Imatinib, Bevacizumab, and Cyclophosphamide in Patients With Refractory Metastatic Solid Tumors

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of imatinib when given together with bevacizumab and metronomic cyclophosphamide in patients with refractory metastatic solid tumors.
• Determine the safety profile of this regimen in these patients.

Secondary

• Determine the effects of cyclophosphamide and bevacizumab on imatinib pharmacokinetics.
• Determine if patients treated with this regimen achieve plasma levels of cyclophosphamide that are predicted to be antiangiogenic.
• Determine the effects of this regimen on the number of circulating endothelial cells, endothelial progenitor cells, activated endothelial cells, and circulating tumor cells.
• Determine the effects of this regimen on parameters measured by CT scan perfusion (e.g., regional blood flow, blood volume, permeability-surface area product, and mean transit time).

OUTLINE: This is a nonrandomized, open-label, pilot, dose-escalation study of imatinib.

Patients receive oral cyclophosphamide and oral imatinib once daily on days 1-28 and bevacizumab IV on days 1 and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of imatinib 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. At least 6 patients are treated at the MTD.

PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of solid tumor

• Advanced or metastatic disease* NOTE: *With the exception of colorectal and lung cancer patients, all patients must receive approval from the insurance carrier that allows for coverage/payment of the study drug bevacizumab
• Refractory to standard therapy OR no standard therapy exists
• No advanced ovarian cancer or peritoneal carcinomatosis
• No metastases from any cancer causing significant ascites
• No lung malignancy with any of the following characteristics:

• In close proximity to a major vessel
• Centrally located
• Cavitary
• Squamous histology
• Hemoptysis > ½ teaspoon per day

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1
• Platelet count ≥ 100,000/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Bilirubin < 2 mg/dL
• AST or ALT < 3 times upper limit of normal
• Creatinine < 2 mg/dL
• Urine protein:creatinine ratio ≤ 1.0
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Able to tolerate oral therapy
• No bleeding diatheses or coagulopathy
• No impairment of gastrointestinal (GI) function or GI disease that may affect or alter absorption of imatinib mesylate and/or cyclophosphamide (e.g., malabsorption syndrome, history of total gastrectomy/significant small bowel resection)
• No abdominal fistula, GI perforation, or intra-abdominal abscess within the past 6 months
• No uncontrolled hypertension (i.e., blood pressure > 150/100 mm Hg)
• No uncontrolled cardiovascular disease, including any of the following:

• Coronary artery disease
• Uncontrolled cardiac arrhythmia
• Symptomatic congestive heart failure (i.e., New York Heart Association class II-IV)
• Unstable angina pectoris
• Clinically significant peripheral vascular disease
• No arterial thromboses within the past year, including any of the following:

• Transient ischemic attack
• Myocardial infarction
• Cerebrovascular event
• Unstable angina
• Angina requiring medical or surgical intervention
• Clinically significant peripheral artery disease
• Any other arterial thromboembolic event
• No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
• No serious nonhealing wound, ulcer, or bone fracture
• No other active second malignancy except nonmelanoma skin cancer or cervical carcinoma in situ unless therapy has been completed and < 30% risk for relapse exists
• No active infection or known HIV infection
• No history of allergic reactions (≥ grade 3 or 4) to compounds of similar chemical or biologic composition to cyclophosphamide (i.e., alkylating agents)
• No history of noncompliance with medical regimens
• No known intolerance or hypersensitivity reaction to bevacizumab, imatinib mesylate, or cyclophosphamide
• No other significant medical illness, psychiatric illness, or social situation that, in the opinion of the investigator, would limit compliance with study requirements
• No inability to grant reliable informed consent

PRIOR CONCURRENT THERAPY:

• No major surgical procedure within the past 28 days or anticipated major surgery during study treatment except for placement of a venous access device or surgery for a diagnostic study