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

• Sponsor: Eastern Cooperative Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00427349
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 46
• Locations: 112
• Arm: 1
• Duration (Months): 78.9
• Patients Per Site: 0.4
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Gastrointestinal Carcinoid Tumor; Islet Cell Tumor; Neoplastic Syndrome	Drug: AMG 706; Drug: octreotide	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Clinical and Biologic Study of AMG 706 and Octreotide in Patients With Low-Grade Neuroendocrine Tumors
• Study Start Date: Sep 1, 2008
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: AMG 706+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.

Drug: AMG 706; 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; Other Names: motesanib diphosphate ; Drug: octreotide; 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.; Other Names: L-cysteinamide Sandostatin SMS 201-995

Outcome Measures

Primary Outcome Measures

1. 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

1. 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

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hematology Oncology Associates of Illinois - Berwyn	Berwyn	Illinois	United States	60402
2	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois	United States	60611-3013
3	Hematology and Oncology Associates	Chicago	Illinois	United States	60611
4	Midwest Center for Hematology/Oncology	Joliet	Illinois	United States	60432
5	North Shore Oncology and Hematology Associates, Limited - Libertyville	Libertyville	Illinois	United States	60048
6	Trinity Cancer Center at Trinity Medical Center - 7th Street Campus	Moline	Illinois	United States	61265
7	La Grange Oncology Associates - Geneva	Naperville	Illinois	United States	60563
8	Cancer Care and Hematology Specialists of Chicagoland - Niles	Niles	Illinois	United States	60714
9	Hematology Oncology Associates - Skokie	Skokie	Illinois	United States	60076
10	McFarland Clinic, PC	Ames	Iowa	United States	50010
11	Hematology & Oncology Care	Bettendorf	Iowa	United States	52722
12	Cedar Rapids Oncology Associates	Cedar Rapids	Iowa	United States	52403
13	Mercy Regional Cancer Center at Mercy Medical Center	Cedar Rapids	Iowa	United States	52403
14	Medical Oncology and Hematology Associates - West Des Moines	Clive	Iowa	United States	50325
15	Mercy Capitol Hospital	Des Moines	Iowa	United States	50307
16	CCOP - Iowa Oncology Research Association	Des Moines	Iowa	United States	50309
17	John Stoddard Cancer Center at Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
18	Medical Oncology and Hematology Associates at John Stoddard Cancer Center	Des Moines	Iowa	United States	50309
19	Medical Oncology and Hematology Associates at Mercy Cancer Center	Des Moines	Iowa	United States	50314
20	Mercy Cancer Center at Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
21	John Stoddard Cancer Center at Iowa Lutheran Hospital	Des Moines	Iowa	United States	50316
22	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa	United States	51101
23	Mercy Medical Center - Sioux City	Sioux City	Iowa	United States	51104
24	St. Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
25	Cancer Center of Kansas, PA - Chanute	Chanute	Kansas	United States	66720
26	Cancer Center of Kansas, PA - Dodge City	Dodge City	Kansas	United States	67801
27	Cancer Center of Kansas, PA - El Dorado	El Dorado	Kansas	United States	67042
28	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas	United States	66701
29	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
30	Cancer Center of Kansas, PA - Kingman	Kingman	Kansas	United States	67068
31	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
32	Southwest Medical Center	Liberal	Kansas	United States	67901
33	Cancer Center of Kansas, PA - Newton	Newton	Kansas	United States	67114
34	Cancer Center of Kansas, PA - Parsons	Parsons	Kansas	United States	67357
35	Cancer Center of Kansas, PA - Pratt	Pratt	Kansas	United States	67124
36	Cancer Center of Kansas, PA - Salina	Salina	Kansas	United States	67401
37	Cancer Center of Kansas, PA - Wellington	Wellington	Kansas	United States	67152
38	Associates in Womens Health, PA - North Review	Wichita	Kansas	United States	67208
39	Cancer Center of Kansas, PA - Medical Arts Tower	Wichita	Kansas	United States	67208
40	Cancer Center of Kansas, PA - Wichita	Wichita	Kansas	United States	67214
41	CCOP - Wichita	Wichita	Kansas	United States	67214
42	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
43	Cancer Center of Kansas, PA - Winfield	Winfield	Kansas	United States	67156
44	Saint Joseph Mercy Cancer Center	Ann Arbor	Michigan	United States	48106-0995
45	CCOP - Michigan Cancer Research Consortium	Ann Arbor	Michigan	United States	48106
46	Oakwood Cancer Center at Oakwood Hospital and Medical Center	Dearborn	Michigan	United States	48123-2500
47	Green Bay Oncology, Limited - Escanaba	Escanaba	Michigan	United States	49431
48	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
49	Hurley Medical Center	Flint	Michigan	United States	48503
50	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan	United States	48236
51	Dickinson County Healthcare System	Iron Mountain	Michigan	United States	49801
52	Foote Memorial Hospital	Jackson	Michigan	United States	49201
53	Borgess Medical Center	Kalamazoo	Michigan	United States	49001
54	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
55	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
56	Sparrow Regional Cancer Center	Lansing	Michigan	United States	48912-1811
57	St. Mary Mercy Hospital	Livonia	Michigan	United States	48154
58	St. Joseph Mercy Oakland	Pontiac	Michigan	United States	48341-2985
59	Mercy Regional Cancer Center at Mercy Hospital	Port Huron	Michigan	United States	48060
60	Seton Cancer Institute at Saint Mary's - Saginaw	Saginaw	Michigan	United States	48601
61	St. John Macomb Hospital	Warren	Michigan	United States	48093
62	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
63	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
64	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
65	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
66	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
67	HealthEast Cancer Care at St. John's Hospital	Maplewood	Minnesota	United States	55109
68	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota	United States	55109
69	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
70	Hennepin County Medical Center - Minneapolis	Minneapolis	Minnesota	United States	55415
71	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota	United States	55422-2900
72	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
73	Park Nicollet Cancer Center	Saint Louis Park	Minnesota	United States	55416
74	United Hospital	Saint Paul	Minnesota	United States	55102
75	St. Francis Cancer Center at St. Francis Medical Center	Shakopee	Minnesota	United States	55379
76	Regions Hospital Cancer Care Center	St. Paul	Minnesota	United States	55101
77	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
78	Minnesota Oncology Hematology, PA - Woodbury	Woodbury	Minnesota	United States	55125
79	Cancer Resource Center - Lincoln	Lincoln	Nebraska	United States	68510
80	CCOP - Missouri Valley Cancer Consortium	Omaha	Nebraska	United States	68106
81	Immanuel Medical Center	Omaha	Nebraska	United States	68122
82	Alegant Health Cancer Center at Bergan Mercy Medical Center	Omaha	Nebraska	United States	68124
83	Creighton University Medical Center	Omaha	Nebraska	United States	68131-2197
84	Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton	Marlton	New Jersey	United States	08053
85	Fox Chase Virtua Health Cancer Program at Virtua West Jersey	Voorhees	New Jersey	United States	08043
86	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio	United States	44309-2090
87	Barberton Citizens Hospital	Barberton	Ohio	United States	44203
88	Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106-5065
89	St. Rita's Medical Center	Lima	Ohio	United States	45801
90	Natalie Warren Bryant Cancer Center at St. Francis Hospital	Tulsa	Oklahoma	United States	74136
91	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania	United States	17822-0001
92	Geisinger Hazleton Cancer Center	Hazleton	Pennsylvania	United States	18201
93	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104-4283
94	Joan Karnell Cancer Center at Pennsylvania Hospital	Philadelphia	Pennsylvania	United States	19107
95	Fox Chase Cancer Center - Philadelphia	Philadelphia	Pennsylvania	United States	19111-2497
96	UPMC Cancer Centers	Pittsburgh	Pennsylvania	United States	15232
97	McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center	Reading	Pennsylvania	United States	19612-6052
98	Geisinger Medical Group - Scenery Park	State College	Pennsylvania	United States	16801
99	Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania	United States	18711
100	Medical X-Ray Center, PC	Sioux Falls	South Dakota	United States	57105
101	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota	United States	57117-5039
102	Green Bay Oncology, Limited at St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54301-3526
103	Green Bay Oncology, Limited at St. Mary's Hospital	Green Bay	Wisconsin	United States	54303
104	St. Mary's Hospital Medical Center - Green Bay	Green Bay	Wisconsin	United States	54303
105	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54307-3508
106	Gundersen Lutheran Center for Cancer and Blood	La Crosse	Wisconsin	United States	54601
107	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Madison	Wisconsin	United States	53792-6164
108	Holy Family Memorial Medical Center Cancer Care Center	Manitowoc	Wisconsin	United States	54221-1450
109	Bay Area Cancer Care Center at Bay Area Medical Center	Marinette	Wisconsin	United States	54143
110	Green Bay Oncology, Limited - Oconto Falls	Oconto Falls	Wisconsin	United States	54154
111	Green Bay Oncology, Limited - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
112	University of Wisconcin Cancer Center at Aspirus Wausau Hospital	Wausau	Wisconsin	United States	54401

Sponsors and Collaborators

• Eastern Cooperative Oncology Group
• National Cancer Institute (NCI)

Investigators

• Study Chair: Mary Mulcahy, MD, Robert H. Lurie Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eastern Cooperative Oncology Group
• ClinicalTrials.gov Identifier: NCT00427349
• Other Study ID Numbers: CDR0000526256; ECOG-E4206; U10CA023318
• First Posted: Jan 29, 2007
• Last Update Posted: Aug 12, 2016
• Last Verified: Jul 1, 2016

• Keywords provided by Eastern Cooperative Oncology Group: 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
• Additional relevant MeSH terms: Neoplasms; Neuroendocrine Tumors; Carcinoid Tumor; Malignant Carcinoid Syndrome; Gastrointestinal Neoplasms; Adenoma, Islet Cell; Octreotide; Motesanib diphosphate; Imetelstat

Study Results

Participant Flow

Recruitment Details	This study was activated on September 16, 2008 and closed on March 18, 2010 with 46 patients registered to the study from 10 ECOG-ACRIN affiliated institutions.

Arm/Group Title	AMG 706+Octreotide
Arm/Group Description	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. AMG 706: 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. octreotide: 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.
Period Title: Overall Study
STARTED	46
Eligible	45
Treated	45
Eligible and Treated	44
COMPLETED	0
NOT COMPLETED	46

Baseline Characteristics

Arm/Group Title	AMG 706+Octreotide
Arm/Group Description	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. AMG 706: 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. octreotide: 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.
Overall Participants	44
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Sex: Female, Male (Count of Participants)
Female	20 45.5%
Male	24 54.5%
Region of Enrollment (participants) [Number]
United States	44 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The analysis population includes all 44 eligible and treated patients. But 2 patients did not have disease assessment after study entry and are excluded from the analysis.

Arm/Group Title	AMG 706+Octreotide
Arm/Group Description	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. AMG 706: 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. octreotide: 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.
Measure Participants	42
Number (90% Confidence Interval) [percentage of participants]	78.5 178.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AMG 706+Octreotide
	Comments	The null hypothesis is that the 4-month progression free survival rate is 20%. Alternatively, AMG 706 will be considered worthy of further study if its true progression-free survival rate is 40% or better at 4 months (alternative hypothesis).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	one sample binomial test
	Comments	The study result was compared to a null hypothesis of 20% 4-month progression free survival rate using one sample binomial test

2. Secondary Outcome

Title	Overall Survival
Description	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
Time Frame	assessed every 3 months if patient is < 2 years from study entry, then every 6 months up to 5 years

Outcome Measure Data

Analysis Population Description

All eligible and treated patients

Arm/Group Title	AMG 706+Octreotide
Arm/Group Description	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. AMG 706: 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. octreotide: 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.
Measure Participants	44
Median (95% Confidence Interval) [months]	27.5

3. Secondary Outcome

Title	Objective Response Rate
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AMG 706+Octreotide
Arm/Group Description	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. AMG 706: 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. octreotide: 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.
Measure Participants	44
Number (90% Confidence Interval) [percentage of participants]	13.6 30.9%

Adverse Events

Time Frame	Assessed at the end of each cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment
Adverse Event Reporting Description	Late adverse events (defined as any adverse events occur prior to diagnosis of progression/relapse and has not been previously reported) are collected via the long-term follow up forms at each follow-up visit.
Arm/Group Title	MG 706+Octreotide
Arm/Group Description	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. Each cycle was defined as 28 days. AMG 706 was started within 7 working days of registration, given on the same day as the octreotide-LAR.
All Cause Mortality
	MG 706+Octreotide
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	MG 706+Octreotide
	Affected / at Risk (%)	# Events
Total	26/45 (57.8%)
Blood and lymphatic system disorders
Anemia	2/45 (4.4%)
Gastrointestinal disorders
Diarrhea	4/45 (8.9%)
Nausea	3/45 (6.7%)
Vomiting	2/45 (4.4%)
Intra-abdominal hemorrhage	1/45 (2.2%)
Abdominal pain	4/45 (8.9%)
General disorders
Fatigue	6/45 (13.3%)
Hepatobiliary disorders
Cholecystitis	5/45 (11.1%)
Infections and infestations
Urinary tract infection	1/45 (2.2%)
Infections and infestations - blood	1/45 (2.2%)
Investigations
Lymphocyte count decreased	1/45 (2.2%)
Platelet count decreased	3/45 (6.7%)
Electrocardiogram QT corrected interval	1/45 (2.2%)
Weight loss	1/45 (2.2%)
INR increased	1/45 (2.2%)
Alkaline phosphatase increased	2/45 (4.4%)
Alanine aminotransferase increased	1/45 (2.2%)
Aspartate aminotransferase increased	1/45 (2.2%)
Blood bilirubin increased	1/45 (2.2%)
Lipase increased	1/45 (2.2%)
Metabolism and nutrition disorders
Anorexia	2/45 (4.4%)
Dehydration	2/45 (4.4%)
Hypocalcemia	1/45 (2.2%)
Hypomagnesemia	1/45 (2.2%)
Hypokalemia	1/45 (2.2%)
Nervous system disorders
Ataxia	2/45 (4.4%)
Dizziness	1/45 (2.2%)
Headache	2/45 (4.4%)
Psychiatric disorders
Confusion	1/45 (2.2%)
Respiratory, thoracic and mediastinal disorders
Pulmonary hypertension	1/45 (2.2%)
Dyspnea	1/45 (2.2%)
Vascular disorders
Hypertension	12/45 (26.7%)
Thromboembolic event	1/45 (2.2%)
Other (Not Including Serious) Adverse Events
	MG 706+Octreotide
	Affected / at Risk (%)	# Events
Total	43/45 (95.6%)
Blood and lymphatic system disorders
Anemia	11/45 (24.4%)
Cardiac disorders
Left ventricular systolic dysfunction	7/45 (15.6%)
Gastrointestinal disorders
Constipation	6/45 (13.3%)
Diarrhea	23/45 (51.1%)
Abdominal distension	8/45 (17.8%)
Dry mouth	3/45 (6.7%)
Flatulence	4/45 (8.9%)
Nausea	13/45 (28.9%)
Vomiting	9/45 (20%)
Abdominal pain	9/45 (20%)
General disorders
Fatigue	29/45 (64.4%)
Edema limbs	3/45 (6.7%)
Investigations
White blood cell decreased	11/45 (24.4%)
Lymphocyte count decreased	7/45 (15.6%)
Neutrophil count decreased	7/45 (15.6%)
Platelet count decreased	13/45 (28.9%)
Weight loss	21/45 (46.7%)
Alkaline phosphatase increased	9/45 (20%)
Alanine aminotransferase increased	4/45 (8.9%)
Aspartate aminotransferase increased	12/45 (26.7%)
Blood bilirubin increased	3/45 (6.7%)
Creatinine increased	3/45 (6.7%)
Metabolism and nutrition disorders
Anorexia	15/45 (33.3%)
Hypoalbuminemia	5/45 (11.1%)
Hyperglycemia	11/45 (24.4%)
Hypokalemia	4/45 (8.9%)
Hyponatremia	4/45 (8.9%)
Musculoskeletal and connective tissue disorders
Back pain	3/45 (6.7%)
Myalgia	6/45 (13.3%)
Nervous system disorders
Dizziness	5/45 (11.1%)
Peripheral sensory neuropathy	3/45 (6.7%)
Headache	16/45 (35.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	5/45 (11.1%)
Voice alteration	4/45 (8.9%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	3/45 (6.7%)
Vascular disorders
Hypertension	26/45 (57.8%)
Hypotension	3/45 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.