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| ID | Type | Description | Link |
|---|---|---|---|
| NCI-2009-00095 | Registry Identifier | CTRP (Clinical Trial Reporting Program) | |
| NCI-6896 | Other Identifier | NCI/CTEP | |
| N01CM62204 | U.S. NIH Grant/Contract | View source | |
| P30CA013330 | U.S. NIH Grant/Contract | View source |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment (vorinostat and isotretinoin) | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| vorinostat | Drug | Given orally |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Course 1, up to 28 days |
| 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. | Once 2 DLT events occur in patients, the preceding dose will be designated the maximum tolerated dose (MTD). |
| 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 | Tumor measurements every 8 weeks until disease progression |
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Inclusion Criteria:
Histologically or cytologically confirmed renal cell carcinoma
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
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:
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
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| Name | Affiliation | Role |
|---|---|---|
| David Nanus | Montefiore Medical Center - Moses Campus | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Weill Medical College of Cornell University | New York | New York | 10065 | United States | ||
| Montefiore Medical Center - Moses Campus |
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A total of 14 patients were enrolled between June 2006 and September 2010
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| ID | Title | Description |
|---|---|---|
| FG000 | Dose Level 1: Vorinostat (300mg) and Isotretinoin (0.25 mg/kg) | 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 |
| FG001 | Dose Level 2 Vorinostat (300mg) and Isotretinoin (0.375 mg/kg) | 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 |
| FG002 | Dose Level 3: Vorinostat (300mg) and Isotretinoin (0.5 mg/kg) | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | Posted | Count of Participants | Participants | No | Course 1, up to 28 days |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fatigue | General disorders |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Weight Loss | General disorders |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Lisa Escobar-Peralta, Program Manager | Montefiore Medical Center | 718-379-6866 | lescobar@montefiore.org |
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| ID | Term |
|---|---|
| D002292 | Carcinoma, Renal Cell |
| ID | Term |
|---|---|
| D000230 | Adenocarcinoma |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| D000077337 | Vorinostat |
| D015474 | Isotretinoin |
| ID | Term |
|---|---|
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 | Aniline Compounds |
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| isotretinoin | Drug | Given orally |
|
|
| The Bronx |
| New York |
| 10467-2490 |
| United States |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | participants |
|
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 |
| OG002 | Dose Level 2 Vorinostat (300mg)and Isotretinoin (0.5 mg/kg) | 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 |
|
|
| 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. | The recommended phase II dose is vorinostat (300 mg bid) + Isotretinoin (0.5 mg/kg PO bid) three days per week | Posted | Number | mg/kg BID | Once 2 DLT events occur in patients, the preceding dose will be designated the maximum tolerated dose (MTD). |
|
|
|
| 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 | Posted | Count of Participants | Participants | Tumor measurements every 8 weeks until disease progression |
|
|
|
| 11 |
| 12 |
| 4 |
| 12 |
| Rash | Skin and subcutaneous tissue disorders |
|
| Dehydration | Gastrointestinal disorders |
|
| Diarrhea | Gastrointestinal disorders |
|
| Nausea | Gastrointestinal disorders |
|
| Vomiting | Gastrointestinal disorders |
|
| Anemia | Blood and lymphatic system disorders |
|
| Muscle cramps | Musculoskeletal and connective tissue disorders |
|
| Anxiety | Nervous system disorders |
|
| Depression | Nervous system disorders |
|
| Anorexia | Gastrointestinal disorders |
|
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| D009369 | Neoplasms |
| D007680 | Kidney Neoplasms |
| D014571 | Urologic Neoplasms |
| D014565 | Urogenital Neoplasms |
| D009371 | Neoplasms by Site |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052801 | Male Urogenital Diseases |
| D000588 |
| Amines |
| D006877 | Hydroxamic Acids |
| D006898 | Hydroxylamines |
| D006880 | Hydroxy Acids |
| D002264 | Carboxylic Acids |
| D012176 | Retinoids |
| D002338 | Carotenoids |
| D011090 | Polyenes |
| D000475 | Alkenes |
| D006839 | Hydrocarbons, Acyclic |
| D006838 | Hydrocarbons |
| D053138 | Cyclohexenes |
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D013729 | Terpenes |
| D010860 | Pigments, Biological |
| D001685 | Biological Factors |
| Progression |
|