CLINICAL STUDIES

14 Figure 1 Progression Free Survival (ITT Principle) Figure 2 Time to Progression to AP or BC (ITT Principle) Figure 3: Study 1 Recurrence-Free Survival (ITT Population) Figure 4: Study 2 Recurrence-Free Survival (ITT Population) Figure 5: Study 2 Overall Survival (ITT Population) 14.1 Chronic Myeloid Leukemia Chronic Phase, Newly Diagnosed: An open-label, multicenter, international randomized Phase 3 study (Gleevec versus IFN+Ara-C) has been conducted in patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.

This study compared treatment with either single-agent Gleevec or a combination of interferon-alpha (IFN) plus cytarabine (Ara-C).

Patients were allowed to cross over to the alternative treatment arm if they failed to show a complete hematologic response (CHR) at 6 months, a major cytogenetic response (MCyR) at 12 months, or if they lost a CHR or MCyR.

Patients with increasing WBC or severe intolerance to treatment were also allowed to cross over to the alternative treatment arm with the permission of the study monitoring committee (SMC).

In the Gleevec arm, patients were treated initially with 400 mg daily.

Dose escalations were allowed from 400 mg daily to 600 mg daily, then from 600 mg daily to 800 mg daily.

In the IFN arm, patients were treated with a target dose of IFN of 5 MIU/m 2 /day subcutaneously in combination with subcutaneous Ara-C 20 mg/m 2 /day for 10 days/month.

A total of 1106 patients were randomized from 177 centers in 16 countries, 553 to each arm.

Baseline characteristics were well balanced between the two arms.

Median age was 51 years (range, 18 to 70 years), with 21.9% of patients greater than or equal to 60 years of age.

There were 59% males and 41% females; 89.9% Caucasian and 4.7% black patients.

At the cut-off for this analysis (7 years after last patient had been recruited), the median duration of first-line treatment was 82 and 8 months in the Gleevec and IFN arm, respectively.

The median duration of second-line treatment with Gleevec was 64 months.

Sixty percent of patients randomized to Gleevec are still receiving first-line treatment.

In these patients, the average dose of Gleevec was 403 mg ± 57 mg.

Overall, in patients receiving first line Gleevec, the average daily dose delivered was 406 mg ± 76 mg.

Due to discontinuations and cross-overs, only 2% of patients randomized to IFN were still on first-line treatment.

In the IFN arm, withdrawal of consent (14%) was the most frequent reason for discontinuation of first-line therapy, and the most frequent reason for cross over to the Gleevec arm was severe intolerance to treatment (26%) and progression (14%).

The primary efficacy endpoint of the study was progression-free survival (PFS).

Progression was defined as any of the following events: progression to accelerated phase or blast crisis (AP/BC), death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management.

The protocol specified that the progression analysis would compare the intent to treat (ITT) population: patients randomized to receive Gleevec were compared with patients randomized to receive IFN.

Patients that crossed over prior to progression were not censored at the time of cross-over, and events that occurred in these patients following cross-over were attributed to the original randomized treatment.

The estimated rate of progression-free survival at 84 months in the ITT population was 81.2% [95% CI: 78, 85] in the Gleevec arm and 60.6% [56, 65] in the IFN arm (p less than 0.0001, log-rank test), (Figure 1).

With 7 years follow up there were 93 (16.8%) progression events in the Gleevec arm: 37 (6.7%) progression to AP/BC, 31 (5.6%) loss of MCyR, 15 (2.7%) loss of CHR or increase in WBC and 10 (1.8%) CML unrelated deaths.

In contrast, there were 165 (29.8%) events in the IFN+Ara-C arm of which 130 occurred during first-line treatment with IFN-Ara-C.

The estimated rate of patients free of progression to accelerated phase (AP) or blast crisis (BC) at 84 months was 92.5% [90, 95] in the Gleevec arm compared to the 85.1%, [82, 89] (p less than or equal to 0.001) in the IFN arm, (Figure 2).

The annual rates of any progression events have decreased with time on therapy.

The probability of remaining progression free at 60 months was 95% for patients who were in complete cytogenetic response (CCyR) with molecular response (greater than or equal to 3 log reduction in BCR-ABL transcripts as measured by quantitative reverse transcriptase polymerase chain reaction) at 12 months, compared to 89% for patients in CCyR but without a major molecular response and 70% in patients who were not in CCyR at this time point (p less than 0.001).

Figure 1: Progression Free Survival (ITT Principle) Figure 2: Time to Progression to AP or BC (ITT Principle) A total of 71 (12.8%) and 85 (15.4%) patients died in the Gleevec and IFN+Ara-C group, respectively.

At 84 months the estimated overall survival is 86.4% (83, 90) vs 83.3% (80, 87) in the randomized Gleevec and the IFN+Ara-C group, respectively (p = 0.073 log-rank test).

The hazard ratio is 0.750 with 95% CI 0.547-1.028.

This time-to-event endpoint may be affected by the high crossover rate from IFN+Ara-C to Gleevec.

Major cytogenetic response, hematologic response, evaluation of minimal residual disease (molecular response), time to accelerated phase or blast crisis and survival were main secondary endpoints.

Response data are shown in Table 18.

Complete hematologic response, major cytogenetic response and CCyR were also statistically significantly higher in the Gleevec arm compared to the IFN + Ara-C arm (no cross-over data considered for evaluation of responses).

Median time to CCyR in the 454 responders was 6 months (range, 2 to 64 months, 25 th to 75 th percentiles = 3 to 11 months) with 10% of responses seen only after 22 months of therapy.

Table 18: Response in Newly Diagnosed CML Study (84-Month Data) *p less than 0.001, Fischer’s exact test.

1 Hematologic response criteria (all responses to be confirmed after greater than or equal to 4 weeks): WBC less than 10 x 10 9 /L, platelet less than 450 x 10 9 /L, myelocyte + metamyelocyte less than 5% in blood, no blasts and promyelocytes in blood, no extramedullary involvement.

2 Cytogenetic response criteria (confirmed after greater than or equal to 4 weeks): complete (0% Ph+ metaphases) or partial (1%-35%).

A major response (0%-35%) combines both complete and partial responses.

3 Unconfirmed cytogenetic response is based on a single bone marrow cytogenetic evaluation, therefore unconfirmed complete or partial cytogenetic responses might have had a lesser cytogenetic response on a subsequent bone marrow evaluation.

Best response rate Gleevec n = 553 IFN+Ara−C n = 553 Hematologic response 1 CHR rate n (%) 534 (96.6%)* 313 (56.6%)* [95% CI] [94.7%, 97.9%] [52.4%, 60.8%] Cytogenetic response 2 Major cytogenetic response n (%) 472 (85.4%)* 93 (16.8%)* [95% CI] [82.1%, 88.2%] [13.8%, 20.2%] Unconfirmed 3 88.6%* 23.3%* Complete cytogenetic response n (%) 413 (74.7%)* 36 (6.5%)* [95% CI] [70.8, 78.3] [4.6, 8.9] Unconfirmed 3 82.5%* 11.6%* Molecular response was defined as follows: in the peripheral blood, after 12 months of therapy, reduction of greater than or equal to 3 logarithms in the amount of BCR-ABL transcripts (measured by real-time quantitative reverse transcriptase PCR assay) over a standardized baseline.

Molecular response was only evaluated in a subset of patients who had a CCyR by 12 months or later (N = 333).

The molecular response rate in patients who had a CCyR in the Gleevec arm was 59% at 12 months and 72% at 24 months.

Physical, functional, and treatment-specific biologic response modifier scales from the FACT-BRM (Functional Assessment of Cancer Therapy – Biologic Response Modifier) instrument were used to assess patient-reported general effects of interferon toxicity in 1,067 patients with CML in chronic phase.

After one month of therapy to 6 months of therapy, there was a 13% to 21% decrease in median index from baseline in patients treated with IFN, consistent with increased symptoms of IFN toxicity.

There was no apparent change from baseline in median index for patients treated with Gleevec.

An open-label, multicenter, randomized trial (Gleevec versus nilotinib) was conducted to determine the efficacy of Gleevec versus nilotinib in adult patients with cytogenetically confirmed, newly diagnosed Ph+ CML-CP.

Patients were within 6 months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea and/or anagrelide.

Efficacy was based on a total of 846 patients: 283 patients in the Gleevec 400 mg once daily group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in the nilotinib 400 mg twice daily group.

Median age was 46 years in the Gleevec group and 47 years in both nilotinib groups, with 12%, 13%, and 10% of patients greater than or equal to 65 years of age in Gleevec 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively.

There were slightly more male than female patients in all groups (56%, 56%, and 62% in Gleevec 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice-daily treatment groups, respectively).

More than 60% of all patients were Caucasian, and 25% were Asian.

The primary data analysis was performed when all 846 patients completed 12 months of treatment or discontinued earlier.

Subsequent analyses were done when patients completed 24, 36, 48, and 60 months of treatment or discontinued earlier.

The median time on treatment was approximately 61 months in all three treatment groups.

The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study medication.

MMR was defined as less than or equal to 0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a greater than or equal to 3 log reduction of BCR-ABL transcript from standardized baseline.

Efficacy endpoints are summarized in Table 19.

Twelve patients in the Gleevec arm progressed to either accelerated phase or blast crises (7 patients within first 6 months, 2 patients within 6 to 12 months, 2 patients within 12 to 18 months and 1 patient within 18 to 24 months) while two patients on the nilotinib arm progressed to either accelerated phase or blast crisis (both within the first 6 months of treatment).

Table 19: Efficacy (MMR and CCyR) of Gleevec Compared to Nilotinib in Newly Diagnosed Ph+ CML-CP Abbreviations: CCyR, complete cytogenetic response; MMR, major molecular response; Ph+ CML-CP, Philadelphia chromosome positive chronic myeloid leukemia-chronic phase.

a CMH test stratified by Sokal risk group.

b CCyR: 0% Ph+ metaphases.

Cytogenetic responses were based on the percentage of Ph-positive metaphases among greater than or equal to 20 metaphase cells in each bone marrow sample.

Gleevec 400 mg once daily Nilotinib 300 mg twice daily N = 283 N = 282 MMR at 12 months (95% CI) 22% (17.6, 27.6) 44% (38.4, 50.3) P-Value a < 0.0001 CCyR b by 12 months (95% CI) 65% (59.2, 70.6) 80% (75.0, 84.6) MMR at 24 months (95% CI) 38% (31.8, 43.4) 62% (55.8, 67.4) CCyR b by 24 months (95% CI) 77% (71.7, 81.8) 87% (82.4, 90.6) By 60 months, MMR was achieved by 60% of patients on Gleevec and 77% of patients on nilotinib.

Median overall survival was not reached in either arm.

At the time of the 60-month final analysis, the estimated survival rate was 91.7% for patients on Gleevec and 93.7% for patients on nilotinib.

Late Chronic Phase CML and Advanced Stage CML : Three international, open-label, single-arm Phase 2 studies were conducted to determine the safety and efficacy of Gleevec in patients with Ph+ CML: 1) in the chronic phase after failure of IFN therapy, 2) in accelerated phase disease, or 3) in myeloid blast crisis.

About 45% of patients were women and 6% were black.

In clinical studies, 38% to 40% of patients were greater than or equal to 60 years of age and 10% to 12% of patients were greater than or equal to 70 years of age.

Chronic Phase, Prior Interferon-Alpha Treatment: 532 patients were treated at a starting dose of 400 mg; dose escalation to 600 mg was allowed.

The patients were distributed in three main categories according to their response to prior interferon: failure to achieve (within 6 months), or loss of a complete hematologic response (29%), failure to achieve (within 1 year) or loss of a major cytogenetic response (35%), or intolerance to interferon (36%).

Patients had received a median of 14 months of prior IFN therapy at doses greater than or equal to 25 x 10 6 units/week and were all in late chronic phase, with a median time from diagnosis of 32 months.

Effectiveness was evaluated on the basis of the rate of hematologic response and by bone marrow exams to assess the rate of major cytogenetic response (up to 35% Ph+ metaphases) or CCyR (0% Ph+ metaphases).

Median duration of treatment was 29 months with 81% of patients treated for greater than or equal to 24 months (maximum = 31.5 months).

Efficacy results are reported in Table 20.

Confirmed major cytogenetic response rates were higher in patients with IFN intolerance (66%) and cytogenetic failure (64%), than in patients with hematologic failure (47%).

Hematologic response was achieved in 98% of patients with cytogenetic failure, 94% of patients with hematologic failure, and 92% of IFN-intolerant patients.

Accelerated Phase: 235 patients with accelerated phase disease were enrolled.

These patients met one or more of the following criteria: greater than or equal to 15% – less than 30% blasts in PB or BM; greater than or equal to 30% blasts + promyelocytes in PB or BM; greater than or equal to 20% basophils in PB; and less than 100 x 10 9 /L platelets.

The first 77 patients were started at 400 mg, with the remaining 158 patients starting at 600 mg.

Effectiveness was evaluated primarily on the basis of the rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia (i.e., clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML.

Cytogenetic responses were also evaluated.

Median duration of treatment was 18 months with 45% of patients treated for greater than or equal to 24 months (maximum = 35 months).

Efficacy results are reported in Table 20.

Response rates in accelerated phase CML were higher for the 600 mg dose group than for the 400 mg group: hematologic response (75% vs 64%), confirmed and unconfirmed major cytogenetic response (31% vs 19%).

Myeloid Blast Crisis: 260 patients with myeloid blast crisis were enrolled.

These patients had greater than or equal to 30% blasts in PB or BM and/or extramedullary involvement other than spleen or liver; 95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165 (63%) had not (“untreated patients”).

The first 37 patients were started at 400 mg; the remaining 223 patients were started at 600 mg.

Effectiveness was evaluated primarily on the basis of rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia, or return to chronic phase CML using the same criteria as for the study in accelerated phase.

Cytogenetic responses were also assessed.

Median duration of treatment was 4 months with 21% of patients treated for greater than or equal to 12 months and 10% for greater than or equal to 24 months (maximum = 35 months).

Efficacy results are reported in Table 20.

The hematologic response rate was higher in untreated patients than in treated patients (36% vs 22%, respectively) and in the group receiving an initial dose of 600 mg rather than 400 mg (33% vs 16%).

The confirmed and unconfirmed major cytogenetic response rate was also higher for the 600-mg dose group than for the 400-mg dose group (17% vs 8%).

Table 20: Response in Chronic Myeloid Leukemia Studies Abbreviations: BM, bone marrow; PB, peripheral blood.

1 Hematologic response criteria (all responses to be confirmed after greater than or equal to 4 weeks): CHR: Chronic phase study [WBC less than 10 x 10 9 /L, platelet less than 450 x 10 9 /L, myelocytes + metamyelocytes less than 5% in blood, no blasts and promyelocytes in blood, basophils less than 20%, no extramedullary involvement] and in the accelerated and blast crisis studies [absolute neutrophil count (ANC) greater than or equal to 1.5 x 10 9 /L, platelets greater than or equal to 100 x 10 9 /L, no blood blasts, BM blasts less than 5% and no extramedullary disease].

NEL: Same criteria as for CHR but ANC greater than or equal to 1 x 10 9 /L and platelets greater than or equal to 20 x 10 9 /L (accelerated and blast crisis studies).

RTC: less than 15% blasts BM and PB, less than 30% blasts + promyelocytes in BM and PB, less than 20% basophils in PB, no extramedullary disease other than spleen and liver (accelerated and blast crisis studies).

2 Cytogenetic response criteria (confirmed after greater than or equal to 4 weeks): complete (0% Ph+ metaphases) or partial (1%-35%).

A major response (0%-35%) combines both complete and partial responses.

3 Unconfirmed cytogenetic response is based on a single bone marrow cytogenetic evaluation, therefore unconfirmed complete or partial cytogenetic responses might have had a lesser cytogenetic response on a subsequent bone marrow evaluation.

4 Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation performed at least 1 month after the initial bone marrow study.

Chronic phase IFN failure (n = 532) Accelerated phase (n = 235) Myeloid blast crisis (n = 260) 600 mg n = 158 600 mg n = 223 400 mg 400 mg n = 77 400 mg n = 37 % of patients [CI 95% ] Hematologic response 1 95% [92.3−96.3] 71% [64.8−76.8] 31% [25.2−36.8] Complete hematologic response (CHR) 95% 38% 7% No evidence of leukemia (NEL) Not applicable 13% 5% Return to chronic phase (RTC) Not applicable 20% 18% Major cytogenetic response 2 60% [55.3−63.8] 21% [16.2−27.1] 7% [4.5−11.2] (Unconfirmed 3 ) (65%) (27%) (15%) Complete 4 (Unconfirmed 3 ) 39% (47%) 16% (20%) 2% (7%) The median time to hematologic response was 1 month.

In late chronic phase CML, with a median time from diagnosis of 32 months, an estimated 87.8% of patients who achieved MCyR maintained their response 2 years after achieving their initial response.

After 2 years of treatment, an estimated 85.4% of patients were free of progression to AP or BC, and estimated overall survival was 90.8% [88.3, 93.2].

In accelerated phase, median duration of hematologic response was 28.8 months for patients with an initial dose of 600 mg (16.5 months for 400 mg).

An estimated 63.8% of patients who achieved MCyR were still in response 2 years after achieving initial response.

The median survival was 20.9 [13.1, 34.4] months for the 400 mg group and was not yet reached for the 600 mg group (p = 0.0097).

An estimated 46.2% [34.7, 57.7] vs 65.8% [58.4, 73.3] of patients were still alive after 2 years of treatment in the 400 mg vs 600 mg dose groups, respectively.

In blast crisis, the estimated median duration of hematologic response is 10 months.

An estimated 27.2% [16.8, 37.7] of hematologic responders maintained their response 2 years after achieving their initial response.

Median survival was 6.9 [5.8, 8.6] months, and an estimated 18.3% [13.4, 23.3] of all patients with blast crisis were alive 2 years after start of study.

Efficacy results were similar in men and women and in patients younger and older than age 65.

Responses were seen in black patients, but there were too few black patients to allow a quantitative comparison.

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 Gleevec 340 mg/m 2 /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 Gleevec and ranged in age from 3 to 20 years old; 3 were 3 to 11 years old, 9 were 12 to 18 years old, and 2 were greater than 18 years old.

Patients were treated at doses of 260 mg/m 2 /day (n = 3), 340 mg/m 2 /day (n = 4), 440 mg/m 2 /day (n = 5) and 570 mg/m 2 /day (n = 2).

In the 13 patients for whom cytogenetic data are available, 4 achieved a major cytogenetic response, 7 achieved a CCyR, 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 CCyR at doses of 242 and 257 mg/m 2 /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 Gleevec dose of 600 mg/day.

In addition 2 patients with relapsed/refractory Ph+ ALL received Gleevec 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 Gleevec on Relapsed/Refractory Ph+ ALL Abbreviations: CCyR, complete cytogenetic response; CHR, complete hematologic response; MCyR, major cytogenetic response; NEL, no evidence of leukemia; PCyR, partial cytogenic response; Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; PHR, partial hematologic response; RTC, return to chronic phase.

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) 14.4 Pediatric ALL Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5-year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol.

The safety and effectiveness of Gleevec (340 mg/m 2 /day) in combination with intensive chemotherapy was evaluated in a subgroup of patients with Ph+ ALL.

The protocol included intensive chemotherapy and hematopoietic stem cell transplant after 2 courses of chemotherapy for patients with an appropriate HLA-matched family donor.

There were 92 eligible patients with Ph+ ALL enrolled.

The median age was 9.5 years (1 to 21 years: 2.2% between 1 and less than 2 years, 56.5% between 2 and less than 12 years, 34.8% between 12 and less than 18 years, and 6.5% between 18 and 21 years).

Sixty-four percent were male, 75% were white, 9% were Asian/Pacific Islander, and 5% were black.

In 5 successive cohorts of patients, Gleevec exposure was systematically increased by earlier introduction and prolonged duration.

Cohort 1 received the lowest intensity and cohort 5 received the highest intensity of Gleevec exposure.

There were 50 patients with Ph+ ALL assigned to cohort 5 all of whom received Gleevec plus chemotherapy; 30 were treated exclusively with chemotherapy and Gleevec and 20 received chemotherapy plus Gleevec and then underwent hematopoietic stem cell transplant, followed by further Gleevec treatment.

Patients in cohort 5 treated with chemotherapy received continuous daily exposure to Gleevec beginning in the first course of post induction chemotherapy continuing through maintenance cycles 1 through 4 chemotherapy.

During maintenance cycles 5 through 12, Gleevec was administered 28 days out of the 56 day cycle.

Patients who underwent hematopoietic stem cell transplant received 42 days of Gleevec prior to HSCT, and 28 weeks (196 days) of Gleevec after the immediate post transplant period.

The estimated 4-year EFS of patients in cohort 5 was 70% (95% CI: 54, 81).

The median follow-up time for EFS at data cutoff in cohort 5 was 40.5 months.

14.5 Myelodysplastic/Myeloproliferative Diseases An open-label, multicenter, Phase 2 clinical trial was conducted testing Gleevec 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 Gleevec 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 Gleevec 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 CCyR).

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 Abbreviations: NE, not evaluable; MDS/MPD, myelodysplastic/myeloproliferative disease.

Number of patients Complete hematologic response Major cytogenetic 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 NE NE 14.6 Aggressive Systemic Mastocytosis One open-label, multicenter, Phase 2 study was conducted testing Gleevec 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 Gleevec 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 Gleevec in 23 additional patients with ASM aged 26 to 85 years who also received 100 mg to 400 mg of Gleevec daily.

Cytogenetic abnormalities were evaluated in 20 of the 28 ASM patients treated with Gleevec 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 Gleevec), 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 (PHR) (61% overall response rate).

Median duration of Gleevec 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 Gleevec in ASM is provided in Table 23.

Response durations of literature patients ranged from 1+ to 30+ months.

Table 23: Response in ASM Abbreviations: ASM, aggressive systemic mastocytosis; PDGFR, platelet-derived growth factor receptor.

*Patient had concomitant chronic myeloid leukemia CML and ASM.

Cytogenetic abnormality Number of patients N Complete hematologic response N (%) Partial hematologic response 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) Gleevec has not been shown to be effective in patients with less aggressive forms of systemic mastocytosis (SM).

Gleevec 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 Gleevec and should not receive Gleevec.

14.7 Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia One open-label, multicenter, Phase 2 study was conducted testing Gleevec 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 Gleevec 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 Gleevec 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 Abbreviations: CEL, chronic eosinophilic leukemia; HES, hypereosinophilic syndrome; PDGFR, platelet-derived growth factor receptor.

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) 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 Gleevec 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 Gleevec 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 Gleevec 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) Gleevec daily.

A single pediatric patient received 400 mg/m 2 /daily, subsequently increased to 520 mg/m 2 /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 Unresectable and/or Malignant Metastatic GIST 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 Abbreviation: GIST, gastrointestinal stromal tumors.

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 Partial response 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 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, Gleevec was investigated in a multicenter, double-blind, placebo-controlled, randomized trial involving 713 patients (Study 1).

Patients were randomized one to one to Gleevec 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 Gleevec 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 Gleevec arm.

Seventy-two of these 79 patients subsequently crossed over to Gleevec 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 Gleevec 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 Gleevec 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) A second randomized, multicenter, open-label, Phase 3 trial in the adjuvant setting (Study 2) compared 12 months of Gleevec treatment to 36 months of Gleevec 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 Gleevec treatment significantly prolonged RFS compared to 12 months of Gleevec 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 Gleevec treatment significantly prolonged OS compared to 12 months of Gleevec 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) Figure 5: Study 2 Overall Survival (ITT Population)