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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase I Study of Bevacizumab in Combination With Everolimus and Erlotinib in Advanced Cancer

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Biological: bevacizumab
* Drug: erlotinib hydrochloride
* Drug: everolimus


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab, Everolimus, and Erlotinib<br>Dose Level Dose Bevacizumab (mg/kg q2wks) Everolimus (mg daily) Erlotinib (mg daily) -1 5 5 --- 10 5 --- 10 10 --- 10* 10* 75 10* 10* 150 | Biological: bevacizumab<br> <br> Drug: erlotinib hydrochloride<br> <br> Drug: everolimus<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | Its primary objective is to estimate the MTD/recommended phase II dose combination or regimen | Until study completion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety | endpoints will be evaluated in an exploratory fashion | Until study completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific