Vorinostat, Paclitaxel, and Carboplatin in Treating Patients With Advanced or Refractory Solid Tumors

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of vorinostat when given together with paclitaxel and carboplatin in treating patients with advanced or refractory solid tumors. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving vorinostat together with paclitaxel and carboplatin may kill more tumor cells

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the recommended phase II dose of vorinostat (SAHA) when administered with paclitaxel and carboplatin in patients with advanced or refractory solid tumors. SECONDARY OBJECTIVES: I. Determine the dose-limiting toxicity (DLT) and other toxic effects of this regimen in these patients. II. Assess, preliminarily, evidence of antitumor activity of this regimen in these patients. III. Determine the pharmacokinetic parameters of this regimen in these patients. IV. Determine the in vivo effects of this regimen in these patients. OUTLINE: This is a multicenter, dose-escalation study of vorinostat (SAHA). Patients receive oral SAHA once or twice daily on days 1-14* and paclitaxel IV over 3 hours followed by carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who have stable disease after the completion of 6 courses may receive single-agent SAHA at the discretion of the treating physician. NOTE: *During the first treatment course only, patients receive SAHA on days -4 to 10.Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience DLT. An additional 6-12 patients are treated at the MTD. After completion of study treatment, patients are followed at 1 month.

Official Title
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Phase I Study Of Suberoylanilide Hydroxamic Acid (SAHA) (NSC 701852) in Combination With Paclitaxel /Carboplatin for Advanced and Refractory Solid Malignancies

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: vorinostat
* Drug: paclitaxel
* Drug: carboplatin
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed solid tumor No untreated brain metastases Patients with stable brain disease (no concurrent corticosteroids) ≥ 4 weeks after completion of appropriate therapy are eligible ECOG performance status ≤ 2 OR Karnofsky performance status 60-100% Life expectancy > 12 weeks WBC ≥ 3,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Bilirubin normal AST/ALT ≤ 2.5 times upper limit of normal Creatinine within normal institutional limits OR creatinine clearance ≥ 60 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective double barrier contraception for at least 1 week before, during, and for at least 2 weeks after study participation No peripheral neuropathy > grade 1 No history of allergic reactions to paclitaxel No history of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs No inability to take oral medications on a continuous basis No psychiatric illness or social situation that would limit compliance with this study No ongoing or active infection No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No other uncontrolled illness No more than 2 prior chemotherapy regimens for advanced/metastatic disease Adjuvant chemotherapy administered ≥ 2 years prior to study entry is not considered a prior chemotherapy regimen for purposes of this study No prior therapy with paclitaxel No chemotherapy or radiotherapy within the past 3 weeks (6 weeks for nitrosoureas or mitomycin C) and recovered At least 4 weeks since prior valproic acid No other concurrent anticancer therapies or agents No other concurrent investigational agents No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent oral contraceptives No concurrent prophylactic growth factors

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (vorinostat, paclitaxel, carboplatin)<br>Patients receive oral SAHA once or twice daily on days 1-14* and paclitaxel IV over 3 hours followed by carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who have stable disease after the completion of 6 courses may receive single-agent SAHA at the discretion of the treating physician. | Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of vorinostat defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience DLT |  | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity graded using the CTC version 2.0 | Tables will be created to summarize these toxicities by dose and by course. | Up to 1 month after completion of study treatment | 
| Overall survival | Summarized with Kaplan-Meier plots. | Up to 1 month after completion of study treatment | 
| Time to failure | Summarized with Kaplan-Meier plots. | Up to 1 month after completion of study treatment | 
| Response defined using the RECIST criteria |  | Up to 1 month after completion of study treatment |