SB939 in Treating Patients With Recurrent or Metastatic Prostate Cancer

Study Overview
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Brief Summary
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RATIONALE: SB939 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase II trial is studying how well SB939 works in treating patients with recurrent or metastatic prostate cancer.

Detailed Description
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OBJECTIVES: Primary To determine the efficacy, as measured by PSA response and progression-free survival, of HDAC inhibitor SB939 in patients with recurrent or metastatic castration-resistant prostate cancer. Secondary To determine the objective response and response duration in patients with measurable disease at baseline. To determine the tolerability and toxicity of this drug in these patients. To determine the number of circulating tumor cells at baseline and after 6 weeks (and 12 weeks if patient is still on study treatment). To explore potential molecular factors predictive of response by assessment of archival prostate tumor tissue. To explore ERG and PTEN expression on circulating tumor cells as a potential prognostic and predictive marker for response to this drug. To determine time to PSA and time to objective progression in these patients. OUTLINE: This is a multicenter study. Patients receive oral HDAC Inhibitor SB939 once daily on days 1, 3, 5, 8, 10, 12, 15, 17, and 19. Treatment repeats every 4 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. Blood samples are collected periodically for correlative studies. Blood samples and Archival tumor tissue are analyzed for TMPRSS2-ERG fusion and PTEN deletion status by FISH; TMPRSS2-ERG fusion by RT-PCR; and for the number of circulating tumor cells. After completion of study therapy, patients are followed up at 4 weeks and then every 3 months thereafter.

Official Title
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A Phase II Study of SB939 in Patients With Recurrent or Metastatic Castration Resistant Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: HDAC inhibitor SB939


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the prostate Presence of clinically and/or radiologically documented disease (target or non-target) Metastatic or locally recurrent disease for which no curative therapy exists AND for which systemic chemotherapy is indicated due to progression, meeting the following criteria: At least two rises in PSA over a reference value OR the development of new metastatic lesions with a stable or rising PSA First rising PSA must be taken at least 1 week after the reference value Third or subsequent PSA must show further increase confirming progression within 2 weeks prior to study enrollment PSA progression must be documented after discontinuation of peripheral antiandrogens (4 weeks for flutamide and 6 weeks for bicalutamide/nilutamide) for patients with documented evidence of progression while receiving peripheral antiandrogens Medically or surgically castrated by androgen ablation Castrate level of testosterone (< 1.7 nmol/L) must be present for patients undergoing medical androgen ablation Received prior hormone therapy Must have hormone-refractory disease Therapy with luteinizing hormone-releasing hormone (LHRH) agonist must continue for patients already receiving this treatment at the time of enrollment Patients who discontinued LHRH agonist must restart therapy (if not surgically castrated) and the castrate level of testosterone must be present PSA ≥ 5 ng/mL Primary or metastatic tumor tissue available No documented CNS metastases PATIENT CHARACTERISTICS: ECOG performance status 0-1 Life expectancy ≥ 12 weeks Absolute granulocyte count ≥ 1.5 x 10^9/L Platelet count ≥ 100 x 10^9/L AST and ALT ≤ 2.5 times upper limit of normal (ULN) Bilirubin normal Serum creatinine normal Potassium normal Calcium normal Fertile patients must use effective contraception QTc ≤ 450 msec LVEF ≥ 50% by Echo or MUGA scan Troponin I or T ≤ ULN Able to take oral medication No preexisting uncontrolled cardiac condition No prior myocardial infarction No history of other malignancies, except adequately treated nonmelanoma skin cancer or other solid tumors curatively treated with no evidence of disease for ≥ 5 years No gastrointestinal abnormalities (e.g., bowel obstruction or previous gastric resection) that would lead to inadequate absorption of HDAC Inhibitor SB939 No known HIV positivity or hepatitis B or C infections No chronic medical condition or comorbidity that may increase the risks associated with study participation/study drug administration or may interfere with the interpretation of study results, including any of the following: Pulmonary disease Active infection Psychiatric condition Laboratory abnormality PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 4 weeks since prior antiandrogens (6 weeks for bicalutamide) At least 4 weeks since prior external-beam radiotherapy Exceptions may be made for low-dose, non-myelosuppressive radiotherapy At least 28 days since other prior investigational therapy or anticancer therapy At least 14 days since prior major surgery and wound healing has occurred No more than 1 prior chemotherapy regimen allowed and recovered from significant toxicity No prior strontium No prior HDAC inhibitors No current agents (dysrhythmic drugs) with a known risk of Torsades de Pointes No other concurrent cytotoxic therapy or radiotherapy No other concurrent investigational therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SB939<br>SB939 given orally every other day 3 times a week (i.e. Monday /Wednesday /Friday, or Tuesday /Thursday / Saturday) for 3 consecutive weeks followed by one week off-dosing. A treatment cycle is 4 weeks (28 days). | Drug: HDAC inhibitor SB939<br>* SB939 given orally every other day 3 times a week (i.e. Monday /Wednesday /Friday, or Tuesday /Thursday / Saturday) for 3 consecutive weeks followed by one week off-dosing. A treatment cycle is 4 weeks (28 days).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA response | Each patient will have PSA response calculated. Required at the end of every cycle. | each cycle | 
| Progression-free survival | Used as an indicator of efficacy, patients with PSA response will have length of progression free survival calculated. | end of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Patients with measurable disease will have objective response evaluated. | every other cycle | 
| Duration of response | Patients with objective response will have duration of response calculated as will be followed until progression/relapse | every other cycle | 
| Safety | Toxicity and tolerability will be evaluated | each cycle | 
| Change in circulating tumor cells during study compared to baseline | Patients will have on study samples compared to baseline to look for chance in number of CTC. | each cycle | 
| Comparison of TMPRSS2-ERG fusion and PTEN deletion in circulating tumor cells | samples will be taken and analyzed each cycle with a comparison made at end of study. | each cycle | 
| Comparison of two systems for counting circulating tumor cells | Two different systems will be used to count CTC. Results will be compared at the end of the study for accuracy. | end of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hormone-resistant prostate cancer, recurrent prostate cancer, stage IV prostate cancer, stage III prostate cancer, adenocarcinoma of the prostate