Combination Chemotherapy and Bevacizumab in Treating Patients With Advanced Neuroendocrine Tumors

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

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

Intervention / Treatment
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* Biological: bevacizumab
* Drug: 5-fluorouracil
* Drug: leucovorin
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FOLFOX with Bevacizumab<br>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<br>* 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.<br>* Other names: Avastin;Drug: 5-fluorouracil<br>* 2400mg/m2 CIV over 46-48 hours D1-2 q2 weeks.<br>* Other names: Adrucil;Drug: leucovorin<br>* 200mg/m2 IV q2 wk on day 1 over a 2-hour period.<br>* Other names: Folinic acid;Drug: oxaliplatin<br>* 200mg/m2 IV q 2 wk on day 1 over a 2-hour period<br>* Other names: Eloxatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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

| Outcome Measure | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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