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

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of vorinostat (SAHA) and bortezomib in patients with metastatic or unresectable solid tumors.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics and antitumor activity of this regimen in these patients.

II. Determine the toxic effects of this regimen in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive oral vorinostat (SAHA) twice daily on days 1-14 in step A. Patients receive oral vorinostat (SAHA) twice daily on days 1-4 and 8-11 in Step B and bortezomib IV over 3-5 seconds on days 2, 5, 9, and 12 during the first course and on days 1, 4, 8, and 11 during subsequent courses in both steps A and B. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 1-6 patients receive escalating doses of bortezomib 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. Up to 6 additional patients receive bortezomib at the MTD. Subsequent cohorts of 3-6 patients receive escalating doses of SAHA until the MTD of that drug is determined.

Inclusion criteria

• Histologically confirmed malignancy, metastatic or unresectable disease
• Standard curative or palliative measures do not exist OR are no longer effective
• Measurable or evaluable disease
• No known brain metastases
• ECOG 0-2 OR Karnofsky 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 and ALT ≤ 2.5 times upper limit of normal
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• No history of myocardial infarction
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No severe pulmonary disease requiring oxygen
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 28 days after study participation
• No history of allergic reaction attributed to compounds of similar chemical or biological composition to study drugs or agents
• No pre-existing neuropathy ≥ grade 2
• No uncontrolled illness
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
• No prior radiotherapy to > 25% of bone marrow
• At least 4 weeks since prior radiotherapy and recovered
• At least 2 weeks since prior valproic acid
• No prior bortezomib
• No concurrent enzyme-inducing anticonvulsant agents
• No other concurrent investigational agents
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent anticancer therapy