Phase I Study of Bevacizumab in Combination With Everolimus and Erlotinib in Advanced Cancer
Phase I Study of Bevacizumab in Combination With Everolimus and Erlotinib in Advanced Cancer
RATIONALE: 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. Erlotinib and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and everolimus may also block blood flow to the tumor. Giving everolimus and erlotinib together with bevacizumab may kill more tumor cells.
PURPOSE: This randomized phase I trial is studying the side effects and best dose of erlotinib and everolimus when given together with bevacizumab in treating patients with advanced solid tumors.
OBJECTIVES:
Primary
Secondary
OUTLINE: This is a dose-escalation study followed by a randomized study.
Cohorts of patients receive escalating doses of everolimus or escalating doses of everolimus and erlotinib hydrochloride* until the maximum tolerated dose (MTD) is determined. Patients in part 2 of the study are treated at the MTD of everolimus and erlotinib hydrochloride.
NOTE: *The first cohort of patients receive bevacizumab and everolimus only until the MTD is determined, the subsequent cohorts of patients receive bevacizumab, everolimus, and erlotinib hydrochloride
Part 2: Patients are randomized to 1 of 2 treatment arms.
After completion of study treatment, patients are followed periodically.
PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.
DISEASE CHARACTERISTICS:
Histologically confirmed malignancy
Standard curative or palliative measures do not exist OR are no longer effective
No CNS metastases
No centrally-located non-small cell lung cancer
PATIENT CHARACTERISTICS:
ECOG performance status 0-2
Leukocytes ≥ 3,000/mm³
Absolute neutrophil count ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST/ALT ≤ 2.5 times ULN (5 times ULN if known hepatic metastases)
Urine protein to creatinine ratio ≤ 1.0 OR urine protein < 1 g by 24 hour urine collection
Creatinine clearance ≥ 50 mL/min OR creatinine normal
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during study and for up to 4 months after study treatment has stopped
No uncontrolled hypertriglyceridemia (i.e., fasting serum triglyceride > 350 mg/dL)
No uncontrolled hypercholesterolemia (i.e., fasting serum cholesterol > 300 mg/dL)
No poorly controlled hypertension (i.e., blood pressure > 160/100 mm Hg)
No poorly controlled or clinically significant atherosclerotic vascular disease
No thrombosis within 6 months
No venous thromboembolic event within 6 months
No arterial thromboembolic events within 12 months
No cerebrovascular accident or transient ischemic attack in past 12 months
No myocardial infarction or unstable angina in past 12 months
No clinically significant peripheral vascular disease in past 12 months
No New York Heart Association class II-IV congestive heart failure
No serious cardiac arrhythmia requiring medication
No other clinically significant cardiovascular disease
No hemoptysis > 1 tablespoon within 6 months
No presence of bleeding diathesis
No coagulopathy
No presence of significant gastrointestinal (GI) disorders that would affect drug absorption
No hemodynamically significant GI bleeding
No history of intolerance to bevacizumab, everolimus, or erlotinib
No other major bleeding event
No ongoing or active infection
No psychiatric illness or social situations that would limit safety or compliance with study requirements
No other uncontrolled intercurrent illness
PRIOR CONCURRENT THERAPY:
No angioplasty or cardiac or vascular stenting within the past 12 months
No major surgery within past 28 days
No other investigational agents within past 28 days
No chemotherapy for cancer within past 21 days
No biologic therapy for cancer within past 21 days
No radiation therapy for cancer within past 21 days
No hormonal therapy for cancer within past 21 days
No minor surgical procedures within past 14 days
No concurrent antiplatelet agents other than aspirin < 325 mg/day
No use of statin drugs other than pravastatin or atorvastatin
Initiation of blood pressure (BP) medication is permitted prior to study entry provided that BP < 150/90 mm Hg on 3 measurements over one week (study day -7 to 1) before starting treatment
No concurrent grapefruit juice
No concurrent therapeutic anticoagulation
No concurrent administration of any of the following drugs: