Clinical Trial Finder

Inclusion Criteria:

• - Patients must have histological confirmation of Solid Tumor or Lymphoma that is metastatic or unresectable; if assessing a single target lesion, histological confirmation of that particular lesion MUST be carried out.

• - Patients may have received an unlimited number of prior therapies; however, At least 4 weeks MUST have passed since the last chemotherapy to day 1 of registration (6 weeks for regimens containing nitrosoureas or Mitomycin C) - ECOG performance status =< 2 (Karnofsky >= 60%) - Leukocytes >= 3,000/mcL.

• - Absolute neutrophil count >= 1,500/mcL.

• - Platelets >= 100,000/mcL.

• - Total bilirubin =< 2.0 mg/dL (does NOT apply to patients with Gilbert's Syndrome) - AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal (Patients with liver involvement will be allowed =< 5.0 X institutional upper normal limit) - Serum creatinine =< 2.0 mg/dL.

• - Patients MUST have recovered from all treatment related toxicities to Grade 1 NCI CTC (v 4.0) in severity.

• - Patients must be willing and able to review, understand, and provide written consent before starting therapy.

• - Patients with stable brain metastasis (stable disease on one MRI assessment at least 4 weeks after completion of whole brain radiation, no evidence of progression on MRI assessment 4 weeks after stereotactic radiosurgery or complete surgical excision) will also be allowed to participate in this trial.

• - Patients with histologically proven intracranial glioblastoma, gliosarcoma or anaplastic astrocytoma will be eligible; patients must have shown unequivocal radiographic evidence for tumor progression by MRI scan; scan should be performed within 14 days prior to registration and on a steroid dose that has been stable for at least 5 days; if the steroid dose is increased between the date of imaging and registration, a new baseline MRI is required.

Exclusion Criteria:

• - Patients with squamous non-small cell lung carcinoma.

• - Serious or non-healing wound, ulcer or bone fracture.

• - History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days of day 1 of registration.

• - Invasive procedures defined as follows: - Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 registration.

• - Anticipation of need for major surgical procedures during the course of the study.

• - Core biopsy within 7 days prior to day 1 of therapy.

• - Patients may not be receiving any other investigational agents.

• - Patients with bleeding diathesis (clinical bleeding, prothrombin time >= 1.5 X upper institutional normal value, INR >= 1.5, activated partial thromboplastin time aPTT >= 1.5 X upper institutional normal value), active gastric or duodenal ulcer.

• - Uncontrolled systemic vascular hypertension (Systolic blood pressure > 140 mmHg, Diastolic Blood Pressure > 90 mmHg) - Urine protein should be screened by dipstick or urine analysis; for proteinuria > 1+ or urine protein:creatinine ratio > 1.0, 24-hour urine protein should be obtained and the level should be < 1000 mg for patient enrollment.

• - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics on Day 1.

• - Patients with clinically significant cardiovascular disease: - History of CVA within 6 months.

• - Myocardial Infarction or unstable angina within 6 months.

• - New York Heart Association Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris.

• - Clinically significant peripheral vascular disease.

• - QTc prolongation > 500msec or other significant ECG abnormality noted within 14 days of registration.

• - Conditions requiring concurrent use of drugs or biologics with proarrythmic potential; these drugs are prohibited during studies with AZD2171 (refer to appendix V for a listing of these agents) - Patients with history of hemoptysis.

• - Patients with tumor mass abutting a major vessel.

- Pregnant women are excluded from this study because AZD-2171 is an angiogenesis inhibiting agent with potential teratogenic or abortifacient effects; because of the potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD-2171, breastfeeding should be discontinued if the mother is treated with AZD-2171; these potential risks may also apply to other agents used in this study; women of child-bearing potential and men must agree to use contraception prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

PRIMARY OBJECTIVES:

• I. To evaluate the safety and toxicity profile of intravenous bevacizumab (avastin) administered in combination with oral AZD2171 (cediranib maleate) for patients with advanced malignancies.

• II. To determine the pharmacokinetic profile of oral AZD2171 in combination with bevacizumab (avastin) administered to patients with advanced malignancies.

SECONDARY OBJECTIVES:

• I. To evaluate the serum concentrations of Nitric Oxide (NO) and Nitric oxide synthase (NOS) among patients treated with this regimen and to correlate with VEGF expression.

• II. To determine changes in the tumor vasculature detected by DCE-MRI among patients treated with this combination of VEGF receptor blocking agents.

• III. To evaluate the potential predictive role of angiogenesis molecular endpoints in malignant effusion samples.

• IV. To assess in a descriptive fashion the efficacy of the studied regimen.

OUTLINE: This is a dose-escalation study. Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral cediranib maleate once daily on days 1-21. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bevacizumab and cediranib maleate 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. Blood samples are acquired at baseline, on day 2, and after 2 courses of treatment for pharmacokinetic studies. Samples are analyzed by TUNEL, immunofluorescence staining, laser-scanning cytometry, flow cytometry, enzyme-linked immunosorbent assay, and immunohistochemistry to assess apoptosis in tumor and endothelial cells, microvessel density mean vessel volume, nitric oxide concentration, and signal transduction pathways (i.e., ERK ½, P38 mitogen-activated protein kinase, protein kinase B, circulating endothelial and progenitor cells, basic fibroblast growth factor, vascular endothelial growth factor (VEGF) receptor phosphorylation, VEGF, and hypoxia inducible factor-1α). Some patients also undergo tissue biopsy at baseline and after 2 courses of treatment for characterization of vascular and angiogenesis markers. Some patients also undergo DCE-MRI at baseline, once between days 22-24, and after every 2 courses of treatment to assess blood perfusion. After completion of study treatment, patients are followed for 6 weeks.

Arms

Experimental: Treatment (cediranib maleate and bevacizumab)

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral cediranib maleate once daily on days 1-21. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bevacizumab and cediranib maleate until the 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.

Interventions

Biological: - bevacizumab

Given IV

Drug: - cediranib maleate

Given orally