Prostate Cancer
Conditions
Keywords
Rising PSA, Recurrent Non Metastatic Prostate Cancer
Brief summary
disulfiram is a DNA methyltransferase inhibitor that may provide benefit for patients with prostate cancer by restoring tumor suppressor genes.
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.
Interventions
DRUGDisulfiram
Cohort 1: 250mg PO daily for 28 days Cohort 2: 500mg PO daily for 28 days
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects With a Demethylation Response at Each Dose Level | 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
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response | 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment dates: 06/04/2010 through 08/01/2011 in medical clinics
Pre-assignment details
Given the toxic effects of disulfiram when administered within 14 days of ingesting ethanol, participants were required to agree not to drink alcohol during the study and for 14 days after its completion.
Participants by arm
| Arm | Count |
|---|---|
| Disulfiram Low Dose 250mg Dose First 9 subjects were assigned to the low dose arm | 9 |
| Disulfiram High Dose 500mg Dose After 9 subjects were enrolled in the low dose arm, the high dose was opened. | 10 |
| Total | 19 |
Baseline characteristics
| Characteristic | Disulfiram High Dose 500mg Dose | Disulfiram Low Dose 250mg Dose | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 6 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 3 Participants | 11 Participants |
| Age, Continuous | 62.6 years STANDARD_DEVIATION 3.4 | 66.6 years STANDARD_DEVIATION 7 | 64.5 years STANDARD_DEVIATION 5.6 |
| Region of Enrollment United States | 10 participants | 9 participants | 19 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 9 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 9 | 8 / 10 |
| serious Total, serious adverse events | 0 / 9 | 0 / 10 |
Outcome results
Primary
Proportion of Subjects With a Demethylation Response at Each Dose Level
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.
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Disulfiram Low Dose 250mg Dose | Proportion of Subjects With a Demethylation Response at Each Dose Level | .22 proportion of participants |
| Disulfiram High Dose 500mg Dose | Proportion of Subjects With a Demethylation Response at Each Dose Level | .30 proportion of participants |
Secondary
Clinical Response
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.
Time frame: Up to 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Disulfiram Low Dose 250mg Dose | Clinical Response | 5 participants |
| Disulfiram High Dose 500mg Dose | Clinical Response | 0 participants |