Phase I Study Of Suberoylanilide Hydroxamic Acid (SAHA) (NSC 701852) in Combination With Paclitaxel /Carboplatin for Advanced and Refractory Solid Malignancies
Phase I Study Of Suberoylanilide Hydroxamic Acid (SAHA) (NSC 701852) in Combination With Paclitaxel /Carboplatin for Advanced and Refractory Solid Malignancies
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
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.
Inclusion Criteria:
Histologically confirmed solid tumor
No untreated brain metastases
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
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