Bortezomib and Celecoxib in Treating Patients With Advanced Solid Tumors

OBJECTIVES:

Primary

• Determine the maximum tolerated dose (MTD) of bortezomib and celecoxib in patients with advanced solid tumors.

Secondary

• Determine the overall pattern of toxicities associated with this combination, including the emergence of any cumulative toxicities, during multiple courses of this regimen.
• Describe the response rate and duration of response or disease stability during therapy in the subset of patients with measurable disease.
• Assess changes in plasma/serum sphingosine-1-phosphate, ceramide, and other markers of the apoptotic pathway before and during therapy.

OUTLINE: This is a dose-escalation study.

Patients receive bortezomib IV on days 1, 4, 8, and 11 or days 1, 8, 15, 22, and 29 and oral celecoxib twice daily on days 1-21 or 1-42. Courses repeat every 21 or 42 days in the absence of disease progression or unacceptable toxicity. Patients are evaluated every 2 courses. Patients achieving complete response (CR) receive 2 additional courses of therapy beyond CR.

Cohorts of 3-6 patients receive escalating doses of bortezomib and celecoxib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

After completion of study treatment, patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 36 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologic or cytologic diagnosis of a malignant neoplasm (solid tumor) arising from any primary site with the exception of bone marrow or lymphoid tissue
• Recurrent or progressive disease after chemotherapy or radiotherapy

• Chemotherapy or radiotherapy-naive disease allowed if patient is not a candidate for standard treatment either due to comorbidities or lack of willingness to undergo standard treatment
• Measurable disease

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 30 mL/min
• Bilirubin ≤ 2 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No active concurrent invasive malignancy
• No peripheral neuropathy ≥ grade 2 within the past 14 days
• No hypersensitivity to bortezomib, boron, mannitol, any of the cyclooxygenase (COX-2) inhibitors, sulfa drugs, or other nonsteroidal anti-inflammatory drugs (NSAIDs)
• No active gastrointestinal (GI) ulcers OR history of GI bleeding resulting from prior therapy with NSAIDs

PRIOR CONCURRENT THERAPY:

• At least 2 weeks since completion of prior radiotherapy
• No prior bortezomib
• No other concurrent investigational agents
• No concurrent chemotherapy, radiotherapy, or anticancer surgery
• No concurrent immune-enhancing therapy