A Study of the Efficacy and Safety of Imatinib Mesylate in Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing C-kit Gene

Study Overview
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Brief Summary
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In the core study, participants with unresectable or metastatic gastrointestinal stromal tumors expressing c-kit were treated with either 400 mg or 600 mg imatinib mesylate for 3 years. The 10 year extension study allowed participants, who successfully completed the core study, to continue study treatment with imatinib mesylate provided they still benefited from treatment and did not demonstrate safety concerns as per the investigator's opinion.

Official Title
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Open, Randomized, Phase II Study of Glivec in Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing C-kit Plus 10 Year Extension Study

Conditions
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Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumor (GIST)

Intervention / Treatment
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* Drug: Imatinib mesylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and non-pregnant women ≥18 years of age with the histopathologically documented diagnosis of malignant GIST that was unresectable and/or metastatic. Confirmation of KIT (CD117) expression via immunohistochemical analysis of tumor sample was also required At least one measurable lesion, as defined by Southwestern Oncology Group (SWOG) Solid Tumor Response Criteria, which had not been previously embolized or irradiated Performance status ≤3 as defined by the Eastern Cooperative Oncology Group (ECOG) criteria, as well as a life expectancy ≥6 months and adequate end organ function defined as follows: Total bilirubin <1.5 times upper limit of normal (ULN), aspartate aminotransferase (SGOT) and alanine aminotransferase (SGPT) <2.5 x ULN (or <5 x ULN if hepatic metastases were present), creatinine <1.5 x ULN, absolute neutrophil count (ANC) >1.5 x 10^9/L, platelet count >100 x 10^9/L Exclusion Criteria: Patients with fewer than five years of disease-free survival from any other (non-GIST) malignancy except if the other malignancy was not currently clinically significant and did not require active intervention or if the other malignancy was a basal cell skin cancer or a cervical carcinoma in situ Patients with known brain metastases Evidence of any of the following disorders: Grade III/IV cardiac failure as defined by the New York Heart Association Criteria, severe concomitant disease, acute or known chronic liver disease (i.e. chronic active hepatitis, cirrhosis) or HIV infection Chemotherapy or other investigational therapy within four weeks prior to study entry (six weeks for nitrosourea or mitomycin-C) and/or radiotherapy to ≥25% of the bone marrow Inability to cooperate Major surgery within two weeks or exposure to other investigational agents within 28 days of entry into the study Other protocol-defined inclusion / exclusion criteria may have applied.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: imatinib mesylate 400 mg<br>400 mg once daily | Drug: Imatinib mesylate<br>* Participants were randomized 1:1 to receive imatinib mesylate 400 mg/day or 600 mg/day. Upon unsatisfactory treatment effect on the starting dose of 400 mg/day or 600 mg/day imatinib mesylate, in the opinion of the treating physician, a dose increase up to 600 mg/day or 800 mg/day, was allowed provided that the participant continued to benefit from the treatment and in the absence of safety concerns.<br>* Other names: Glivec, Gleevec;|
| Experimental: imatinib mesylate 600 mg<br>600 mg once daily | Drug: Imatinib mesylate<br>* Participants were randomized 1:1 to receive imatinib mesylate 400 mg/day or 600 mg/day. Upon unsatisfactory treatment effect on the starting dose of 400 mg/day or 600 mg/day imatinib mesylate, in the opinion of the treating physician, a dose increase up to 600 mg/day or 800 mg/day, was allowed provided that the participant continued to benefit from the treatment and in the absence of safety concerns.<br>* Other names: Glivec, Gleevec;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Tumor Response (Core) | Best tumor response was based on the Southwestern Oncology Group (SWOG) criteria. Objective tumor response assessments were categorized according to the following criteria: complete response (CR), partial response (PR), no change or stable disease (SD), progression of disease (PD), unknown where the progression has not been documented and one or more measurable or evaluable sites have not been assessed (UNK), status after resection for progression (RP), status after resection for safety (RS), status after preventive resection (RPR), progressive after first resection (PDR) and not evaluable. Any tumor assessment after surgical resection for preventative reasons was treated like tumor assessments of UNK for calculation of best response. Tumor assessments with current objective status = RP, RS or PDR were treated like assessments with objective tumor status = PD n the calculation of best response. | Month 36 | 
| Best Tumor Response (Core + Extension) | Best tumor response was based on the Southwestern Oncology Group (SWOG) criteria. Objective tumor response assessments were categorized according to the following criteria: complete response (CR), partial response (PR), no change or stable disease (SD), progression of disease (PD), unknown where the progression has not been documented and one or more measurable or evaluable sites have not been assessed (UNK), status after resection for progression (RP), status after resection for safety (RS), status after preventive resection (RPR), progressive after first resection (PDR) and not evaluable. Any tumor assessment after surgical resection for preventative reasons was treated like tumor assessments of UNK for calculation of best response. Tumor assessments with current objective status = RP, RS or PDR were treated like assessments with objective tumor status = PD n the calculation of best response. | Month 156 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (Core) | Overall survival was analyzed as time to event for all participants. Participants who did not die were censored at the last date known alive, which is the last date of any study medication, laboratory sample, tumor assessment, adverse event end date or date of last contact. | Date of first imatinib dose to the date of death during the core period, up to 36 months. | 
| Overall Survival (Core + Extension) | Overall survival was analyzed as time to event for all participants. Participants who did not die were censored at the last date known alive, which is the last date of any study medication, laboratory sample, tumor assessment, adverse event end date or date of last contact. | Date of first imatinib dose to the date of death during the core and extension periods, up to 156 months. | 
| Duration of Response (Core) | Duration of response was analyzed as time to event for all participants whose best response was at least a PR. The onset of response was the first tumor assessment that was subsequently confirmed to constitute at least a partial best response. The end of response was the first tumor assessment noting PD. | Date of confirmed best PR or CR to date of confirmed disease progression during the core period, up to 36 months. | 
| Duration of Response (Core + Extension) | Duration of response was analyzed as time to event for all participants whose best response was at least a PR. The onset of response was the first tumor assessment that was subsequently confirmed to constitute at least a partial best response. The end of response was the first tumor assessment noting PD. | Date of confirmed best PR or CR to date of confirmed disease progression during the core and extension periods, up to 156 months | 
| Progression Free Survival (PFS) (Core + Extension) | Progression free survival was analyzed as a time to event for each participant. If a participant had no event, then the PFS was censored at the last tumor assessment. | Date of first imatinib dose to earliest date of progression, resection due to safety/progression, death due to any cause or discontinuation due to unsatisfactory therapeutic effect during the core and extension periods, up to 156 months. | 
| Time to Treatment Failure (Core) | Time to treatment failure was analyzed as time to event for all participants. Participants who had neither progressed, died nor discontinued from the trial for any reason other than the condition no longer required therapy were censored for analysis ate the time of their last tumor assessment. | Date of first imatinib dose to date of earliest occurrence of progression, death due to any cause, or discontinuation from the trial for any reason other than the condition no longer required therapy during the core period, up to 36 months. | 
| Time to Treatment Failure (Core + Extension) | Time to treatment failure was analyzed as time to event for all participants. Participants who had neither progressed, died nor discontinued from the trial for any reason other than the condition no longer required therapy were censored for analysis at the time of their last tumor assessment. | Date of first imatinib dose to date of earliest occurrence of progression, death due to any cause, or discontinuation from the trial for any reason other than the condition no longer required therapy during the core and extension periods, up to 156 month. | 
| Time to Onset of Response (Core) | Time to response was analyzed as time to event for all participants. Participants who did not meet the definition of confirmed PR/CR were censored at the time of their last progression-free tumor assessment. | Date of first imatinib dose to the date of the first tumor assessment that was later confirmed to be at least a partial response during the core period, up to 36 months. | 
| Time to Onset of Response (Core + Extension) | Time to response was analyzed as time to event for all participants. Participants who did not meet the definition of confirmed PR/CR were censored at the time of their last progression-free tumor assessment. | Date of first imatinib dose to the date of the first tumor assessment that was later confirmed to be at least a partial response during the core and extension periods, up to 156 months. | 
| Time to Progression (Core + Extension) | Time to progression was analyzed as time to event for all participants. Participants who had neither progressed, died nor discontinued from the trial for any reason other than the condition no longer required therapy were censored for analysis at the time of their last tumor assessment. | Date of first imatinib dose to date of progression or death due to disease indication or discontinuation due to unsatisfactory therapeutic effect during the core and extension periods, up to 156 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GIST, c-kit, imatinib mesylate