Imatinib Mesylate With or Without Bevacizumab in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor

Gastrointestinal Stromal Tumor Clinical Trial

Official title:

A Phase III Randomized Study of Imatinib, With or Without Bevacizumab (NSC-704865), in Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00324987
• Other study ID #: NCI-2009-00776
• Secondary ID: NCI-2009-00776CD
• Status: Completed
• Phase: Phase 3
• First received: May 10, 2006
• Last updated: August 28, 2015
• Start date: April 2008
• Est. completion date: July 2015

Study information

• Verified date: April 2015
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This randomized phase III trial studies imatinib mesylate and bevacizumab to see how well they work compared to imatinib mesylate alone in treating patients with gastrointestinal stromal tumor that has spread to other parts of the body or cannot be removed by surgery. Imatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether imatinib mesylate and bevacizumab are more effective than imatinib mesylate alone in treating gastrointestinal stromal tumor.

Description:

PRIMARY OBJECTIVES:

I. To determine whether treatment with imatinib (imatinib mesylate) plus bevacizumab leads to improved progression free survival (PFS) versus treatment with imatinib alone in first-line treatment of incurable gastrointestinal stromal tumor (GIST).

SECONDARY OBJECTIVES:

I. To compare response probabilities (confirmed and unconfirmed complete response [CR] and partial response [PR] for subset of patients with measurable disease), overall survival, and central-review based progression-free survival (CRb-PFS) in patients treated with imatinib and bevacizumab versus those treated with imatinib alone.

II. To compare the frequency and severity of toxicities associated with imatinib plus bevacizumab versus imatinib alone.

TERTIARY OBJECTIVES:

I. To explore the association between soluble vascular endothelial growth factor (VEGF), VEGF-factor D (VEGF-D), VEGF receptor (VEGFR)-1, VEGFR-2, angiopoietin-2 (Ang-2), platelet-derived growth factor receptor (PDGFR)-AA and PDGFR-BB levels, positron emission tomography (PET) imaging and immunohistochemistry for cyclin-dependent kinase inhibitor 2A (p16), VEGF and VEGFR, with kinase mutation status and clinical outcomes.

II. To explore imatinib pharmacokinetics with single nucleotide polymorphisms involving the adenosine triphospate (ATP)-binding cassette, sub-family G (WHITE), member 2 (ABCG2) and cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) genes, as well as other genes that are reported to influence the absorption, distribution, metabolism and elimination of imatinib.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (CLOSED TO ACCRUAL 10/1/2009): Patients receive imatinib mesylate orally (PO) once daily (QD) on days 1-21 and bevacizumab intravenously (IV) over 30-90 minutes on day 1.

ARM II (CLOSED TO ACCRUAL 10/1/2009): Patients receive imatinib mesylate PO QD on days 1-21.

In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 1 month, every 6 months for 2 years, and then annually for 5 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: July 2015
• Est. primary completion date: July 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• REGISTRATION # 1

• Patient must have a biopsy proven diagnosis of gastrointestinal stromal tumor (GIST) that is distantly metastatic or unresectable; patients must be determined to be unresectable for cure

• Patient may have measurable and/or non-measurable disease; computed tomography (CT) or magnetic resonance imaging (MRI) used for measurable disease must have been completed within 28 days prior to registration; CT or MRI used for non-measurable disease must have been completed within 42 days prior to registration; PET scans are not sufficient for disease assessment; all disease must be assessed and documented on the Baseline Tumor Assessment Form

• CT/MRI scans must be performed and submitted for central review; archived tissue must be submitted as outlined

• Institutions must seek additional patient consent for PET scans as outlined; if patient consents to the submission of PET scans, the patient must also be registered to Registration #2

• Patient must not have known brain metastasis

• Patient must have a Zubrod performance status of 0 - 3

• Patient must have resolution of transient toxicities from any prior chemotherapy, radiation therapy or surgery to =< grade 1 (Common Terminology Criteria for Adverse Events [CTCAE] version 3.0)

• Patient may have previously received traditional chemotherapeutic agents in any setting, provided at least 28 days have elapsed since completing chemotherapy and they have recovered to =< grade 1 from all drug-induced toxicities

• Patient must not have received prior treatment with bevacizumab or other agents targeting VEGF, VEGFR, or PDGFR for advanced disease; those agents may have been used in the adjuvant setting if the patient did not recur for at least 12 months following the completion of treatment; patients may be receiving imatinib for advanced disease prior to registration provided they meet ALL of the following criteria:

• Patient must not have received more than 30 days of imatinib treatment prior to registration

• Patients have not been restaged; (baseline disease assessments prior to initiation of imatinib must fulfill requirements)

• Patients must have no clinical signs of progression

• Prior radiotherapy is allowed, provided at least 28 days have elapsed since the last treatment and there is evidence of progressive disease within the radiation field or disease outside the radiation field

• Patient must not have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to registration, or anticipation of need for major surgical procedure during the course of the study; no fine needle aspirations or core biopsies are allowed within 7 days prior to registration; no procedure to place a port-a-cath is allowed within 7 days prior to registration

• Patient must have a total bilirubin =< 2.0 x institutional upper limit of normal (IULN), obtained within 28 days prior to registration

• Patients without liver involvement must have serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) =< 2.5 x IULN, obtained within 28 days prior to registration; patients with liver involvement must have SGOT or SGPT =< 5 x IULN

• Patient must have adequate renal function as defined by a serum creatinine =< 1.5 x IULN obtained within 28 days prior to registration

• Patient must have urine protein/creatinine ratio (UPC) < 1; this result must be obtained within 28 days prior to registration

• Patient must have an absolute neutrophil count (ANC) >= 1,000/mcl obtained within 28 days prior to registration

• Patient must have a platelet count >= 100,000/mcl obtained within 28 days prior to registration

• Patient must have hemoglobin >= 9 gm/dl (this may be achieved by transfusion if needed) obtained within 28 days prior to registration

• Patient must have an international normalized ratio (INR) =< 1.5, obtained within 28 days prior to registration

• Patient must have a partial thromboplastin time (PTT) =< IULN, obtained within 28 days prior to registration

• Patient must not be taking therapeutic doses of Coumadin (warfarin) as anticoagulation at the time of registration; patients requiring therapeutic anticoagulation may use low-molecular weight heparin (e.g., Lovenox) or other agents, and mini-dose Coumadin (1 mg PO QD) as prophylaxis is allowed

• Patient must not have had a cerebrovascular accident (CVA), transient ischemic attack (TIA), myocardial infarction or unstable angina within 6 months prior to registration; patient must not have serious cardiac arrhythmia requiring medication, New York Heart Association (NYHA) class II or greater congestive heart failure, or clinically significant peripheral vascular disease

• Patient must not have had an abdominal fistula, gastrointestinal perforation or intraabdominal abscess within 28 days prior to registration

• Patient must not plan to use other investigational agents while on protocol treatment

• Patient must have no contraindication to oral medications (e.g., severe dysphagia); patients with gastrostomy (G)- or jejunostomy (J)- tubes are eligible

• Patient must not have blood pressure > 160/90; patients with a history of hypertension must be on a stable regimen of anti-hypertensive therapy

• Patient must not have a serious, non-healing wound, ulcer, or bone fracture

• Patient must not be pregnant or nursing; male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout protocol treatment and for up to 6 months following discontinuation of study drugs

• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years

• If day 28 or 42 falls on a weekend or holiday, the limit may be extended to the next working day; in calculating days of tests and measurements, the day a test or measurement is done is considered day 0; therefore, if a test is done on a Monday, the Monday four weeks later would be considered day 28

• All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines

• At the time of patient registration, the treating institution's name and identification (ID) number must be provided to the Data Operations Center in Seattle in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered into the data base

• REGISTRATION #2 - PET SUBSTUDY:

• Patient must have been registered to the main study

• Patient must have consented to the submission of PET scans

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Gastrointestinal Stromal Tumor
• Gastrointestinal Stromal Tumors

Intervention

Biological:
• Bevacizumab
Given IV

Drug:
• Imatinib Mesylate
Given PO

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Pharmacological Study
Correlative studies

Locations

Country	Name	City	State
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	BCCA-Vancouver Cancer Centre	Vancouver	British Columbia
United States	Bixby Medical Center	Adrian	Michigan
United States	Hickman Cancer Center	Adrian	Michigan
United States	McFarland Clinic PC-William R Bliss Cancer Center	Ames	Iowa
United States	Michigan Cancer Research Consortium CCOP	Ann Arbor	Michigan
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	Franciscan St. Francis Health-Beech Grove	Beech Grove	Indiana
United States	PeaceHealth Saint Joseph Medical Center	Bellingham	Washington
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Frontier Cancer Center and Blood Institute-Billings	Billings	Montana
United States	Montana Cancer Consortium CCOP	Billings	Montana
United States	Northern Rockies Radiation Oncology Center	Billings	Montana
United States	Saint Vincent Healthcare	Billings	Montana
United States	Mid Dakota Clinic	Bismarck	North Dakota
United States	Saint Alexius Medical Center	Bismarck	North Dakota
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Toledo Clinic Cancer Centers-Bowling Green	Bowling Green	Ohio
United States	Bozeman Deaconess Cancer Center	Bozeman	Montana
United States	Bozeman Deaconess Hospital	Bozeman	Montana
United States	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Mills - Peninsula Hospitals	Burlingame	California
United States	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana
United States	Cancer Center of Kansas - Chanute	Chanute	Kansas
United States	West Virginia University Charleston	Charleston	West Virginia
United States	Presence Resurrection Medical Center	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Marshfield Clinic-Chippewa Center	Chippewa Falls	Wisconsin
United States	University of Cincinnati	Cincinnati	Ohio
United States	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa
United States	North Coast Cancer Care-Clyde	Clyde	Ohio
United States	John B Amos Cancer Center	Columbus	Georgia
United States	Genesis Medical Center - East Campus	Davenport	Iowa
United States	Genesis Medical Center - West Campus	Davenport	Iowa
United States	Dayton CCOP	Dayton	Ohio
United States	Good Samaritan Hospital - Dayton	Dayton	Ohio
United States	Grandview Hospital	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Samaritan North Health Center	Dayton	Ohio
United States	Veteran Affairs Medical Center	Dayton	Ohio
United States	Oakwood Hospital and Medical Center	Dearborn	Michigan
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Iowa Lutheran Hospital	Des Moines	Iowa
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Iowa Oncology Research Association CCOP	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa
United States	Mercy Capitol	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Saint John Hospital and Medical Center	Detroit	Michigan
United States	Cancer Center of Kansas - Dodge City	Dodge City	Kansas
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	Marshfield Clinic Cancer Center at Sacred Heart	Eau Claire	Wisconsin
United States	Sacred Heart Hospital	Eau Claire	Wisconsin
United States	Cancer Center of Kansas - El Dorado	El Dorado	Kansas
United States	Hematology Oncology Center Incorporated	Elyria	Ohio
United States	Blanchard Valley Hospital	Findlay	Ohio
United States	Genesys Regional Medical Center-West Flint Campus	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Fredericksburg Oncology Inc	Fredericksburg	Virginia
United States	Glens Falls Hospital	Glens Falls	New York
United States	Berdeaux, Donald MD (UIA Investigator)	Great Falls	Montana
United States	Great Falls Clinic	Great Falls	Montana
United States	Marin General Hospital	Greenbrae	California
United States	Wayne Hospital	Greenville	Ohio
United States	Northern Montana Hospital	Havre	Montana
United States	Saint Peter's Community Hospital	Helena	Montana
United States	Hutchinson Area Health Care	Hutchinson	Minnesota
United States	Cancer Center of Kansas-Independence	Independence	Kansas
United States	Allegiance Health	Jackson	Michigan
United States	Joliet Oncology-Hematology Associates Limited	Joliet	Illinois
United States	Glacier Oncology PLLC	Kalispell	Montana
United States	Kalispell Medical Oncology	Kalispell	Montana
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	Kadlec Clinic Hematology and Oncology	Kennewick	Washington
United States	Kettering Medical Center	Kettering	Ohio
United States	Cancer Center of Kansas-Kingman	Kingman	Kansas
United States	Kinston Medical Specialists PA	Kinston	North Carolina
United States	Adventist La Grange Memorial Hospital	La Grange	Illinois
United States	Sparrow Hospital	Lansing	Michigan
United States	Lawrence Memorial Hospital	Lawrence	Kansas
United States	Lima Memorial Hospital	Lima	Ohio
United States	Meeker County Memorial Hospital	Litchfield	Minnesota
United States	Saint Mary Mercy Hospital	Livonia	Michigan
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Marshfield Clinic	Marshfield	Wisconsin
United States	Saint Joseph's Hospital	Marshfield	Wisconsin
United States	Saint Luke's Hospital	Maumee	Ohio
United States	Toledo Clinic Cancer Centers-Maumee	Maumee	Ohio
United States	Toledo Radiation Oncology at Northwest Ohio Onocolgy Center	Maumee	Ohio
United States	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana
United States	Orange Regional Medical Center	Middletown	New York
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Virginia Piper Cancer Institute	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Community Medical Hospital	Missoula	Montana
United States	Guardian Oncology and Center for Wellness	Missoula	Montana
United States	Montana Cancer Specialists	Missoula	Montana
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	Fox Chase Cancer Center at Virtua Memorial Hospital of Burlington County	Mount Holly	New Jersey
United States	Edward Hospital/Cancer Center	Naperville	Illinois
United States	Cancer Center of Kansas - Newton	Newton	Kansas
United States	Sutter Cancer Research Consortium	Novato	California
United States	Saint Charles Hospital	Oregon	Ohio
United States	Toledo Clinic Cancer Centers-Oregon	Oregon	Ohio
United States	Cancer Center of Kansas - Parsons	Parsons	Kansas
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Saint Joseph Mercy Port Huron	Port Huron	Michigan
United States	Adventist Medical Center	Portland	Oregon
United States	Cancer Center of Kansas - Pratt	Pratt	Kansas
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Marshfield Clinic at James Beck Cancer Center	Rhinelander	Wisconsin
United States	Marshfield Clinic-Rice Lake Center	Rice Lake	Wisconsin
United States	Reid Hospital and Health Care Services	Richmond	Indiana
United States	Highland Hospital	Rochester	New York
United States	Interlakes Foundation Inc-Rochester	Rochester	New York
United States	University of Rochester	Rochester	New York
United States	Saint Mary's of Michigan	Saginaw	Michigan
United States	Oncology Care Associates PLLC	Saint Joseph	Michigan
United States	Regions Hospital	Saint Paul	Minnesota
United States	Saint Joseph's Hospital - Healtheast	Saint Paul	Minnesota
United States	Cancer Center of Kansas - Salina	Salina	Kansas
United States	Salina Regional Health Center	Salina	Kansas
United States	Audie L Murphy Veterans Affairs Hospital	San Antonio	Texas
United States	University Hospital	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	California Pacific Medical Center-Pacific Campus	San Francisco	California
United States	North Coast Cancer Care	Sandusky	Ohio
United States	Memorial University Medical Center	Savannah	Georgia
United States	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington
United States	Group Health Cooperative of Puget Sound Oncology Consortium	Seattle	Washington
United States	Group Health Cooperative-Seattle	Seattle	Washington
United States	Harborview Medical Center	Seattle	Washington
United States	Minor and James Medical PLLC	Seattle	Washington
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	The Polyclinic	Seattle	Washington
United States	University of Washington Medical Center	Seattle	Washington
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
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	Providence Hospital-Southfield Cancer Center	Southfield	Michigan
United States	Cancer Care Northwest - Spokane South	Spokane	Washington
United States	Cancer Research for the Ozarks NCORP	Springfield	Missouri
United States	Memorial Medical Center	Springfield	Illinois
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Flower Hospital	Sylvania	Ohio
United States	Mercy Hospital of Tiffin	Tiffin	Ohio
United States	Mercy Saint Anne Hospital	Toledo	Ohio
United States	Saint Vincent Mercy Medical Center	Toledo	Ohio
United States	The Toledo Hospital/Toledo Children's Hospital	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	Upper Valley Medical Center	Troy	Ohio
United States	Carle Cancer Center	Urbana	Illinois
United States	Carle Clinic-Urbana Main	Urbana	Illinois
United States	South Georgia Medical Center	Valdosta	Georgia
United States	Sutter Solano Medical Center/Cancer Center	Vallejo	California
United States	Virtua West Jersey Hospital Voorhees	Voorhees	New Jersey
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Marshfield Clinic-Wausau Center	Wausau	Wisconsin
United States	Fulton County Health Center	Wauseon	Ohio
United States	Cancer Center of Kansas - Wellington	Wellington	Kansas
United States	Wenatchee Valley Hospital and Clinics	Wenatchee	Washington
United States	Diagnostic and Treatment Center	Weston	Wisconsin
United States	Marshfield Clinic - Weston Center	Weston	Wisconsin
United States	Associates In Womens Health	Wichita	Kansas
United States	Cancer Center of Kansas - Main Office	Wichita	Kansas
United States	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas
United States	Via Christi Regional Medical Center	Wichita	Kansas
United States	Wichita CCOP	Wichita	Kansas
United States	Geisinger South Wilkes-Barre	Wilkes-Barre	Pennsylvania
United States	Clinton Memorial Hospital	Wilmington	Ohio
United States	Cancer Center of Kansas - Winfield	Winfield	Kansas
United States	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin
United States	Woodwinds Health Campus	Woodbury	Minnesota
United States	Greene Memorial Hospital	Xenia	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	Changes in angiogenic factors (PDGF-AA, PDGF-BB) and angiogenesis-related soluble factors (VEGF, VEGF-D, VEGFR-1, VEGFR-2 angiopoietin-2, PDGFR-AA and PDGFR-BB)	For assessment of the relationship of markers to clinical response, PET response and toxicity, logistic models will be used.	Baseline to up to 7 years	No
Primary	PFS	Analyzed using stratified logrank statistic, calculated from the stratified Cox-model.	From date of registration (defined as date of randomization) to date of first observation of progressive disease, death due to any cause or symptomatic deterioration, assessed up to 7 years	No
Secondary	CRb-PFS, based on increase in image tumor size will be centrally assessed by the American College of Radiology Imaging Network	Analyzed using the stratified logrank statistic, calculated from the stratified Cox-model.	From date of registration to date of first documentation of one of the following events: death; first documentation of progression; development of new lesions or disease not identified on CT or MRI; or symptomatic deterioration, assessed up to 7 years	No
Secondary	Response probabilities in patients with measurable disease, assessed using modified RECIST	A 0.025 one-sided test will be used.	Up to 7 years	No