Combination Chemotherapy and Bevacizumab in Treating Patients With Advanced Neuroendocrine Tumors

NCT00227617 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: 04458NCI-2011-01214
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (4)

• Time to Progression

  From beginning of treatment up to 18 months; Post-study survival follow-up up to 8 years

• Overall Median Survival

  until death, up to 8 years

• Overall Time to Treatment Failure

  From initial complete or partial response to disease progression, up to 8 years

• Biochemical Marker Response

  From Baseline until end of treatment, up to 8 years

Study Arms (1)

FOLFOX with Bevacizumab

EXPERIMENTAL

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; Drug: 5-fluorouracil; Drug: leucovorin; Drug: oxaliplatin

Interventions

bevacizumab BIOLOGICAL

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, all subsequent infusions maybe be delivered over 30 +/- 10 minutes.

Also known as: Avastin

FOLFOX with Bevacizumab

5-fluorouracil DRUG

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

Also known as: 5-FU, Adrucil

FOLFOX with Bevacizumab

leucovorin DRUG

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

Also known as: Folinic acid

FOLFOX with Bevacizumab

oxaliplatin DRUG

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

Also known as: Eloxatin

FOLFOX with Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• University of California, San Francisco: lead
• Genentech, Inc.: collaborator
• Sanofi: collaborator

Study Sites (2)

Univeristy of California, San Francisco

San Francisco, California, 94115, United States

Location

Kaiser Permanente Medical Center - Vallejo

Vallejo, California, 94589, United States

Location

MeSH Terms

Conditions

Adenoma, Islet Cell; Lung Neoplasms; Neoplasms; Neuroendocrine Tumors; Gastrinoma; Insulinoma; Vipoma; Glucagonoma; Somatostatinoma; Carcinoma, Islet Cell

Interventions

Bevacizumab; Fluorouracil; Leucovorin; Oxaliplatin

Condition Hierarchy (Ancestors)

Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Adenocarcinoma; Carcinoma; Carcinoma, Neuroendocrine

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Coordination Complexes; Organic Chemicals

Limitations and Caveats

Early termination leading to small numbers of subjects analyzed; Technical problems with database migration lead to missing treatment assignment values.

Results Point of Contact

• Title: Dr. Emily Bergsland
• Organization: UCSF Helen Diller Family Comprehensive Cancer Center

Emily.Bergsland@ucsf.edu

415-885-7810

Study Officials

• Emily K. Bergsland, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 26, 2005
• First Posted: September 28, 2005
• Study Start: June 8, 2005
• Primary Completion: January 1, 2012
• Study Completion: February 1, 2016
• Last Updated: May 22, 2023
• Results First Posted: December 26, 2019

Record last verified: 2019-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)