Bevacizumab, Everolimus, and Erlotinib in Treating Patients With Advanced Solid Tumors

OBJECTIVES:

Primary

• Estimate the maximum tolerated dose (MTD)/recommended phase II regimen of everolimus and erlotinib hydrochloride when given with bevacizumab in patients with advanced solid tumors.
• Evaluate safety of bevacizumab, everolimus, and erlotinib hydrochloride in these patients.

Secondary

• Describe the impact of this combination therapy on dermal wound angiogenesis and inhibition of vascular endothelial growth factor receptor 1 (VEGFR1), mTOR/p70S6K, and other related markers in granulation tissue.
• Evaluate clinical activity (partial response, complete response, or stable disease > 6 months) associated with this regimen.

OUTLINE: This is a dose-escalation study followed by a randomized study.

• Part 1: Patients receive bevacizumab IV on days 1 and 15 and oral everolimus and oral erlotinib hydrochloride* once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

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.

• Arm I: Patients receive oral everolimus once daily beginning on day 1, oral erlotinib hydrochloride once daily beginning on day 15, and bevacizumab IV once every 2 weeks beginning on day 15. Treatment continues in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive oral erlotinib hydrochloride once daily beginning on day 1, oral everolimus once daily beginning on day 15, and bevacizumab IV once every 2 weeks beginning on day 15. Treatment continues in the absence of disease progression or unacceptable toxicity.

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

• Metastatic or unresectable disease
• 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

• Atrial or supraventricular tachycardias well controlled with beta blocker or calcium channel blocker allowed
• Chronic pacemaker use allowed
• 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

• Prophylactic low-dose anticoagulation for indwelling catheters is permitted
• No concurrent administration of any of the following drugs:

• Nicardipine
• Verapamil
• Clotrimazole
• Fluconazole
• Itraconazole
• Ketoconazole
• Clarithromycin
• Erythromycin
• Troleandomycin
• Cisapride
• Metoclopramide
• Bromocriptine
• Cimetidine
• Danazol
• HIV-protease inhibitors (e.g., ritonavir, indinavir)
• Hypericum perforatum (St. John's wort)
• Carbamazepine
• Phenobarbital
• Phenytoin
• Diltiazem
• Rifabutin
• Rifapentine
• Rifampin