Bevacizumab and Cediranib Maleate in Treating Patients With Metastatic or Unresectable Solid Tumor, Lymphoma, Intracranial Glioblastoma, Gliosarcoma or Anaplastic Astrocytoma
Bevacizumab and Cediranib Maleate in Treating Patients With Metastatic or Unresectable Solid Tumor, Lymphoma, Intracranial Glioblastoma, Gliosarcoma or Anaplastic Astrocytoma
This phase I trial is studying the side effects and best dose of bevacizumab and cediranib
 maleate in treating patients with metastatic or unresectable solid tumor, lymphoma,
 intracranial glioblastoma, gliosarcoma or anaplastic astrocytoma. Monoclonal antibodies, such
 as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer
 cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing
 substances to them. Cediranib maleate may stop the growth of cancer cells by blocking some of
 the enzymes needed for cell growth. Bevacizumab and cediranib maleate may also stop the
 growth of cancer cells by blocking blood flow to the cancer. Giving bevacizumab together with
 cediranib maleate may kill more cancer cells.
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.
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