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Phase II Evaluation of Suberoylanilide Hydroxamic Acid (NSC 701852) in Patients With Advanced Prostate Cancer That Has Progressed on One Prior Chemotherapy

Phase 2
18 Years
Not Enrolling
Recurrent Prostate Cancer, Stage IV Prostate Cancer

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Trial Information

Phase II Evaluation of Suberoylanilide Hydroxamic Acid (NSC 701852) in Patients With Advanced Prostate Cancer That Has Progressed on One Prior Chemotherapy


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.


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.

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


- Reversible defect - Exclude

- Fixed defect alone - Include

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of patients who do not demonstrate disease progression

Outcome Description:

Fisher's Exact Test will be used.

Outcome Time Frame:

At 6 months

Safety Issue:


Principal Investigator

Maha Hussain

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Michigan University Hospital


United States: Food and Drug Administration

Study ID:




Start Date:

March 2006

Completion Date:

Related Keywords:

  • Recurrent Prostate Cancer
  • Stage IV Prostate Cancer
  • Prostatic Neoplasms



University of Michigan University HospitalAnn Arbor, Michigan  48109