Study of Recurrent Prostate Cancer With Rising Prostate Specific Antigen (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 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