Combination Chemotherapy and Bevacizumab in Treating Patients With Advanced Neuroendocrine Tumors

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed neuroendocrine tumor (NET)

• Carcinoid at any site, with or without carcinoid syndrome

• Pancreatic islet cell tumor

• Prior streptozocin-based therapy not required

• Poorly differentiated NET of any primary site (this arm closed to accrual May

• Progression with prior treatment with cisplatin-, or carboplatin-based chemotherapy required (unless contraindicated)

• The following tumors are not allowed:

• Endocrine organ carcinoma

• Adrenal gland malignancies

• Thyroid carcinoma of any histology

• Pheochromocytoma/paraganglioma

• Advanced disease

• Disease not amenable to surgery, radiotherapy, or combined modality therapy with curative intent

• Radiologically or clinically confirmed progressive disease

• At least 25% increase in radiologically or clinically measurable disease

• At least 20% increase in the longest diameter (LD) of any previously documented lesion

• Increase in the sum of the LD of multiple lesions in aggregate of 20%, OR appearance of new lesions OR deterioration in clinical status

• Measurable disease

• At least 1 unidimensionally measurable lesion ≥ 20 mm by conventional radiographic techniques OR ≥ 10 mm by spiral CT scan

• Ultrasound or positron-emission tomography alone not sufficient

• Bone lesions, ascites, peritoneal carcinomatosis, pleural or pericardial effusion, and irradiated lesions are not considered measurable disease

• Primary tumors of the pancreas should not invade adjacent organs (e.g., stomach or duodenum)

• No history or evidence of brain or leptomeningeal disease (baseline CNS imaging required if clinical suspicion of CNS metastases)

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• More than 12 weeks

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• No history of hemoptysis or bleeding diathesis

• No coagulopathy unrelated to therapeutic anticoagulation

• No significant bleeding events within the past 6 months unless the source of the bleeding has been resected

Hepatic

• Bilirubin < 2 mg/dL

• ALT ≤ 2.5 times upper limit of normal (ULN) (5 times ULN if due to liver metastases)

Renal

• Creatinine ≤ 2 mg/dL

• Protein ≤ 1+ OR

• Protein < 1 gm on 24-hour urine collection

• Urine protein:creatinine ratio < 1.0

Cardiovascular

• History of thromboembolic condition allowed provided patient is on therapeutic anticoagulation at a stable dose for ≥ 4 weeks

• Concurrent daily prophylactic aspirin (< 325 mg/day) allowed

• No uncontrolled hypertension, myocardial infarction, clinically significant peripheral arterial ischemia, visceral arterial ischemia or angina within the past 6 months

• No serious cardiac arrhythmia requiring medication

• No cerebrovascular event (e.g., stroke or transient ischemic attack) within the past 12 months

• No history of peripheral vascular disease ≥ grade 2

• No history New York Heart Association class II-IV congestive heart failure

• Blood pressure ≤ 160/90 mm Hg

Gastrointestinal

• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months

• No predisposing uncontrolled small bowel or colonic disorder

• Baseline disease-related diarrhea allowed if symptoms are stable and well-characterized (i.e., # stools/day stable)

• No gastric or esophageal varices

• No gastroduodenal ulcers determined to be active by endoscopy

Pulmonary

• No interstitial pneumonia or extensive and symptomatic interstitial fibrosis

• No lung tumor in close proximity to a major vessel, or with associated cavitation

• No pleural effusion or ascites that causes ≥ grade 2 dyspnea

Other

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for at least 3 months after completion of study treatment

• No significant traumatic injury within the past 28 days

• No currently active second malignancy other than, non-melanoma skin cancer or carcinoma in situ

• Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at ≤ 30% risk for relapse

• No known hypersensitivity reaction attributed to study drugs or to compounds of similar chemical or biological composition

• No symptomatic peripheral neuropathy > grade 1

• No other severe disease or comorbidity that would preclude study participation

• No medically uncontrolled seizures

• No active infection

• No serious non-healing wound, ulcer, or bone fracture

• No psychiatric illness or social situation that would preclude study compliance

• No other severe, concurrent disease, infection, or co-morbidity that in the judgement of the investigator would constitute a hazard for study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Recovered from prior cytokine therapy

• At least 4 weeks since prior immunotherapy

• No prior tyrosine kinase inhibitors or anti-vascular endothelial growth factor (VEGF) angiogenic inhibitors

Chemotherapy

• See Disease Characteristics

• At least 4 weeks since prior chemotherapy

• No prior oxaliplatin

• Prior chemoembolization therapy allowed provided it did not affect areas of measurable disease

Endocrine therapy

• Prior and concurrent somatostatin analogs allowed for symptomatic control and/or control of hormone hypersecretion only provided treatment was initiated > 3 months prior to study entry

Radiotherapy

• See Disease Characteristics

• At least 4 weeks since prior radiotherapy and recovered

• Prior radiotherapy must not affect areas of measurable disease

• No concurrent radiotherapy to only site of measurable disease

Surgery

• Recovered from prior surgery

• Prior cryotherapy allowed provided it did not affect areas of measurable disease

• At least 28 days since prior major surgical procedure or open biopsy

• At least 7 days since minor surgical procedure, fine-needle aspirations, or core biopsy

• No prior organ allograft

• No concurrent major surgery

Other

• At least 4 weeks since prior participation in an experimental drug study

• No other concurrent investigational agents

• No other concurrent anticancer therapy

• No halogenated antiviral agents

• Concurrent antiplatelet agents allowed