Prostate Cancer
Conditions
Keywords
recurrent prostate cancer, stage I prostate cancer, stage IIB prostate cancer, stage IIA prostate cancer, stage III prostate cancer, stage IV prostate cancer
Brief summary
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
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.
Interventions
DRUGvalproic acid
given orally
OTHERstandard of care follow-up
participant follow the standard of care for patient with metastatic prostate cancer
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Exhibiting an Increase in Observed or Predicted Prostate-specific Antigen (PSA) Doubling Time | 1 year | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of PSA Response as Assessed by PSA Doubling Time (PSADT) | pre-study, mid-study, end of study (up to 1 year) | 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. |
| Number of Participants Who Achieve a Complete Response | one year | 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. |
| Number of Participants Who Achieve a Partial Response | one year | Partial Response was defined as any participant that showed an increase in PSA doubling time |
| Functional Assessment of Cancer Therapy - Prostate (FACT-P) Score | at time of enrollment, mid-study, end of study (up to 1 year) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
standard of care follow-up: participant follow the standard of care for patient with metastatic prostate cancer | 6 |
| 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.
valproic acid: given orally | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Arm I (Standard of Care) | Arm II (Valproic Acid) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 8 |
| other Total, other adverse events | 0 / 7 | 0 / 8 |
| serious Total, serious adverse events | 0 / 7 | 0 / 8 |
Outcome results
Primary
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).
Time frame: 1 year
Population: One participant from Arm 1 was lost to follow-up; One participant from Arm II was lost to follow-up and another withdrew consent
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Standard of Care) | Number of Participants Exhibiting an Increase in Observed or Predicted Prostate-specific Antigen (PSA) Doubling Time | 3 Participants |
| Arm II (Valproic Acid) | Number of Participants Exhibiting an Increase in Observed or Predicted Prostate-specific Antigen (PSA) Doubling Time | 5 Participants |
Secondary
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.
Time frame: pre-study, mid-study, end of study (up to 1 year)
Population: One participant from Arm 1 was lost to follow-up; One participant from Arm II was lost to follow-up and another withdrew consent.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Standard of Care) | Duration of PSA Response as Assessed by PSA Doubling Time (PSADT) | Pre-Study | 6.3 months | Standard Deviation 1.9 |
| Arm I (Standard of Care) | Duration of PSA Response as Assessed by PSA Doubling Time (PSADT) | Mid-Study | 6.9 months | Standard Deviation 4 |
| Arm I (Standard of Care) | Duration of PSA Response as Assessed by PSA Doubling Time (PSADT) | End of study | 7.0 months | Standard Deviation 3.8 |
| Arm II (Valproic Acid) | Duration of PSA Response as Assessed by PSA Doubling Time (PSADT) | Pre-Study | 4.0 months | Standard Deviation 2.8 |
| Arm II (Valproic Acid) | Duration of PSA Response as Assessed by PSA Doubling Time (PSADT) | Mid-Study | 14.1 months | Standard Deviation 9.9 |
| Arm II (Valproic Acid) | Duration of PSA Response as Assessed by PSA Doubling Time (PSADT) | End of study | 40.7 months | Standard Deviation 46.1 |
Secondary
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.
Time frame: at time of enrollment, mid-study, end of study (up to 1 year)
Population: One participant from Arm 1 was lost to follow-up; One participant from Arm II was lost to follow-up and another withdrew consent; Average FACT-P scores for both arms at Study enrollment, mid study and at end of study is being reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Standard of Care) | Functional Assessment of Cancer Therapy - Prostate (FACT-P) Score | at time of Study Enrollment | 133 units on a scale | Standard Deviation 7.5 |
| Arm I (Standard of Care) | Functional Assessment of Cancer Therapy - Prostate (FACT-P) Score | Mid Study | 134.8 units on a scale | Standard Deviation 4.1 |
| Arm I (Standard of Care) | Functional Assessment of Cancer Therapy - Prostate (FACT-P) Score | End of Study | 133.2 units on a scale | Standard Deviation 10.3 |
| Arm II (Valproic Acid) | Functional Assessment of Cancer Therapy - Prostate (FACT-P) Score | at time of Study Enrollment | 138.5 units on a scale | Standard Deviation 5.5 |
| Arm II (Valproic Acid) | Functional Assessment of Cancer Therapy - Prostate (FACT-P) Score | Mid Study | 126.6 units on a scale | Standard Deviation 23.4 |
| Arm II (Valproic Acid) | Functional Assessment of Cancer Therapy - Prostate (FACT-P) Score | End of Study | 90.4 units on a scale | Standard Deviation 42.3 |
Secondary
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.
Time frame: one year
Population: One participant from Arm 1 was lost to follow-up; One participant from Arm II was lost to follow-up and another withdrew consent
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Standard of Care) | Number of Participants Who Achieve a Complete Response | 1 Participants |
| Arm II (Valproic Acid) | Number of Participants Who Achieve a Complete Response | 4 Participants |
Secondary
Number of Participants Who Achieve a Partial Response
Partial Response was defined as any participant that showed an increase in PSA doubling time
Time frame: one year
Population: One participant from Arm 1 was lost to follow-up; One participant from Arm II was lost to follow-up and another withdrew consent
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Standard of Care) | Number of Participants Who Achieve a Partial Response | 2 Participants |
| Arm II (Valproic Acid) | Number of Participants Who Achieve a Partial Response | 1 Participants |