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A Multi-institutional Translational Clinical Trial of Disulfiram in Men With Recurrent Prostate Cancer as Evident by a Rising PSA

18 Years
Not Enrolling
Prostate Cancer

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Trial Information

A Multi-institutional Translational Clinical Trial of Disulfiram in Men With Recurrent Prostate Cancer as Evident by a Rising PSA

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.

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

- 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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Bio-availability Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Outcome Description:

To determine the dosage and duration of disulfiram for achieving its biological target effects as a DNMT1 inhibitor

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Michael A Carducci, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University


United States: Food and Drug Administration

Study ID:




Start Date:

May 2010

Completion Date:

June 2012

Related Keywords:

  • Prostate Cancer
  • Rising PSA
  • Recurrent Non Metastatic Prostate Cancer
  • Prostatic Neoplasms



Duke University Durham, North Carolina  27710
Johns Hopkins Hospital Baltimore, Maryland  21287
Thomas Jefferson Universith Philadelphia, Pennsylvania  19107