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

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

Status
Terminated
Phases
Phase 3
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00324987
Acronym
S0502
Enrollment
12
Registered
2006-05-11
Start date
2008-04-30
Completion date
2015-07-31
Last updated
2017-09-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Gastrointestinal Stromal Tumor

Brief 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.

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 triphosphate (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.

Interventions

BIOLOGICALBevacizumab

Given IV

DRUGImatinib Mesylate

Given PO

OTHERLaboratory Biomarker Analysis

Correlative studies

OTHERPharmacological Study

Correlative studies

Sponsors

National Cancer Institute (NCI)
Lead SponsorNIH

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

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

Design outcomes

Primary

MeasureTime frameDescription
Progression Free SurvivalUp to 7 yearsFrom date of registration (defined as date of randomization) to date of first observation of progressive disease, death due to any cause or symptomatic deterioration. Patients last known to be alive and progression free are censored at last date of contact. Progression is defined as one or more of the following: 20% increase in the sum of longest diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy), provided at least one target lesion does NOT demonstrate uniform hypoattenuation over \> 90% of maximal cross sectional area; unequivocal progression of non-measurable disease; appearance of new lesion/site that is not uniformly hypoattenuating; a hyperattenuating region within a previously cystic/uniformly hypoattenuating lesion will be considered progressive disease if hyperattenuating region is either \>= 1 cm in longest diameter or round/oval and forms acute margins with border of target lesion; death due to disease.

Secondary

MeasureTime frameDescription
Response RateUp to 7 yearsConfirmed response (CR) is two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. Partial response (PR) is two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration. Unconfirmed CR is one objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.
Overall Survivalup to 7 yearsFrom date of registration (defined as date of randomization) to date of death due to any cause. Patients last known to be alive are censored at last date of contact. Note: median was not reached in the Imatinib arm due to limited follow-up data.
Central-review Based Progression-free Survival (CRb-PFS)up to 7 yearsFrom date of registration (defined as date of randomization) to date of first documentation of one of the following events: death; first documentation of progression based on central review of the appropriate computed tomography (CT) or magnetic resonance imaging (MRI) scans; development of new lesions or disease not identified on CT or MRI; or symptomatic deterioration. Patients not experiencing any of these events will be censored at last date of contact.
Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study DrugUp to 7 yearsOnly adverse events that are possibly, probably or definitely related to study drug are reported.

Countries

Canada, United States

Participant flow

Participants by arm

ArmCount
Imatinib + Bevacizumab
Patients receive 400 or 800mg imatinib mesylate PO QD on days 1-21 and 15 mg/kg bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
6
Imatinib
Patients receive 400 or 800mg imatinib mesylate PO QD on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
6
Total12

Withdrawals & dropouts

PeriodReasonFG000FG001
Overall StudyAdverse Event21
Overall StudyProgression11
Overall Studysymptomatic deterioration, toxicity, etc23
Overall StudyWithdrawal by Subject11

Baseline characteristics

CharacteristicImatinib + BevacizumabImatinibTotal
Age, Continuous64.7 years57.9 years59.9 years
Disease Status
Measurable
5 participants5 participants10 participants
Disease Status
Non-measurable
1 participants1 participants2 participants
Ethnicity (NIH/OMB)
Hispanic or Latino
0 Participants0 Participants0 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
5 Participants5 Participants10 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
1 Participants1 Participants2 Participants
Performance Status
0
5 participants4 participants9 participants
Performance Status
>=1
1 participants2 participants3 participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Asian
1 Participants1 Participants2 Participants
Race (NIH/OMB)
Black or African American
0 Participants0 Participants0 Participants
Race (NIH/OMB)
More than one race
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants1 Participants1 Participants
Race (NIH/OMB)
White
5 Participants4 Participants9 Participants
Sex: Female, Male
Female
3 Participants5 Participants8 Participants
Sex: Female, Male
Male
3 Participants1 Participants4 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
— / —— / —
other
Total, other adverse events
2 / 55 / 6
serious
Total, serious adverse events
2 / 50 / 6

Outcome results

Primary

Progression Free Survival

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. Patients last known to be alive and progression free are censored at last date of contact. Progression is defined as one or more of the following: 20% increase in the sum of longest diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy), provided at least one target lesion does NOT demonstrate uniform hypoattenuation over \> 90% of maximal cross sectional area; unequivocal progression of non-measurable disease; appearance of new lesion/site that is not uniformly hypoattenuating; a hyperattenuating region within a previously cystic/uniformly hypoattenuating lesion will be considered progressive disease if hyperattenuating region is either \>= 1 cm in longest diameter or round/oval and forms acute margins with border of target lesion; death due to disease.

Time frame: Up to 7 years

Population: No scientific conclusions were forthcoming because of the small number of patients entered in the study.

ArmMeasureValue (MEDIAN)
Imatinib + BevacizumabProgression Free Survival30 months
ImatinibProgression Free Survival81 months
Secondary

Central-review Based Progression-free Survival (CRb-PFS)

From date of registration (defined as date of randomization) to date of first documentation of one of the following events: death; first documentation of progression based on central review of the appropriate computed tomography (CT) or magnetic resonance imaging (MRI) scans; development of new lesions or disease not identified on CT or MRI; or symptomatic deterioration. Patients not experiencing any of these events will be censored at last date of contact.

Time frame: up to 7 years

Population: Data not collected as study accrued only 2% of the 572 patients planned. No scientific conclusions were forthcoming because of the small number of patients entered in the study.

Secondary

Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug

Only adverse events that are possibly, probably or definitely related to study drug are reported.

Time frame: Up to 7 years

Population: Eligible patients who received any treatment and were assessed for adverse events are included in this summary.

ArmMeasureGroupValue (NUMBER)
Imatinib + BevacizumabNumber of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study DrugFatigue (asthenia, lethargy, malaise)1 Participants
Imatinib + BevacizumabNumber of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study DrugHemoglobin1 Participants
Imatinib + BevacizumabNumber of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study DrugHemorrhage, GI - Upper GI NOS1 Participants
Imatinib + BevacizumabNumber of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study DrugINR (of prothrombin time)0 Participants
Imatinib + BevacizumabNumber of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study DrugProteinuria1 Participants
Imatinib + BevacizumabNumber of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study DrugThrombosis/embolism (vascular access-related)0 Participants
ImatinibNumber of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study DrugProteinuria0 Participants
ImatinibNumber of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study DrugFatigue (asthenia, lethargy, malaise)0 Participants
ImatinibNumber of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study DrugINR (of prothrombin time)1 Participants
ImatinibNumber of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study DrugHemoglobin0 Participants
ImatinibNumber of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study DrugThrombosis/embolism (vascular access-related)1 Participants
ImatinibNumber of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study DrugHemorrhage, GI - Upper GI NOS0 Participants
Secondary

Overall Survival

From date of registration (defined as date of randomization) to date of death due to any cause. Patients last known to be alive are censored at last date of contact. Note: median was not reached in the Imatinib arm due to limited follow-up data.

Time frame: up to 7 years

Population: No scientific conclusions were forthcoming because of the small number of patients entered in the study.

ArmMeasureValue (MEDIAN)
Imatinib + BevacizumabOverall Survival30 months
ImatinibOverall Survival0 months
Secondary

Response Rate

Confirmed response (CR) is two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. Partial response (PR) is two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration. Unconfirmed CR is one objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.

Time frame: Up to 7 years

Population: Only eligible and evaluable patients included. No scientific conclusions were forthcoming because of the small number of patients entered in the study.

ArmMeasureCategoryValue (COUNT_OF_PARTICIPANTS)
Imatinib + BevacizumabResponse RateAssessment Inadequate2 Participants
Imatinib + BevacizumabResponse RateUnconfirmed CR0 Participants
Imatinib + BevacizumabResponse RateStable/No Response1 Participants
ImatinibResponse RateAssessment Inadequate2 Participants
ImatinibResponse RateUnconfirmed CR1 Participants
ImatinibResponse RateStable/No Response2 Participants

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026