Vandetanib and Bevacizumab in Treating Patients With Advanced Solid Tumors or Lymphoma

OBJECTIVES:

Primary

• Determine the maximum tolerated dose, safety, and toxicity of vandetanib and bevacizumab in patients with advanced solid tumors or lymphoma.

Secondary

• Characterize the pharmacokinetic profile of this regimen in these patients.
• Measure changes in VEGF and other angiogenic cytokines in plasma samples from these patients.
• Determine the biochemical changes in the EGF signal transduction pathways in tumor biopsy samples from these patients.
• Determine the anti-angiogenic effects of this regimen in tumor biopsy samples from these patients.
• Evaluate the application of dynamic contrast-enhanced MRI to determine early changes in tumor vascular permeability during treatment.
• Evaluate the effects of this regimen on circulating endothelial progenitors and mature circulating endothelial cells in these patients.

OUTLINE: Patients receive oral vandetanib once daily on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection periodically for correlative laboratory studies, including pharmacokinetic, biomarker (VEGF and other angiogenic cytokines), and circulating endothelial cell analysis. Patients may also undergo optional tumor biopsies for additional correlative laboratory studies.

DISEASE CHARACTERISTICS:

• Histologically confirmed advanced malignancy, including the following:

• Solid tumor that is refractory to standard therapy or for which no standard therapy exists

• No lung carcinoma of squamous cell or small cell histology (mixed tumors will be categorized by the predominant cell type)

• Histological confirmation based on sputum cytology alone is not acceptable
• Lymphoma (Hodgkin or non-Hodgkin lymphoma) that has progressed after standard therapy AND for which stem cell transplantation is not indicated or has been refused
• No known CNS disease, except for treated brain metastasis meeting the following criteria:

• No ongoing requirement for steroids
• No evidence of progression or hemorrhage by clinical examination and brain imaging (MRI or CT scan) for ≥ 3 months after treatment

• Stable dose of anticonvulsants allowed
• Prior treatment for brain metastases may have included whole-brain radiotherapy, radiosurgery (gamma knife, linear accelerator, or equivalent), or a combination of therapy as deemed appropriate by the treating physician

• Neurosurgical resection or brain biopsy for treatment of CNS metastases allowed provided treatment was completed more than 3 months ago

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Life expectancy > 3 months
• Absolute neutrophil count ≥ 1,500/μL
• Platelet count ≥ 100,000/μL
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN
• Creatinine < 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
• Urine protein:creatinine ratio ≤ 0.5 OR urine protein < 1,000 mg by 24-hour urine collection
• Activated partial thromboplastin time ≤ 1.5 times ULN
• Prothrombin time OR INR < 1.5 times ULN
• Potassium between 4 mmol/L and ULN (supplementation allowed)
• Magnesium normal (supplementation allowed)
• Serum calcium (adjusted for albumin) or ionized calcium normal (supplementation allowed)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 6 months after completion of study therapy
• HIV-positivity allowed provided the following criteria are met:

• Patient does not require anti-HIV therapy
• CD4 count > 350/mm^3
• HIV viral load < 25,000 copies/mm^3
• No history of opportunistic infections
• No evidence of severe or uncontrolled systemic disease or any concurrent condition that could compromise participation in the study, including any of the following:

• Active or uncontrolled infection
• Immune deficiencies
• HIV infection requiring anti-HIV therapy
• Hepatitis B
• Hepatitis C
• Uncontrolled diabetes
• Uncontrolled hypertension
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Myocardial infarction within the past 6 months
• Uncontrolled cardiac arrhythmia
• Stroke/cerebrovascular accident within the past 6 months
• Psychiatric illness/social situation that, in the investigator's opinion, would make it undesirable for the patient to participate in the study or that would jeopardize study compliance
• No New York Heart Association class III or IV heart disease within the past 6 months
• No history of arrhythmia (i.e., multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment

• Atrial fibrillation allowed provided it is controlled with medication
• No asymptomatic sustained ventricular tachycardia
• No other cardiac disease that, in the investigator's opinion, would increase the risk of ventricular arrhythmia
• QTc < 480 msec (with measurable Bazett correction) by screening ECG
• No history of QTc prolongation as a result of other medications that required discontinuation
• No congenital long QT syndrome
• No first-degree relative with unexplained sudden death at under 40 years of age
• No left bundle branch block
• No hypertension not controlled by medical therapy, defined as systolic blood pressure > 150 mm Hg or diastolic blood pressure > 90 mm Hg despite optimal medical management
• No other clinically significant cardiac event
• No thromboembolic disease within the past 6 months
• No significant vascular disease (e.g., aortic aneurysm or aortic dissection) or clinically significant peripheral vascular disease
• No serious non-healing wounds (including wounds healing by secondary intention)
• No acute or non-healing ulcers
• No bone fractures within the past 3 months
• No abdominal fistula, gastointestinal perforation, or intra-abdominal abscess within the past 28 days
• No currently active diarrhea that may affect the ability of the patient to absorb or tolerate vandetanib
• No hemoptysis (bright red blood of ≥ ½ teaspoon per episode) within the past 3 months
• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Prior anti-VEGF therapy allowed
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) or radiotherapy and recovered
• More than 4 weeks since prior major surgery and recovered
• At least 2 weeks since prior investigational drugs given in a phase 0 clinical trial
• More than 10 days since prior and no concurrent aspirin (> 325 mg/day) or chronic use of other NSAIDs
• No concurrent regular, therapeutic anticoagulation
• No concurrent medication that may cause QTc prolongation, induce Torsades de Pointes, or induce CYP3A4 function, including any of the following:

• Rifampin
• Rifabutin
• Phenytoin
• Carbamazepine
• Phenobarbital
• Hypericum perforatum (St. John's wort)
• No other concurrent antineoplastic therapy, except for gonadotropin-releasing hormone therapy for prostate cancer