Vorinostat and Isotretinoin in Treating Patients With Advanced Kidney Cancer

Phase 1

Terminated

Conditions: Recurrent Renal Cell Cancer
Stage III Renal Cell Cancer
Stage IV Renal Cell Cancer

Interventions: Drug: vorinostat
Drug: isotretinoin

Registration Number: NCT00324740

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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. 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 14

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (vorinostat and isotretinoin)	vorinostat	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.
Treatment (vorinostat and isotretinoin)	isotretinoin	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With at Least One Dose Limiting Toxicity Associated With Vorinostat Concurrently Administered With Isotretinoin	Course 1, up to 28 days	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
Maximum Tolerated Dose of Vorinostat in Combination With Isotretinoin	Once 2 DLT events occur in patients, the preceding dose will be designated the maximum tolerated dose (MTD).	Hematologic: Any Grade 3/4 Thrombocytopenia and/or Grade 3/4 Neutropenia Non-Hematologic: Any \>/= Grade3 non-hematologic toxicity considered by the investigator to be possibly related to study drug and/or any non-hematologic toxicity that results in a dose-delay of more than three weeks.
Objective Response Rate	Tumor measurements every 8 weeks until disease progression	The Response Evaluation Criteria in Solid Tumors (RECIST 1.0) was used and tumor responses were defined as complete response (CR), partial response (PR), stable disease (SD) or Progression

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (2): Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States
Weill Medical College of Cornell University
🇺🇸
New York, New York, United States