Combination Chemotherapy And Bevacizumab In Treating Patients With Advanced Neuroendocrine Tumors

Study Overview

Combination Chemotherapy and Bevacizumab in Treating Patients With Advanced Neuroendocrine Tumors

RATIONALE: Drugs used in chemotherapy, such as fluorouracil, leucovorin, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of neuroendocrine tumors by blocking blood flow to the tumor. Giving combination chemotherapy together with bevacizumab may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects of giving combination chemotherapy together with bevacizumab and to see how well it works in treating patients with advanced neuroendocrine tumors.

OBJECTIVES: Primary * 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. Secondary * Determine the overall survival of patients treated with this regimen. * Determine the time to treatment failure and progression in patients treated with this regimen. * 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 study.

Gastrointestinal Carcinoid Tumor
Islet Cell Tumor
Lung Cancer
Neoplastic Syndrome
Neuroendocrine Tumor

BIOLOGICAL: bevacizumab
DRUG: 5-fluorouracil
DRUG: leucovorin
DRUG: oxaliplatin

04458
NCI-2011-01214 (REGISTRY Identifier) (REGISTRY: NCI Clinical Trials Reporting Program)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2005-09-26	Results First Submitted 2019-08-07	Last Update Submitted that met QC Criteria 2023-05-18
First Submitted that Met QC Criteria 2005-09-26	Results First Submitted that Met QC Criteria 2019-12-12	Last Update Posted (ACTUAL) 2023-05-22
First Posted (ACTUAL) 2005-09-28	Results First Posted 2019-12-26	Last Verified 2019-12

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: FOLFOX with Bevacizumab Starting on Day 1, administered every two weeks: 5-fluorouracil: 2400 mg/ m2 CIV; over 46-48 hours Leucovorin: 200 mg/ m2; over 2 hours Oxaliplatin : 85 mg/m2; over 2 hours Bevacizumab: 5 mg/kg IV over 30-90 minutes	BIOLOGICAL: bevacizumab 5mg/kg IV q 2 wk on day 1. Initial study drug dose will be delivered over 90 +/- 15 minutes x1. If the first infusion is tolerated without fever/chills, the second infusion may be delivered over 60 +/- 10 minutes. If 60 minutes infusion is well tolerated, DRUG: 5-fluorouracil 2400mg/m2 CIV over 46-48 hours D1-2 q2 weeks. DRUG: leucovorin 200mg/m2 IV q2 wk on day 1 over a 2-hour period. DRUG: oxaliplatin 200mg/m2 IV q 2 wk on day 1 over a 2-hour period

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: FOLFOX with Bevacizumab

Starting on Day 1, administered every two weeks: 5-fluorouracil: 2400 mg/ m2 CIV; over 46-48 hours Leucovorin: 200 mg/ m2; over 2 hours Oxaliplatin : 85 mg/m2; over 2 hours Bevacizumab: 5 mg/kg IV over 30-90 minutes

BIOLOGICAL: bevacizumab

5mg/kg IV q 2 wk on day 1. Initial study drug dose will be delivered over 90 +/- 15 minutes x1. If the first infusion is tolerated without fever/chills, the second infusion may be delivered over 60 +/- 10 minutes. If 60 minutes infusion is well tolerated,

DRUG: 5-fluorouracil

2400mg/m2 CIV over 46-48 hours D1-2 q2 weeks.

DRUG: leucovorin

200mg/m2 IV q2 wk on day 1 over a 2-hour period.

DRUG: oxaliplatin

200mg/m2 IV q 2 wk on day 1 over a 2-hour period

Primary Outcome Measures	Measure Description	Time Frame
Rate of Discontinuation Due to Adverse Events Possibly Related to Study Treatment	Rates of discontinuation were calculated as counts and percentages of patients whom discontinued treatment due to adverse events possibly related to the investigational treatments not including neuropathy.	From beginning of treatment up to 18 months; Post-study survival follow-up up to 8 years
Best Objective Response	Best Objective Response by RECIST with Exact 95% Binomial CIs across all tumor types. The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria Target lesions response + Non-Target lesions response + Evaluation of non-target lesions (Yes / No) = Overall response	From Baseline until disease progression, up to 8 years

Secondary Outcome Measures	Measure Description	Time Frame
Time to Progression	Time to disease progression will be defined as the time from baseline until documented disease progression or death (whichever occurs first).	From beginning of treatment up to 18 months; Post-study survival follow-up up to 8 years
Overall Median Survival	The overall survival is defined as the time from baseline until death (Carcinoid, PNET, PDNEC) using Kaplan-Meier Survival analysis methods.	until death, up to 8 years
Overall Time to Treatment Failure	Time to treatment failure is defined as the time from the initial complete or partial response to documented disease progression or death (whichever occurs first) across treatment groups and inclusive of drug holidays and estimated using Kaplan-Meier survival analysis methods	From initial complete or partial response to disease progression, up to 8 years
Biochemical Marker Response	Biochemical marker response is defined as >=50% reduction in marker or hormone(s) that were elevated at baseline. Markers/hormones tested are: Chromagranin A (CGA), 5-HIAA, Insulin, Proinsulin, C-peptide, Pancreatic polypeptide, Gastrin, Glucagon, and Vasointestinal Peptide.	From Baseline until end of treatment, up to 8 years

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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)

18 and over

ECOG 0-1

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 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

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 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

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

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 biopsy
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Genentech, Inc.
Sanofi

Investigators

PRINCIPAL_INVESTIGATOR: Emily K. Bergsland, MD, University of California, San Francisco

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

No publications available

Learn

Resources

PatientS

Caregivers

Clinical Trial Record