A Pilot Study of FOLFOX in Combination With Bevacizumab in Patients With Advanced Neuroendocrine Tumors

Inclusion Criteria

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