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

Phase 2/Phase 3
18 Years
Open (Enrolling)
Gastrointestinal Carcinoid Tumor, Islet Cell Tumor, Lung Cancer, Neoplastic Syndrome, Neuroendocrine Tumor

Thank you

Trial Information

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



- Determine the safety of fluorouracil, leucovorin calcium, and oxaliplatin (FOLFOX) with
bevacizumab in patients with advanced neuroendocrine tumors.

- Determine the best overall response rate in patients treated with this regimen.


- Determine the overall survival of patients treated with this regimen.

- Determine the time to treatment failure and progression in patients treated with this

- Determine the biochemical marker response in patients treated with this regimen.

OUTLINE: This is an open-label, pilot study. Patients are stratified according to tumor type
(carcinoid vs islet cell vs poorly differentiated neuroendocrine).

Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1
and fluorouracil IV continuously over 46-48 hours beginning on day 1. Patients also receive
bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 14 days for up to 26
courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 39-102 patients (13-34 per stratum) will be accrued for this

Inclusion Criteria


- 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

- 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

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



- 18 and over

Performance status

- ECOG 0-1

Life expectancy

- More than 12 weeks


- 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


- Bilirubin < 2 mg/dL

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


- Creatinine ≤ 2 mg/dL

- Protein ≤ 1+ OR

- Protein < 1 gm on 24-hour urine collection

- Urine protein:creatinine ratio < 1.0


- 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

- 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


- 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


- 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


- 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

- 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


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


- 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


- 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


- 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

- No prior organ allograft

- No concurrent major surgery


- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Outcome Time Frame:

Until patient went off study

Safety Issue:


Principal Investigator

Emily K. Bergsland, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of California, San Francisco


United States: Food and Drug Administration

Study ID:




Start Date:

June 2005

Completion Date:

June 2012

Related Keywords:

  • Gastrointestinal Carcinoid Tumor
  • Islet Cell Tumor
  • Lung Cancer
  • Neoplastic Syndrome
  • Neuroendocrine Tumor
  • recurrent gastrointestinal carcinoid tumor
  • regional gastrointestinal carcinoid tumor
  • pulmonary carcinoid tumor
  • gastrinoma
  • insulinoma
  • WDHA syndrome
  • glucagonoma
  • pancreatic polypeptide tumor
  • somatostatinoma
  • recurrent islet cell carcinoma
  • metastatic gastrointestinal carcinoid tumor
  • Neoplasms
  • Carcinoid Tumor
  • Lung Neoplasms
  • Neuroendocrine Tumors
  • Malignant Carcinoid Syndrome
  • Gastrointestinal Neoplasms
  • Adenoma, Islet Cell



Kaiser Permanente Medical Center - Vallejo Vallejo, California  94589
UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California  94115