DAURISMO™ Clinical Studies

(glasdegib)

14 CLINICAL STUDIES

The efficacy of DAURISMO in combination with low-dose cytarabine was evaluated in a multicenter, open-label, randomized study (Study BRIGHT AML 1003, NCT01546038) that included 115 patients age 55 years or older with newly-diagnosed AML who met at least one of the following criteria: a) age ≥75 years, b) severe cardiac disease, c) baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2, or d) baseline serum creatinine >1.3 mg/dL. Patients were randomized 2:1 to receive DAURISMO at a 100 mg daily dose with low-dose cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of a 28-day cycle (N=77) or low-dose cytarabine alone (N=38) in 28-day cycles until disease progression or unacceptable toxicity. Patients were stratified by cytogenetic risk (good/intermediate or poor).

The baseline demographic and disease characteristics are shown in Table 6. The two treatment arms were generally balanced with respect to the baseline demographics and disease characteristics (see Table 6).

Table 6. Baseline Demographic and Disease Characteristics in Patients with AML in BRIGHT AML 1003
Demographic and Disease CharacteristicsDAURISMO With Low-Dose Cytarabine
(N=77)		Low-Dose Cytarabine Alone
(N=38)
Abbreviations: AML = acute myeloid leukemia; N = number of patients; ECOG PS = Eastern Cooperative Oncology Group Performance Status.
*
Baseline ECOG PS was not reported for one patient in the DAURISMO with low-dose cytarabine arm.

Demographics

Age

Median (Min, Max) (Years)

77 (64, 92)

76 (58, 83)

≥75 years N (%)

47 (61)

23 (61)

Sex, N (%)

Male

59 (77)

23 (61)

Female

18 (23)

15 (39)

Race, N (%)

White

75 (97)

38 (100)

Black or African American

1 (1)

0 (0)

Asian

1 (1)

0 (0)

Disease History, N (%)

De Novo AML

38 (49)

18 (47)

Secondary AML

39 (51)

20 (53)

Prior Hypomethylating Agent Use

11 (14)

6 (16)

ECOG PS*, N (%)

0 to 1

35 (46)

20 (53)

2

41 (53)

18 (47)

Cytogenetic Risk Status, N (%)

Good/Intermediate

48 (62)

21 (55)

Poor

29 (38)

17 (45)

Baseline Severe Cardiac Disease

51 (66)

20 (53)

Baseline Serum Creatinine >1.3 mg/dL

15 (19)

5 (13)

Efficacy was established on the basis of overall survival (OS) from the date of randomization to death from any cause. With a median follow-up of approximately 20 months, the DAURISMO with low-dose cytarabine arm was superior to low-dose cytarabine alone arm (Figure 1). The efficacy results are shown in Table 7. Improvement in OS was consistent across prespecified cytogenetic risk subgroups.

Table 7. Efficacy Results From BRIGHT AML 1003
Endpoint/Study PopulationDAURISMO With Low-Dose CytarabineLow-Dose Cytarabine Alone
Abbreviations: AML = acute myeloid leukemia; N = number of patients; OS = overall survival; CI = confidence interval; CR = complete response.
*
Hazard ratio (DAURISMO with low-dose cytarabine/low-dose cytarabine alone) based on the Cox Proportional hazards model stratified by cytogenetic risk.
†
1-sided p-value from log-rank test stratified by cytogenetic risk.

OS

N=77

N=38

    Median survival, months (95% CI)

8.3 (4.4, 12.2)

4.3 (1.9, 5.7)

    Hazard ratio (95% CI)*

0.46 (0.30, 0.71)

    p-value†

0.0002

CR

N=14

N=1

    CR rate (in %, 95% CI)

18.2 (10.3, 28.6)

2.6 (0.1, 13.8)

Figure 1. BRIGHT AML 1003 – Kaplan-Meier Plot of Overall Survival for Patients with AML

Figure 1

Abbreviations: CI = confidence interval; OS = overall survival; LDAC = low-dose cytarabine.

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Clinical Studies

14 CLINICAL STUDIES

The efficacy of DAURISMO in combination with low-dose cytarabine was evaluated in a multicenter, open-label, randomized study (Study BRIGHT AML 1003, NCT01546038) that included 115 patients age 55 years or older with newly-diagnosed AML who met at least one of the following criteria: a) age ≥75 years, b) severe cardiac disease, c) baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2, or d) baseline serum creatinine >1.3 mg/dL. Patients were randomized 2:1 to receive DAURISMO at a 100 mg daily dose with low-dose cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of a 28-day cycle (N=77) or low-dose cytarabine alone (N=38) in 28-day cycles until disease progression or unacceptable toxicity. Patients were stratified by cytogenetic risk (good/intermediate or poor).

The baseline demographic and disease characteristics are shown in Table 6. The two treatment arms were generally balanced with respect to the baseline demographics and disease characteristics (see Table 6).

Table 6. Baseline Demographic and Disease Characteristics in Patients with AML in BRIGHT AML 1003
Demographic and Disease CharacteristicsDAURISMO With Low-Dose Cytarabine
(N=77)		Low-Dose Cytarabine Alone
(N=38)
Abbreviations: AML = acute myeloid leukemia; N = number of patients; ECOG PS = Eastern Cooperative Oncology Group Performance Status.
*
Baseline ECOG PS was not reported for one patient in the DAURISMO with low-dose cytarabine arm.

Demographics

Age

Median (Min, Max) (Years)

77 (64, 92)

76 (58, 83)

≥75 years N (%)

47 (61)

23 (61)

Sex, N (%)

Male

59 (77)

23 (61)

Female

18 (23)

15 (39)

Race, N (%)

White

75 (97)

38 (100)

Black or African American

1 (1)

0 (0)

Asian

1 (1)

0 (0)

Disease History, N (%)

De Novo AML

38 (49)

18 (47)

Secondary AML

39 (51)

20 (53)

Prior Hypomethylating Agent Use

11 (14)

6 (16)

ECOG PS*, N (%)

0 to 1

35 (46)

20 (53)

2

41 (53)

18 (47)

Cytogenetic Risk Status, N (%)

Good/Intermediate

48 (62)

21 (55)

Poor

29 (38)

17 (45)

Baseline Severe Cardiac Disease

51 (66)

20 (53)

Baseline Serum Creatinine >1.3 mg/dL

15 (19)

5 (13)

Efficacy was established on the basis of overall survival (OS) from the date of randomization to death from any cause. With a median follow-up of approximately 20 months, the DAURISMO with low-dose cytarabine arm was superior to low-dose cytarabine alone arm (Figure 1). The efficacy results are shown in Table 7. Improvement in OS was consistent across prespecified cytogenetic risk subgroups.

Table 7. Efficacy Results From BRIGHT AML 1003
Endpoint/Study PopulationDAURISMO With Low-Dose CytarabineLow-Dose Cytarabine Alone
Abbreviations: AML = acute myeloid leukemia; N = number of patients; OS = overall survival; CI = confidence interval; CR = complete response.
*
Hazard ratio (DAURISMO with low-dose cytarabine/low-dose cytarabine alone) based on the Cox Proportional hazards model stratified by cytogenetic risk.
†
1-sided p-value from log-rank test stratified by cytogenetic risk.

OS

N=77

N=38

    Median survival, months (95% CI)

8.3 (4.4, 12.2)

4.3 (1.9, 5.7)

    Hazard ratio (95% CI)*

0.46 (0.30, 0.71)

    p-value†

0.0002

CR

N=14

N=1

    CR rate (in %, 95% CI)

18.2 (10.3, 28.6)

2.6 (0.1, 13.8)

Figure 1. BRIGHT AML 1003 – Kaplan-Meier Plot of Overall Survival for Patients with AML

Figure 1

Abbreviations: CI = confidence interval; OS = overall survival; LDAC = low-dose cytarabine.
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