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 2009)

    • 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