Valproic Acid in Treating Patients With Progressive, Non-Metastatic Prostate Cancer

Study Overview
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Brief Summary
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RATIONALE: Valproic acid may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether valproic acid is more effective than observation in treating patients with prostate cancer. PURPOSE: This randomized phase II trial is studying how well valproic acid works in treating patients with progressive, non-metastatic prostate cancer.

Detailed Description
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OBJECTIVES: Primary Assess whether treatment with valproic acid (a type I histone deacetylase inhibitor) can alter the kinetics of prostate-specific antigen (PSA) progression in patients with non-metastatic prostate cancer and biochemical progression. Secondary Determine the duration of PSA response. Assess the percentage of patients who achieve a complete response. Assess the percentage of patients who achieve a partial response. Assess the quality of life of these patients. OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 arms. Arm I (observation): Patients undergo observation according to standard of care. Arm II (valproic acid): Patients receive oral valproic acid twice daily for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients complete quality of life questionnaires at baseline, 6 months, and 1 year.

Official Title
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Randomized, Controlled Phase II Study of Valproic Acid in Patients With Non-metastatic Biochemical Progression of Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: valproic acid
* Other: standard of care follow-up


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed prostate cancer Asymptomatic, non-metastatic disease Biochemical progression after definitive local therapy (radical prostatectomy) Most recent prostate-specific antigen (PSA) level ≥ 1.0 ng/mL AND rising over the prior value No clinical or radiological evidence of local progression PSA doubling time (DT) < 10 months after local therapy (in patients who have not received prior hormone therapy) At least three PSA values (each at least 4 weeks apart) are required to calculate the PSA-DT No clinical or radiological evidence of metastatic disease, including bone metastasis PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy > 3 months Total bilirubin normal AST/ALT < 2.5 times upper limit of normal Creatinine ≤ 2.5 mg/dL Platelet count > 125,000/mm^3 PT and aPTT ≤ 1.3 times above the standard reference Albumin ≥ 3.5 g/dL Geographically accessible and willing to participate in all stages of study treatment No active second malignancy No known HIV positivity No active, uncontrolled infection (e.g., hepatitis A, B, or C infection) No history of allergic reactions attributed to compounds of similar chemical or biological composition to valproic acid No debilitating medical or psychiatric illness that would preclude giving informed consent or receiving optimal study treatment and follow-up No history of hepatic disease or significant hepatic dysfunction No history of pancreatitis No history of seizure disorder or clinically treated bipolar disorder PRIOR CONCURRENT THERAPY: More than 6 months since prior hormone therapy No prior valproic acid At least 2 weeks since prior drugs specifically known to interact with valproic acid including, but are not limited to, aspirin, felbamate, rifampin, amitriptyline/nortriptyline, carbamazepine, clonazepam, diazepam, ethosuximide, lamotrigine, phenobarbital, primidone, phenytoin, tolbutamide, warfarin, or zidovudine No concurrent systemic chemotherapy for prostate cancer No other concurrent investigational drugs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Arm I (standard of care)<br>Patients undergo observation according to the standard of care. Patients complete quality of life questionnaires at baseline, 6 months, and 1 year. | Other: standard of care follow-up<br>* participant follow the standard of care for patient with metastatic prostate cancer<br>|
| Experimental: Arm II (valproic acid)<br>Patients receive oral valproic acid twice daily for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients complete quality of life questionnaires at baseline, 6 months, and 1 year. | Drug: valproic acid<br>* given orally<br>* Other names: VPA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Exhibiting an Increase in Observed or Predicted Prostate-specific Antigen (PSA) Doubling Time | Number of participants exhibiting an increase in observed or predicted prostate-specific antigen (PSA) doubling time after initiation of the study. Blood was drawn monthly during study period (1 year), serum PSA was measured & PSADT calculated. A doubling time of > 10 month is defined as complete response (3. Secondary Outcome) and this criteria was based on the Pound et al JAMA 1999, Vol 281(No 17) pgs 1591-1697 paper. Any increase in PSADT is defined as partial response (4. Secondary Outcome). | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of PSA Response as Assessed by PSA Doubling Time (PSADT) | Serum PSA was measured once a month, each month for the one year the subjects were on the protocol. PSA Doubling time is defined as the duration for PSA levels in the blood to increase by 100 percent, and is calculated based on the rate of change in serum PSA values. Prostate-specific antigen doubling time (PSADT) was calculated by natural log of 2 (0.693) divided by the slope of the relationship between the log of PSA and time of PSA measurement for each patient (Pound et al JAMA 1999, Vol 281(No 17) pgs 1591-1697), therefore it can be much greater than the 12 months that we followed the patients for. PSADT was calculated for pre enrollment, at the mid point of the study & at the end of study. | pre-study, mid-study, end of study (up to 1 year) | 
| Number of Participants Who Achieve a Complete Response | Complete response was defined as PSA Doubling Time increasing to greater than 10 months. Blood was drawn monthly during study period (1 year), serum PSA was measured & PSADT calculated. The > 10 month criteria was based on the Pound et al JAMA 1999, Vol 281(No 17) pgs 1591-1697 paper. | one year | 
| Number of Participants Who Achieve a Partial Response | Partial Response was defined as any participant that showed an increase in PSA doubling time | one year | 
| Functional Assessment of Cancer Therapy - Prostate (FACT-P) Score | Study questionnaire, known as Functional Assessment of Cancer Therapy - Prostate (FACT-P), were given to participant to complete during study participation. FACT-P is a validated tool to assess self-perceived functionality, psychosocial well-being, and quality of life; and the scoring of the questionnaire was based on the technique published by FACIT (Functional Assessment of Chronic Illness Therapy). The FACT-P is a 39-item questionnaire, with each item being scored from on a Likert scale of 0-4. The total score ranges from 0-156, with a higher score reflecting a better outcome. | at time of enrollment, mid-study, end of study (up to 1 year) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent prostate cancer, stage I prostate cancer, stage IIB prostate cancer, stage IIA prostate cancer, stage III prostate cancer, stage IV prostate cancer