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