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Trial record 24 of 46 for:    disulfiram

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01118741
Recruitment Status : Completed
First Posted : May 7, 2010
Results First Posted : June 6, 2014
Last Update Posted : June 12, 2018
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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

Condition or disease Intervention/treatment Phase
Prostate Cancer Drug: Disulfiram Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 19 participants
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : May 2010
Actual Primary Completion Date : June 2012
Actual Study Completion Date : June 2012

Resource links provided by the National Library of Medicine

Drug Information available for: Disulfiram

Intervention Details:
  • Drug: Disulfiram
    Cohort 1: 250mg PO daily for 28 days Cohort 2: 500mg PO daily for 28 days
    Other Name: Antabuse

Primary Outcome Measures :
  1. Proportion of Subjects With a Demethylation Response at Each Dose Level [ Time Frame: 24 months ]
    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 :
  1. Clinical Response [ Time Frame: Up to 6 months ]

    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. Reported as number of participants with PSA progression by 6 months.

    Criteria used to assess: A rise in PSA noted at 6 months, greater than 50% over PSA value at baseline and > 2 ng/ml, above the nadir. The rise was confirmed by a second PSA value obtained at least 1 week from that reference value.

Information from the National Library of Medicine

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

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

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 identifier (NCT number): NCT01118741

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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
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
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Principal Investigator: Michael A Carducci, MD Johns Hopkins University

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Identifier: NCT01118741     History of Changes
Other Study ID Numbers: J0972
First Posted: May 7, 2010    Key Record Dates
Results First Posted: June 6, 2014
Last Update Posted: June 12, 2018
Last Verified: May 2018
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
Rising PSA
Recurrent Non Metastatic Prostate Cancer
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Alcohol Deterrents
Acetaldehyde Dehydrogenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action