Vorinostat and Isotretinoin in Treating Patients With Advanced Kidney Cancer

PRIMARY OBJECTIVES:

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
II)

SECONDARY OBJECTIVES:

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
toxicity.

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

- Negative pregnancy test

Exclusion criteria:

- Not pregnant or nursing

- 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
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situation that would preclude study compliance

- 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