Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy and Bevacizumab in Treating Patients With Advanced Neuroendocrine Tumors

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Treatment	Active	18 and over	NCI	UCSF-04458 NCT00227617

Objectives

Primary

1. Determine the safety of fluorouracil, leucovorin calcium, and oxaliplatin (FOLFOX) with bevacizumab in patients with advanced neuroendocrine tumors.
2. Determine the best overall response rate in patients treated with this regimen.

Secondary

1. Determine the overall survival of patients treated with this regimen.
2. Determine the time to treatment failure and progression in patients treated with this regimen.
3. Determine the biochemical marker response in patients treated with this regimen.

Entry 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
    • 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)

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

Patient Characteristics:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• More than 12 weeks

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• 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

Expected Enrollment

A total of 39-102 patients (13-34 per stratum) will be accrued for this study.

Outcomes

Safety
Objective radiographic response rate

Overall survival
Time to treatment failure
Time to progression
Biochemical marker response

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.

Trial Contact Information

Trial Lead Organizations

UCSF Helen Diller Family Comprehensive Cancer Center

Emily Bergsland, MD, Principal investigator		Ph: 415-353-7463

U.S.A.
California
	San Francisco
	UCSF Helen Diller Family Comprehensive Cancer Center
		Clinical Trials Office - UCSF Helen Diller Family Comprehensive Cancer Center	Ph:  877-827-3222
	Vallejo
	Kaiser Permanente Medical Center - Vallejo
		Louis Fehrenbacher, MD	Ph:  707-651-2797

Registry Information
Official Title		A Pilot Study of FOLFOX in Combination with Bevacizumab in Patients with Advanced Neuroendocrine Tumors
Trial Start Date		2005-06-17
Trial Completion Date		2009-12-31 (estimated)
Registered in ClinicalTrials.gov		NCT00227617 1
Date Submitted to PDQ		2005-08-04
Information Last Verified		2007-01-22
NCI Grant/Contract Number		CA82103

Table of Links

1	http://clinicaltrials.gov/ct/show/NCT00227617