AMG 706 and Octreotide in Treating Patients With Low-Grade Neuroendocrine Tumors

Study Overview
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Brief Summary
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RATIONALE: AMG 706 and octreotide may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. PURPOSE: This phase II trial is studying how well AMG 706 and octreotide work in treating patients with low-grade neuroendocrine tumors.

Detailed Description
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OBJECTIVES: Primary Determine the 4-month progression-free survival (PFS) of patients with low-grade neuroendocrine tumors treated with AMG 706 and octreotide acetate. Secondary Determine the response rate and overall survival of patients treated with these drugs. Determine the toxicity and tolerability of AMG 706 in these patients. Determine the effect of AMG 706 on tumor perfusion by functional computerized tomography (CT) scan. Determine the effect of AMG 706 on tumor markers (e.g., chromogranin A, 5-hydroxyindoleacetic acid, and gastrin) specific for neuroendocrine tumors. Determine the effect of AMG 706 on serum vascular endothelial growth factor (VEGF) levels. Determine the expression of VEGF, VEGF receptor-2 (VEGFR-2), chromogranin A, human achaete-scute homolog-1 (hASH1), and Notch1 markers of neuroendocrine tumors. OUTLINE: This is a multicenter study. Patients receive oral AMG 706 and octreotide acetate intramuscularly once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Plasma samples are collected at baseline, periodically during study treatment, and at 4 weeks after the completion of study treatment. Samples are used to determine plasma VEGF levels. Gene expression of downstream markers of Raf kinase expression (raf, MEK, and ERK) as well as hASH1 and Notch1 are evaluated at baseline. Tumor tissue collected at diagnosis or prior surgery is examined by reverse transcriptase-polymerase chain reaction assay. Contrast CT scans are conducted at baseline, day 2 of course 1, and week 8 to assess tumor perfusion. After the completion of study treatment, patients are followed periodically for 5 years. PROJECTED ACCRUAL: A total of 44 patients will be accrued for this study.

Official Title
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A Phase II Clinical and Biologic Study of AMG 706 and Octreotide in Patients With Low-Grade Neuroendocrine Tumors

Conditions
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Gastrointestinal Carcinoid Tumor, Islet Cell Tumor, Neoplastic Syndrome

Intervention / Treatment
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* Drug: AMG 706
* Drug: octreotide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed low-grade neuroendocrine neoplasm Measurable disease Radiographic evidence of disease progression after any prior systemic therapy, chemoembolization, bland embolization, or observation, defined by either of the following: Appearance of a new lesion At least 20% increase in the longest diameter of any previously documented lesion or in the sum of the longest diameters of multiple lesions Tissue block from original diagnostic or surgical specimen required Concurrent stable-dose octreotide acetate required Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Negative pregnancy test Fertile patients must use effective contraception Must be able to receive a contrast-enhanced CT scan Absolute neutrophil count ≥ 1,000/mm³ Platelet count ≥ 75,000/mm³ Hemoglobin level ≥ 8.0 g/dL Bilirubin ≤ 2.0 times upper limit of normal (ULN) Aspartate aminotransferase (AST) ≤ 3 times ULN (5 times ULN if liver metastases are present) Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit of normal as evaluated by echocardiography or multigated acquisition (MUGA) scan No history of uncontrolled hypertension (resting blood pressure > 150/90 mm Hg) Antihypertensive medications allowed if patients is stable on their current dose One prior systemic chemotherapy regimen for low-grade neuroendocrine neoplasm allowed Chemoembolization is not considered systemic chemotherapy At least 4 weeks since prior major surgery, chemotherapy, radiation therapy, other systemic therapy, or local liver therapy Exclusion criteria: Prior procedures that would adversely affect intestinal absorption Prior anti-vascular endothelial growth factors Concurrent chemotherapy or radiation therapy History of the following within the past 12 months: New York Heart Association class III or IV congestive heart failure Unstable angina pectoris Myocardial infarction Symptomatic cardiac arrhythmia Cerebrovascular accident or transient ischemic attack Arterial or venous thrombosis Known history of allergic reactions to AMG 706 or derivatives or to octreotide acetate injections Gastrointestinal tract disease resulting in an inability to take oral medication (i.e., ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, bowel obstruction, or inability to swallow tablets) Pregnant or nursing Small cell lung cancer, medullary thyroid cancer, paraganglioma, or pheochromocytoma Requirement for intravenous alimentation

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: AMG 706+Octreotide<br>Patients receive oral AMG 706 and octreotide acetate intramuscularly (IM) once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. AMG 706 was administered on a flat scale of mg/day and not by weight or body surface area (BSA). AMG 706 was provided as a 25 mg tablet; the daily dose was 125 mg administered as five 25 mg tablets in the morning. AMG 706 was taken daily without breaks in treatment. One dose consisted of octreotide-LAR 30 mg administered IM on day 1 of each cycle. The first octreotide-LAR injection would correspond with the first day of AMG 706 and then on day 1 of subsequent cycles. | Drug: AMG 706<br>* AMG 706 was administered on a flat scale of mg/day and not by weight or body surface area (BSA). AMG 706 was provided as a 25 mg tablet; the daily dose was 125 mg administered as five 25 mg tablets in the AM. AMG 706 was taken daily without breaks in treatment<br>* Other names: motesanib diphosphate;Drug: octreotide<br>* One dose consisted of octreotide-LAR 30 mg administered IM on day 1 of each cycle. The first octreotide-LAR injection would correspond with the first day of AMG 706 and then on day 1 of subsequent cycles.<br>* Other names: SMS 201-995;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Four-month Progression-free Survival Rate | Four-month progression-free survival (PFS) rate is defined as number of patients who are still progression free at 4 months after study entry divided by number of eligible and treated patients enrolled to the study. Progression is evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s), or unequivocal progression of existing non-target lesions. | assessed every 4 weeks while on treatment and at three months post-treatment for participants treated for one cycle, up to month four | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival (OS) is defined as the time from registration until death (event), or censored at last date known alive. OS was estimated using the Kaplan-Meier method , with 95% confidence intervals calculated using Greenwood's formula | assessed every 3 months if patient is < 2 years from study entry, then every 6 months up to 5 years | 
| Objective Response Rate | Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Objective response rate is defined as number of patients with complete response (CR) or partial response (PR) divided by the total number of analyzable patients. CR is defined as complete disappearance of all tumor lesions, and partial response is defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter. | assessed every 8 weeks while on treatment, and frequency of tumor measurements during follow-up were determined by the treating physician, assessed up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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localized gastrointestinal carcinoid tumor, recurrent gastrointestinal carcinoid tumor, metastatic gastrointestinal carcinoid tumor, regional gastrointestinal carcinoid tumor, gastrinoma, insulinoma, WDHA syndrome, glucagonoma, pancreatic polypeptide tumor, somatostatinoma, recurrent islet cell carcinoma, neuroendocrine tumor