Bortezomib and Paclitaxel in Treating Patients With Locally Advanced or Metastatic Solid Tumors

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of bortezomib when given in combination with paclitaxel in patients with locally advanced or metastatic solid tumors.

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

Patients receive bortezomib IV on days 2 and 9 and paclitaxel IV over 1 hour on days 1 and 8. For the first course only, patients do not receive paclitaxel on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 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 or greater than 80% 20S proteasome inhibition. Once the MTD is determined, an additional 6-9 patients are accrued and treated at that dose.

Patients are followed at 21 days.

PROJECTED ACCRUAL: A total of 45 patients will be accrued for this study.

Inclusion criteria

• Histologically or cytologically confirmed locally advanced or metastatic solid tumor for which there is no curative treatment
• No known brain metastases
• Performance status - ECOG 0-2
• Performance status - Karnofsky 60-100%
• WBC at least 3,000/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Bilirubin normal
• AST/ALT no greater than 2.5 times upper limit of normal (ULN)
• Creatinine no greater than ULN
• Left ventricular function at least lower limit of normal if received prior doxorubicin
• No grade II or IV tilt-table test
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No thrombotic event within the past 6 months
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No prior allergic reaction to compounds of similar chemical or biological composition to study drugs
• No other concurrent uncontrolled illness
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• Prior paclitaxel allowed
• At least 2 weeks since prior hormonal therapy
• No concurrent steroids or hormonal therapy except steroids to prevent hypersensitivity reactions to paclitaxel or hormonal therapy for non-disease-related conditions (e.g., insulin for diabetes)
• At least 4 weeks since prior radiotherapy
• At least 4 weeks since prior surgery
• Recovered from prior therapy
• No other concurrent investigational agents
• No concurrent combination anti-retroviral therapy for HIV-positive patients
• No concurrent anticoagulation therapy
• Concurrent pamidronate or zoledronate allowed for treatment of hypercalcemia or for palliation of skeletal metastases