Author: druginteractionchecker_lgaiz4

CLINICAL STUDIES

The efficacy of IMITREX Tablets in the acute treatment of migraine headaches was demonstrated in 3, randomized, double-blind, placebo-controlled studies.

Patients enrolled in these 3 studies were predominately female (87%) and Caucasian (97%), with a mean age of 40 years (range, 18 to 65 years).

Patients were instructed to treat a moderate to severe headache.

Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 4 hours after dosing.

Associated symptoms such as nausea, photophobia, and phonophobia were also assessed.

Maintenance of response was assessed for up to 24 hours postdose.

A second dose of IMITREX Tablets or other medication was allowed 4 to 24 hours after the initial treatment for recurrent headache.

Acetaminophen was offered to patients in Studies 2 and 3 beginning at 2 hours after initial treatment if the migraine pain had not improved or worsened.

Additional medications were allowed 4 to 24 hours after the initial treatment for recurrent headache or as rescue in all 3 studies.

The frequency and time to use of these additional treatments were also determined.

In all studies, doses of 25, 50, and 100 mg were compared to placebo in the treatment of migraine attacks.

In 1 study, doses of 25, 50, and 100 mg were also compared to each other.

In all 3 trials, the percentage of patients achieving headache response 2 and 4 hours after treatment was significantly greater among patients receiving IMITREX Tablets at all doses compared to those who received placebo.

In 1 of the 3 studies, there was a statistically significant greater percentage of patients with headache response at 2 and 4 hours in the 50- or 100-mg group when compared to the 25-mg dose groups.

There were no statistically significant differences between the 50- and 100-mg dose groups in any study.

The results from the 3 controlled clinical trials are summarized in Table 1.

Comparisons of drug performance based upon results obtained in different clinical trials are never reliable.

Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.

Table 1.

Percentage of Patients With Headache Response (No or Mild Pain) 2 and 4 Hours Following Treatment Placebo 2 hr 4 hr IMITREX Tablets 25 mg 2 hr 4 hr IMITREX Tablets 50 mg 2 hr 4 hr IMITREX Tablets 100 mg 2 hr 4 hr Study 1 27% 38% 52% a 67% a 61% ab 78% ab 62% ab 79% ab (N = 94) (N = 298) (N = 296) (N = 296) Study 2 26% 38% 52% a 70% a 50% a 68% a 56% a 71% a (N = 65) (N = 66) (N = 62) (N = 66) Study 3 17% 19% 52% a 65% a 54% a 72% a 57% a 78% a (N = 47) (N = 48) (N = 46) (N = 46) a P <0.05 in comparison with placebo.

b P <0.05 in comparison with 25 mg.

The estimated probability of achieving an initial headache response over the 4 hours following treatment is depicted in Figure 1.

Figure 1.

Estimated Probability of Achieving Initial Headache Response Within 240 Minutes a a The figure shows the probability over time of obtaining headache response (no or mild pain) following treatment with sumatriptan.

The averages displayed are based on pooled data from the 3 clinical controlled trials providing evidence of efficacy.

Kaplan-Meier plot with patients not achieving response and/or taking rescue within 240 minutes censored to 240 minutes.

For patients with migraine-associated nausea, photophobia, and/or phonophobia at baseline, there was a lower incidence of these symptoms at 2 hours (Study 1) and at 4 hours (Studies 1, 2, and 3) following administration of IMITREX Tablets compared to placebo.

As early as 2 hours in Studies 2 and 3 or 4 hours in Study 1, through 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication.

The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.

Figure 2.

The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraine Over the 24 Hours Following the Initial Dose of Study Treatment a a Kaplan-Meier plot based on data obtained in the 3 clinical controlled trials providing evidence of efficacy with patients not using additional treatments censored to 24 hours.

Plot also includes patients who had no response to the initial dose.

No remedication was allowed within 2 hours postdose.

There is evidence that doses above 50 mg do not provide a greater effect than 50 mg.

There was no evidence to suggest that treatment with sumatriptan was associated with an increase in the severity of recurrent headaches.

The efficacy of IMITREX Tablets was unaffected by presence of aura; duration of headache prior to treatment; gender, age, or weight of the patient; relationship to menses; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants).

There were insufficient data to assess the impact of race on efficacy.

Figure 1.

Estimated Probability of Achieving Initial Headache Response Within 240 Minutes* Figure 2.

The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraine Over the 24 Hours Following the Initial Dose of Study Treatment*

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)

CLINICAL STUDIES

14 14.1 Chronic Obstructive Pulmonary Disease The safety and efficacy of BREO ELLIPTA were evaluated in 7,700 subjects with COPD.

The development program included 4 confirmatory trials of 6 and 12 months’ duration, three 12-week active comparator trials with fluticasone propionate/salmeterol 250 mcg/50 mcg, and dose-ranging trials of shorter duration.

The efficacy of BREO ELLIPTA is based primarily on the dose-ranging trials and the 4 confirmatory trials described below.

Dose Selection for Vilanterol Dose selection for vilanterol in COPD was supported by a 28-day, randomized, double-blind, placebo-controlled, parallel-group trial evaluating 5 doses of vilanterol (3 to 50 mcg) or placebo dosed in the morning in 602 subjects with COPD.

Results demonstrated dose-related increases from baseline in FEV 1 at Day 1 and Day 28 (Figure 3).

Figure 3.

Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV 1 (0-24 h) (mL) on Days 1 and 28 Day 1 Day 28 The differences in trough FEV 1 on Day 28 from placebo for the 3-, 6.25-, 12.5-, 25-, and 50-mcg doses were 92 mL (95% CI: 39, 144), 98 mL (95% CI: 46, 150), 110 mL (95% CI: 57, 162), 137 mL (95% CI: 85, 190), and 165 mL (95% CI: 112, 217), respectively.

These results supported the evaluation of vilanterol 25 mcg once daily in the confirmatory trials for COPD.

Dose Selection for Fluticasone Furoate Dose selection of fluticasone furoate for Phase III trials in subjects with COPD was based on dose-ranging trials conducted in subjects with asthma; these trials are described in detail below [see Clinical Studies (14.2)] .

Confirmatory Trials The 4 confirmatory trials evaluated the efficacy of BREO ELLIPTA on lung function (Trials 1 and 2) and exacerbations (Trials 3 and 4).

Lung Function: Trials 1 and 2 were 24-week, randomized, double-blind, placebo-controlled trials designed to evaluate the efficacy of BREO ELLIPTA on lung function in subjects with COPD.

In Trial 1, subjects were randomized to BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, and placebo.

In Trial 2, subjects were randomized to BREO ELLIPTA 100/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate 100 mcg, vilanterol 25 mcg, and placebo.

All treatments were administered as 1 inhalation once daily.

Of the 2,254 patients, 70% were male and 84% were white.

They had a mean age of 62 years and an average smoking history of 44 pack years, with 54% identified as current smokers.

At screening, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 14% to 87%), mean postbronchodilator FEV 1 /FVC ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%).

The co-primary efficacy variables in both trials were weighted mean FEV 1 (0 to 4 hours) postdose on Day 168 and change from baseline in trough FEV 1 on Day 169 (the mean of the FEV 1 values obtained 23 and 24 hours after the final dose on Day 168).

The weighted mean comparison of the fluticasone furoate/vilanterol combination with fluticasone furoate was assessed to evaluate the contribution of vilanterol to BREO ELLIPTA.

The trough FEV 1 comparison of the fluticasone furoate/vilanterol combination with vilanterol was assessed to evaluate the contribution of fluticasone furoate to BREO ELLIPTA.

BREO ELLIPTA 100/25 demonstrated a larger increase in the weighted mean FEV 1 (0 to 4 hours) relative to placebo and fluticasone furoate 100 mcg at Day 168 (Table 4).

Table 4.

Least Squares Mean Change from Baseline in Weighted Mean FEV 1 (0-4 h) and Trough FEV 1 at 6 Months Treatment n Weighted Mean FEV 1 (0-4 h) a (mL) Trough FEV 1 b (mL) Difference from Difference from Placebo (95% CI) Fluticasone Furoate 100 mcg (95% CI) Fluticasone Furoate 200 mcg (95% CI) Placebo (95% CI) Vilanterol 25 mcg (95% CI) Trial 1 BREO ELLIPTA 100/25 204 214 (161, 266) 168 (116, 220) –– 144 (91, 197) 45 (-8, 97) BREO ELLIPTA 200/25 205 209 (157, 261) –– 168 (117, 219) 131 (80, 183) 32 (-19, 83) Trial 2 BREO ELLIPTA 100/25 206 173 (123, 224) 120 (70, 170) –– 115 (60, 169) 48 (-6, 102) a At Day 168.

b At Day 169.

Serial spirometric evaluations were performed predose and up to 4 hours after dosing.

Results from Trial 1 at Day 1 and Day 168 are shown in Figure 4.

Similar results were seen in Trial 2 (not shown).

Figure 4.

Raw Mean Change from Baseline in Postdose Serial FEV 1 (0-4 h) (mL) on Days 1 and 168 Day 1 Day 168 The second co-primary variable was change from baseline in trough FEV 1 following the final treatment day.

At Day 169, both Trials 1 and 2 demonstrated significant increases in trough FEV 1 for all strengths of the fluticasone furoate/vilanterol combination compared with placebo (Table 4).

The comparison of BREO ELLIPTA 100/25 with vilanterol did not achieve statistical significance (Table 4).

Trials 1 and 2 evaluated FEV 1 as a secondary endpoint.

Peak FEV 1 was defined as the maximum postdose FEV 1 recorded within 4 hours after the first dose of trial medicine on Day 1 (measurements recorded at 5, 15, and 30 minutes and 1, 2, and 4 hours).

In both trials, differences in mean change from baseline in peak FEV 1 were observed for the groups receiving BREO ELLIPTA 100/25 compared with placebo (152 and 139 mL, respectively).

The median time to onset, defined as a 100-mL increase from baseline in FEV 1 , was 16 minutes in subjects receiving BREO ELLIPTA 100/25.

Exacerbations: Trials 3 and 4 were randomized, double-blind, 52-week trials designed to evaluate the effect of BREO ELLIPTA on the rate of moderate and severe COPD exacerbations.

All subjects were treated with fluticasone propionate/salmeterol 250 mcg/50 mcg twice daily during a 4-week run-in period prior to being randomly assigned to 1 of the following treatment groups: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, or vilanterol 25 mcg.

The primary efficacy variable in both trials was the annual rate of moderate/severe exacerbations.

The comparison of the fluticasone furoate/vilanterol combination with vilanterol was assessed to evaluate the contribution of fluticasone furoate to BREO ELLIPTA.

In these 2 trials, exacerbations were defined as worsening of 2 or more major symptoms (dyspnea, sputum volume, and sputum purulence) or worsening of any 1 major symptom together with any 1 of the following minor symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, and increased cough or wheeze for at least 2 consecutive days.

COPD exacerbations were considered to be of moderate severity if treatment with systemic corticosteroids and/or antibiotics was required and were considered to be severe if hospitalization was required.

Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were white.

They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers.

At screening, the mean postbronchodilator percent predicted FEV 1 was 45% (range: 12% to 91%), and mean postbronchodilator FEV 1 /FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction.

The mean percent reversibility was 15% (range: -65% to 313%).

Subjects treated with BREO ELLIPTA 100/25 had a lower annual rate of moderate/severe COPD exacerbations compared with vilanterol in both trials (Table 5).

Table 5.

Moderate and Severe Chronic Obstructive Pulmonary Disease Exacerbations Treatment n Mean Annual Rate (exacerbations/year) Ratio vs.

Vilanterol 95% CI Trial 3 BREO ELLIPTA 100/25 403 0.90 0.79 0.64, 0.97 BREO ELLIPTA 200/25 409 0.79 0.69 0.56, 0.85 Fluticasone furoate/vilanterol 50 mcg/25 mcg 412 0.92 0.81 0.66, 0.99 Vilanterol 25 mcg 409 1.14 –– –– Trial 4 BREO ELLIPTA 100/25 403 0.70 0.66 0.54, 0.81 BREO ELLIPTA 200/25 402 0.90 0.85 0.70, 1.04 Fluticasone furoate/vilanterol 50 mcg/25 mcg 408 0.92 0.87 0.72, 1.06 Vilanterol 25 mcg 409 1.05 –– –– Comparator Trials Three 12-week, randomized, double-blind, double-dummy trials were conducted with BREO ELLIPTA 100/25 once daily versus fluticasone propionate/salmeterol 250 mcg/50 mcg twice daily to evaluate the efficacy of serial lung function of BREO ELLIPTA in subjects with COPD.

The primary endpoint of each study was change from baseline in weighted mean FEV 1 (0 to 24 hours) on Day 84.

Of the 519 patients in Trial 5, 64% were male and 97% were white; mean age was 61 years; average smoking history was 40 pack years, with 55% identified as current smokers.

At screening in the treatment group using BREO ELLIPTA 100/25, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 19% to 70%), the mean (SD) FEV 1 /FVC ratio was 0.51 (0.11), and the mean percent reversibility was 11% (range: -12% to 83%).

At screening in the treatment group using fluticasone propionate/salmeterol 250 mcg/50 mcg, the mean postbronchodilator percent predicted FEV 1 was 47% (range: 14% to 71%), the mean (SD) FEV 1 /FVC ratio was 0.49 (0.10), and the mean percent reversibility was 11% (range: -13% to 50%).

Of the 511 patients in Trial 6, 68% were male and 94% were white; mean age was 62 years; average smoking history was 35 pack years, with 52% identified as current smokers.

At screening in the treatment group using BREO ELLIPTA 100/25, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 18% to 70%), the mean (SD) FEV 1 /FVC ratio was 0.51 (0.10), and the mean percent reversibility was 12% (range: -56% to 77%).

At screening in the treatment group using fluticasone propionate/salmeterol 250 mcg/50 mcg, the mean postbronchodilator percent predicted FEV 1 was 49% (range: 15% to 70%), the mean (SD) FEV 1 /FVC ratio was 0.50 (0.10), and the mean percent reversibility was 12% (range: -66% to 72%).

Of the 828 patients in Trial 7, 72% were male and 98% were white; mean age was 61 years; average smoking history was 38 pack years, with 60% identified as current smokers.

At screening in the treatment group using BREO ELLIPTA 100/25, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 18% to 70%), the mean (SD) FEV 1 /FVC ratio was 0.52 (0.10), and the mean percent reversibility was 12% (range: -26% to 84%).

At screening in the treatment group using fluticasone propionate/salmeterol 250 mcg/50 mcg, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 16% to 70%), the mean (SD) FEV 1 /FVC ratio was 0.51 (0.10), and the mean percent reversibility was 12% (range: -15% to 67%).

In Trial 5, the mean (SE) change from baseline in weighted mean FEV 1 (0 to 24 hours) with BREO ELLIPTA 100/25 was 174 (15) mL compared with 94 (16) mL with fluticasone propionate/salmeterol 250 mcg/50 mcg (treatment difference 80 mL; 95% CI: 37, 124; P <0.001).

In Trials 6 and 7, the mean (SE) change from baseline in weighted mean FEV 1 (0 to 24 hours)with BREO ELLIPTA 100/25 was 142 (18) mL and 168 (12) mL, respectively, compared with 114 (18) mL and 142 (12) mL, respectively, for fluticasone propionate/salmeterol 250 mcg/50 mcg (Trial 6 treatment difference 29 mL; 95% CI: -22, 80; P = 0.267; Trial 7 treatment difference 25 mL; 95% CI: -8, 59; P = 0.137).

Figure 3.

Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28, Day 1 Figure 3.

Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28, Day 28 Figure 4.

Raw Mean Change from Baseline in Postdose Serial FEV1 (0-4 h) (mL) on Days 1 and 168, Day 1 Figure 4.

Raw Mean Change from Baseline in Postdose Serial FEV1 (0-4 h) (mL) on Days 1 and 168, Day 168 14.2 Asthma The safety and efficacy of BREO ELLIPTA were evaluated in 9,969 subjects with asthma.

The development program included 4 confirmatory trials (2 of 12 weeks’ duration, 1 of 24 weeks’ duration, 1 exacerbation trial of 24 to 76 weeks’ duration), one 24-week active comparator trial with fluticasone propionate/salmeterol 250 mcg/50 mcg, and dose-ranging trials of shorter duration.

The efficacy of BREO ELLIPTA is based primarily on the dose-ranging trials and the 4 confirmatory trials described below.

Dose Selection for Vilanterol Dose selection for vilanterol in asthma was supported by a 28-day, randomized, double-blind, placebo-controlled, parallel-group trial evaluating 5 doses of vilanterol (3 to 50 mcg) or placebo dosed in the evening in 607 subjects with asthma.

Results demonstrated dose-related increases from baseline in FEV 1 at Day 1 and Day 28 (Figure 5).

Figure 5.

Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV 1 (0-24 h) (mL) on Days 1 and 28 Day 1 Day 28 The differences in trough FEV 1 on Day 28 from placebo for the 3-, 6.25-, 12.5-, 25-, and 50-mcg doses were 64 mL (95% CI: -36, 164), 69 mL (95% CI: -29, 168), 130 mL (95% CI: 30, 230), 121 mL (95% CI: 23, 220), and 162 mL (95% CI: 62, 261), respectively.

These results and results of the secondary endpoints supported the evaluation of vilanterol 25 mcg once daily in the confirmatory trials for asthma.

Dose Selection for Fluticasone Furoate Eight doses of fluticasone furoate ranging from 25 to 800 mcg once daily were evaluated in 3 randomized, double-blind, placebo-controlled, 8-week trials in subjects with asthma.

A dose-related increase in trough FEV 1 at Week 8 was seen for doses from 25 to 200 mcg with no consistent additional benefit for doses above 200 mcg.

To evaluate dosing frequency, a separate trial compared fluticasone furoate 200 mcg once daily and fluticasone furoate 100 mcg twice daily.

The results supported the selection of the once-daily dosing frequency (Figure 6).

Figure 6.

Fluticasone Furoate Dose-Ranging and Dose-Frequency Trials FF = fluticasone furoate, FP = fluticasone propionate, QD = once daily, BID = twice daily.

Confirmatory Trials The efficacy of BREO ELLIPTA was evaluated in 4 randomized, double‑blind, parallel-group clinical trials in adolescent and adult subjects with asthma.

Three trials were designed to evaluate the safety and efficacy of BREO ELLIPTA given once daily in subjects who were not controlled on their current treatments of inhaled corticosteroid or combination therapy consisting of an inhaled corticosteroid plus a LABA (Trials 1, 2, and 3).

A 24- to 76-week exacerbation trial was designed to demonstrate that treatment with BREO ELLIPTA 100/25 significantly decreased the risk of asthma exacerbations as measured by time to first asthma exacerbation when compared with fluticasone furoate 100 mcg (Trial 5).

This trial enrolled subjects who had one or more asthma exacerbations in the year prior to trial entry.

The demographics of these 4 trials and the comparator trial (Trial 6) are provided in Table 6.

While subjects aged 12 to 17 years were included in these trials, BREO ELLIPTA is not approved for use in this age-group [see Indications (1.2), Adverse Reactions (6.2), Use in Specific Populations (8.4)] .

Table 6.

Demography of Asthma Trials 1, 2, 3, 5, and 6 Parameter Trial 1 n = 609 Trial 2 n = 1,039 Trial 3 n = 586 Trial 5 n = 2,019 Trial 6 n = 806 Mean age (years) (range) 40 (12, 84) 46 (12, 82) 46 (12, 76) 42 (12, 82) 43 (12, 80) Female (%) 58 60 59 67 61 White (%) 84 88 84 73 59 Duration of asthma (years) 12 18 16 16 21 Never smoked a (%) N/A 84 N/A 86 81 Predose FEV 1 (L) at baseline 2.32 1.97 2.15 2.20 2.03 Mean percent predicted FEV 1 at baseline (%) 70 62 67 72 68 % Reversibility 29 30 29 24 28 Absolute reversibility (mL) 614 563 571 500 512 N/A = Data not collected.

a Trials did not include current smokers; past smokers had less than 10 packs per year history.

Trials 1, 2, and 3 were 12- or 24-week trials that evaluated the efficacy of BREO ELLIPTA on lung function in subjects with asthma.

In Trial 1, subjects were randomized to BREO ELLIPTA 100/25, fluticasone furoate 100 mcg, or placebo.

In Trial 2, subjects were randomized to BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, or fluticasone furoate 100 mcg.

In Trial 3, subjects were randomized to BREO ELLIPTA 200/25, fluticasone furoate 200 mcg, or fluticasone propionate 500 mcg.

All inhalations were administered once daily, with the exception of fluticasone propionate, which was administered twice daily.

Subjects receiving an inhaled corticosteroid or an inhaled corticosteroid plus a LABA (doses of inhaled corticosteroid varied by trial and asthma severity) entered a 4-week run-in period during which LABA treatment was stopped.

Subjects reporting symptoms and/or rescue beta 2 -agonist medication use during the run-in period were continued in the trial.

In Trials 1 and 3, change from baseline in weighted mean FEV 1 (0 to 24 hours) and change from baseline in trough FEV 1 at approximately 24 hours after the last dose at study endpoint (12 and 24 weeks, respectively) were co-primary efficacy endpoints.

In Trial 2, change from baseline in weighted mean FEV 1 (0 to 24 hours) at Week 12 was the primary efficacy endpoint; change from baseline in trough FEV 1 at approximately 24 hours after the last dose at Week 12 was a secondary endpoint.

(See Table 7.) Weighted mean FEV 1 (0 to 24 hours) was derived from serial measurements taken within 30 minutes prior to dosing and postdose assessments at 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours after the final dose.

Other secondary endpoints included change from baseline in percentage of rescue‑free 24-hour periods and percentage of symptom‑free 24-hour periods over the treatment period.

Table 7.

Change from Baseline in Weighted Mean FEV 1 (0-24 h) (mL) and Trough FEV 1 (mL) at Study Endpoint (Trials 1, 2, and 3) Study (Duration) Background Treatment n Weighted Mean FEV 1 (0-24 h) (mL) Difference from Placebo (95% CI) Fluticasone Furoate 100 mcg (95% CI) Fluticasone Furoate 200 mcg (95% CI) Treatment Trial 1 (12 Weeks) Low- to mid-dose ICS or low-dose ICS + LABA BREO ELLIPTA 100/25 108 302 (178, 426) 116 (-5, 236) –– Trial 2 (12 Weeks) Mid- to high-dose ICS or mid-dose ICS + LABA BREO ELLIPTA 100/25 312 –– 108 (45, 171) –– Trial 3 (24 Weeks) High-dose ICS or mid-dose ICS + LABA BREO ELLIPTA 200/25 89 –– –– 136 (1, 270) Study (Duration) Background Treatment n Trough FEV 1 (mL) Difference from Placebo (95% CI) Fluticasone Furoate 100 mcg (95% CI) Fluticasone Furoate 200 mcg (95% CI) Treatment Trial 1 (12 Weeks) Low- to mid-dose ICS or low-dose ICS + LABA BREO ELLIPTA 100/25 200 172 (87, 258) 36 (-48, 120) –– Trial 2 (12 Weeks) Mid- to high-dose ICS or mid-dose ICS + LABA BREO ELLIPTA 100/25 334 –– 77 (16, 138) –– Trial 3 (24 Weeks) High-dose ICS or mid-dose ICS + LABA BREO ELLIPTA 200/25 187 –– –– 193 (108, 277) ICS = inhaled corticosteroid, LABA = long-acting beta 2 -adrenergic agonist.

In Trial 1, weighted mean FEV 1 (0 to 24 hours) was assessed in a subset of subjects (n = 309).

At Week 12, change from baseline in weighted mean FEV 1 (0 to 24 hours) was significantly greater for BREO ELLIPTA 100/25 compared with placebo (302 mL; 95% CI: 178, 426; P <0.001) (Table 7); change from baseline in weighted mean FEV 1 (0 to 24 hours) for BREO ELLIPTA 100/25 was numerically greater than fluticasone furoate 100 mcg, but not statistically significant (116 mL; 95% CI: -5, 236).

At Week 12, change from baseline in trough FEV 1 was significantly greater for BREO ELLIPTA 100/25 compared with placebo (172 mL; 95% CI: 87, 258; P <0.001) (Table 7); change from baseline in trough FEV 1 for BREO ELLIPTA 100/25 was numerically greater than fluticasone furoate 100 mcg, but not statistically significant (36 mL; 95% CI: -48, 120).

In Trial 2, the change from baseline in weighted mean FEV 1 (0 to 24 hours) was significantly greater for BREO ELLIPTA 100/25 compared with fluticasone furoate 100 mcg (108 mL; 95% CI: 45, 171; P <0.001) at Week 12 (Table 7).

In a descriptive analysis, the change from baseline in weighted mean FEV 1 (0 to 24 hours) for BREO ELLIPTA 200/25 was numerically greater than BREO ELLIPTA 100/25 (24 mL; 95% CI: -37, 86) at Week 12.

The change from baseline in trough FEV 1 was significantly greater for BREO ELLIPTA 100/25 compared with fluticasone furoate 100 mcg (77 mL, 95% CI: 16, 138; P = 0.014) at Week 12 (Table 7).

In a descriptive analysis, the change from baseline in trough FEV 1 for BREO ELLIPTA 200/25 was numerically greater than BREO ELLIPTA 100/25 (16 mL; 95% CI: -46, 77) at Week 12.

In Trial 3, the change from baseline in weighted mean FEV 1 (0 to 24 hours) was significantly greater for BREO ELLIPTA 200/25 compared with fluticasone furoate 200 mcg (136 mL; 95% CI: 1, 270; P = 0.048) at Week 24 (Table 7).

The change from baseline in trough FEV 1 was significantly greater for BREO ELLIPTA 200/25 compared with fluticasone furoate 200 mcg (193 mL, 95% CI: 108, 277; P <0.001) at Week 24.

Lung function improvements were demonstrated through weighted mean FEV 1 (0 to 24 hours) over the 24-hour period following the final dose of BREO ELLIPTA in Trials 2 and 3.

Serial FEV 1 measurements were taken within 30 minutes prior to dosing and postdose assessments at 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours in Trials 1, 2, and 3.

A representative figure is shown from Trial 2 in Figure 7.

Figure 7.

Least Squares (LS) Mean Change from Baseline in Individual Serial FEV 1 (mL) Assessments over 24 Hours after 12 Weeks of Treatment (Trial 2) Subjects receiving BREO ELLIPTA 100/25 (Trial 2) or BREO ELLIPTA 200/25 (Trial 3) had significantly greater improvements from baseline in percentage of 24-hour periods without need of beta 2 -agonist rescue medication use and percentage of 24-hour periods without asthma symptoms compared with subjects receiving fluticasone furoate 100 mcg or fluticasone furoate 200 mcg, respectively.

In a descriptive analysis (Trial 2), subjects receiving BREO ELLIPTA 200/25 had numerical improvements from baseline in percentage of 24-hour periods without need of beta 2 -agonist rescue medication use and percentage of 24-hour periods without asthma symptoms compared with subjects receiving BREO ELLIPTA 100/25.

Trial 5 was a 24- to 76-week event-driven exacerbation trial that evaluated whether BREO ELLIPTA 100/25 significantly decreased the risk of asthma exacerbations as measured by time to first asthma exacerbation when compared with fluticasone furoate 100 mcg in subjects with asthma.

Subjects receiving low- to high-dose inhaled corticosteroid (fluticasone propionate 100 mcg to 500 mcg twice daily or equivalent) or low- to mid-dose inhaled corticosteroid plus a LABA (fluticasone propionate/salmeterol 100 mcg/50 mcg to 250 mcg/50 mcg twice daily or equivalent) and a history of 1 or more asthma exacerbations that required treatment with oral/systemic corticosteroid or emergency department visit or in-patient hospitalization for the treatment of asthma in the year prior to trial entry, entered a 2-week run-in period during which LABA treatment was stopped.

Subjects reporting symptoms and/or rescue beta 2 -agonist medication use during the run-in period were continued in the trial.

The primary endpoint was time to first asthma exacerbation.

Asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroid for at least 3 days or an in‑patient hospitalization or emergency department visit due to asthma that required systemic corticosteroid.

Rate of asthma exacerbation was a secondary endpoint.

The hazard ratio from the Cox Model for the analysis of time to first asthma exacerbation for BREO ELLIPTA 100/25 compared with fluticasone furoate 100 mcg was 0.795 (95% CI: 0.642, 0.985).

This represents a 20% reduction in the risk of experiencing an asthma exacerbation for subjects treated with BREO ELLIPTA 100/25 compared with fluticasone furoate 100 mcg ( P = 0.036).

Mean yearly rates of asthma exacerbations of 0.14 and 0.19 in subjects treated with BREO ELLIPTA 100/25 compared with fluticasone furoate 100 mcg, respectively, were observed (25% reduction in rate; 95% CI: 5%, 40%).

Comparator Trial Trial 6 was a 24-week trial that compared the efficacy of BREO ELLIPTA 100/25 once daily with fluticasone propionate/salmeterol 250 mcg/50 mcg twice daily (N = 806).

Subjects receiving mid-dose inhaled corticosteroid (fluticasone propionate 250 mcg twice daily or equivalent) entered a 4-week run-in period during which all subjects received fluticasone propionate 250 mcg twice daily.

The primary endpoint was change from baseline in weighted mean FEV 1 (0 to 24 hours) at Week 24.

The mean change (SE) from baseline in weighted mean FEV 1 (0 to 24 hours) for BREO ELLIPTA 100/25 was 341 (18.4) mL compared with 377 (18.5) mL for fluticasone propionate/salmeterol 250 mcg/50 mcg (treatment difference -37 mL; 95% CI: -88, 15; P = 0.162).

Figure 5.

Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28, Day 1 Figure 5.

Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28, Day 28 Figure 6: Fluticasone Furoate Dose-Ranging and Dose-Frequency Trials Figure 7.

Least Squares (LS) Mean Change from Baseline in Individual Serial FEV1 (mL) Assessments over 24 Hours at Day 1 (Trial 1)

CLINICAL STUDIES

14 14.1 Parkinson’s Disease The effectiveness of ropinirole tablets in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of 11 randomized, controlled trials.

Four trials were conducted in patients with early Parkinson’s disease and no concomitant L-dopa and seven trials were conducted in patients with advanced Parkinson’s disease with concomitant L-dopa.

Three placebo-controlled trials provide evidence of effectiveness of ropinirole tablets in the management of patients with Parkinson’s disease who were and were not receiving concomitant L-dopa.

Two of these three trials enrolled patients with early Parkinson’s disease (without L-dopa) and one enrolled patients receiving L-dopa.

In these trials a variety of measures were used to assess the effects of treatment (e.g., the Unified Parkinson’s Disease Rating Scale [UPDRS], Clinical Global Impression [CGI] scores, patient diaries recording time “on” and “off,” tolerability of L-dopa dose reductions).

In both trials of patients with early Parkinson’s disease (without L-dopa), the motor component (Part III) of the UPDRS was the primary outcome assessment.

The UPDRS is a multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor performance (Part III), and complications of therapy (Part IV).

Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings in patients with Parkinson’s disease (e.g., tremor, rigidity, bradykinesia, postural instability) scored for different body regions and has a maximum (worst) score of 108.

In the trial of patients with advanced Parkinson’s disease (with L-dopa), both reduction in percent awake time spent “off” and the ability to reduce the daily use of L-dopa were assessed as a combined endpoint and individually.

Trials in Patients with Early Parkinson’s Disease (without L-dopa) Trial 1 was a 12-week multicenter trial in which 63 patients with idiopathic Parkinson’s disease receiving concomitant anti-Parkinson medication (but not L-dopa) were enrolled and 41 were randomized to ropinirole tablets and 22 to placebo.

Patients had a mean disease duration of approximately 2 years.

Patients were eligible for enrollment if they presented with bradykinesia and at least tremor, rigidity, or postural instability.

In addition, they must have been classified as Hoehn & Yahr Stage I-IV.

This scale, ranging from I = unilateral involvement with minimal impairment to V = confined to wheelchair or bed, is a standard instrument used for staging patients with Parkinson’s disease.

The primary outcome measure in this trial was the proportion of patients experiencing a decrease (compared with baseline) of at least 30% in the UPDRS motor score.

Patients were titrated for up to 10 weeks, starting at 0.5 mg twice daily, with weekly increments of 0.5 mg twice daily to a maximum of 5 mg twice daily.

Once patients reached their maximally tolerated dose (or 5 mg twice daily), they were maintained on that dose through 12 weeks.

The mean dose achieved by patients at trial endpoint was 7.4 mg/day.

Mean baseline UPDRS motor score was 18.6 for patients treated with ropinirole tablets and 19.9 for patients treated with placebo.

At the end of 12 weeks, the percentage of responders was greater on ropinirole tablets than on placebo and the difference was statistically significant (Table 6).

Table 6.

Percent Responders for UPDRS Motor Score in Trial 1 (Intent-to-Treat Population) % Responders Difference from Placebo Placebo 41% NA Ropinirole tablets 71% 30% Trial 2 in patients with early Parkinson’s disease (without L-dopa) was a double-blind, randomized, placebo-controlled, 6-month trial.

In this trial, 241 patients were enrolled and 116 were randomized to ropinirole tablets and 125 to placebo.

Patients were essentially similar to those in the trial described above; concomitant use of selegiline was allowed, but patients were not permitted to use anticholinergics or amantadine during the trial.

Patients had a mean disease duration of 2 years and limited (not more than a 6-week period) or no prior exposure to L-dopa.

The starting dosage of ropinirole tablets in this trial was 0.25 mg three times daily.

The dosage was titrated at weekly intervals by increments of 0.25 mg three times daily to a dosage of 1 mg three times daily.

Further titrations at weekly intervals were at increments of 0.5 mg three times daily up to a dosage of 3 mg three times daily, and then weekly at increments of 1 mg three times daily.

Patients were to be titrated to a dosage of at least 1.5 mg three times daily and then to their maximally tolerated dosage, up to a maximum of 8 mg three times daily.

The mean dose attained in patients at trial endpoint was 15.7 mg/day.

The primary measure of effectiveness was the mean percent reduction (improvement) from baseline in the UPDRS motor score.

At the end of the 6-month trial, patients treated with ropinirole tablets showed improvement in motor score compared with placebo and the difference was statistically significant (Table 7).

Table 7.

Mean Percentage Change from Baseline in UPDRS Motor Score at End of Treatment in Trial 2 (Intent-to-Treat Population) Treatment Baseline UPDRS Motor Score Mean Change from Baseline Difference from Placebo Placebo 17.7 +4% NA Ropinirole tablets 17.9 -22% -26% Trial in Patients with Advanced Parkinson’s Disease (with L-dopa) Trial 3 was a double-blind, randomized, placebo-controlled, 6-month trial that randomized 149 patients (Hoehn & Yahr II-IV) who were not adequately controlled on L-dopa.

Ninety-five patients were randomized to ropinirole tablets and 54 were randomized to placebo.

Patients in this trial had a mean disease duration of approximately 9 years, had been exposed to L-dopa for approximately 7 years, and had experienced “on-off” periods with L-dopa therapy.

Patients previously receiving stable doses of selegiline, amantadine, and/or anticholinergic agents could continue on these agents during the trial.

Patients were started at a dosage of 0.25 mg three times daily of ropinirole tablets and titrated upward by weekly intervals until an optimal therapeutic response was achieved.

The maximum dosage of trial medication was 8 mg three times daily.

All patients had to be titrated to at least a dosage of 2.5 mg three times daily.

Patients could then be maintained on this dosage level or higher for the remainder of the trial.

Once a dosage of 2.5 mg three times daily was achieved, patients underwent a mandatory reduction in their L-dopa dosage, to be followed by additional mandatory reductions with continued escalation of the dosage of ropinirole tablets.

Reductions in the dosage of L-dopa were also allowed if patients experienced adverse reactions that the investigator considered related to dopaminergic therapy.

The mean dose attained at trial endpoint was 16.3 mg/day.

The primary outcome was the proportion of responders, defined as patients who were able both to achieve a decrease (compared with baseline) of at least 20% in their L-dopa dosage and a decrease of at least 20% in the proportion of the time awake in the “off” condition (a period of time during the day when patients are particularly immobile), as determined by subject diary.

In addition, the mean change in “off” time from baseline and the percent change from baseline in daily L-dopa dosage were examined.

At the end of 6 months, the percentage of responders was greater on ropinirole tablets than on placebo and the difference was statistically significant (Table 8).

Based on the protocol-mandated reductions in L-dopa dosage with escalating doses of ropinirole tablets, patients treated with ropinirole tablets had a 19.4% mean reduction in L-dopa dosage while patients treated with placebo had a 3% reduction.

Mean daily L-dopa dosage at baseline was 759 mg for patients treated with ropinirole tablets and 843 mg for patients treated with placebo.

The mean number of daily “off” hours at baseline was 6.4 hours for patients treated with ropinirole tablets and 7.3 hours for patients treated with placebo.

At the end of the 6-month trial, there was a mean reduction of 1.5 hours of “off” time in patients treated with ropinirole tablets and a mean reduction of 0.9 hours of “off” time in patients treated with placebo, resulting in a treatment difference of 0.6 hours of “off” time.

Table 8.

Mean Responder Percentage of Patients Reducing Daily L-Dopa Dosage by at Least 20% and Daily Proportion of “Off” Time by at Least 20% at End of Treatment in Trial 3 (Intent-to-Treat Population) Treatment % Responders Difference from Placebo Placebo 11% NA Ropinirole tablets 28% 17% 14.2 Restless Legs Syndrome The effectiveness of ropinirole tablets in the treatment of RLS was demonstrated in randomized, double-blind, placebo-controlled trials in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria.

Patients were required to have a history of a minimum of 15 RLS episodes/month during the previous month and a total score of ≥15 on the International RLS Rating Scale (IRLS scale) at baseline.

Patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, anemia) were excluded.

All trials employed flexible dosing, with patients initiating therapy at 0.25 mg ropinirole tablets once daily.

Patients were titrated based on clinical response and tolerability over 7 weeks to a maximum of 4 mg once daily.

All doses were taken between 1 and 3 hours before bedtime.

A variety of measures were used to assess the effects of treatment, including the IRLS scale and Clinical Global Impression-Global Improvement (CGI-I) scores.

The IRLS scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS.

The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms.

Three of the controlled trials utilized the change from baseline in the IRLS scale at the Week 12 endpoint as the primary efficacy outcome.

Three hundred eighty patients were randomized to receive ropinirole tablets (n = 187) or placebo (n = 193) in a US trial (RLS-1); 284 were randomized to receive either ropinirole tablets (n = 146) or placebo (n = 138) in a multinational trial (excluding US) (RLS-2); and 267 patients were randomized to ropinirole tablets (n = 131) or placebo (n = 136) in a multinational trial (including US) (RLS-3).

Across the three trials, the mean duration of RLS was 16 to 22 years (range: 0 to 65 years), mean age was approximately 54 years (range: 18 to 79 years), and approximately 61% were women.

The mean dose at Week 12 was approximately 2 mg/day for the three trials.

At baseline, mean total IRLS score was 22 for ropinirole tablets and 21.6 for placebo in RLS-1, was 24.4 for ropinirole tablets and 25.2 for placebo in RLS-2, and was 23.6 for ropinirole tablets and 24.8 for placebo in RLS-3.

In all three trials, a statistically significant difference between the treatment group receiving ropinirole tablets and the treatment group receiving placebo was observed at Week 12 for both the mean change from baseline in the IRLS scale total score and the percentage of patients rated as responders (much improved or very much improved) on the CGI-I (see Table 9).

Table 9.

Mean Change in Total IRLS Score and Percent Responders on CGI-I Ropinirole Tablets Placebo Difference from Placebo Mean change in total IRLS score at Week 12 RLS-1 -13.5 -9.8 -3.7 RLS-2 -11.0 -8.0 -3.0 RLS-3 -11.2 -8.7 -2.5 Percent responders on CGI-I at Week 12 RLS-1 73.3% 56.5% 16.8% RLS-2 53.4% 40.9% 12.5% RLS-3 59.5% 39.6% 19.9% Long-term maintenance of efficacy in the treatment of RLS was demonstrated in a 36-week trial.

Following a 24-week, single-blind treatment phase (flexible dosages of ropinirole tablets of 0.25 to 4 mg once daily), patients who were responders (defined as a decrease of >6 points on the IRLS scale total score relative to baseline) were randomized in double-blind fashion to placebo or continuation of ropinirole tablets for an additional 12 weeks.

Relapse was defined as an increase of at least 6 points on the IRLS scale total score to a total score of at least 15, or withdrawal due to lack of efficacy.

For patients who were responders at Week 24, the mean dose of ropinirole tablets was 2 mg (range: 0.25 to 4 mg).

Patients continued on ropinirole tablets demonstrated a significantly lower relapse rate compared with patients randomized to placebo (32.6% versus 57.8%, P = 0.0156).

CLINICAL STUDIES

14 Figure 1.

Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival (ITT Population) in the METRIC Study Figure 2.

Kaplan-Meier Curves of Overall Survival in the COMBI-d Study Figure 3.

Kaplan-Meier Curves for Relapse-Free Survival in COMBI-AD in the Adjuvant Treatment of Melanoma Figure 4.

Kaplan-Meier Curves for Progression-Free Survival in Study G2201 (LGG cohort) 14.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma MEKINIST as a Single Agent The safety and efficacy of MEKINIST were evaluated in an international, multi-center, randomized (2:1), open-label, active-controlled trial (the METRIC study; NCT01245062) in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma.

In the METRIC study, patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted.

Patients were randomized to receive MEKINIST 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1000 mg/m 2 intravenously every 3 weeks or paclitaxel 175 mg/m 2 intravenously every 3 weeks.

Treatment continued until disease progression or unacceptable toxicity.

Randomization was stratified according to prior use of chemotherapy for advanced or metastatic disease (yes vs.

no) and LDH level (normal vs.

greater than ULN).

Tumor tissue was evaluated for BRAF mutations at a central testing site using a clinical trial assay.

Tumor samples from 289 patients (196 patients treated with MEKINIST and 93 chemotherapy-treated patients) were also tested retrospectively using an FDA-approved companion diagnostic test, THxID ® -BRAF assay.

The major efficacy outcome measure was progression-free survival (PFS).

The median age for randomized patients was 54 years, 54% were male, greater than 99% were White, and all patients had baseline ECOG performance status of 0 or 1.

Most patients had metastatic disease (94%), had M1c disease (64%), had elevated LDH (36%), had no history of brain metastasis (97%), and received no prior chemotherapy for advanced or metastatic disease (66%).

The distribution of BRAF V600 mutations was BRAF V600E (87%), V600K (12%), or both (less than 1%).

The median durations of follow-up prior to initiation of alternative treatment were 4.9 months for patients treated with MEKINIST and 3.1 months for patients treated with chemotherapy.

Fifty-one (47%) patients crossed over from the chemotherapy arm at the time of disease progression to receive MEKINIST.

The METRIC study demonstrated a statistically significant increase in PFS in the patients treated with MEKINIST.

Table 20 and Figure 1 summarize the PFS results.

Table 20.

Efficacy Results in the METRIC Study Abbreviations: CI, confidence interval; DoR, duration of response; HR, hazard ratio; NR, not reached.

a Pike estimator.

Investigator – A ssessed Endpoints MEKINIST N = 214 Chemotherapy N = 108 P rogression- F ree S urvival Number of events (%) 117 (55%) 77 (71%) Progressive disease 107 (50%) 70 (65%) Death 10 (5%) 7 (6%) Median, months (95% CI) 4.8 (4.3, 4.9) 1.5 (1.4, 2.7) HR a (95% CI) 0.47 (0.34, 0.65) P value (log-rank test) < 0.0001 Confirmed Tumor Responses Overall response rate (95% CI) 22% (17%, 28%) 8% (4%, 15%) Complete response, n (%) 4 (2%) 0 Partial response, n (%) 43 (20%) 9 (8%) Duration of Response Median DoR, months (95% CI) 5.5 (4.1, 5.9) NR (3.5, NR) Figure 1.

Kaplan-Meier Curves of Investigator-Assessed Progression-Free Survival (ITT Population) in the METRIC Study In supportive analyses based on independent radiologic review committee (IRRC) assessment, the PFS results were consistent with those of the primary efficacy analysis.

MEKINIST with Dabrafenib COMBI-d Study The safety and efficacy of MEKINIST administered with dabrafenib were evaluated in an international, randomized, double-blind, active-controlled trial (the COMBI-d study; NCT01584648).

The COMBI-d study compared dabrafenib plus MEKINIST to dabrafenib plus placebo as first-line treatment for patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma.

Patients were randomized (1:1) to receive MEKINIST 2 mg once daily plus dabrafenib 150 mg twice daily or dabrafenib 150 mg twice daily plus matching placebo.

Randomization was stratified by LDH level (> ULN vs.

≤ ULN) and BRAF mutation subtype (V600E vs.

V600K).

The major efficacy outcome was investigator-assessed PFS per RECIST v1.1 with additional efficacy outcome measures of overall survival (OS) and confirmed overall response rate (ORR).

In the COMBI-d study, 423 patients were randomized to MEKINIST plus dabrafenib (n = 211) or dabrafenib plus placebo (n = 212).

The median age was 56 years (range: 22 to 89), 53% were male, > 99% were White, 72% had ECOG performance status of 0, 4% had Stage IIIC, 66% had M1c disease, 65% had normal LDH, and 2 patients had a history of brain metastases.

All patients had tumor containing BRAF V600E or V600K mutations as determined by centralized testing with the FDA-approved companion diagnostic test; 85% had BRAF V600E mutation-positive melanoma and 15% had BRAF V600K mutation-positive melanoma.

The COMBI-d study demonstrated statistically significant improvements in PFS and OS.

Table 21 and Figure 2 summarize the efficacy results.

Table 21.

Efficacy Results in the COMBI-d Study Abbreviations: CI, confidence interval; DoR, duration of response; HR, hazard ratio; NR, not reached; ORR, overall response rate.

a PFS and ORR were assessed by investigator.

b Based on stratified log-rank test.

Endpoint MEKINIST plus D abrafenib N = 211 Placebo plus Dabrafenib N = 212 Progression-Free Survival a Number of events (%) 102 (48%) 109 (51%) Median, months (95% CI) 9.3 (7.7, 11.1) 8.8 (5.9, 10.9) HR (95% CI) 0.75 (0.57, 0.99) P value b 0.035 Overall Survival Number of deaths (%) 99 (47%) 123 (58%) Median, months (95% CI) 25.1 (19.2, NR) 18.7 (15.2, 23.1) HR (95% CI) 0.71 (0.55, 0.92) P value b 0.01 Overall Response Rate a ORR (95% CI) 66% (60%, 73%) 51% (44%, 58%) P value < 0.001 Complete response 10% 8% Partial response 56% 42% Median DoR, months (95% CI) 9.2 (7.4, NR) 10.2 (7.5, NR) Figure 2.

Kaplan-Meier Curves of Overall Survival in the COMBI-d Study COMBI-MB Study The activity of MEKINIST with dabrafenib for the treatment of BRAF V600E or V600K mutation-positive melanoma, metastatic to the brain, was evaluated in a non-randomized, open-label, multi-center, multi-cohort trial (the COMBI-MB study; NCT02039947).

Eligible patients were required to have at least one measurable intracranial lesion and to have no leptomeningeal disease, parenchymal brain metastasis greater than 4 cm in diameter, ocular melanoma, or primary mucosal melanoma.

Patients received MEKINIST 2 mg orally once daily and dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity.

The major efficacy outcome measure was intracranial response rate, defined as the percentage of patients with a confirmed intracranial response per RECIST v1.1, modified to allow up to five intracranial target lesions at least 5 mm in diameter, as assessed by independent review.

The COMBI-MB study enrolled 121 patients with a BRAF V600E (85%) or V600K (15%) mutation.

The median age was 54 years (range: 23 to 84), 58% were male, 100% were White, 8% were from the United States, 65% had normal LDH at baseline, and 97% had an ECOG performance status of 0 or 1.

Intracranial metastases were asymptomatic in 87% and symptomatic in 13% of patients, 22% received prior local therapy for brain metastases, and 87% also had extracranial metastases.

The intracranial response rate was 50% (95% CI: 40, 60), with a complete response rate of 4.1% and a partial response rate of 46%.

The median duration of intracranial response was 6.4 months (range: 1 to 31).

Of the patients with an intracranial response, 9% had stable or progressive disease as their best overall response.

14.2 Adjuvant Treatment of BRAF V600E or V600K Mutation-Positive Melanoma The safety and efficacy of MEKINIST administered with dabrafenib were evaluated in an international, multi-center, randomized, double-blind, placebo-controlled trial (COMBI-AD; NCT01682083) that enrolled patients with Stage III melanoma with BRAF V600E or V600K mutations as detected by the THxID ® -BRAF assay and pathologic involvement of regional lymph node(s).

Enrollment required complete resection of melanoma with complete lymphadenectomy within 12 weeks prior to randomization.

The trial excluded patients with mucosal or ocular melanoma, unresectable in-transit metastases, distant metastatic disease, or prior systemic anti-cancer treatment, including radiotherapy.

Patients were randomized (1:1) to receive MEKINIST 2 mg once daily in combination with dabrafenib 150 mg twice daily or two placebos for up to 1 year.

Randomization was stratified by BRAF mutation status (V600E or V600K) and American Joint Committee on Cancer (AJCC; 7 th Edition) Stage (IIIA, IIIB, or IIIC).

The major efficacy outcome measure was relapse-free survival (RFS) defined as the time from randomization to disease recurrence (local, regional, or distant metastasis), new primary melanoma, or death from any cause, whichever occurred first as assessed by the investigator.

Patients underwent imaging for tumor recurrence every 3 months for the first two years and every 6 months thereafter.

In COMBI-AD, a total of 870 patients were randomized: 438 to the MEKINIST in combination with dabrafenib and 432 to placebo.

Median age was 51 years (range: 18 to 89), 55% were male, 99% were White, and 91% had an ECOG performance status of 0.

Disease characteristics were AJCC Stage IIIA (18%), Stage IIIB (41%), Stage IIIC (40%), stage unknown (1%); BRAF V600E mutation (91%), BRAF V600K mutation (9%); macroscopic lymph nodes (65%); and tumor ulceration (41%).

The median duration of follow-up (time from randomization to last contact or death) was 2.8 years.

COMBI-AD showed a statistically significant improvement in RFS in patients randomized to MEKINIST in combination with dabrafenib arm compared to those randomized to placebo.

Efficacy results are presented in Table 22 and Figure 3.

Table 22.

Efficacy Results in COMBI-AD in the Adjuvant Treatment of Melanoma Abbreviations: HR, hazard ratio; CI, confidence interval; NE, not estimable.

a Pike estimator obtained from the stratified log-rank test.

b Log-rank test stratified by disease stage (IIIA vs.

IIIB vs.

IIIC) and BRAF V600 mutation type (V600E vs.

V600K).

Endpoint MEKINIST plus Dabrafenib N = 438 Placebo N = 432 Relapse-Free Survival Number of events (%) 166 (38) 248 (57) Median, months (95% CI) NE (44.5, NE) 16.6 (12.7, 22.1) HR (95% CI) a 0.47 (0.39, 0.58) P value b < 0.0001 Figure 3.

Kaplan-Meier Curves for Relapse-Free Survival in COMBI-AD in the Adjuvant Treatment of Melanoma 14.3 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer The safety and efficacy of dabrafenib alone or administered with MEKINIST were evaluated in a multi-center, three-cohort, non-randomized, activity-estimating, open-label trial (Study BRF113928; NCT01336634).

Key eligibility criteria were locally confirmed BRAF V600E mutation-positive metastatic NSCLC, no prior exposure to BRAF or MEK inhibitor, and absence of EGFR mutation or ALK rearrangement (unless patients had progression on prior tyrosine kinase inhibitor therapy).

Patients enrolled in Cohorts A and B were required to have received at least one previous platinum-based chemotherapy regimen with demonstrated disease progression but no more than three prior systemic regimens.

Patients in Cohort C could not have received prior systemic therapy for metastatic disease.

Patients in Cohort A received dabrafenib 150 mg twice daily.

Patients in Cohorts B and C received MEKINIST 2 mg once daily and dabrafenib 150 mg twice daily.

The major efficacy outcome was ORR per RECIST v1.1 as assessed by independent review committee (IRC) and duration of response.

There were a total of 171 patients enrolled which included 78 patients enrolled in Cohort A, 57 patients enrolled in Cohort B, and 36 patients enrolled in Cohort C.

The characteristics of the population were: a median age of 66 years; 48% male; 81% White, 14% Asian, 3% Black, and 2% Hispanic; 60% former smokers, 32% never smokers, and 8% current smokers; 27% had ECOG performance status (PS) of 0, 63% had ECOG PS of 1, and 11% had ECOG PS of 2; 99% had metastatic disease of which 6% had brain metastasis at baseline and 14% had liver metastasis at baseline; 11% had systemic anti-cancer therapy in the adjuvant setting, 58% of the 135 previously treated patients had only one line of prior systemic therapy for metastatic disease; 98% had non-squamous histology.

Efficacy results are summarized in Table 23.

Table 23.

Efficacy Results Based on Independent Review in Study BRF113928 Abbreviations: CI, confidence interval; DoR, duration of response.

a Represents final analysis results (cutoff date of 24 Feb 2021) for the primary analysis responder cohorts.

Treatment Dabrafenib MEKINIST plus Dabrafenib Population Previously Treated N = 78 Previously Treated N = 57 Treatment Naïve N = 36 Overall Response Rate a ORR (95% CI) 27% (18%, 38%) 61% (48%, 74%) 61% (44%, 77%) Complete response 1% 5% 8% Partial response 26% 56% 53% Duration of Response a n = 21 n = 35 n = 22 Median DoR, months (95% CI) 18.0 (4.2, 40.1) 9.0 (5.8, 26.2) 15.2 (7.8, 23.5) In a subgroup analysis of patients with retrospectively centrally confirmed BRAF V600E mutation-positive NSCLC with the Oncomine ™ Dx Target Test, the ORR results were similar to those presented in Table 16.

14.4 BRAF V600E Mutation-Positive Locally Advanced or Metastatic Anaplastic Thyroid Cancer The safety and efficacy of MEKINIST administered with dabrafenib was evaluated in an activity-estimating, nine-cohort, multi-center, non-randomized, open-label trial (Study BRF117019; NCT02034110) in patients with rare cancers with the BRAF V600E mutation, including locally advanced, unresectable, or metastatic ATC with no standard locoregional treatment options.

Trial BRF117019 excluded patients who could not swallow or retain the medication; who received prior treatment with BRAF or MEK inhibitors; with symptomatic or untreated CNS metastases; or who had airway obstruction.

Patients received MEKINIST 2 mg once daily and dabrafenib 150 mg twice daily.

The major efficacy outcome measure was ORR per RECIST v1.1 as assessed by independent review committee (IRC) and duration of response (DoR).

Thirty-six patients were enrolled and were evaluable for response in the ATC cohort.

The median age was 71 years (range: 47 to 85); 44% were male, 50% White, 44% Asian; and 94% had ECOG performance status of 0 or 1.

Prior anti-cancer treatments included surgery and external beam radiotherapy (83% each), and systemic therapy (67%).

Efficacy results are summarized in Table 24.

Table 24.

Efficacy Results in the ATC Cohort Based on Independent Review of Study BRF117019 Abbreviations: ATC, anaplastic thyroid cancer; CI, confidence interval; DoR, duration of response; ORR, overall response rate; NE, not estimable.

ATC Cohort Population N = 36 Overall Response Rate ORR (95% CI) 53% (35.5%, 69.6%) Complete response 6% Partial response 47% Duration of Response n = 19 Median DoR, months (95% CI) 13.6 (3.8, NE) % with DoR ≥ 6 months 68% % with DoR ≥ 12 months 53% 14.5 Lack of Clinical Activity in Metastatic Melanoma Following BRAF-Inhibitor Therapy The clinical activity of MEKINIST as a single agent was evaluated in a single-arm, multi-center, international trial in 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor.

All patients received MEKINIST at a dose of 2 mg orally once daily until disease progression or unacceptable toxicity.

The median age was 58 years, 63% were male, all were White, 98% had baseline ECOG PS of 0 or 1, and the distribution of BRAF V600 mutations was V600E (83%), V600K (10%), and the remaining patients had multiple V600 mutations (5%), or unknown mutational status (2%).

No patient achieved a confirmed partial or complete response as determined by the clinical investigators.

14.6 BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors The safety and efficacy of MEKINIST in combination with dabrafenib for the treatment of BRAF V600E mutation-positive unresectable or metastatic solid tumors were evaluated in Trials BRF117019, NCI-MATCH, and CTMT212X2101, and supported by results in COMBI-d, COMBI-v [see Clinical Studies (14.2)] , and BRF113928 [see Clinical Studies (14.4)] .

In adult studies, patients received MEKINIST 2 mg once daily and dabrafenib 150 mg twice daily.

The major efficacy outcome measures were ORR per RECIST v1.1, RANO [HGG] or modified RANO [LGG] criteria and duration of response (DoR).

BRF117019 Study and NCI-MATCH Study Study BRF117019 (NCT02034110) [see Clinical Studies (14.5)] is a multi-cohort, multi-center, non-randomized, open-label trial in adult patients with selected tumors with the BRAF V600E mutation, including high grade glioma (HGG) (n = 45), biliary tract cancer (BTC) (n = 43), low grade glioma (LGG) (n = 13), adenocarcinoma of small intestine (ASI) (n = 3), gastrointestinal stromal tumor (GIST) (n = 1), and anaplastic thyroid cancer [see Clinical Studies (14.5)] .

Patients were enrolled based on local assessments of BRAF V600E mutation status; a central laboratory confirmed the BRAF V600E mutation in 93 of 105 patients.

Arm H (EAY131-H) of the NCI-MATCH study (NCT02465060) is a single-arm, open-label study that enrolled patients with a BRAF V600E mutation.

Patients with melanoma, thyroid cancer, or CRC were excluded.

BRAF mutation status for enrollment was determined either by central or local laboratory test.

The study included adult patients with solid tumors including gastrointestinal tumors (n = 14), lung tumors (n = 7), gynecologic or peritoneal tumors (n = 6), CNS tumors (n = 4), and ameloblastoma of mandible (n = 1).

Among the 131 patients enrolled in BRF117019 and NCI-MATCH with the tumor types shown in Table 21, the baseline characteristics were: median age of 51 years with 20% age 65 or older; 56% female; 85% White, 9% Asian, 3% Black, 3% other; and 37% ECOG 0, 56% ECOG 1, and 6% ECOG 2.

Of the 131 patients, 90% received prior systemic therapy.

Efficacy results in patients with solid tumors are summarized in Table 25.

Table 25.

Efficacy Results Based on Independent Review in Study BRF117019 and NCI-MATCH Arm H Abbreviations: PR, partial response.

a Excludes NSCLC (n = 6) and ATC (n = 36) (previously approved tumor types for MEKINIST in combination with dabrafenib).

b Median DoR 9.8 months (95% CI: 5.3, 20.4).

c Median DoR 13.6 months (95% CI: 5.5, 26.7).

d Denotes a right-censored DoR.

Tumor Type a N Objective Response Rate Duration of Response % 95% CI Range (months) Biliary tract cancer b 48 46 (31, 61) 1.8 d , 40 d High grade glioma c 48 33 (20, 48) 3.9, 44 Glioblastoma 32 25 (12, 43) 3.9, 27 Anaplastic pleomorphic xanthoastrocytoma 6 67 (22, 96) 6, 43 Anaplastic astrocytoma 5 20 (0.5, 72) 15 Astroblastoma 2 100 (16, 100) 15, 23 d Undifferentiated 1 PR (2.5, 100) 6 Anaplastic ganglioglioma 1 0 NA NA Anaplastic oligodendroglioma 1 0 NA NA Low grade glioma 14 50 (23, 77) 6, 29 d Astrocytoma 4 50 (7, 93) 7, 23 Ganglioglioma 4 50 (7, 93) 6, 13 Pleomorphic xanthoastrocytoma 2 50 (1.3, 99) 6 Pilocytic astrocytoma 2 0 NA NA Choroid plexus papilloma 1 PR (2.5, 100) 29 d Gangliocytoma/ganglioglioma 1 PR (2.5, 100) 18 d Low grade serous ovarian carcinoma 5 80 (28, 100) 12, 42 d Adenocarcinoma small intestine 4 50 (7, 93) 7, 8 Adenocarcinoma pancreas 3 0 NA NA Mixed ductal/adenoneuroendocrine carcinoma 2 0 NA NA Neuroendocrine carcinoma of colon 2 0 NA NA Ameloblastoma of mandible 1 PR (2.5, 100) 30 Combined small cell-squamous carcinoma of lung 1 PR (2.5, 100) 5 Mucinous-papillary serous adenocarcinoma of peritoneum 1 PR (2.5, 100) 8 Adenocarcinoma of anus 1 0 NA NA Gastrointestinal stromal tumor 1 0 NA NA CTMT212X2101 (X2101) Study Study X2101 (NCT02124772) was a multi-center, open-label, multi-cohort study in pediatric patients with refractory or recurrent solid tumors.

Part C was a dose escalation of MEKINIST in combination with dabrafenib in patients with a BRAF V600E mutation.

Part D was a cohort expansion phase of MEKINIST in combination with dabrafenib in patients with LGG with a BRAF V600E mutation.

The major efficacy outcome measure was ORR as assessed by independent review committee per RANO criteria.

The efficacy of MEKINIST in combination with dabrafenib was evaluated in 48 pediatric patients, including 34 patients with LGG and 2 patients with HGG.

For patients with BRAF V600E mutant LGG and HGG in Parts C and D, the median age was 10 years (range: 1 to 17); 50% were male, 75% White, 8% Asian, 3% Black; and 58% had Karnofsky/Lansky performance status of 100.

Prior anti-cancer treatments included surgery (83%), external beam radiotherapy (2.8%), and systemic therapy (92%).

The ORR was 25% (95% CI: 12%, 42%).

For the 9 patients who responded, DoR was ≥ 6 months for 78% of patients and ≥ 24 months for 44% of patients.

CDRB436G2201 (G2201) Study – High-Grade Glioma Cohort Study G2201 (NCT02684058) was a multi-center, randomized, open-label, Phase II study of dabrafenib and trametinib in chemotherapy naïve pediatric patients with BRAF V600E mutant low-grade glioma (LGG) and patients with relapsed or progressive BRAF V600E mutant HGG.

Patients with HGG were enrolled in a single-arm cohort.

The major efficacy outcome measure for the HGG cohort was ORR as assessed by independent review committee per RANO 2010 criteria.

The efficacy of MEKINIST in combination with dabrafenib was evaluated in 41 pediatric patients with relapsed or progressive HGG.

For patients with BRAF V600E mutant HGG enrolled in the HGG cohort, the median age was 13 years (range: 2 to 17); 56% were female, 61% White, 27% Asian, 2.4% Black, and 37% had Karnofsky/Lansky performance status of 100.

Prior anti-cancer treatments included surgery (98%), radiotherapy (90%), and chemotherapy (81%).

The ORR was 56% (95% CI: 40, 72).

The median DoR was not reached (95% CI: 9.2, NE).

For the 23 patients who responded in the HGG cohort, DoR was ≥ 6 months for 78% of patients, ≥ 12 months for 48% of patients, and ≥ 24 months for 22% of patients.

14.7 BRAF V600E Mutation-Positive Low-Grade Glioma CDRB436G2201 (G2201) Study – Low-Grade Glioma Cohort The safety and efficacy of MEKINIST in combination with dabrafenib for the treatment of BRAF V600E mutation-positive low-grade glioma (LGG) in pediatric patients aged 1 to < 18 years of age were evaluated in the multi-center, open-label trial (Study CDRB436G2201; NCT02684058).

Patients with LGG (WHO grades 1 and 2) who required first systemic therapy were randomized in a 2:1 ratio to dabrafenib plus trametinib (D + T) or carboplatin plus vincristine (C + V).

BRAF mutation status was identified prospectively via a local assessment or a central laboratory test.

In addition, retrospective testing of available tumor samples by the central laboratory was performed to evaluate BRAF V600E mutation status.

Patients received age- and weight-based dosing of MEKINIST and dabrafenib until loss of clinical benefit or until unacceptable toxicity.

Carboplatin and vincristine were dosed based on body surface area at doses 175 mg/m 2 and 1.5 mg/m 2 (0.05 mg/kg for patients < 12 kg), respectively, as one 10-week induction course followed by eight 6-week cycles of maintenance therapy.

The major efficacy outcome measure was overall response rate (ORR) by independent review based on RANO LGG (2017) criteria.

Additional efficacy outcome measures were progression-free survival and overall survival.

The primary analysis was performed when all patients had completed at least 32 weeks of therapy.

In the LGG cohort, 110 patients were randomized to D + T (n = 73) or C + V (n = 37).

Median age was 9.5 years (range: 1 to 17); 60% were female.

Study G2201 showed a statistically significant improvement in ORR and PFS in patients with LGG randomized to D + T compared to those randomized to C + V.

Efficacy results are shown in Table 26.

Table 26.

Efficacy Results Based on Independent Review in Study G2201 (LGG cohort) Abbreviations: CI, confidence interval; NE, not estimable.

a Based on Clopper-Pearson exact confidence interval b Based on Kaplan-Meier method c Based on proportional hazards model MEKINIST plus Dabrafenib N = 73 Carboplatin plus Vincristine N = 37 Overall Response Rate ORR% (95% CI) a 46.6 (34.8, 58.6) 10.8 (3.0, 25.4) P value < 0.001 Complete response, n (%) 2 (2.7) 1 (2.7) Partial response, n (%) 32 (44) 3 (8) Duration of Response Median (95% CI) b , months 23.7 (14.5, NE) NE (6.6, NE) % with observed DoR ≥ 12 months 56 50 % with observed DoR ≥ 24 months 15 25 Progression-Free Survival Median (95% CI) b , months 20.1 (12.8, NE) 7.4 (3.6, 11.8) Hazard ratio (95% CI) c 0.31 (0.17, 0.55) P value < 0.001 Figure 4.

Kaplan-Meier Curves for Progression-Free Survival in Study G2201 (LGG cohort) At the time of the interim analysis of overall survival (OS), conducted when all patients had completed at least 32 weeks of treatment or had discontinued earlier, there was one death on the C + V arm.

The OS results at interim analysis did not reach statistical significance.