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

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

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.

Study Overview

• Status: Terminated
• Conditions: Prostate Cancer
• Intervention / Treatment: Other: standard of care follow-up; Drug: valproic acid

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Arm I (standard of care); 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; participant follow the standard of care for patient with metastatic prostate cancer
Experimental: 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.	Drug: valproic acid; given orally; Other Names: VPA

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Ronald Rodriguez, MD, PhD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study record dates

Study Major Dates

• Study Start: May 1, 2008
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: April 30, 2008
• First Submitted That Met QC Criteria: April 30, 2008
• First Posted (Estimate): May 1, 2008

Study Record Updates

• Last Update Posted (Actual): September 28, 2018
• Last Update Submitted That Met QC Criteria: September 26, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: stage III prostate cancer; stage IV prostate cancer; recurrent prostate cancer; stage I prostate cancer; stage IIB prostate cancer; stage IIA prostate cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid
• Other Study ID Numbers: J07122; P30CA068485 (U.S. NIH Grant/Contract); CDR0000595004; NA_00010227 (Other Identifier: JHM IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No