Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors

Metastatic Digestive System Neuroendocrine Tumor G1 Clinical Trial

Official title:

Prospective Randomized Phase II Trial of Pazopanib (NSC #737754) Versus Placebo in Patients With Progressive Carcinoid Tumors

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01841736
• Other study ID #: NCI-2013-00831
• Secondary ID: NCI-2013-00831AL
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 20, 2013
• Est. completion date: September 13, 2024

Study information

• Verified date: September 2023
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase II trial studies how well pazopanib hydrochloride works in treating patients with carcinoid tumors that are growing, spreading, or getting worse. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Description:

PRIMARY OBJECTIVE: I. For patients with progressive carcinoid tumors, progression-free survival (PFS defined by central review according to Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) will be compared between patients randomized to treatment with pazopanib (pazopanib hydrochloride) versus placebo. SECONDARY OBJECTIVES: I. Overall survival (OS) will be compared between treatment arms. II. Objective response rate, duration of response, and time to treatment failure will be compared between treatment arms. III. Progression free survival (PFS) as assessed by central radiology review and local radiology review will be compared overall and within treatment arms. IV. Safety and tolerability of treatment with pazopanib/placebo will be evaluated within each treatment arm. V. PFS and other indicators of efficacy will be estimated in patients who crossover to pazopanib from placebo. VI. To determine the turn-around time for timely adjudicated central review. VII. To characterize the nature of discordance between local and central radiology review in assessment of progression. VIII. To characterize the type and rate of progression in carcinoid (at study entry, on-study, and at progression). IX. To develop new methods for modeling carcinoid growth and detecting treatment effects, and to perform simulations that advance new clinical trial designs to apply to future trials of carcinoid therapeutics. X. To assess for differences in quality of life (QOL)-related domains between the two treatment groups (pazopanib versus placebo). XI. To determine if the more brief measures of QOL-related domains provide comparable information to that which is provided by the longer assessments (European Organization for Research and Treatment of Cancer [EORTC], neuroendocrine tumors [NET]21). XII. To provide validation data for the EORTC NET21 module in terms of responsiveness over time and differences across arms. XIII. To determine whether components of the plasma angiome panel that have been shown to be predictive previously (interleukin-6 [IL-6] and vascular endothelial growth factor [VEGF]-D) are predictive of a therapeutic advantage for pazopanib treatment in baseline samples from the patients treated on A021202. XIV. To determine whether other components of the plasma angiome panel tested (not IL-6 and VEGF-D) are predictive of a therapeutic advantage for pazopanib treatment in baseline samples from the patients treated on A021202. XV. To evaluate the changes in the plasma angiome markers after treatment with or without pazopanib over time. EXPLORATORY OBJECTIVES: I. PFS at 6 months will be estimated within each treatment arm. II. Biochemical response (for chromogranin A, defined as a decrease of 50% or more in chromogranin A levels from baseline and for 5-hydroxyindoleacetic acid [5-HIAA], defined as a decrease of 50% or more in urinary 5-HIAA levels from baseline) will be compared between treatment arms among patients with elevated baseline levels of chromogranin A (CGA) and 5-HIAA. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening. Patients also undergo computed tomography (CT), magnetic resonance imaging (MRI), and chest x-ray throughout the trial. Patients may optionally undergo blood sample collection during screening and on study. ARM II: Patients receive placebo PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. At the time of progressive disease, patients may cross-over to Arm I. Patients undergo ECHO or MUGA during screening. Patients also undergo CT, MRI, and chest x-ray throughout the trial. Patients may optionally undergo blood sample collection during screening and on study. After completion of study treatment, patients are followed up every 3-6 months for 5 years.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 171
• Est. completion date: September 13, 2024
• Est. primary completion date: March 5, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Low- or intermediate-grade neuroendocrine carcinoma, including the following subtypes:

carcinoid tumor, low- to intermediate-grade or well- to moderately-differentiated neuroendocrine carcinoma or tumor, atypical carcinoid tumor; documentation from a primary tumor or metastatic site is sufficient; patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid tumor, or goblet cell carcinoid tumor are not eligible

• Locally unresectable or metastatic carcinoid tumors
• Patients must have histologic documentation or clinical evidence of a carcinoid tumor of primary site (including foregut, midgut, hindgut or other non-pancreatic site); tumors of unknown primary site are eligible provided the treating physician does not suspect medullary thyroid cancer, pancreatic neuroendocrine tumor, paraganglioma, or pheochromocytoma; unknown primary tumors will be classified as small bowel tumors for the purpose of stratification; functional (associated with a clinical syndrome) or nonfunctional tumors are allowed; target lesions must have shown disease progression if therapy included peptide receptor radiotherapy (PRRT) and PRRT must be completed at least 8 weeks prior to registration
• Radiological evidence for progressive disease (measurable or non-measurable) within 12 months prior to registration; patients who have received anti-tumor therapy during the past 12 months (including octreotide analogs) must have had radiological documentation of progression of disease while on or after receiving therapy
• No known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage; patients with lesions infiltrating major pulmonary vessels (contiguous tumor and vessels) are excluded; however, the presence of a tumor that is touching, but not infiltrating (abutting) the vessels is acceptable (computed tomography [CT] with contrast is strongly recommended to evaluate such lesions); patients with large protruding endobronchial lesions in the main or lobar bronchi are excluded; however, endobronchial lesions in the segmented bronchi are allowed
• Patients must have measurable disease per RECIST 1.1 by computed tomography (CT) scan or magnetic resonance imaging (MRI); lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as >= 1 cm with CT or MRI (or >= 1.5 cm for lymph nodes); index lesions for the purpose of RECIST 1.1 measurements will not be selected from within the radiation therapy treatment field; however, if there is evidence of disease progression within the radiation treatment field, measurement of the progressing lesions will be documented
• No prior treatment with an inhibitor of vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR)
• Prior treatment (somatostatin analogs excepted) must be completed at least 2 weeks prior to registration; in addition, prior treatment (somatostatin analogs excepted) must be completed at least 4 weeks prior to initiation of study drug; treatment-related toxicities must have improved to =< grade 1 prior to registration, with the exception of alopecia
• Concurrent use of somatostatin analogs (SSTa) is allowed, provided that the patient is on a stable dose for at least two months and progressive disease on somatostatin analog has been documented; progression on octreotide is required for patients with tumors arising in the midgut
• Prior treatment with embolization (including bland embolization, chemoembolization, and selective internal radiation therapy) or ablative therapies is allowed if measurable disease remains outside of the treated area or there is documented disease progression in a treated site; there is no limit on the prior number of procedures; prior liver-directed or other ablative treatment must be completed at least 8 weeks prior to registration; index lesions for the purpose of RECIST 1.1 measurements will not be selected from within the radiation therapy treatment field; however, if there is evidence of disease progression within the radiation treatment field, measurement of the progressing lesions will be documented
• Patients should have completed any major surgery >= 4 weeks prior to registration and must have completed any minor surgery >= 2 weeks prior to registration; patients must have fully recovered from the procedure
• The following are examples of procedures considered to be minor: port placement, laparoscopy, thoracoscopy, bronchoscopy, mediastinoscopy, skin biopsies, incisional biopsies, imaging-guided biopsy for diagnostic purposes, and dental extraction procedures
• Insertion of a vascular access device, thoracentesis, paracentesis, and endoscopic ultrasonographic procedures are not considered to be major or minor surgeries
• No concurrent condition resulting in immune compromise, including chronic treatment with corticosteroids or other immunosuppressive agents
• No clinical evidence of central nervous system (CNS) metastases (including carcinomatous meningitis) at baseline, with the exception of those patients who have previously-treated CNS metastases (surgery +/- radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria: a) are asymptomatic and b) had no requirement for steroids or enzyme-inducing anticonvulsants within 6 months prior to registration
• No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to registration
• No clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding within 28 days prior to registration including, but not

limited to:

• Active peptic ulcer
• Known endoluminal metastatic lesion(s) with history of bleeding
• Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation
• No history of serious (i.e., requiring active medical therapy with medication or medical device under the supervision of a physician) non-healing wound, ulcer, trauma, or bone fracture within 28 days prior to study entry
• Patients with a history of hypertension must have blood pressure that is adequately controlled on antihypertensives; (< 140/90 mm Hg)
• No symptomatic congestive heart failure (New York Heart Association class II, III, or IV) within 6 months prior to registration
• No arterial thrombotic events within 6 months of registration, including transient ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial thrombus, myocardial infarction (MI), or unstable angina or angina requiring surgical or medical intervention in 6 months prior to registration; patients with clinically significant peripheral artery disease (i.e., claudication on less than one block) are ineligible; patients who have experienced a deep venous thrombosis or pulmonary embolus within 6 months prior to registration must be on stable therapeutic anticoagulation for at least 6 weeks prior to enrollment of this study
• Patients on therapeutic anticoagulation with low molecular weight heparins, fondaparinux, rivaroxaban or warfarin are eligible, provided that they are on a stable dose of anticoagulants; patients who are currently receiving antiplatelet therapy of prasugrel or clopidogrel or antiaggregation agents (e.g., eptifibatide, epoprostenol, dipyridamole) or low doses of acetylsalicylic acid (up to 100 mg daily) are also eligible
• No ongoing cardiac dysrhythmias, atrial fibrillation, or prolongation of corrected QT (QTc) interval to > 480 msec
• No evidence of active bleeding, bleeding diathesis, or hemoptysis (>= 1/2 teaspoon of red blood) within 8 weeks prior to registration
• No currently unstable angina and/or uncontrolled cardiac arrhythmias
• Patients with symptomatic peripheral vascular disease are ineligible
• Ejection fraction on echocardiogram (Echo) or multi gated acquisition scan (MUGA) > 50%
• Chronic concomitant treatment with strong inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) is not allowed on this trial; patients on strong CYP3A4 inhibitors must discontinue the drug 14 days prior to the start of study treatment
• Women must not be pregnant or nursing; women of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours prior to registration; women of child-bearing potential include any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >= 12 consecutive months; or women on hormone replacement therapy [HRT] with documented serum follicle stimulating hormone [FSH] level > 35 mIU/mL)
• Age >= 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Granulocytes >= 1,500/mcL
• Platelets >= 100,000/mcL
• International normalized ratio (INR) =< 1.2 X upper limit of normal (ULN); only required for patients receiving anticoagulant therapy; patients are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation
• QTc =< 480 msecs
• Thyroid stimulating hormone (TSH) within normal limits (WNL); medications for thyroid dysfunction are allowed as long as TSH is normal at registration; in patients with abnormal TSH, if the free thyroxine (free T4) and free thyroxine index (FTI) are normal and patient is clinically euthyroid, patient is eligible
• Bilirubin =< 1.5 x ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) & alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN; concomitant elevations in bilirubin and AST/ALT above 1.0 X ULN are NOT permitted; also, if liver metastases are present, AST & ALT =< 5 x ULN is allowed
• Serum creatinine =< 1.5 x ULN
• Urine protein to creatinine ratio < 1, or, 24-hour urine protein < 1 g; if urine protein to creatinine (UPC) >= 1, then a 24-hour urine protein must be assessed; patients must have a 24-hour urine protein value < 1 g to be eligible; use of urine dipstick for renal function assessment is not acceptable

Related Conditions & MeSH terms

• Carcinoid Tumor
• Gastrointestinal Neoplasms
• Intestinal Neoplasms
• Malignant Carcinoid Syndrome
• Metastatic Carcinoid Tumor
• Metastatic Digestive System Neuroendocrine Tumor G1
• Midgut Neuroendocrine Tumor G1
• Neoplasms
• Neuroendocrine Tumors
• Pancreatic Neoplasms
• Recurrent Digestive System Neuroendocrine Tumor G1
• Regional Digestive System Neuroendocrine Tumor G1
• Stomach Neoplasms

Intervention

Procedure:
• Biospecimen Collection
Undergo blood sample collection
• Computed Tomography
Undergo CT
• Echocardiography
Undergo ECHO

Other:
• Laboratory Biomarker Analysis
Correlative studies

Procedure:
• Magnetic Resonance Imaging
Undergo MRI
• Multigated Acquisition Scan
Undergo MUGA

Drug:
• Pazopanib Hydrochloride
Given PO

Other:
• Placebo Administration
Given PO
• Quality-of-Life Assessment
Ancillary studies

Procedure:
• X-Ray Imaging
Undergo chest x-ray

Locations

Country	Name	City	State
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	QEII Health Sciences Centre/Nova Scotia Health Authority	Halifax	Nova Scotia
Canada	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario
Canada	Grand River Regional Cancer Centre at Grand River Hospital	Kitchener	Ontario
Canada	The Vitalite Health Network - Dr Leon Richard Oncology Centre	Moncton	New Brunswick
Canada	CHUM - Centre Hospitalier de l'Universite de Montreal	Montreal	Quebec
Canada	CHUM - Hopital Notre-Dame	Montreal	Quebec
Canada	Ottawa Hospital and Cancer Center-General Campus	Ottawa	Ontario
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	University Health Network-Princess Margaret Hospital	Toronto	Ontario
Canada	BCCA-Vancouver Cancer Centre	Vancouver	British Columbia
United States	Pali Momi Medical Center	'Aiea	Hawaii
United States	Queen's Cancer Center - Pearlridge	'Aiea	Hawaii
United States	Bixby Medical Center	Adrian	Michigan
United States	Hickman Cancer Center	Adrian	Michigan
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah
United States	Mary Greeley Medical Center	Ames	Iowa
United States	McFarland Clinic - Ames	Ames	Iowa
United States	Kaiser Permanente-Anaheim	Anaheim	California
United States	Alaska Breast Care and Surgery LLC	Anchorage	Alaska
United States	Alaska Women's Cancer Care	Anchorage	Alaska
United States	Anchorage Oncology Centre	Anchorage	Alaska
United States	Katmai Oncology Group	Anchorage	Alaska
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	Michigan Cancer Research Consortium NCORP	Ann Arbor	Michigan
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	The Medical Center of Aurora	Aurora	Colorado
United States	Kaiser Permanente-Baldwin Park	Baldwin Park	California
United States	Ochsner Health Center-Summa	Baton Rouge	Louisiana
United States	Bronson Battle Creek	Battle Creek	Michigan
United States	Strecker Cancer Center-Belpre	Belpre	Ohio
United States	Southwestern Vermont Medical Center	Bennington	Vermont
United States	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania
United States	University of Iowa Healthcare Cancer Services Quad Cities	Bettendorf	Iowa
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Montana Cancer Consortium NCORP	Billings	Montana
United States	Saint Vincent Healthcare	Billings	Montana
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	McFarland Clinic - Boone	Boone	Iowa
United States	Boulder Community Hospital	Boulder	Colorado
United States	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado
United States	Toledo Clinic Cancer Centers-Bowling Green	Bowling Green	Ohio
United States	Bozeman Deaconess Hospital	Bozeman	Montana
United States	Cox Cancer Center Branson	Branson	Missouri
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana
United States	Cooper Hospital University Medical Center	Camden	New Jersey
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Southeast Cancer Center	Cape Girardeau	Missouri
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Rocky Mountain Oncology	Casper	Wyoming
United States	Sandra L Maxwell Cancer Center	Cedar City	Utah
United States	Mercy Hospital	Cedar Rapids	Iowa
United States	Oncology Associates at Mercy Medical Center	Cedar Rapids	Iowa
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Marshfield Clinic-Chippewa Center	Chippewa Falls	Wisconsin
United States	Oncology Hematology Care Inc-Anderson	Cincinnati	Ohio
United States	Oncology Hematology Care Inc-Blue Ash	Cincinnati	Ohio
United States	Oncology Hematology Care Inc-Eden Park	Cincinnati	Ohio
United States	Oncology Hematology Care Inc-Kenwood	Cincinnati	Ohio
United States	Oncology Hematology Care Inc-Mercy West	Cincinnati	Ohio
United States	Clackamas Radiation Oncology Center	Clackamas	Oregon
United States	Case Western Reserve University	Cleveland	Ohio
United States	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa
United States	Mercy Cancer Center-West Lakes	Clive	Iowa
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Rocky Mountain Cancer Centers-Penrose	Colorado Springs	Colorado
United States	MU Health - University Hospital/Ellis Fischel Cancer Center	Columbia	Missouri
United States	Columbus NCI Community Oncology Research Program	Columbus	Ohio
United States	Columbus Oncology and Hematology Associates Inc	Columbus	Ohio
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	John B Amos Cancer Center	Columbus	Georgia
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	The Mark H Zangmeister Center	Columbus	Ohio
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Oncology Hematology Care Inc-Crestview	Crestview Hills	Kentucky
United States	Baylor University Medical Center	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton NCI Community Oncology Research Program	Dayton	Ohio
United States	Good Samaritan Hospital - Dayton	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Miami Valley Hospital North	Dayton	Ohio
United States	Beaumont Hospital - Dearborn	Dearborn	Michigan
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Delaware Health Center-Grady Cancer Center	Delaware	Ohio
United States	Delaware Radiation Oncology	Delaware	Ohio
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	Porter Adventist Hospital	Denver	Colorado
United States	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado
United States	Rocky Mountain Cancer Centers-Midtown	Denver	Colorado
United States	Rocky Mountain Cancer Centers-Rose	Denver	Colorado
United States	Rose Medical Center	Denver	Colorado
United States	SCL Health Saint Joseph Hospital	Denver	Colorado
United States	Western States Cancer Research NCORP	Denver	Colorado
United States	Iowa Lutheran Hospital	Des Moines	Iowa
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Iowa-Wide Oncology Research Coalition NCORP	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Laurel	Des Moines	Iowa
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota
United States	Miller-Dwan Hospital	Duluth	Minnesota
United States	Mercy Medical Center	Durango	Colorado
United States	HSHS Sacred Heart Hospital	Eau Claire	Wisconsin
United States	Marshfield Clinic Cancer Center at Sacred Heart	Eau Claire	Wisconsin
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Baptist Health Hardin	Elizabethtown	Kentucky
United States	Elkhart Clinic	Elkhart	Indiana
United States	Elkhart General Hospital	Elkhart	Indiana
United States	Michiana Hematology Oncology PC-Elkhart	Elkhart	Indiana
United States	Newman Regional Health	Emporia	Kansas
United States	Mountain Blue Cancer Care Center - Swedish	Englewood	Colorado
United States	Swedish Medical Center	Englewood	Colorado
United States	Green Bay Oncology - Escanaba	Escanaba	Michigan
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Oncology Hematology Care Inc-Healthplex	Fairfield	Ohio
United States	Essentia Health Cancer Center-South University Clinic	Fargo	North Dakota
United States	Blanchard Valley Hospital	Findlay	Ohio
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	McLeod Regional Medical Center	Florence	South Carolina
United States	Kaiser Permanente-Fontana	Fontana	California
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Fredericksburg Oncology Inc	Fredericksburg	Virginia
United States	Unity Hospital	Fridley	Minnesota
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Saint Catherine Hospital	Garden City	Kansas
United States	Glens Falls Hospital	Glens Falls	New York
United States	Mountain Blue Cancer Care Center	Golden	Colorado
United States	Wayne Memorial Hospital	Goldsboro	North Carolina
United States	Cancer Research Consortium of West Michigan NCORP	Grand Rapids	Michigan
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Trinity Health Grand Rapids Hospital	Grand Rapids	Michigan
United States	Saint Rose Ambulatory and Surgery Center	Great Bend	Kansas
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	North Colorado Medical Center	Greeley	Colorado
United States	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin
United States	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin
United States	Prisma Health Cancer Institute - Butternut	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Prisma Health Greenville Memorial Hospital	Greenville	South Carolina
United States	Wayne Hospital	Greenville	Ohio
United States	Rocky Mountain Cancer Centers-Greenwood Village	Greenwood Village	Colorado
United States	Prisma Health Cancer Institute - Greer	Greer	South Carolina
United States	Kaiser Permanente - Harbor City	Harbor City	California
United States	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut
United States	Ingalls Memorial Hospital	Harvey	Illinois
United States	HaysMed University of Kansas Health System	Hays	Kansas
United States	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania
United States	Saint Peter's Community Hospital	Helena	Montana
United States	Cancer and Blood Specialists-Henderson	Henderson	Nevada
United States	Comprehensive Cancer Centers of Nevada - Henderson	Henderson	Nevada
United States	Comprehensive Cancer Centers of Nevada-Southeast Henderson	Henderson	Nevada
United States	GenesisCare USA - Henderson	Henderson	Nevada
United States	Las Vegas Cancer Center-Henderson	Henderson	Nevada
United States	Hendersonville Hematology and Oncology at Pardee	Hendersonville	North Carolina
United States	Margaret R Pardee Memorial Hospital	Hendersonville	North Carolina
United States	Hawaii Cancer Care Inc - Waterfront Plaza	Honolulu	Hawaii
United States	Hawaii Cancer Care Inc-Liliha	Honolulu	Hawaii
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Queen's Cancer Center - Kuakini	Honolulu	Hawaii
United States	Queen's Medical Center	Honolulu	Hawaii
United States	Straub Clinic and Hospital	Honolulu	Hawaii
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Houston Methodist Hospital	Houston	Texas
United States	Edwards Comprehensive Cancer Center	Huntington	West Virginia
United States	Hutchinson Area Health Care	Hutchinson	Minnesota
United States	Centerpoint Medical Center LLC	Independence	Missouri
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan
United States	Kaiser Permanente-Irvine	Irvine	California
United States	Allegiance Health	Jackson	Michigan
United States	McFarland Clinic - Jefferson	Jefferson	Iowa
United States	Capital Region Southwest Campus	Jefferson City	Missouri
United States	Mercy Hospital Joplin	Joplin	Missouri
United States	Castle Medical Center	Kailua	Hawaii
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	Heartland Hematology and Oncology Associates Incorporated	Kansas City	Missouri
United States	Research Medical Center	Kansas City	Missouri
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	The University of Kansas Cancer Center-South	Kansas City	Missouri
United States	Truman Medical Centers	Kansas City	Missouri
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	University of Kansas Cancer Center - North	Kansas City	Missouri
United States	University of Kansas Cancer Center-West	Kansas City	Kansas
United States	Kettering Medical Center	Kettering	Ohio
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Vidant Oncology-Kinston	Kinston	North Carolina
United States	Community Howard Regional Health	Kokomo	Indiana
United States	IU Health La Porte Hospital	La Porte	Indiana
United States	Rocky Mountain Cancer Centers-Lakewood	Lakewood	Colorado
United States	Saint Anthony Hospital	Lakewood	Colorado
United States	Fairfield Medical Center	Lancaster	Ohio
United States	Lancaster Radiation Oncology	Lancaster	Ohio
United States	Sparrow Hospital	Lansing	Michigan
United States	Memorial Medical Center - Las Cruces	Las Cruces	New Mexico
United States	Cancer and Blood Specialists-Shadow	Las Vegas	Nevada
United States	Cancer and Blood Specialists-Tenaya	Las Vegas	Nevada
United States	Cancer Therapy and Integrative Medicine	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada - Central Valley	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada - Northwest	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada-Summerlin	Las Vegas	Nevada
United States	GenesisCare USA - Fort Apache	Las Vegas	Nevada
United States	GenesisCare USA - Las Vegas	Las Vegas	Nevada
United States	GenesisCare USA - Vegas Tenaya	Las Vegas	Nevada
United States	HealthCare Partners Medical Group Oncology/Hematology-Centennial Hills	Las Vegas	Nevada
United States	HealthCare Partners Medical Group Oncology/Hematology-Maryland Parkway	Las Vegas	Nevada
United States	HealthCare Partners Medical Group Oncology/Hematology-San Martin	Las Vegas	Nevada
United States	HealthCare Partners Medical Group Oncology/Hematology-Tenaya	Las Vegas	Nevada
United States	Las Vegas Cancer Center-Medical Center	Las Vegas	Nevada
United States	Nevada Cancer Research Foundation NCORP	Las Vegas	Nevada
United States	OptumCare Cancer Care at Fort Apache	Las Vegas	Nevada
United States	Radiation Oncology Centers of Nevada Central	Las Vegas	Nevada
United States	Radiation Oncology Centers of Nevada Southeast	Las Vegas	Nevada
United States	University Medical Center of Southern Nevada	Las Vegas	Nevada
United States	Cancer Centers of Southwest Oklahoma Research	Lawton	Oklahoma
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri
United States	University of Kansas Cancer Center - Lee's Summit	Lee's Summit	Missouri
United States	Beebe Medical Center	Lewes	Delaware
United States	Baptist Health Lexington	Lexington	Kentucky
United States	Liberty Radiation Oncology Center	Liberty	Missouri
United States	Wilcox Memorial Hospital and Kauai Medical Clinic	Lihue	Hawaii
United States	Lima Memorial Hospital	Lima	Ohio
United States	Nebraska Cancer Research Center	Lincoln	Nebraska
United States	Littleton Adventist Hospital	Littleton	Colorado
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Logan Regional Hospital	Logan	Utah
United States	Rocky Mountain Cancer Centers-Sky Ridge	Lone Tree	Colorado
United States	Sky Ridge Medical Center	Lone Tree	Colorado
United States	Longmont United Hospital	Longmont	Colorado
United States	Rocky Mountain Cancer Centers-Longmont	Longmont	Colorado
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Kaiser Permanente West Los Angeles	Los Angeles	California
United States	Los Angeles General Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	McKee Medical Center	Loveland	Colorado
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Holy Family Memorial Hospital	Manitowoc	Wisconsin
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Marietta Memorial Hospital	Marietta	Ohio
United States	McFarland Clinic - Marshalltown	Marshalltown	Iowa
United States	Marshfield Medical Center	Marshfield	Wisconsin
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Toledo Clinic Cancer Centers-Maumee	Maumee	Ohio
United States	Toledo Radiation Oncology at Northwest Ohio Onocolgy Center	Maumee	Ohio
United States	Loyola University Medical Center	Maywood	Illinois
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Providence Milwaukie Hospital	Milwaukie	Oregon
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Health Partners Inc	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Michiana Hematology Oncology PC-Mishawaka	Mishawaka	Indiana
United States	Saint Joseph Regional Medical Center-Mishawaka	Mishawaka	Indiana
United States	Saint Patrick Hospital - Community Hospital	Missoula	Montana
United States	Mercy Memorial Hospital	Monroe	Michigan
United States	Toledo Clinic Cancer Centers-Monroe	Monroe	Michigan
United States	Good Samaritan Regional Health Center	Mount Vernon	Illinois
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	Intermountain Medical Center	Murray	Utah
United States	Trinity Health Muskegon Hospital	Muskegon	Michigan
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Cancer Center of Western Wisconsin	New Richmond	Wisconsin
United States	New Ulm Medical Center	New Ulm	Minnesota
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Christiana Gynecologic Oncology LLC	Newark	Delaware
United States	Delaware Clinical and Laboratory Physicians PA	Newark	Delaware
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Licking Memorial Hospital	Newark	Ohio
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Newark Radiation Oncology	Newark	Ohio
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	Corewell Health Lakeland Hospitals - Niles Hospital	Niles	Michigan
United States	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin
United States	McKay-Dee Hospital Center	Ogden	Utah
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Olathe Health Cancer Center	Olathe	Kansas
United States	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska
United States	Alegent Health Immanuel Medical Center	Omaha	Nebraska
United States	Alegent Health Lakeside Hospital	Omaha	Nebraska
United States	Creighton University Medical Center	Omaha	Nebraska
United States	Missouri Valley Cancer Consortium	Omaha	Nebraska
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Saint Charles Hospital	Oregon	Ohio
United States	Toledo Clinic Cancer Centers-Oregon	Oregon	Ohio
United States	Providence Willamette Falls Medical Center	Oregon City	Oregon
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Menorah Medical Center	Overland Park	Kansas
United States	Saint Luke's South Hospital	Overland Park	Kansas
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	Palo Alto Medical Foundation Health Care	Palo Alto	California
United States	Stanford Cancer Institute Palo Alto	Palo Alto	California
United States	Kaiser Permanente - Panorama City	Panorama City	California
United States	Parker Adventist Hospital	Parker	Colorado
United States	Rocky Mountain Cancer Centers-Parker	Parker	Colorado
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Ascension Via Christi - Pittsburg	Pittsburg	Kansas
United States	Michiana Hematology Oncology PC-Plymouth	Plymouth	Indiana
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Lake Huron Medical Center	Port Huron	Michigan
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Southern Ohio Medical Center	Portsmouth	Ohio
United States	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho
United States	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Rocky Mountain Cancer Centers - Pueblo	Pueblo	Colorado
United States	Saint Mary Corwin Medical Center	Pueblo	Colorado
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Corewell Health Reed City Hospital	Reed City	Michigan
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	Ascension Saint Mary's Hospital	Rhinelander	Wisconsin
United States	Saint Mary's Hospital	Rhinelander	Wisconsin
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	Reid Health	Richmond	Indiana
United States	Kaiser Permanente-Riverside	Riverside	California
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri
United States	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Saint George Regional Medical Center	Saint George	Utah
United States	Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center	Saint Joseph	Michigan
United States	Heartland Regional Medical Center	Saint Joseph	Missouri
United States	Lakeland Medical Center Saint Joseph	Saint Joseph	Michigan
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Salina Regional Health Center	Salina	Kansas
United States	LDS Hospital	Salt Lake City	Utah
United States	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Kaiser Permanente-San Diego Mission	San Diego	California
United States	Kaiser Permanente-San Diego Zion	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	UCSF Medical Center-Mount Zion	San Francisco	California
United States	Kaiser Permanente-San Marcos	San Marcos	California
United States	Palo Alto Medical Foundation-Santa Cruz	Santa Cruz	California
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Guthrie Medical Group PC-Robert Packer Hospital	Sayre	Pennsylvania
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	TidalHealth Nanticoke / Allen Cancer Center	Seaford	Delaware
United States	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	HSHS Saint Nicholas Hospital	Sheboygan	Wisconsin
United States	Welch Cancer Center	Sheridan	Wyoming
United States	Mercy Medical Center-Sioux City	Sioux City	Iowa
United States	Saint Luke's Regional Medical Center	Sioux City	Iowa
United States	Siouxland Regional Cancer Center	Sioux City	Iowa
United States	Memorial Hospital of South Bend	South Bend	Indiana
United States	Michiana Hematology Oncology PC-South Bend	South Bend	Indiana
United States	Northern Indiana Cancer Research Consortium	South Bend	Indiana
United States	South Bend Clinic	South Bend	Indiana
United States	Cancer Research for the Ozarks NCORP	Springfield	Missouri
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Springfield Regional Medical Center	Springfield	Ohio
United States	Geisinger Medical Group	State College	Pennsylvania
United States	Iredell Memorial Hospital	Statesville	North Carolina
United States	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Lakeview Hospital	Stillwater	Minnesota
United States	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin
United States	Palo Alto Medical Foundation-Sunnyvale	Sunnyvale	California
United States	ProMedica Flower Hospital	Sylvania	Ohio
United States	Syracuse Veterans Administration Medical Center	Syracuse	New York
United States	Moffitt Cancer Center	Tampa	Florida
United States	Mercy Hospital of Tiffin	Tiffin	Ohio
United States	Mercy Health - Saint Anne Hospital	Toledo	Ohio
United States	Saint Vincent Mercy Medical Center	Toledo	Ohio
United States	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio
United States	Toledo Community Hospital Oncology Program CCOP	Toledo	Ohio
United States	University of Toledo	Toledo	Ohio
United States	University of Kansas Health System Saint Francis Campus	Topeka	Kansas
United States	Munson Medical Center	Traverse City	Michigan
United States	Upper Valley Medical Center	Troy	Ohio
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	Compass Oncology Vancouver	Vancouver	Washington
United States	PeaceHealth Southwest Medical Center	Vancouver	Washington
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	Marshfield Clinic-Wausau Center	Wausau	Wisconsin
United States	Fulton County Health Center	Wauseon	Ohio
United States	Mercy Medical Center-West Lakes	West Des Moines	Iowa
United States	Methodist West Hospital	West Des Moines	Iowa
United States	Saint Ann's Hospital	Westerville	Ohio
United States	Ascension Saint Clare's Hospital	Weston	Wisconsin
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Michiana Hematology Oncology PC-Westville	Westville	Indiana
United States	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado
United States	Cancer Center of Kansas - Wichita	Wichita	Kansas
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	UPMC Susquehanna	Williamsport	Pennsylvania
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Christiana Care Health System-Wilmington Hospital	Wilmington	Delaware
United States	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin
United States	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota
United States	Kaiser Permanente-Woodland Hills	Woodland Hills	California
United States	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	PFS Within Each Arm	Kaplan-Meier methods will be used including calculations of 95% confidence intervals.	At 6 months
Other	Biochemical Response	Biochemical response (for chromogranin A, defined as a decrease of 50% or more in chromogranin A levels from baseline, and for 5-hydroxyindoleacetic acid [5-HIAA], defined as a decrease of 50% or more in urinary 5-HIAA levels from baseline) will be compared between treatment arms among patients with elevated baseline levels of serum chromogranin A (CGA) and 5-HIAA.	Up to 5 years
Primary	Progression-free Survival (PFS)	PFS will be measured from date of patient entry until documented progression of disease as determined by central review or death from any cause. If a patient does not have a documented date of progression or death, then PFS will be censored at the date of last adequate assessment. PFS will be estimated within treatment arm using the Kaplan-Meier method. Progression is defined as any new lesion or increase by =20% of previously involved sites from nadir based on RECIST criteria.	From date of patient entry until documented progression of disease or death from any cause, assessed up to 5 years
Secondary	Best Response	The best response per RECIST 1.1 criteria of participants receiving randomized treatment assignment. Complete response (CR): Disappearance of all evidence of disease, Partial response (PR): Regression of measurable disease and no new sites, Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum diameters while on study. Progressive disease (PD): Any new lesion or increase by =20% of previously involved sites from nadir. Note that those considered evaluable for best response here were those who had disease measurements while on treatment. Those who discontinued therapy early prior to a disease evaluation were not included.	Up to 5 years
Secondary	Overall Survival	Overall survival (OS) will be measured from randomization until death from any cause. A patient who is alive at the time of the statistical analysis will be considered censored at the last date of known contact. OS will be estimated by the Kaplan-Meier method within each treatment arm.	From randomization until death from any cause, assessed up to 5 years
Secondary	Duration of Response for the Subset of Patients With a Confirmed Complete Response or Partial Response	Duration of response is defined as the time from documented response to time of progression and/or death. This time-to-event outcome will be summarized descriptively using the methods of Kaplan and Meier to characterize the cohort and distribution of this outcome.	From first documented evidence of complete response or partial response until first documented disease progression or death from any cause, assessed up to 5 years
Secondary	Time to Treatment Failure	Time to treatment failure is defined as the time from randomization to the time that treatment is terminated, including the reasons of disease progression, adverse events, withdrawal from study, or death. This time-to-event outcome will be evaluated using the methods of Kaplan and Meier.	From randomization until termination of protocol therapy for any reason including progression of disease, adverse events, and death, assessed up to 5 years
Secondary	Time to Second Progression for Patients Who Crossover From Placebo to Active Therapy		Up to 5 years