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

Phase 2

Completed

Conditions: Islet Cell Tumor
Neoplastic Syndrome
Gastrointestinal Carcinoid Tumor

Interventions: Drug: AMG 706
Drug: octreotide

Registration Number: NCT00427349

Lead Sponsor: Eastern Cooperative Oncology Group

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 46

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
AMG 706+Octreotide	AMG 706	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.
AMG 706+Octreotide	octreotide	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.

Primary Outcome Measures

Name	Time	Method
Four-month Progression-free Survival Rate	assessed every 4 weeks while on treatment and at three months post-treatment for participants treated for one cycle, up to month four	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.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate	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	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.
Overall Survival	assessed every 3 months if patient is < 2 years from study entry, then every 6 months up to 5 years	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

Trial Locations

Locations (112): Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
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Minneapolis, Minnesota, United States
Associates in Womens Health, PA - North Review
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Wichita, Kansas, United States
Cancer Center of Kansas, PA - Newton
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Newton, Kansas, United States
Cancer Center of Kansas, PA - Wichita
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Wichita, Kansas, United States
Cancer Center of Kansas, PA - Dodge City
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Dodge City, Kansas, United States
Via Christi Cancer Center at Via Christi Regional Medical Center
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Wichita, Kansas, United States
Cancer Center of Kansas, PA - Kingman
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Kingman, Kansas, United States
Cancer Center of Kansas, PA - Wellington
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Wellington, Kansas, United States
Cancer Center of Kansas, PA - El Dorado
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El Dorado, Kansas, United States
Mercy Regional Cancer Center at Mercy Medical Center
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Cedar Rapids, Iowa, United States
Hematology & Oncology Care
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Bettendorf, Iowa, United States
Robert H. Lurie Comprehensive Cancer Center at Northwestern University
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Chicago, Illinois, United States
Hematology Oncology Associates of Illinois - Berwyn
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Berwyn, Illinois, United States
Hematology and Oncology Associates
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Chicago, Illinois, United States
La Grange Oncology Associates - Geneva
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Naperville, Illinois, United States
Cedar Rapids Oncology Associates
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Cedar Rapids, Iowa, United States
Cancer Center of Kansas-Independence
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Independence, Kansas, United States
McFarland Clinic, PC
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Ames, Iowa, United States
Hematology Oncology Associates - Skokie
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Skokie, Illinois, United States
Mercy Medical Center - Sioux City
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Sioux City, Iowa, United States
St. Luke's Regional Medical Center
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Sioux City, Iowa, United States
Cancer Center of Kansas, PA - Chanute
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Chanute, Kansas, United States
Lawrence Memorial Hospital
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Lawrence, Kansas, United States
Cancer Center of Kansas, PA - Winfield
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Winfield, Kansas, United States
Cancer Center of Kansas, PA - Medical Arts Tower
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Wichita, Kansas, United States
Oakwood Cancer Center at Oakwood Hospital and Medical Center
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Dearborn, Michigan, United States
Dickinson County Healthcare System
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Iron Mountain, Michigan, United States
Seton Cancer Institute at Saint Mary's - Saginaw
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Saginaw, Michigan, United States
Borgess Medical Center
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Kalamazoo, Michigan, United States
West Michigan Cancer Center
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Kalamazoo, Michigan, United States
Fairview Southdale Hospital
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Edina, Minnesota, United States
St. Joseph Mercy Oakland
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Pontiac, Michigan, United States
St. John Macomb Hospital
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Warren, Michigan, United States
Hutchinson Area Health Care
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Hutchinson, Minnesota, United States
Fairview Ridges Hospital
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Burnsville, Minnesota, United States
Park Nicollet Cancer Center
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Saint Louis Park, Minnesota, United States
Case Comprehensive Cancer Center
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Cleveland, Ohio, United States
Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton
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Marlton, New Jersey, United States
Natalie Warren Bryant Cancer Center at St. Francis Hospital
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Tulsa, Oklahoma, United States
Midwest Center for Hematology/Oncology
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Joliet, Illinois, United States
Medical Oncology and Hematology Associates - West Des Moines
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Clive, Iowa, United States
CCOP - Michigan Cancer Research Consortium
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Ann Arbor, Michigan, United States
CCOP - Missouri Valley Cancer Consortium
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Omaha, Nebraska, United States
Immanuel Medical Center
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Omaha, Nebraska, United States
Creighton University Medical Center
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Omaha, Nebraska, United States
Bronson Methodist Hospital
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Kalamazoo, Michigan, United States
North Shore Oncology and Hematology Associates, Limited - Libertyville
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Libertyville, Illinois, United States
Trinity Cancer Center at Trinity Medical Center - 7th Street Campus
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Moline, Illinois, United States
Cancer Care and Hematology Specialists of Chicagoland - Niles
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Niles, Illinois, United States
Siouxland Hematology-Oncology Associates, LLP
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Sioux City, Iowa, United States
Cancer Center of Kansas, PA - Parsons
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Parsons, Kansas, United States
Cancer Center of Kansas, PA - Pratt
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Pratt, Kansas, United States
Cancer Center of Kansas, PA - Salina
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Salina, Kansas, United States
Saint Joseph Mercy Cancer Center
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Ann Arbor, Michigan, United States
Green Bay Oncology, Limited - Escanaba
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Escanaba, Michigan, United States
Genesys Hurley Cancer Institute
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Flint, Michigan, United States
Van Elslander Cancer Center at St. John Hospital and Medical Center
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Grosse Pointe Woods, Michigan, United States
Foote Memorial Hospital
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Jackson, Michigan, United States
Hurley Medical Center
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Flint, Michigan, United States
Sparrow Regional Cancer Center
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Lansing, Michigan, United States
St. Mary Mercy Hospital
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Livonia, Michigan, United States
Mercy Regional Cancer Center at Mercy Hospital
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Port Huron, Michigan, United States
Mercy and Unity Cancer Center at Mercy Hospital
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Coon Rapids, Minnesota, United States
Mercy and Unity Cancer Center at Unity Hospital
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Fridley, Minnesota, United States
Minnesota Oncology Hematology, PA - Maplewood
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Maplewood, Minnesota, United States
HealthEast Cancer Care at St. John's Hospital
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Maplewood, Minnesota, United States
Hennepin County Medical Center - Minneapolis
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Minneapolis, Minnesota, United States
Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center
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Robbinsdale, Minnesota, United States
CCOP - Metro-Minnesota
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Saint Louis Park, Minnesota, United States
Regions Hospital Cancer Care Center
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Saint Paul, Minnesota, United States
Ridgeview Medical Center
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Waconia, Minnesota, United States
United Hospital
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Saint Paul, Minnesota, United States
Minnesota Oncology Hematology, PA - Woodbury
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Woodbury, Minnesota, United States
St. Francis Cancer Center at St. Francis Medical Center
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Shakopee, Minnesota, United States
Cancer Resource Center - Lincoln
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Lincoln, Nebraska, United States
Alegant Health Cancer Center at Bergan Mercy Medical Center
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Omaha, Nebraska, United States
Summa Center for Cancer Care at Akron City Hospital
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Akron, Ohio, United States
St. Rita's Medical Center
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Lima, Ohio, United States
Geisinger Hazleton Cancer Center
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Hazleton, Pennsylvania, United States
Barberton Citizens Hospital
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Barberton, Ohio, United States
Geisinger Cancer Institute at Geisinger Health
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Danville, Pennsylvania, United States
Abramson Cancer Center of the University of Pennsylvania
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Philadelphia, Pennsylvania, United States
Fox Chase Cancer Center - Philadelphia
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Philadelphia, Pennsylvania, United States
McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center
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Reading, Pennsylvania, United States
Joan Karnell Cancer Center at Pennsylvania Hospital
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Philadelphia, Pennsylvania, United States
Geisinger Medical Group - Scenery Park
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State College, Pennsylvania, United States
UPMC Cancer Centers
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Pittsburgh, Pennsylvania, United States
Green Bay Oncology, Limited at St. Vincent Hospital Regional Cancer Center
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Green Bay, Wisconsin, United States
Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center
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Wilkes-Barre, Pennsylvania, United States
Sanford Cancer Center at Sanford USD Medical Center
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Sioux Falls, South Dakota, United States
Medical X-Ray Center, PC
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Sioux Falls, South Dakota, United States
Gundersen Lutheran Center for Cancer and Blood
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La Crosse, Wisconsin, United States
Green Bay Oncology, Limited at St. Mary's Hospital
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Green Bay, Wisconsin, United States
St. Mary's Hospital Medical Center - Green Bay
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Green Bay, Wisconsin, United States
Green Bay Oncology, Limited - Oconto Falls
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Oconto Falls, Wisconsin, United States
St. Vincent Hospital Regional Cancer Center
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Green Bay, Wisconsin, United States
Bay Area Cancer Care Center at Bay Area Medical Center
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Marinette, Wisconsin, United States
Holy Family Memorial Medical Center Cancer Care Center
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Manitowoc, Wisconsin, United States
Green Bay Oncology, Limited - Sturgeon Bay
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Sturgeon Bay, Wisconsin, United States
University of Wisconcin Cancer Center at Aspirus Wausau Hospital
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Wausau, Wisconsin, United States
Fox Chase Virtua Health Cancer Program at Virtua West Jersey
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Voorhees, New Jersey, United States
Medical Oncology and Hematology Associates at John Stoddard Cancer Center
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Des Moines, Iowa, United States
Medical Oncology and Hematology Associates at Mercy Cancer Center
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Des Moines, Iowa, United States
Mercy Cancer Center at Mercy Medical Center - Des Moines
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Des Moines, Iowa, United States
John Stoddard Cancer Center at Iowa Lutheran Hospital
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Des Moines, Iowa, United States
University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
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Madison, Wisconsin, United States
Mercy Capitol Hospital
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Des Moines, Iowa, United States
CCOP - Iowa Oncology Research Association
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Des Moines, Iowa, United States
John Stoddard Cancer Center at Iowa Methodist Medical Center
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Des Moines, Iowa, United States
CCOP - Wichita
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Wichita, Kansas, United States
Southwest Medical Center
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Liberal, Kansas, United States
Cancer Center of Kansas - Fort Scott
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Fort Scott, Kansas, United States