500mg PO daily for 28 days
    Other Name: Antabuse
Detailed Description:

The primary hypothesis of this study is that disulfiram is a DNA methyltransferase inhibitor and may provide benefit for patients with prostate cancer by restoration of tumor suppressor genes. Disulfiram is a potent DNA methyltransferase 1 (DNMT1) inhibitor in vitro in our laboratory and it was recently found as one of the most potent inhibitors for PCa growth in vitro by screening the Johns Hopkins Drug Library. Based on this data, extensive in vitro and in vivo studies have been performed to explore its potential antitumor activities in prostate PCa. Using both androgen sensitive and insensitive PCa cell lines, we have confirmed that disulfiram can demethylate known highly methylated tumor suppressor genes such as APC and RARß in PCa cell lines. Disulfiram inhibited PCa cell growth in vitro and in vivo. In addition to these new findings, the antitumor activity of disulfiram and its other possible mechanisms of action are well documented in literature. Disulfiram has been shown to induce apoptosis in a number of cell lines including PCa. A variety of underlying mechanisms of anticancer activity have been reported. Disulfiram has been shown to reduce angiogenesis, inhibit DNA topoisomerases, inhibit nuclear factor κB, induce p21 and p53 with G1/S cell cycle arrest, induce pro-apoptotic redox-related mitochondrial membrane permeabilization, inactivate Cu/Zn superoxide dismutase by Cu2+ complexation, inhibit Zn2+-dependent matrix metalloproteinases, and prevent tumor invasion or metastasis. The disulfiram analogue pyrrolidine dithiocarbamate (PDTC) has been shown to inhibit proteasomal activity in combination with copper in human breast and PCa cell lines. Also, disulfiram or its metabolites permanently inactivate the human multidrug resistance P-glycoprotein or reverses either MDR1- or MRP1-mediated drug efflux.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Provide written informed consent and HIPAA authorization for the release of personal health information.
  • Adult male ≥18 years of age
  • No desire to drink any alcohol during the study period. (The potential for ethanol interactions may last 7 to 14 days. Patient is allowed to drink alcohol 2 weeks after the study is finished)
  • Histological confirmed diagnosis of adenocarcinoma of the prostate (M0) with evidence of biochemical relapse after local therapy (i.e., surgery, radiation therapy, or both). Baseline PSA must be ≥ 1 ng/ml.
  • There must be a confirmed rise in PSA shown by 2 PSA values at least 1 week apart, higher than a reference value noted within 12 months of study entry. Interim PSA values during the immediate pre-study 12-month interval may demonstrate a "fluctuation" including a decline; however the study baseline PSA must have show a rise within the pre-study 12-months period. Baseline PSA must be determined within 4 weeks of study entry. At least 3 PSA values are necessary to calculate PSA doubling time via PSADT calculator.
  • All previous local modalities of treatment, including radiation and surgery, must have been discontinued at least 4 weeks prior to treatment in this study. Patients may have received prior systemic chemotherapy, hormonal therapy, biologic or vaccine therapy
  • Patients receiving intermittent hormonal therapy for their rising PSA state are considered eligible if testosterone level is above 150ng/dl and treatment was discontinued > 6 months and agree not to have additional injections while on study drug.
  • No history of or current clinical or radiological evidence of distant metastases (excluding prostascint scan/PET in absence of radiographic disease in Bone scan, CT scan or MRI if used). Retroperitoneal/pelvic lymph node up to 2 cm size is allowed for the study.
  • ECOG performance score < 2 within 14 days before being registered for protocol therapy
  • Normal organ function with acceptable initial laboratory values:

    • Absolute neutrophil count ≥ 1 x 109/L
    • Platelets > 50 x 109/L
    • Creatinine <2 mg/dL
    • Bilirubin <1.5 X ULN (institutional upper limits of normal)
    • AST (SGOT) and ALT (SGPT) ≤ 1.5 x ULN
    • Willingness to use adequate methods of contraception throughout study participation and for at least 3 months after completing therapy

Exclusion Criteria:

  • Metastatic disease or currently active second malignancy
  • History of alcohol dependence, seizures or psychoses.
  • Medical conditions such as uncontrolled hypertension, uncontrolled diabetes mellitus, cardiac disease, active infectious hepatitis, type A, B or C, hypothyroidism, which would, in the opinion of the investigator, make this protocol unreasonably hazardous
  • Major thoracic or abdominal surgery within the prior 3 weeks. Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis).
  • Use of any prohibited concomitant medications: Metronidazole, Amprenavir, Paraldehyde, Phenytoin, Coumadin, alcohol or alcohol-containing preparations, Isoniazid, Amitriptyline (please see Appendix B for other potential drug-drug interactions). The washout period is at least 2 weeks before starting the study
  • Insufficient time from last prior regimen or radiation exposure: Systemic therapies for prostate cancer within 28 days prior to disulfiram; strontium-89 within 12 weeks; bicalutamide within 6 weeks.
  • Persistent Grade >2 treatment-related toxicity from prior therapy
  • History of any disulfiram-related or drug induced anaphylactic reaction
  • Receipt of another investigational agent within 28 days of study entry. Patient must have recovered from all side effects of prior investigational therapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01118741

Locations
United States, Maryland
Johns Hopkins Hospital
Baltimore, Maryland, United States, 21231
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Thomas Jefferson Universith
Philadelphia, Pennsylvania, United States, 19107
Sponsors and Collaborators
Johns Hopkins University
Investigators
Principal Investigator: Michael A Carducci, MD Johns Hopkins University
  More Information

No publications provided

Responsible Party: Michael A. Carducci, MD, Professor of Oncology and Urology, Johns Hopkins University
ClinicalTrials.gov Identifier: NCT01118741     History of Changes
Other Study ID Numbers: J0972
Study First Received: April 29, 2010
Results First Received: December 13, 2013
Last Updated: May 15, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Johns Hopkins University:
Rising PSA
Recurrent Non Metastatic Prostate Cancer

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Diseases, Male
Genital Neoplasms, Male
Neoplasms
Neoplasms by Site
Prostatic Diseases
Urogenital Neoplasms
Disulfiram
Alcohol Deterrents
Central Nervous System Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014