Vorinostat and Isotretinoin in Treating Patients With Advanced Kidney Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00324740
• Collaborator: (none)
• Enrollment: 14
• Locations: 2
• Arm: 1
• Duration (Months): 98
• Patients Per Site: 7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Renal Cell Cancer; Stage III Renal Cell Cancer; Stage IV Renal Cell Cancer	Drug: vorinostat; Drug: isotretinoin	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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)
2. Define dose-limiting and other toxicities in patients treated with this regimen. (Phase

1. 1. Determine the objective response rate of patients treated with this regimen. (Phase

SECONDARY OBJECTIVES:

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Mar 1, 2006
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: vorinostat; Given orally; Other Names: L-001079038 SAHA suberoylanilide hydroxamic acid Zolinza ; Drug: isotretinoin; Given orally; Other Names: 13-CRA Amnesteem Cistane Claravis Sotret

Outcome Measures

Primary Outcome Measures

1. 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

2. 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.

3. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467-2490
2	Weill Medical College of Cornell University	New York	New York	United States	10065

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: David Nanus, Montefiore Medical Center - Moses Campus

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00324740
• Other Study ID Numbers: NCI-2009-00095; NCI-2009-00095; NCI-6896; N01CM62204; P30CA013330
• First Posted: May 11, 2006
• Last Update Posted: Feb 23, 2021
• Last Verified: Feb 1, 2021

• Additional relevant MeSH terms: Carcinoma, Renal Cell; Vorinostat; Isotretinoin

Study Results

Participant Flow

Recruitment Details	A total of 14 patients were enrolled between June 2006 and September 2010

Arm/Group Title	Dose Level 1: Vorinostat (300mg) and Isotretinoin (0.25 mg/kg)	Dose Level 2 Vorinostat (300mg) and Isotretinoin (0.375 mg/kg)	Dose Level 3: Vorinostat (300mg) and Isotretinoin (0.5 mg/kg)
Arm/Group Description	Patients receive oral vorinostat (SAHA-300 mg) twice daily and oral isotretinoin (0.25 mg/kg) twice daily for 3 consecutive days per week (Tues/Wed/Thurs). Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. vorinostat: Given orally isotretinoin: Given orally	Patients receive oral vorinostat (SAHA-300 mg) twice daily and oral isotretinoin (0.375 mg/kg) twice daily for 3 consecutive days per week (Tues/Wed/Thurs). Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. vorinostat: Given orally isotretinoin: Given orally	Patients receive oral vorinostat (SAHA-300 mg) twice daily and oral isotretinoin (0.5 mg/kg) twice daily for 3 consecutive days per week (Tues/Wed/Thurs). Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. vorinostat: Given orally isotretinoin: Given orally
Period Title: Overall Study
STARTED	7	3	4
COMPLETED	6	3	3
NOT COMPLETED	1	0	1

Baseline Characteristics

Arm/Group Title	Treatment (Vorinostat and Isotretinoin)
Arm/Group Description	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
Overall Participants	12
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55
Sex: Female, Male (Count of Participants)
Female	9 75%
Male	3 25%
Race/Ethnicity, Customized (participants) [Number]
White	6 50%
Asian	1 8.3%
Black	1 8.3%
Native Hawaiin or other Pacific Islander	1 8.3%
Unknown	3 25%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With at Least One Dose Limiting Toxicity Associated With Vorinostat Concurrently Administered With Isotretinoin
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
Time Frame	Course 1, up to 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 1: Vorinostat (300mg) and Isotretinoin (0.25 mg/kg)	Dose Level 2 Vorinostat (300mg)and Isotretinoin (0.375 mg/kg)	Dose Level 2 Vorinostat (300mg)and Isotretinoin (0.5 mg/kg)
Arm/Group Description	Patients receive oral vorinostat (SAHA) and oral isotretinoin twice daily for 3 consecutive days per week (Tues/Wed/Thurs). Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. vorinostat: Given orally isotretinoin: Given orally	Patients receive oral vorinostat (SAHA) and oral isotretinoin twice daily for 3 consecutive days per week (Tues/Wed/Thurs). Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. vorinostat: Given orally isotretinoin: Given orally	Patients receive oral vorinostat (SAHA) and oral isotretinoin twice daily for 3 consecutive days per week (Tues/Wed/Thurs). Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. vorinostat: Given orally isotretinoin: Given orally
Measure Participants	6	3	3
Count of Participants [Participants]	1 8.3%	0 NaN	0 NaN

2. Primary Outcome

Title	Maximum Tolerated Dose of Vorinostat in Combination With Isotretinoin
Description	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).

Outcome Measure Data

Analysis Population Description

The recommended phase II dose is vorinostat (300 mg bid) + Isotretinoin (0.5 mg/kg PO bid) three days per week

Arm/Group Title	Treatment (Vorinostat and Isotretinoin)
Arm/Group Description	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
Measure Participants	12
Number [mg/kg BID]	0.5

3. Primary Outcome

Title	Objective Response Rate
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 1: Vorinostat (300mg) and Isotretinoin (0.25 mg/kg)	Dose Level 2 Vorinostat (300mg)and Isotretinoin (0.375 mg/kg)	Dose Level 2 Vorinostat (300mg)and Isotretinoin (0.5 mg/kg)
Arm/Group Description	Patients receive oral vorinostat (SAHA) and oral isotretinoin twice daily for 3 consecutive days per week (Tues/Wed/Thurs). Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. vorinostat: Given orally isotretinoin: Given orally	Patients receive oral vorinostat (SAHA) and oral isotretinoin twice daily for 3 consecutive days per week (Tues/Wed/Thurs). Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. vorinostat: Given orally isotretinoin: Given orally	Patients receive oral vorinostat (SAHA) and oral isotretinoin twice daily for 3 consecutive days per week (Tues/Wed/Thurs). Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. vorinostat: Given orally isotretinoin: Given orally
Measure Participants	5	3	3
Partial Response	0 0%	1 NaN	0 NaN
Stable Disease	4 33.3%	2 NaN	3 NaN
Progression	1 8.3%	0 NaN	0 NaN

Adverse Events

Arm/Group Title	Treatment (Vorinostat and Isotretinoin)
Arm/Group Description	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
All Cause Mortality
	Treatment (Vorinostat and Isotretinoin)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Vorinostat and Isotretinoin)
	Affected / at Risk (%)	# Events
Total	11/12 (91.7%)
Blood and lymphatic system disorders
Anemia	1/12 (8.3%)	1
Gastrointestinal disorders
Dehydration	1/12 (8.3%)	1
Diarrhea	1/12 (8.3%)	1
Nausea	1/12 (8.3%)	1
Vomiting	1/12 (8.3%)	1
General disorders
Fatigue	2/12 (16.7%)	2
Musculoskeletal and connective tissue disorders
Muscle cramps	1/12 (8.3%)	1
Nervous system disorders
Anxiety	1/12 (8.3%)	1
Depression	1/12 (8.3%)	1
Skin and subcutaneous tissue disorders
Rash	1/12 (8.3%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Vorinostat and Isotretinoin)
	Affected / at Risk (%)	# Events
Total	4/12 (33.3%)
Gastrointestinal disorders
Anorexia	3/12 (25%)	3
General disorders
Weight Loss	1/12 (8.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.