Vatalanib and Everolimus in Treating Patients With Advanced Solid Tumors

OBJECTIVES:

Primary

- Determine the maximum tolerated dose (MTD) of vatalanib and everolimus in patients with
advanced solid tumors.

- Determine the safety and tolerability of vatalanib and everolimus in patients with
advanced solid tumors.

- Evaluate the safety and tolerability of vatalanib and everolimus at the MTD in patients
with metastatic renal cell carcinoma (RCC).

Secondary

- Describe the non dose-limiting toxic effects associated with vatalanib and everolimus.

- Describe the pharmacokinetics of vatalanib and everolimus in patients with advanced
solid tumors.

- Determine the functional extent of mTOR inhibition by changes in the phosphorylation
status of S6K protein in peripheral blood mononuclear cells in patients treated with
vatalanib and everolimus.

- Describe any clinical responses seen in patients with metastatic RCC in a
dose-expansion cohort treated at the MTD.

- Observe overall survival of RCC patients treated with vatalanib and everolimus.

- Determine the time to progression of patients with RCC treated with vatalanib and
everolimus.

OUTLINE: This is a phase I dose-escalation study followed by a phase Ib study.

- Phase I (solid tumors): Patients receive oral vatalanib on days 1-28 and oral
everolimus on days 15-28 during course 1 and on days 1-28 during all subsequent
courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease
progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of vatalanib and everolimus 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.

- Phase Ib (renal cell carcinoma only): Patients receive oral vatalanib and oral
everolimus at the MTD on days 1-28. Treatment repeats every 28 days for up to 12
courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 6 months.

PROJECTED ACCRUAL: A total of 44 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

- Histologically confirmed solid tumor with radiographic evidence of metastatic disease

- No standard therapy exists (phase I)

- Unresectable or metastatic renal cell carcinoma (phase Ib)

PATIENT CHARACTERISTICS:

- Karnofsky performance status 70-100%

- Absolute neutrophil count ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 9 g/dL

- AST or ALT ≤ 2.5 times upper limit of normal (ULN)

- Total cholesterol < 300 mg/dL

- Triglycerides < 350 mg/dL

- Bilirubin ≤ 1.5 times ULN

- Creatinine ≤ 1.5 times ULN OR creatinine clearance > 40 mL/min

- Negative proteinuria by dip stick OR total urinary protein ≤ 500 mg

- No uncontrolled high blood pressure, history of labile hypertension, or history of
poor compliance with antihypertensive regimen

- No unstable angina pectoris

- No symptomatic congestive heart failure (New York Heart Association class III or IV
heart disease)

- No uncontrolled serious cardiac arrhythmia (symptomatic supraventricular tachycardia
or any ventricular tachycardia/fibrillation)

- No myocardial infarction in the past 6 months

- No uncontrolled diabetes

- No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the
lung

- No active or uncontrolled infection

- No uncontrolled hyperlipidemia

- No chronic renal disease

- No acute or chronic liver disease (e.g., hepatitis or cirrhosis)

- No impaired gastrointestinal (GI) function OR GI disease that may significantly alter
the absorption of vatalanib or everolimus, including any of the following:

- Ulcerative disease

- Uncontrolled nausea and vomiting with solid food

- Watery diarrhea > 5 times daily

- Malabsorption syndrome

- Bowel obstruction

- Inability to swallow the tablets

- No confirmed HIV infection

- Not pregnant

- Negative pregnancy test

- Fertile patients must use effective contraception

- No other concurrent severe and/or uncontrolled medical condition that would preclude
study participation

PRIOR CONCURRENT THERAPY:

- Recovered from prior therapy

- No prior antivascular endothelial growth factor therapy

- More than 4 weeks since prior major surgery* (laparotomy)

- More than 2 weeks since prior minor surgery*

- More than 4 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)

- More than 6 weeks since prior antibody therapy

- More than 2 weeks since prior biologic/immunotherapy

- More than 2 weeks since prior limited-field radiotherapy

- More than 4 weeks since prior full-field radiotherapy

- More than 4 weeks since prior investigational agents

- Prior transfusions allowed provided blood counts are stable for > 2 weeks

- Concurrent epoetin alfa allowed

- No concurrent warfarin or similar oral anticoagulants that are metabolized by the
cytochrome P450 system

- Heparin and low molecular weight heparin allowed NOTE: *Insertion of a vascular
access device is not considered major or minor surgery