tinational Phase 3 studies were conducted in patients with unresectable or metastatic malignant gastrointestinal stromal tumors (GIST). The two study designs were similar allowing a predefined combined analysis of safety and efficacy. A total of 1640 patients were enrolled into the two studies and randomized 1:1 to receive either 400 mg or 800 mg orally dailycontinuously until disease progression or unacceptable toxicity. Patients in the 400 mg dailytreatment group who experienced disease progression were permitted to crossover to receive treatment with 800 mg daily.The studies were designed to compare response rates, progression-free survival and overall survival between the dose groups. Median age at patient entry was 60 years. Males comprised 58% of the patients enrolled. All patients had a pathologic diagnosis of CD117 positive unresectable and/or metastatic malignant GIST.
The primary objective of the two studies was to eva luate either progression-free survival (PFS) with a secondary objective of overall survival (OS) in one study or overall survival with a secondary objective of PFS in the other study. A planned analysis of both OS and PFS from the combined datasets from these two studies was conducted. Results from this combined analysis are shown in Table 21.
Table 21 Overall Survival, Progression-Free Survival and Tumor Response Rates in the Phase 3 GIST Trials Gleevec 400 mg
N=818 Gleevec 800 mg
N=822
Progression-Free Survival (months)
Median 18.9 23.2
95% CI 17.4-21.2 20.8-24.9
Overall Survival (months) 49.0 48.7
95% CI 45.3-60.0 45.3-51.6
Best Overall Tumor Response
Complete Response (CR)
Partial Response (PR) 43 (5.3%)
377 (46.1%) 41 (5.0%)
402 (48.9%)
Median follow up for the combined studies was 37.5 months. There were no observed differences in overall survival between the treatment groups (p=0.98).Patients who crossed over following disease progression from the 400 mg/day treatment group to the 800 mg/day treatment group (n=347) had a 3.4 month median and a 7.7 month mean exposure to Gleevec following crossover.
One open-label, multinational Phase 2 study was conducted in patients withKit (CD117) positive unresectable or metastatic malignant GIST. In this study, 147 patients were enrolled and randomized to receive either 400 mg or 600 mg orally q.d. for up to 36 months. The primary outcome of the study was objective response rate. Tumors were required to be measurable at entry in at least one site of disease, and response characterization was based on Southwestern Oncology Group (SWOG) criteria. There were no differences in response rates between the 2 dose groups. The response rate was 68.5% for the 400 mg group and 67.6% for the 600 mg group.The median time to response was 12 weeks (range was 3-98 weeks) and the estimated median duration of response is 118 weeks (95% CI: 86, not reached).
Adjuvant Treatment of GIST
In the adjuvant setting, Gleevec was investigated in a multicenter, double-blind, placebo-controlled, randomized study involving 713 patients. After complete gross resection of primary GIST, patients were randomized to one of the two arms: Gleevec at 400mg/day or matching placebo for one year. The ages of these patients ranged from 18 to 91years. Patients were included who had a histologic diagnosis of primary GIST expressing KIT protein by immunochemistry and a tumor size ≥3cm in maximum dimension, with complete gross resection of primary GIST within 14 to 70 days prior
