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A Phase I/II Study of Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Combination With Isotretinoin (13-cis Retinoic Acid, 13-CRA) in the Treatment of Patients With Advanced Renal Cell Carcinoma

Phase 1/Phase 2
21 Years
Open (Enrolling)
Recurrent Renal Cell Cancer, Stage III Renal Cell Cancer, Stage IV Renal Cell Cancer

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Trial Information

A Phase I/II Study of Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Combination With Isotretinoin (13-cis Retinoic Acid, 13-CRA) in the Treatment of Patients With Advanced Renal Cell Carcinoma


I. Determine the maximum tolerated dose and phase II dose of isotretinoin when given in
combination with vorinostat (SAHA) in patients with advanced renal cell carcinoma. (Phase I)
II. Define dose-limiting and other toxicities in patients treated with this regimen. (Phase
I) III. Determine the objective response rate of patients treated with this regimen. (Phase


I. Conduct a pharmacokinetic analysis of this regimen in these patients. (Phase I) II.
Conduct gene profiling analysis of pre-study, paraffin-embedded tissues from patients
treated with this regimen. (Phase I) III. Conduct correlative studies to identify the effect
of SAHA and isotretinoin on RAR-B, LRAT, and STAT1-3 expression. (Phase I)

OUTLINE: This is a multicenter, phase I, dose-escalation study of isotretinoin, followed by
a multicenter, phase II, prospective, non-randomized study.

Phase I: Patients receive oral vorinostat (SAHA) twice daily and oral isotretinoin twice
daily on days 3-5, 10-12, 17-19, and 24-26. Treatment repeats every 28 days in the absence
of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating
doses of isotretinoin until the maximum tolerated dose (MTD) is determined. The MTD is
defined as the dose preceding that at which 2 of 6 patients experience dose-limiting

Phase II: Patients receive SAHA as in phase I and isotretinoin as in phase I at the MTD
determined in phase I. Tissue and blood samples are obtained for biomarker/laboratory
studies in weeks 1 and 4.

Gene profile analysis is conducted on tumor tissue. After completion of study treatment,
patients are followed for 12 weeks.

Inclusion Criteria:

- Histologically or cytologically confirmed renal cell carcinoma

- Advanced or metastatic disease

- Measurable disease, defined as ≥ 1 unidimensionally measurable lesion > 20 mm by
conventional techniques or > 10 mm by spiral CT scan (phase II only)

- Failed ≥ 2 prior treatment regimens, including chemotherapy, immunotherapy (i.e.,
interleukin or interferon), biological agents (i.e., kinase inhibitors), or
combinations thereof

- An overlap between classes of therapies given concurrently will be counted as 2
prior treatment regimens

- No known brain metastases

- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%

- Life expectancy > 3 months

- WBC ≥ 3,000/mm^3

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Bilirubin ≤ 1.5 mg/dL

- AST and ALT < 2.5 times upper limit of normal

- Creatinine ≤ 2 mg/dL OR creatinine clearance > 50 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective double-method contraception for 1 month before,
during, and for 1 month after completion of study treatment

- No history of allergic reactions or hypersensitivity attributed to compounds of
similar chemical or biologic composition to vorinostat (SAHA), isotretinoin, or other
agents or components (e.g., parabens) used in this study

- No uncontrolled intercurrent illness, including, but not limited to, any of the

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situation that would preclude study compliance

- See Disease Characteristics

- Recovered from prior therapy

- At least 2 weeks since prior valproic acid or any other histone deacetylase inhibitor

- At least 4 weeks since prior radiotherapy

- At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

- At least 6 weeks since prior chemoimmunotherapy

- No concurrent antiretroviral therapy for HIV-positive patients

- No other concurrent anticancer therapy, including radiation, biologic, or
chemotherapeutic agents, for renal cell carcinoma or other tumors

- No other concurrent investigational agents, valproic acid, or other retinoid

Type of Study:


Study Design:

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Dose limiting and other toxicities associated with vorinostat concurrently administered with isotretinoin

Outcome Description:

Defined as the occurrence of one or more of the following toxicities as graded by the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

Outcome Time Frame:

Course 1

Safety Issue:


Principal Investigator

David Nanus

Investigator Role:

Principal Investigator

Investigator Affiliation:

Montefiore Medical Center


United States: Food and Drug Administration

Study ID:




Start Date:

March 2006

Completion Date:

Related Keywords:

  • Recurrent Renal Cell Cancer
  • Stage III Renal Cell Cancer
  • Stage IV Renal Cell Cancer
  • Carcinoma, Renal Cell



Montefiore Medical Center Bronx, New York  10467-2490