Vorinostat and Isotretinoin in Treating Patients With Advanced Kidney Cancer

Condition(s) targeted: Kidney Cancer

Intervention: isotretinoin (Drug); vorinostat (Drug); gene expression analysis (Genetic); microarray analysis (Genetic); laboratory biomarker analysis (Other); pharmacological study (Other); biopsy (Procedure)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Weill Medical College of Cornell University

Official(s) and/or principal investigator(s):
David M. Nanus, MD, Study Chair, Affiliation: Weill Medical College of Cornell University

RATIONALE: Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Isotretinoin may cause kidney cancer cells to look more like normal cells, and to grow and spread more slowly. Giving vorinostat together with isotretinoin may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of isotretinoin when given together with vorinostat and to see how well they work in treating patients with advanced kidney cancer.

Official title: 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

Study design: Treatment, Non-Randomized

Primary outcome:

Dose-limiting toxicities

Maximum tolerated dose

Objective response rate

Secondary outcome: Pharmacokinetics

Detailed description: OBJECTIVES:

Primary

- 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)

- Define dose-limiting and other toxicities in patients treated with this regimen. (Phase

I)

- Determine the objective response rate of patients treated with this regimen. (Phase II)

Secondary

- Conduct a pharmacokinetic analysis of this regimen in these patients. (Phase I)

- Conduct gene profiling analysis of pre-study, paraffin-embedded tissues from patients

treated with this regimen. (Phase I)

- 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.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Minimum age: 21 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- 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

PATIENT CHARACTERISTICS:

- 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 componenets (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

PRIOR CONCURRENT THERAPY:

- 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

Albert Einstein Cancer Center at Albert Einstein College of Medicine, Bronx, New York 10461, United States; Recruiting
Clinical Trials Office - Albert Einstein Cancer Center at Albe, Phone: 718-904-2730, Email: aecc@aecom.yu.edu

Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, New York, New York 10032, United States; Recruiting
Clinical Trials Office - Herbert Irving Comprehensive Cancer C, Phone: 212-305-8615

Mount Sinai Medical Center, New York, New York 10029, United States; Recruiting
Max W. Sung, MD, Phone: 212-241-7902, Email: max.sung@mssm.edu

New York Weill Cornell Cancer Center at Cornell University, New York, New York 10021, United States; Recruiting
Clinical Trials Office - New York Weill Cornell Cancer Center, Phone: 212-746-1848

NYU Cancer Institute at New York University Medical Center, New York, New York 10016, United States; Recruiting
Anna C. Ferrari, MD, Phone: 212-731-5389, Email: anna.ferrari@nyumc.org

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: March 2006
Last updated: June 9, 2009