Bevacizumab and Sunitinib in Treating Patients With Solid Tumors

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of bevacizumab in combination with sunitinib malate (SU11248) in patients with solid tumors.

SECONDARY OBJECTIVES:

I. Evaluate the objective response rate, time to disease progression, and overall survival of these patients.

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive bevacizumab IV over 30-90 minutes on days 1, 15, and 29 and oral sunitinib malate (SU11248) once daily on days 1-28. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of bevacizumab and SU11248 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 10 patients are treated at the MTD.

After completion of study therapy, patients are followed for 30 days.

Inclusion criteria

• Histologically proven metastatic/unresectable adrenocortical carcinoma or melanoma not amenable to curative surgical or radiation therapy.
• Accrual closed as of 5/27/2009 to patients with renal cell carcinoma
• No squamous cell histology
• No histology in close proximity to a major blood vessel
• No history of or known brain metastases, spinal cord compression, or carcinomatous meningitis
• No new evidence of brain or leptomeningeal disease on screening CT scan or MRI
• ECOG performance status (PS) 0-1 OR Karnofsky PS 60-100%
• AST and ALT ≤ 2.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN
• Creatinine ≤ 1.5 times ULN
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥100,000/mm³
• Hemoglobin ≥ 10.0 g/dL
• Calcium ≤ 12.0 mg/dL
• Urine protein:creatinine ratio ≤ 0.5 by urinalysis
• Patients with urine protein:creatinine ratio > 0.5 must have proteinuria < 1,000 mg by 24-hour urine collection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 6 months after completion of study therapy
• None of the following within the past 12 months:

• Myocardial infarction
• Severe/unstable angina
• Severe peripheral vascular disease (claudication) or procedure on peripheral vasculature
• Coronary/peripheral artery bypass graft
• New York Heart Association (NYHA) grade III-IV congestive heart failure
• Cerebrovascular accident or transient ischemic attack
• Clinically significant bleeding
• Deep venous thrombosis
• Pulmonary embolism
• No ongoing cardiac dysrhythmias of NCI CTCAE ≥ grade 2, atrial fibrillation of any grade, or prolongation of the QTc interval to > 450 msec (males) or > 470 msec (females)
• No history of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)
• No condition classified as NYHA grade III or IV
• No hypertension that cannot be controlled by medications
• Blood pressure < 140/90 mm Hg
• No evidence of bleeding diathesis or coagulopathy
• No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days
• No history of or known brain metastases, spinal cord compression or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease on screening CT or MRI scan unless without progression on * MRI or CT for 3 months."
• No significant traumatic injury within the past 28 days
• No serious, non-healing wound, ulcer, or bone fracture
• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
• No known HIV or AIDS-related illness
• No other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would preclude study participation.
• Recovered from prior radiation therapy, surgery, or other prior therapy
• No prior bevacizumab or sunitinib malate (SU11248)
• Other antiangiogenic therapies allowed
• No prior tyrosine kinase inhibitor of the VEGF receptor or bevacizumab for patients with metastatic renal cell carcinoma
• No major surgical procedures or open biopsy within the past 28 days
• No core biopsy within the past 7 days
• No radiation therapy or systemic therapy within the past 4 weeks
• No concurrent full-dose anticoagulants (e.g., warfarin)
• Concurrent low-dose anticoagulation (e.g., prophylactic port patency) allowed
• No concurrent treatment on another clinical trial
• No other concurrent investigational drugs
• No concurrent major surgery
• No other concurrent anticancer agents or therapies, including chemotherapy, biological response modifiers, hormonal therapy, surgery, palliative radiation therapy, or immunotherapy