Imatinib Mesylate: Package Insert and Label Information (Page 5 of 6)

14.2 Pediatric CML

A total of 51 pediatric patients with newly diagnosed and untreated CML in chronic phase were enrolled in an open-label, multicenter, single-arm Phase 2 trial. Patients were treated with Imatinib mesylate tablet 340 mg/m2 /day, with no interruptions in the absence of dose limiting toxicity. Complete hematologic response (CHR) was observed in 78% of patients after 8 weeks of therapy. The complete cytogenetic response rate (CCyR) was 65%, comparable to the results observed in adults. Additionally, partial cytogenetic response (PCyR) was observed in 16%. The majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 6.74 months. Patients were allowed to be removed from protocol therapy to undergo alternative therapy including hematopoietic stem cell transplantation. Thirty-one children received stem cell transplantation. Of the 31 children, 5 were transplanted after disease progression on study and 1 withdrew from study during first week treatment and received transplant approximately 4 months after withdrawal. Twenty-five children withdrew from protocol therapy to undergo stem cell transplant after receiving a median of 9 twenty-eight day courses (range 4 to 24). Of the 25 patients 13 (52%) had CCyR and 5 (20%) had PCyR at the end of protocol therapy.

One open-label, single-arm study enrolled 14 pediatric patients with Ph+ chronic phase CML recurrent after stem cell transplant or resistant to interferon-alpha therapy. These patients had not previously received Imatinib mesylate tablet and ranged in age from 3 to 20 years old; 3 were 3 — 11 years old, 9 were 12 to 18 years old, and 2 were > 18 years old. Patients were treated at doses of 260 mg/m2 /day (n = 3), 340 mg/m2 /day (n = 4), 440 mg/m2 /day (n = 5) and 570 mg/m2 /day (n = 2). In the 13 patients for whom cytogenetic data are available, 4 achieved a major cytogenetic response, 7 achieved a complete cytogenetic response, and 2 had a minimal cytogenetic response.

In a second study, 2 of 3 patients with Ph+ chronic phase CML resistant to interferon-alpha therapy achieved a complete cytogenetic response at doses of 242 and 257 mg/m2 /day.

14.3 Acute Lymphoblastic Leukemia

A total of 48 Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) patients with relapsed/refractory disease were studied, 43 of whom received the recommended Imatinib Mesylate dose of 600 mg/day. In addition 2 patients with relapsed/refractory Ph+ ALL received Imatinib Mesylate 600 mg/day in a phase 1 study.

Confirmed and unconfirmed hematologic and cytogenetic response rates for the 43 relapsed/refractory Ph+ALL phase 2 study patients and for the 2 phase 1 patients are shown in Table 21. The median duration of hematologic response was 3.4 months and the median duration of MCyR was 2.3 months.

Table 21: Effect of Imatinib mesylate tablet on Relapsed/Refractory Ph+ ALL.

Phase 2 Study (N = 43) n(%) Phase 1 Study (N = 2) n(%)
CHR 8 (19) 2 (100)
NEL 5 (12)
RTC/PHR 11 (26)
MCyR 15 (35)
CCyR 9 (21)
PCyR 6 (14)

14.5 Myelodysplastic/Myeloproliferative Diseases

An open-label, multicenter, phase 2 clinical trial was conducted testing Imatinib mesylate tablet in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD. These patients were treated with Imatinib mesylate tablet 400 mg daily. The ages of the enrolled patients ranged from 20 to 86 years. A further 24 patients with MDS/MPD aged 2 to 79 years were reported in 12 published case reports and a clinical study. These patients also received Imatinib mesylate tablet at a dose of 400 mg daily with the exception of three patients who received lower doses. Of the total population of 31 patients treated for MDS/MPD, 14 (45%) achieved a complete hematological response and 12 (39%) a major cytogenetic response (including 10 with a complete cytogenetic response). Sixteen patients had a translocation, involving chromosome 5q33 or 4q12, resulting in a PDGFR gene re-arrangement. All of these patients responded hematologically (13 completely). Cytogenetic response was evaluated in 12 out of 14 patients, all of whom responded (10 patients completely). Only 1 (7%) out of the 14 patients without a translocation associated with PDGFR gene re-arrangement achieved a complete hematological response and none achieved a major cytogenetic response. A further patient with a PDGFR gene re-arrangement in molecular relapse after bone marrow transplant responded molecularly. Median duration of therapy was 12.9 months (0.8 to 26.7) in the 7 patients treated within the phase 2 study and ranged between 1 week and more than 18 months in responding patients in the published literature. Results are provided in Table 22. Response durations of phase 2 study patients ranged from 141+ days to 457+ days.

Table 22: Response in MDS/MPD

Number of patients Complete Hematologic Major Cytogenetic
Response Response
N n (%) n (%)
Overall Population 31 14 (45) 12 (39)
Chromosome 5 Translocation 14 11 (79) 11 (79)
Chromosome 4 Translocation 2 2 (100) 1 (50)
Others / no Translocation 14 1 (7) 0
Molecular Relapse 1 NE1 NE1
1 NE: Not Evaluable

14.6 Aggressive Systemic Mastocytosis

One open-label, multicenter, phase 2 study was conducted testing Imatinib mesylate tablet in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 5 patients with ASM treated with 100 mg to 400 mg of Imatinib mesylate tablet daily. These 5 patients ranged from 49 to 74 years of age. In addition to these 5 patients, 10 published case reports and case series describe the use of Imatinib mesylate tablet in 23 additional patients with ASM aged 26 to 85 years who also received 100 mg to 400 mg of Imatinib mesylate tablet daily.

Cytogenetic abnormalities were evaluated in 20 of the 28 ASM patients treated with Imatinib mesylate tablet from the published reports and in the phase 2 study. Seven of these 20 patients had the FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion). Patients with this cytogenetic abnormality were predominantly males and had eosinophilia associated with their systemic mast cell disease. Two patients had a Kit mutation in the juxtamembrane region (one Phe522Cys and one K509I) and four patients had a D816V c-Kit mutation (not considered sensitive to Imatinib mesylate tablet), one with concomitant CML.

Of the 28 patients treated for ASM, 8 (29%) achieved a complete hematologic response and 9 (32%) a partial hematologic response (61% overall response rate). Median duration of Imatinib mesylate tablet therapy for the 5 ASM patients in the phase 2 study was 13 months (range 1.4 to 22.3 months) and between 1 month and more than 30 months in the responding patients described in the published medical literature. A summary of the response rates to Imatinib mesylate tablet in ASM is provided in Table 23. Response durations of literature patients ranged from 1+ to 30+ months.

Table 23 Response in ASM

Cytogenetic Abnormality Number of Patients Complete Hematologic Response Partial Hematologic Response
N N (%) N (%)
FIP1L1-PDGFRα Fusion Kinase (or CHIC2 Deletion) 7 7 (100) 0
Juxtamembrane Mutation 2 0 2 (100)
Unknown or No Cytogenetic Abnormality Detected 15 0 7 (44)
D816V Mutation 4 1* (25) 0
Total 28 8 (29) 9 (32)
* Patient had concomitant CML and ASM

Imatinib mesylate tablet has not been shown to be effective in patients with less aggressive forms of systemic mastocytosis (SM). Imatinib mesylate is therefore not recommended for use in patients with cutaneous mastocytosis, indolent systemic mastocytosis (smoldering SM or isolated bone marrow mastocytosis), SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma or extracutaneous mastocytoma. Patients that harbor the D816V mutation of c-Kit are not sensitive to Imatinib mesylate tablet and should not receive Imatinib mesylate tablet.

14.7 Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia

One open-label, multicenter, phase 2 study was conducted testing Imatinib mesylate tablet 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 1000 mg of Imatinib mesylate tablet 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 tablet 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 Partial Hematological Response
N (%) 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)

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 tablet 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 tablet 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 tablet 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.

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