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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00324987
First received: May 10, 2006
Last updated: October 16, 2014
Last verified: October 2014
  Purpose

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.


Condition Intervention Phase
Gastrointestinal Stromal Tumor
Drug: imatinib mesylate
Biological: bevacizumab
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III Randomized Study of Imatinib, With or Without Bevacizumab (NSC-704865), in Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumors

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • PFS [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Analyzed using stratified logrank statistic, calculated from the stratified Cox-model.


Secondary Outcome Measures:
  • Response probabilities in patients with measurable disease, assessed using modified RECIST [ Time Frame: Up to 7 years ] [ Designated as safety issue: No ]
    A 0.025 one-sided test will be used.

  • CRb-PFS, based on increase in image tumor size will be centrally assessed by the American College of Radiology Imaging Network [ Time Frame: 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 ] [ Designated as safety issue: No ]
    Analyzed using the stratified logrank statistic, calculated from the stratified Cox-model.


Other Outcome Measures:
  • 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) [ Time Frame: Baseline to up to 7 years ] [ Designated as safety issue: No ]
    For assessment of the relationship of markers to clinical response, PET response and toxicity, logistic models will be used.


Estimated Enrollment: 572
Study Start Date: April 2008
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (CLOSED TO ACCRUAL 10/1/2009) (imatinib and bevacizumab)
Patients receive imatinib mesylate PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: imatinib mesylate
Given PO
Other Names:
  • CGP 57148
  • Gleevec
  • Glivec
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Active Comparator: Arm II (CLOSED TO ACCRUAL 10/1/2009) (imatinib)
Patients receive imatinib mesylate PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: imatinib mesylate
Given PO
Other Names:
  • CGP 57148
  • Gleevec
  • Glivec
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00324987

  Show 193 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Charles Blanke Southwest Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00324987     History of Changes
Other Study ID Numbers: NCI-2009-00776, NCI-2009-00776, CDR0000482236, S0502, S0502, U10CA180888, U10CA032102
Study First Received: May 10, 2006
Last Updated: October 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Gastrointestinal Stromal Tumors
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Connective and Soft Tissue
Neoplasms, Connective Tissue
Antibodies
Antibodies, Monoclonal
Bevacizumab
Imatinib
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antineoplastic Agents
Enzyme Inhibitors
Growth Inhibitors
Growth Substances
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014