Recurrent Renal Cell Cancer, Stage III Renal Cell Cancer, Stage IV Renal Cell Cancer
Conditions
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.
Interventions
DRUGvorinostat
Given orally
DRUGisotretinoin
Given orally
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Recruitment details
A total of 14 patients were enrolled between June 2006 and September 2010
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Vorinostat and 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.
vorinostat: Given orally
isotretinoin: Given orally | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Treatment (Vorinostat and Isotretinoin) |
|---|---|
| Age, Continuous | 55 years |
| Race/Ethnicity, Customized Asian | 1 participants |
| Race/Ethnicity, Customized Black | 1 participants |
| Race/Ethnicity, Customized Native Hawaiin or other Pacific Islander | 1 participants |
| Race/Ethnicity, Customized Unknown | 3 participants |
| Race/Ethnicity, Customized White | 6 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 12 |
| serious Total, serious adverse events | 11 / 12 |
Outcome results
Primary
Maximum Tolerated Dose of Vorinostat in Combination With Isotretinoin
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.
Time frame: Once 2 DLT events occur in patients, the preceding dose will be designated the maximum tolerated dose (MTD).
Population: The recommended phase II dose is vorinostat (300 mg bid) + Isotretinoin (0.5 mg/kg PO bid) three days per week
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 1: Vorinostat (300mg) and Isotretinoin (0.25 mg/kg) | Maximum Tolerated Dose of Vorinostat in Combination With Isotretinoin | 0.5 mg/kg BID |
Primary
Number of Participants With at Least One Dose Limiting Toxicity Associated With Vorinostat Concurrently Administered With Isotretinoin
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
Time frame: Course 1, up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1: Vorinostat (300mg) and Isotretinoin (0.25 mg/kg) | Number of Participants With at Least One Dose Limiting Toxicity Associated With Vorinostat Concurrently Administered With Isotretinoin | 1 Participants |
| Dose Level 2 Vorinostat (300mg)and Isotretinoin (0.375 mg/kg) | Number of Participants With at Least One Dose Limiting Toxicity Associated With Vorinostat Concurrently Administered With Isotretinoin | 0 Participants |
| Dose Level 2 Vorinostat (300mg)and Isotretinoin (0.5 mg/kg) | Number of Participants With at Least One Dose Limiting Toxicity Associated With Vorinostat Concurrently Administered With Isotretinoin | 0 Participants |
Primary
Objective Response Rate
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
Time frame: Tumor measurements every 8 weeks until disease progression
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1: Vorinostat (300mg) and Isotretinoin (0.25 mg/kg) | Objective Response Rate | Progression | 1 Participants |
| Dose Level 1: Vorinostat (300mg) and Isotretinoin (0.25 mg/kg) | Objective Response Rate | Stable Disease | 4 Participants |
| Dose Level 1: Vorinostat (300mg) and Isotretinoin (0.25 mg/kg) | Objective Response Rate | Partial Response | 0 Participants |
| Dose Level 2 Vorinostat (300mg)and Isotretinoin (0.375 mg/kg) | Objective Response Rate | Stable Disease | 2 Participants |
| Dose Level 2 Vorinostat (300mg)and Isotretinoin (0.375 mg/kg) | Objective Response Rate | Partial Response | 1 Participants |
| Dose Level 2 Vorinostat (300mg)and Isotretinoin (0.375 mg/kg) | Objective Response Rate | Progression | 0 Participants |
| Dose Level 2 Vorinostat (300mg)and Isotretinoin (0.5 mg/kg) | Objective Response Rate | Partial Response | 0 Participants |
| Dose Level 2 Vorinostat (300mg)and Isotretinoin (0.5 mg/kg) | Objective Response Rate | Progression | 0 Participants |
| Dose Level 2 Vorinostat (300mg)and Isotretinoin (0.5 mg/kg) | Objective Response Rate | Stable Disease | 3 Participants |