A Phase I Trial of Imatinib, Bevacizumab, & Metronomic Cyclophosphamide as Antiangiogenic Therapy in Refractory Metastatic Solid Tumors
A Phase I Trial of Imatinib, Bevacizumab, & Metronomic Cyclophosphamide as Antiangiogenic Therapy in Refractory Metastatic Solid Tumors
RATIONALE: Imatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bevacizumab and cyclophosphamide may also stop the growth of tumor cells by blocking blood flow to the tumor. Imatinib and bevacizumab may help cyclophosphamide work better by making tumor cells more sensitive to the drug. Giving cyclophosphamide once a day together with imatinib and bevacizumab may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of imatinib when given together with bevacizumab and cyclophosphamide in treating patients with refractory metastatic solid tumors.
OBJECTIVES:
Primary
Secondary
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
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:
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:
No arterial thromboses within the past year, including any of the following:
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: