Vorinostat in Treating Patients With Progressive Metastatic Prostate Cancer

Phase 2

Completed

Conditions: Recurrent Prostate Cancer
Stage IV Prostate Cancer

Interventions: Drug: vorinostat
Other: laboratory biomarker analysis

Registration Number: NCT00330161

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial is studying how well vorinostat works in treating patients with progressive metastatic prostate cancer. Drugs used in chemotherapy, such as vorinostat, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description: PRIMARY OBJECTIVES:

I. To evaluate the efficacy of oral SAHA in patients with castrate metastatic prostate cancer who have progressed on one prior chemotherapy, as measured by the proportion of patients not progressed at 6 months.

SECONDARY OBJECTIVES:

I. To evaluate the safety of oral SAHA in patients with castrate metastatic prostate cancer who have progressed on one prior chemotherapy.

II. To assess the objective response rate of oral SAHA in patients with measurable disease when present.

III. To assess the rate of PSA decline of \>= 50%. IV. To assess progression free and median survival in patients with castrate metastatic prostate cancer who have progressed on one prior chemotherapy.

V. To evaluate pre and post-treatment tumor biopsies when available for the presence of changes in the expression of AR and Hsp90 client proteins, Thioredoxin, Thioredoxin Binding Protein, HDAC 3 (class I), HDAC 7 (class II), EZH2 and p21 expression.

VI. To determine the effects of oral SAHA on IL-6, soluble IL-6 receptor and soluble gp130 levels in the blood.

VII. To determine the accumulation and biodistribution of 18FDHT and correlate these findings with standard FDG PET, radionuclide bone scan, CT and/or MRI scans, as well as 18FDHT pharmacokinetics and tumor tissue staining for androgen receptor (AR) and Hsp90 client proteins (this applies only to patients at MSKCC under a separate protocol #00-095).

OUTLINE: This is a multicenter study.

Patients receive oral vorinostat (SAHA) once daily on days 1-21. Treatment repeats every 21 days for at least 4 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response (CR) after 4 courses receive an additional 3 courses. All other patients may continue treatment in the absence of disease progression or unacceptable toxicity.

Blood samples are taken on day 15 of course 1, day 1 of course 2, during the last week of course 4, and at completion of study treatment. Blood is examined for interleukin (IL)-6, IL-6 receptor, and gp130 levels.

After completion of study treatment, patients are followed periodically for survival.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 29

Inclusion Criteria

A histologic or cytologic diagnosis of prostate cancer
Metastatic prostate cancer with measurable and/or bony disease that has progressed despite androgen deprivation therapy and one prior chemotherapy for castrate metastatic disease; all patients must have PSA progression defined as:
- At least 2 rises in PSA to be documented over a reference value (measure 1); the first rising PSA (measure 2) must be taken at least 7 days after the reference value; a third confirmatory PSA measure is required to be greater than the second measure and must be obtained at least 7 days after the 2nd measure; if this is not the case, a fourth PSA is required to be taken and be greater then the 2nd measure
All patients must have a minimum PSA of >= 5 ng/ml
ECOG performance status of 0-2
Testosterone < 50 ng/dL; patients must continue primary androgen deprivation with an LHRH analogue if they have not undergone orchiectomy
No investigational or commercial agents (other than LHRH analogue) or therapies including other hormonal agents such as megestrol acetate (unless low dose given for hot flashes), antiandrogens or herbal medications may be administered with the intent to treat the patient's malignancy
Four weeks must have elapsed since major surgery
Prior radiotherapy is allowed as long as the bone marrow function is adequate and at least 4 weeks has elapsed since completion of radiation; no prior radiopharmaceuticals are allowed
Life expectancy of greater than 6 months
Ability to understand and the willingness to sign a written informed consent document that is approved by the Institutional Human Investigation Committee (HIC)
Patients must have normal organ and marrow function as defined below obtained within two weeks from treatment initiation:
Leukocytes >= 3,000/mcL
Absolute neutrophil count >= 1,500/mcL
Platelets >= 100,000/mcL
Serum creatinine < 2 mg/DL
Total bilirubin within normal institutional limits
AST/ALT =< 2.5 X institutional upper limit of normal
Patients must be willing to provide blood samples for the correlative studies and consent to providing paraffin blocks/slides from primary prostate cancer or other prior diagnostic samples; fresh tissue sample donation is optional
The effects of SAHA on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because HDAC inhibitors are known to be teratogenic, men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
Patients with treated and controlled epidural disease are permitted into the study

Exclusion Criteria

Significant cardiovascular disease including congestive heart failure (New York Heart Association Class III or IV), active angina pectoris or recent myocardial infarction (within the last 6 months)
Patients on Valproic Acid (a histone deacetylase inhibitor) must have stopped taking it at least 2 weeks prior to registration
Oral anti-androgens must be stopped; no washout period is necessary prior to enrollment if anti-androgens were used as second line therapy and not as part of combined androgen deprivation; in the unlikely case that a patient may have continued on antiandrogen therapy as part of combined androgen deprivation and has never had antiandrogen withdrawal despite progression on combined androgen deprivation then a washout period will be needed (4 weeks for flutamide and 6 weeks for bicalutamide or nilutamide) prior to study enrollment
Patients who have developed progression as defined in this protocol on stable doses of oral corticosteroids are eligible; the steroids may be continued
No "currently active" second malignancy other than non-melanoma skin cancer; patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be with no evidence of disease
Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; however, brain scans will not be required as part of the pre-study workup
History of allergic reactions attributed to compounds of similar chemical or biologic composition to SAHA
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; patients with history of HIV receiving combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with SAHA; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
Patients with the following history or clinical findings require ADDITIONAL diagnostic TESTING:
- Patients who require diuretics for reasons other than hypertension, digoxin for reasons other than atrial fibrillation, or patients with a history of mild to moderate congestive heart failure
- Patients with the following EKG results:
  - Significant q waves (greater than 3 mm or greater than 1/3 the height of the QRS complex
  - ST elevation or depressions of greater than 2 mm that are not attributable to hypertension strain
  - The absence of a regular sinus rhythm
  - The presence of a bundle block
- ADDITIONAL TESTING: (if required)
  - Radionuclide angiocardiography (RNCA): Patients can be treated if the ejection fraction is > 45% and there is no evidence of ventricular aneurysm or other abnormal wall motion; patients with an ejection fraction < 45% on RNCA, with a worrisome but nonexclusive cardiovascular history, or an abnormal ECG as described above should also have a thallium stress test
    - STRESS TEST RESULTS:
      - Reversible defect - Exclude
      - Fixed defect alone - Include

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (vorinostat)	laboratory biomarker analysis	Patients receive oral vorinostat (SAHA) once daily on days 1-21. Treatment repeats every 21 days for at least 4 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response (CR) after 4 courses receive an additional 3 courses. All other patients may continue treatment in the absence of disease progression or unacceptable toxicity. Blood samples are taken on day 15 of course 1, day 1 of course 2, during the last week of course 4, and at completion of study treatment. Blood is examined for interleukin (IL)-6, IL-6 receptor, and gp130 levels.
Treatment (vorinostat)	vorinostat	Patients receive oral vorinostat (SAHA) once daily on days 1-21. Treatment repeats every 21 days for at least 4 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response (CR) after 4 courses receive an additional 3 courses. All other patients may continue treatment in the absence of disease progression or unacceptable toxicity. Blood samples are taken on day 15 of course 1, day 1 of course 2, during the last week of course 4, and at completion of study treatment. Blood is examined for interleukin (IL)-6, IL-6 receptor, and gp130 levels.

Primary Outcome Measures

Name	Time	Method
Proportion of Patients Who do Not Demonstrate Disease Progression	At 6 months	Fisher's Exact Test will be used.

Secondary Outcome Measures

Name	Time	Method
Incidence of Toxicity	Up to 3 years	The percentage of eligible participants that experience grade 3 or 4 toxicities.
Rate of PSA Decline	Up to 3 years	Rate of Prostate Specific Antigen (PSA) decline of greater than or equal to 50%.
Progression-free Survival	From the start of treatment to time of progression, assessed up to 3 years	Median time to progression was determined.
Median Survival	Up to 3 years	Median overall survival.
Objective Response Rate	Up to 3 years	Percentage of participants that obtain the best objective response, stable disease.