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

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Completed
• CT.gov ID: NCT01118741
• Collaborator: (none)
• Enrollment: 19
• Locations: 3
• Duration (Months): 25
• Patients Per Site: 6.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• 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 1, 2010
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins Hospital	Baltimore	Maryland	United States	21231
2	Duke University	Durham	North Carolina	United States	27710
3	Thomas Jefferson Universith	Philadelphia	Pennsylvania	United States	19107

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Investigators

• Principal Investigator: Michael A Carducci, MD, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT01118741
• Other Study ID Numbers: J0972
• First Posted: May 7, 2010
• Last Update Posted: Jun 12, 2018
• Last Verified: May 1, 2018

• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: Rising PSA; Recurrent Non Metastatic Prostate Cancer
• Additional relevant MeSH terms: Prostatic Neoplasms; Disulfiram

Study Results

Participant Flow

Recruitment Details	Recruitment dates: 06/04/2010 through 08/01/2011 in medical clinics
Pre-assignment Detail	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.

Arm/Group Title	Disulfiram Low Dose 250mg Dose	Disulfiram High Dose 500mg Dose
Arm/Group Description	First 9 subjects were assigned to the low dose (250mg) arm. These subjects took 250mg daily for 28 days per cycle.	After accrual to the low dose was complete,ten subjects were assigned to the high dose (500mg) arm. These subjects took 500mg daily for 28 days per cycle.
Period Title: Overall Study
STARTED	9	10
COMPLETED	9	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Disulfiram Low Dose 250mg Dose	Disulfiram High Dose 500mg Dose	Total
Arm/Group Description	First 9 subjects were assigned to the low dose arm	After 9 subjects were enrolled in the low dose arm, the high dose was opened.	Total of all reporting groups
Overall Participants	9	10	19
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	3 33.3%	8 80%	11 57.9%
>=65 years	6 66.7%	2 20%	8 42.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.6 (7.0)	62.6 (3.4)	64.5 (5.6)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	9 100%	10 100%	19 100%
Region of Enrollment (participants) [Number]
United States	9 100%	10 100%	19 100%

Outcome Measures

1. Primary Outcome

Title	Proportion of Subjects With a Demethylation Response at Each Dose Level
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Disulfiram Low Dose 250mg Dose	Disulfiram High Dose 500mg Dose
Arm/Group Description	First 9 subjects were assigned to the low dose arm
Measure Participants	9	10
Number (95% Confidence Interval) [proportion of participants]	.22 2.4%	.30 3%

2. Secondary Outcome

Title	Clinical Response
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Disulfiram Low Dose 250mg Dose	Disulfiram High Dose 500mg Dose
Arm/Group Description	First 9 subjects were assigned to the low dose (250mg) arm. These subjects took 250mg daily for 28 days per cycle.	After accrual to the low dose was complete,ten subjects were assigned to the high dose (500mg) arm. These subjects took 500mg daily for 28 days per cycle.
Measure Participants	9	10
Number [participants]	5 55.6%	0 0%

Adverse Events

Time Frame	7/16/10-9/27/11 (14 months)
Arm/Group Title	Disulfiram Low Dose 250mg Dose		Disulfiram High Dose 500mg Dose
Arm/Group Description	First 9 subjects were assigned to the low dose arm		After 9 subjects were enrolled in the low dose arm, the high dose was opened.
All Cause Mortality
	Disulfiram Low Dose 250mg Dose		Disulfiram High Dose 500mg Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Disulfiram Low Dose 250mg Dose		Disulfiram High Dose 500mg Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Disulfiram Low Dose 250mg Dose		Disulfiram High Dose 500mg Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/9 (66.7%)		8/10 (80%)
Ear and labyrinth disorders
HEARING LOSS	1/9 (11.1%)	1	0/10 (0%)	0
Eye disorders
DIPLOPIA	1/9 (11.1%)	1	0/10 (0%)	0
Gastrointestinal disorders
TASTE ALTERATION	2/9 (22.2%)	2	4/10 (40%)	4
DIARRHEA	1/9 (11.1%)	1	3/10 (30%)	3
CONSTIPATION	2/9 (22.2%)	2	2/10 (20%)	2
General disorders
FATIGUE	6/9 (66.7%)	6	8/10 (80%)	8
Investigations
ALT	1/9 (11.1%)	1	0/10 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.