Vorinostat in Treating Patients With Progressive Metastatic Prostate Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00330161
• Collaborator: (none)
• Enrollment: 29
• Location: 1
• Arm: 1
• Duration (Months): 62
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Prostate Cancer; Stage IV Prostate Cancer	Drug: vorinostat; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

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

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

3. 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.

4. 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.

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

6. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Evaluation of Suberoylanilide Hydroxamic Acid (NSC 701852) in Patients With Advanced Prostate Cancer That Has Progressed on One Prior Chemotherapy
• Study Start Date: Mar 1, 2006
• Actual Primary Completion Date: Sep 1, 2009
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (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.

Drug: vorinostat; Given orally; Other Names: L-001079038 SAHA suberoylanilide hydroxamic acid Zolinza ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients Who do Not Demonstrate Disease Progression [At 6 months]

   Fisher's Exact Test will be used.

Secondary Outcome Measures

1. Incidence of Toxicity [Up to 3 years]

   The percentage of eligible participants that experience grade 3 or 4 toxicities.

2. Rate of PSA Decline [Up to 3 years]

   Rate of Prostate Specific Antigen (PSA) decline of greater than or equal to 50%.

3. Progression-free Survival [From the start of treatment to time of progression, assessed up to 3 years]

   Median time to progression was determined.

4. Median Survival [Up to 3 years]

   Median overall survival.

5. Objective Response Rate [Up to 3 years]

   Percentage of participants that obtain the best objective response, stable disease.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Maha Hussain, University of Michigan

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00330161
• Other Study ID Numbers: NCI-2012-03067; NCI-2012-03067; UMCC 2005.127; 6862; N01CM62206; N01CM62201; U01CA062491; P30CA046592
• First Posted: May 26, 2006
• Last Update Posted: May 26, 2014
• Last Verified: Dec 1, 2012

• Additional relevant MeSH terms: Prostatic Neoplasms; Vorinostat

Study Results

Participant Flow

Recruitment Details	Participants were recruited at 5 medical centers between May 2006 and February 2007.

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	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.
Period Title: Overall Study
STARTED	29
COMPLETED	29
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	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.
Overall Participants	27
Age (years) [Median (Full Range) ]
Age	68
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	27 100%
Region of Enrollment (participants) [Number]
United States	27 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The primary objective was to determine the number of patients wtih progression-free survival at 6 months. Unfortunately all eligible patients were off therapy before the 6 month time point. 13 (48%) were removed due to progression, 11 (41%) secondary to toxicity, and 3 (11%) for other reasons.

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	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.
Measure Participants	0

2. Secondary Outcome

Title	Incidence of Toxicity
Description	The percentage of eligible participants that experience grade 3 or 4 toxicities.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Of the 29 patients enrolled, 2 were deemed ineligible after treatment and therefore excluded from outcome analysis.

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	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.
Measure Participants	27
Number [percentage of participants]	48 177.8%

3. Secondary Outcome

Title	Rate of PSA Decline
Description	Rate of Prostate Specific Antigen (PSA) decline of greater than or equal to 50%.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

No PSA declines of greater than or equal to 50% were observed, therefore the rate could not be determined.

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	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.
Measure Participants	0

4. Secondary Outcome

Title	Progression-free Survival
Description	Median time to progression was determined.
Time Frame	From the start of treatment to time of progression, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

Of the 29 patients enrolled, two patients were deemed ineligible after treatment and therefore excluded from analysis.

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	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.
Measure Participants	27
Median (Full Range) [months]	2.8

5. Secondary Outcome

Title	Median Survival
Description	Median overall survival.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Of the 29 patients enrolled, two patients were deemed ineligible after treatment and therefore excluded from analysis. Of the 27 patients analyzed, one patient was censored with an outlying overall survival of 15.1 months.

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	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.
Measure Participants	26
Median (Full Range) [months]	11.7

6. Secondary Outcome

Title	Objective Response Rate
Description	Percentage of participants that obtain the best objective response, stable disease.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Of the 29 patients enrolled, two patients were deemed ineligible after treatment and therefore excluded from analysis.

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	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.
Measure Participants	27
Number [percentage of participants]	7 25.9%

Adverse Events

Time Frame	Serious Adverse Events (SAEs) were reported that occurred within 30 days of the last dose of study drug.
Adverse Event Reporting Description	All patients were evaluable for toxicity from the time of their first treatment with SAHA.
Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	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.
All Cause Mortality
	Treatment (Vorinostat)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Vorinostat)
	Affected / at Risk (%)	# Events
Total	8/29 (27.6%)
Cardiac disorders
Arrhythmia	1/29 (3.4%)	1
Gastrointestinal disorders
Abdominal Pain	1/29 (3.4%)	1
Nausea	1/29 (3.4%)	1
Proctitis	1/29 (3.4%)	1
Vomiting	1/29 (3.4%)	1
General disorders
Pain	1/29 (3.4%)	1
Infections and infestations
Infection, Bone (Osteomyelitis)	1/29 (3.4%)	1
Skin Infection	1/29 (3.4%)	1
Investigations
Creatinine Increased	1/29 (3.4%)	1
Metabolism and nutrition disorders
Dehydration	1/29 (3.4%)	1
Musculoskeletal and connective tissue disorders
Back Pain	1/29 (3.4%)	1
Renal and urinary disorders
Hemorrhage Urinary Tract	1/29 (3.4%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/29 (3.4%)	1
Vascular disorders
Thrombosis	2/29 (6.9%)	2
Other (Not Including Serious) Adverse Events
	Treatment (Vorinostat)
	Affected / at Risk (%)	# Events
Total	29/29 (100%)
Blood and lymphatic system disorders
Anemia	11/29 (37.9%)	19
Ear and labyrinth disorders
Hearing Loss	2/29 (6.9%)	2
Gastrointestinal disorders
Abdominal Distention	2/29 (6.9%)	2
Constipation	5/29 (17.2%)	8
Diarrhea	11/29 (37.9%)	18
Dry Mouth	4/29 (13.8%)	4
Dyspepsia	2/29 (6.9%)	2
Dysphagia	2/29 (6.9%)	2
Mucositis Oral	3/29 (10.3%)	4
Vomiting	2/29 (6.9%)	2
General disorders
Edema Limbs	2/29 (6.9%)	3
Fatigue	25/29 (86.2%)	57
Fever	3/29 (10.3%)	3
Hypersensitivity	2/29 (6.9%)	2
Pain	2/29 (6.9%)	2
Investigations
Activated Partial Thromboplastin Time Prolonged	2/29 (6.9%)	18
Alanine Aminotransferase Increased	5/29 (17.2%)	5
Alkaline Phosphatase Increased	8/29 (27.6%)	8
Aspartate Aminotransferase Increased	6/29 (20.7%)	14
INR Increased	3/29 (10.3%)	28
Leukopenia (White Blood Cells Decreased)	4/29 (13.8%)	12
Lymphopenia	3/29 (10.3%)	4
Platelet Count Decreased	15/29 (51.7%)	20
Weight Decreased	9/29 (31%)	11
Metabolism and nutrition disorders
Anorexia	21/29 (72.4%)	36
Hyperglycemia	11/29 (37.9%)	24
Hyperkalemia	2/29 (6.9%)	3
Hypernatremia	3/29 (10.3%)	5
Hypoalbuminemia	6/29 (20.7%)	12
Hypocalcemia	2/29 (6.9%)	2
Hypokalemia	3/29 (10.3%)	3
Hyponatremia	3/29 (10.3%)	5
Hypophosphatemia	3/29 (10.3%)	5
Musculoskeletal and connective tissue disorders
Arthritis	2/29 (6.9%)	2
Bone Pain	4/29 (13.8%)	4
Joint Pain	2/29 (6.9%)	3
Muscle Weakness	2/29 (6.9%)	2
Pain in Extremity	5/29 (17.2%)	6
Nervous system disorders
Taste Alteration	6/29 (20.7%)	7
Renal and urinary disorders
Bladder Hemorrhage	2/29 (6.9%)	2
Urinary Frequency	5/29 (17.2%)	9
Reproductive system and breast disorders
Erectile Dysfunction	2/29 (6.9%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/29 (10.3%)	4
Skin and subcutaneous tissue disorders
Alopecia	2/29 (6.9%)	2
Vascular disorders
Hot Flashes	2/29 (6.9%)	2

Limitations/Caveats

The primary objective was to determine the number of patients wtih progression-free survival at 6 months. Unfortunately all eligible patients were off therapy before the 6 month time point.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.