Imatinib (Page 9 of 10)

14.7 Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia

One open-label, multicenter, Phase 2 study was conducted testing imatinib mesylate in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 14 patients with Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia (HES/CEL). HES patients were treated with 100 mg to 1,000 mg of imatinib mesylate daily. The ages of these patients ranged from 16 to 64 years. A further 162 patients with HES/CEL aged 11 to 78 years were reported in 35 published case reports and case series. These patients received imatinib mesylate at doses of 75 mg to 800 mg daily. Hematologic response rates are summarized in Table 24. Response durations for literature patients ranged from 6+ weeks to 44 months.

Table 24: Response in HES/CEL

Cytogenetic Abnormality Number of Patients Complete Hematological Response N (%) Partial Hematological Response N (%)
Positive FIP1L1-PDGFRα Fusion Kinase 61 61 (100) 0
Negative FIP1L1-PDGFRα Fusion Kinase 56 12 (21) 9 (16)
Unknown Cytogenetic Abnormality 59 34 (58) 7 (12)
Total 176 107 (61) 23 (13)

Abbreviations: CEL, chronic eosinophilic leukemia; HES, hypereosinophilic syndrome; PDGFR, platelet-derived growth factor receptor.

14.8 Dermatofibrosarcoma Protuberans

Dermatofibrosarcoma Protuberans (DFSP) is a cutaneous soft tissue sarcoma. It is characterized by a translocation of chromosomes 17 and 22 that results in the fusion of the collagen type 1 alpha 1 gene and the PDGF B gene.

An open-label, multicenter, Phase 2 study was conducted testing imatinib mesylate in a diverse population of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 12 patients with DFSP who were treated with imatinib mesylate 800 mg daily (age range 23 to 75 years). DFSP was metastatic, locally recurrent following initial surgical resection and not considered amenable to further surgery at the time of study entry. A further 6 DFSP patients treated with imatinib mesylate are reported in 5 published case reports, their ages ranging from 18 months to 49 years. The total population treated for DFSP therefore comprises 18 patients, 8 of them with metastatic disease. The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) imatinib mesylate daily. A single pediatric patient received 400 mg/m2 /daily, subsequently increased to 520 mg/m2 /daily. Ten patients had the PDGF B gene rearrangement, 5 had no available cytogenetics and 3 had complex cytogenetic abnormalities. Responses to treatment are described in Table 25.

Table 25: Response in DFSP

Number of Patients (n=18) %
Complete Response 7 39
Partial Response * 8 44
Total Responders 15 83

* 5 patients made disease free by surgery.

Twelve of these 18 patients either achieved a complete response (7 patients) or were made disease free by surgery after a partial response (5 patients, including one child) for a total complete response rate of 67%. A further 3 patients achieved a partial response, for an overall response rate of 83%. Of the 8 patients with metastatic disease, five responded (62%), three of them completely (37%). For the 10 study patients with the PDGF B gene rearrangement, there were 4 complete and 6 partial responses. The median duration of response in the Phase 2 study was 6.2 months, with a maximum duration of 24.3 months, while in the published literature it ranged between 4 weeks and more than 20 months.

14.9 Gastrointestinal Stromal Tumors

Two open-label, randomized, multinational Phase 3 studies were conducted in patients with unresectable or metastatic malignant 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 daily continuously until disease progression or unacceptable toxicity. Patients in the 400 mg daily treatment 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 evaluate 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 26.

Table 26: Overall Survival, Progression-Free Survival and Tumor Response Rates in the Phase 3 GIST Trials

Imatinib Mesylate 400 mg N=818 Imatinib Mesylate 800 mg N=822
Progression-Free Survival (months)
Median 18.9 23.2
95% CI 17.4 to 21.2 20.8 to 24.9
Overall Survival (months) 49.0 48.7
95% CI 45.3 to 60.0 45.3 to 51.6
Best Overall Tumor Response
Complete Response (CR) 43 (5.3%) 41 (5.0%)
Partial Response (PR) 377 (46.1%) 402 (48.9%)

Abbreviation: GIST, gastrointestinal stromal tumors.

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 imatinib mesylate following crossover.

One open-label, multinational Phase 2 study was conducted in patients with Kit (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 every day 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 to 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, imatinib mesylate was investigated in a multicenter, double-blind, placebo-controlled, randomized trial involving 713 patients (Study 1). Patients were randomized one to one to imatinib mesylate at 400 mg/day or matching placebo for 12 months. The ages of these patients ranged from 18 to 91 years. Patients were included who had a histologic diagnosis of primary GIST, expressing KIT protein by immunochemistry and a tumor size greater than or equal to 3 cm in maximum dimension with complete gross resection of primary GIST within 14 to 70 days prior to registration.

Recurrence-free survival (RFS) was defined as the time from date of randomization to the date of recurrence or death from any cause. In a planned interim analysis, the median follow up was 15 months in patients without a RFS event; there were 30 RFS events in the 12-month imatinib mesylate arm compared to 70 RFS events in the placebo arm with a hazard ratio of 0.398 (95% CI: 0.259, 0.610), p less than 0.0001. After the interim analysis of RFS, 79 of the 354 patients initially randomized to the placebo arm were eligible to cross over to the 12-month imatinib mesylate arm. Seventy-two of these 79 patients subsequently crossed over to imatinib mesylate therapy. In an updated analysis, the median follow-up for patients without a RFS event was 50 months. There were 74 (21%) RFS events in the 12-month imatinib mesylate arm compared to 98 (28%) events in the placebo arm with a hazard ratio of 0.718 (95% CI: 0.531-0.971) (Figure 3). The median follow-up for OS in patients still living was 61 months. There were 26 (7%) and 33 (9%) deaths in the 12-month imatinib mesylate and placebo arms, respectively with a hazard ratio of 0.816 (95% CI: 0.488-1.365).

Figure 3: Study 1 Recurrence-Free Survival (ITT Population)

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A second randomized, multicenter, open-label, Phase 3 trial in the adjuvant setting (Study 2) compared 12 months of imatinib mesylate treatment to 36 months of imatinib mesylate treatment at 400 mg/day in adult patients with KIT (CD117) positive GIST after surgical resection with one of the following: tumor diameter greater than 5 cm and mitotic count greater than 5/50 high power fields (HPF), or tumor diameter greater than 10 cm and any mitotic count, or tumor of any size with mitotic count greater than 10/50 HPF, or tumors ruptured into the peritoneal cavity. There were a total of 397 patients randomized in the trial with 199 patients on the 12-month treatment arm and 198 patients on the 36-month treatment arm. The median age was 61 years (range 22 to 84 years).

RFS was defined as the time from date of randomization to the date of recurrence or death from any cause. The median follow-up for patients without a RFS event was 42 months. There were 84 (42%) RFS events in the 12-month treatment arm and 50 (25%) RFS events in the 36-month treatment arm. Thirty-six months of imatinib mesylate treatment significantly prolonged RFS compared to 12 months of imatinib mesylate treatment with a hazard ratio of 0.46 (95% CI: 0.32, 0.65), p less than 0.0001 (Figure 4).

The median follow-up for overall survival (OS) in patients still living was 48 months. There were 25 (13%) deaths in the 12-month treatment arm and 12 (6%) deaths in the 36-month treatment arm. Thirty-six months of imatinib mesylate treatment significantly prolonged OS compared to 12 months of imatinib mesylate treatment with a hazard ratio of 0.45 (95% CI: 0.22, 0.89), p=0.0187 (Figure 5).

Figure 4: Study 2 Recurrence-Free Survival (ITT Population)

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Figure 5: Study 2 Overall Survival (ITT Population)

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