Vorinostat and Capecitabine in Treating Patients With Metastatic or Unresectable Solid Tumors

OBJECTIVES:

Primary

• Determine the maximum tolerated dose and recommended phase II dose of vorinostat (SAHA) and capecitabine in patients with metastatic or unresectable solid tumors.
• Determine the safety and tolerability of this regimen in these patients.

Secondary

• Correlate the clinical effects with the pharmacokinetic effects of this regimen in these patients.

OUTLINE: This is a dose-escalation, multicenter study.

Patients receive oral vorinostat (SAHA) once or twice daily and oral capecitabine twice daily on days 1-14. Treatment repeats every 21 days for at least 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a complete response (CR) receive 2 courses beyond documentation of CR. Patients achieving a partial response receive 2 courses beyond documentation of best response.

Cohorts of 3-6 patients receive escalating doses of SAHA and capecitabine 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 dose-limiting toxicity. An additional 12 patients are treated at the MTD.

After completion of study treatment, patients are followed at 3-4 weeks and then every 3 months thereafter.

PROJECTED ACCRUAL: Approximately 18-30 patients will be accrued for this study within 6-10 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed malignant solid tumor

• Metastatic or unresectable disease
• Standard curative or palliative measures do not exist or are no longer effective
• Patients who received prior radiotherapy must have measurable disease outside a previously irradiated field OR disease progression after prior radiotherapy
• No known brain metastases

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy

• More than 12 weeks

Hematopoietic

• WBC ≥ 3,000/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin normal
• AST and ALT ≤ 2.5 times upper limit normal (ULN)

Renal

• Creatinine normal OR
• Creatinine clearance ≥ 60 mL/min

Cardiovascular

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Able to swallow oral medication
• No clinical or radiological diagnosis of bowel obstruction
• No ongoing or active infection
• No history of allergic reaction attributed to compounds of similar chemical or biological composition to suberoylanilide hydroxamic acid or other agents used in this study
• No known dihydropyrimidine dehydrogenase deficiency
• No psychiatric illness or social situation that would preclude study compliance
• No other uncontrolled illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
• Prior fluorouracil allowed
• No prior capecitabine

Endocrine therapy

• Not specified

Radiotherapy

• See Disease Characteristics
• More than 4 weeks since prior radiotherapy and recovered
• No prior radiotherapy to > 40% of bone marrow

Surgery

• At least 4 weeks since prior surgery and recovered

Other

• At least 2 weeks since prior valproic acid
• No other concurrent investigational agents
• No other concurrent anticancer therapy
• No concurrent combination antiretroviral therapy for HIV-positive patients