Final Abbreviated Clinical Study Report – Non-intensive
Protocol B1371019

CLINICAL STUDY REPORT SYNOPSISSYNOPSIS
Study Title: A Randomized (1:1), Double-Blind, Multi-Center, Placebo Controlled Study
Evaluating Intensive Chemotherapy With or Without Glasdegib (PF-04449913) or
Azacitidine (AZA) With or Without Glasdegib in Patients With Previously Untreated Acute
Myeloid Leukemia
Study Number: B1371019
Regulatory Agency or Public Disclosure Identifier Number:
EudraCT Number: 2017-002822-19
ClinicalTrials.gov ID: NCT03416179
Study Phase: Phase 3
Name of Study Intervention: Glasdegib (PF-04449913)
Trade Name: DAURISMO™
Name of Sponsor/Company: Pfizer Inc.
CSR Version and Report Date: version 1.0; 23 June 2022
Number of Study Center(s) and Investigator(s):A total of 325 participants were randomized for participation at 83 centers in
21 countries/regions.
A list of study centers and investigators involved in this study is provided inAppendix 16.1.4.1.
Publications: Not Applicable
Study Period:
Study Initiation Date (First Participant First Visit [FPFV]) – Non-intensive Cohort:
18 June 2018
Primary Completion Date (PCD) – Non-intensive Cohort: 05 June 2020
Data Cutoff Date – Non-intensive Cohort: The analyses presented in this report are based ona database lock date of 17 January 2022.
The non-intensive cohort was terminated due to the futility at an interim analysis by external
data monitoring committee (E-DMC). The participants of the non-intensive cohort (in the
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investigator’s clinical judgement) can continue to derive clinical benefit to access study
medication(s) and can enroll in the continuation study.
Rationale:
The non-intensive B1371019 study was designed to investigate if glasdegib in combination
with azacitidine is superior to placebo in combination with azacitidine in prolonging overall
survival (OS) in patients with untreated acute myelogenous leukemia (AML).
Objectives, Endpoints, and Statistical Methods:
The objectives and endpoints of the study are listed in Table S1.
Table S1. Study Objectives and Endpoints – Non-Intensive StudyType
Primary
Efficacy

Secondary
EfficacyPRO

Objectives

Endpoints

Presentation of
Results

To demonstrate that glasdegib
was superior to placebo in
combination with azacitidine inprolonging OS in participants
with untreated AML.



OS.

To compare fatigue scorepost-baseline as measured by
MDASI-AML/MDS in both
treatment arms.



Fatigue score measured
by theMDASI-AML/MDS
questionnaire.

Analyzed

To compare glasdegib versus
placebo in combination withazacitidine in improving otherclinical efficacy measures.



Rate of CR (including
CRMRD- as assessed bymultiparametric flow
cytometry), CRi as
defined by the ELN
recommendations (2017),
MLFS, PR, and CRh.

Analyzed

To estimate the DoR in both
treatment arms.



DoR (defined as CRi or
better or CRh or better if
applicable).a

Not Analyzed

To estimate the TTR in both
treatment arms.



TTR (CRi or better or
CRh or better).a

Analyzed

To compare EFS in both
treatment arms.
To compare PRO measurements
in both treatment arms.



EFS.

Not Analyzed

PROs as measured by the
MDASI-AML/MDS,
EQ-5D-5L, PGI-S andPGI-C.

Not Analyzed

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Table S1. Study Objectives and Endpoints – Non-Intensive Study
SafetyPK

To evaluate the overall safety
profile in both treatment arms.



AEs as characterized bytype, frequency, severity(as graded by NCI
CTCAE version 4.03),
timing, seriousness, andrelationship to study
therapy.

Analyzed

To evaluate laboratory
abnormalities in both treatment
arms.



Laboratory abnormalities
as characterized by type,
frequency, severity (asgraded by NCI CTCAE
version 4.03) and timing.

Analyzed

To characterize treatment effects
on the QTc interval.
To characterize the PK ofglasdegib.



QTc interval

AnalyzedPK of glasdegib.

Analyzed

Bone marrow and bloodbiomarkers of response and/or
resistance to glasdegib in
combination with azacitidine.

Molecular, cellular, andsoluble markers inperipheral blood and/or
bone marrow which might
include, but were notlimited to: Hh pathway
and/or AML gene andprotein expression,
epigenetic status andchanges, and genemutation profiling.

Transfusion
independence.



As measured by aquestionnaire containing
2 items from the
PRO-CTCAE item libraryversion 1.0 and an add-on
item on muscle spasm.

Exploratory
Biomarker and
Other

PRO

PROs for symptomatic AEs.

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Not Analyzed

Not Analyzed

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CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and Endpoints – Non-Intensive Study
Abbreviations: AE = adverse event; CR = complete remission; CRh = complete remission with partial
hematologic recovery; CRi = complete remission with incomplete hematologic recovery; CRMRD- = complete
remission with negative minimal residual disease; CTCAE = common terminology criteria for adverse
events; DoR = duration of response; EFS = event-free survival; ELN = European Leukemia Net;
EQ-5D-5L = EuroQol 5-Dimension questionnaire 5-Level version; MDASI-AML/MDS = M.D. Anderson
Symptom Inventory AML/MDS Module; MDS = myelodysplastic syndrome; MLFS = morphologic
leukemia-free state; MRD = minimal residual disease; NCI = National Cancer Institute; OS = overall
survival; PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of Symptoms;
PK = pharmacokinetic; PR = partial remission; PRO = patient reported outcomes; QTc = QT interval
corrected for rate; TTR = time to response;
a. CRi or better included CR (including CRMRD-), CRh, or CRi for non-intensive chemotherapy
participants. CRh or better was only defined for non-intensive chemotherapy participants as CR(including CRMRD-) or CRh.

The non-intensive cohort achieved PCD on 05 June 2020 but was terminated thereafter(May 2020) for futility. The data as of the cutoff date (17 January 2022) was determined tobe final data for the non-intensive study. This abbreviated CSR presents the final results forthe non-intensive AML population.
There are participants who continue this study as of the data cutoff date (17 January 2022)
and can have access to the study medication(s) and receive the benefit of treatment. For
these participants, only safety and dosing data are to be collected after the data cutoff.
Some participants discontinued from the study after the E-DMC’s conclusion that the study
would not meet its primary objective. Due to this, some secondary and exploratory endpoints
could not be analyzed as originally planned (see Table S1 for the endpoints that were notanalyzed).
OS: the primary efficacy analysis compared OS between the experimental arm and thecontrol arm, and was performed using a 1-sided stratified log-rank test. OS was defined as
the time from randomization to the date of death due to any cause. OS time associated witheach treatment arm was summarized using the Kaplan-Meier method (product-limit
estimates). The OS rate at 6, 12, and 18 months was estimated with corresponding 2-sided
95% confidence intervals (CIs) for the non-intensive chemotherapy participants.
Fatigue: the “Fatigue” single-item from the MDASI-AML/MDS questionnaire was the key
secondary endpoint. A repeated measures model was used to determine Clinically Important
Responder (CIR). The change in Fatigue from baseline was used as the outcome and Subject
Global Impression of Change using PGIS (SGIC-S) score was used as the anchor.
Responses: The proportion of participants achieving CRMRD-, CR (including CRMRD-), CRi,
CRh, MLFS, and PR as their best overall response was estimated with 2-sided 95% CI (using
normal approximation). The proportion and 2-sided 95% CI (using exact method) ofparticipants achieving each response category for each stratum were also to be provided. The
proportion of participants with CRMRD-, CR (including CRMRD-), CRi or better and CRh or
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better respectively was compared between the 2 treatment arms using a 1-sided CochranMantel Haenszel (CMH) stratified test and an unstratified chi-square test.
TTR: Time to Response (TTRi or TTRh) was defined, for participants achieved CRi or betteror CRh or better, as the time from the date of randomization to the first documentation of
response (CRi or better or CRh or better).
PK: the plasma trough concentration (Ctrough) was reported. Descriptive statistics were
provided for these PK parameters in tabular form by cycle and day. For drug concentrations,individual values and descriptive statistics were presented by cycle, day of assessment, andnominal time in tabular form.
Methodology:
The B1371019 non-intensive study was a randomized (1:1), double-blind, multicenter,
placebo-controlled study of azacitidine chemotherapy in combination with glasdegib versus(vs) azacitidine chemotherapy in combination with placebo in adult participants withpreviously untreated AML who were not candidates for intensive induction chemotherapy(Figure S1).
Study assignment was made by the investigator based on the 2017 ELN recommendations.
Participants were stratified at randomization by genetic risk (favorable vs intermediate vsadverse by ELN genetic risk categories) and age (<75 years vs ≥75 years).
Figure S1. Schematic of Non-Intensive Study Design

Throughout this report the glasdegib + azacitidine arm will be referred to as the glasdegib
arm, and the placebo + azacitidine arm will be referred to as the placebo arm.
Number of Participants (planned and analyzed):
A total of 320 participants who were not candidates to receive intensive chemotherapy wereplanned to receive the treatment of non-intensive chemotherapy.
A total of 325 participants were randomized for participation at 83 centers in
21 countries/regions; 163 participants were randomized to the glasdegib arm and
162 participants to the placebo arm. A total of 322 (99.1%) participants were treated.
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As of the data cutoff date (17 January 2022) for this abbreviated CSR, 306 (95.0%)
participants discontinued from the study treatment.
The most common reason for glasdegib/placebo treatment discontinuations was
progressive disease; 38 (23.5%) and 41 (25.6%) participants in the glasdegib and placeboarms, respectively, had progressive disease. This was followed by death (36 [22.2%] and29 [18.1%] participants in glasdegib and placebo arms, respectively).



The most common reason for azacitidine treatment discontinuations was progressive
disease; 44 (27.2%) and 48 (30.0%) participants in the glasdegib and placebo arms,
respectively, had progressive disease. This was followed by death (37 [22.8%] and35 [21.9%] participants in glasdegib and placebo arms, respectively).

Participants who discontinued study treatment could go into either the follow-up phase, orthe long-term follow-up phase (if a subsequent anti-cancer therapy was initiated at end oftreatment or at the participant’s request). In the follow-up phase, 11 (6.7%) participants inglasdegib arm and 6 (3.7%) participants in placebo arm were ongoing as of the cutoff date.
In the long-term follow-up phase, 12 (7.4%) participants in glasdegib arm and6 (3.7%) participants in placebo arm were ongoing as of the cutoff date.
Death was the primary reason for discontinuation from follow-up (98 [60.1%] participants in
the glasdegib arm and 98 [60.5%] participants in the placebo arm), as well as from long-term
follow-up (117 [71.8%] participants in the glasdegib arm and 113 [69.8%] participants in theplacebo arm).
No participants in this non-intensive study discontinued study intervention or werediscontinued from study due to coronavirus disease 2019 (COVID-19).
Diagnosis and Main Criteria for Inclusion and Exclusion:
Enrolled in this non-intensive study were adult participants with previously untreated AML
who were not candidates for intensive induction chemotherapy. Participants with Acute
Promyelocytic Leukemia (APL) and APL with promyelocytic leukemia – retinoic acidreceptor alpha (PML-RARA), or AML with known breakpoint cluster region-Abelson 1(BCR-ABL1) mutation or known t(9;22)(q34;q11.2) as a sole abnormality were excluded
from this study.
Study Interventions, Dose, Mode of Administration, and Batch Number(s):Glasdegib 100 mg QD or matching placebo was administered by mouth (PO) daily beginningon Day 1 of chemotherapy with azacitidine administered by subcutaneous (SC) injection or
intravenous (IV) infusion daily for 7 days in 28-day cycles until disease progression,unacceptable toxicity, consent withdrawal, or death.
The manufacturing lot numbers for the study intervention(s) that were dispensed in this study
are provided in Table S2.
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CLINICAL STUDY REPORT SYNOPSIS
Table S2. Manufacturing Lot Numbers for Study Drugs Administered
Investigational Product Description
Glasdegib 100 mg Round Pale Orange
Film Coated Tablet (Drug Count [DC])Glasdegib 100 mg Round Pale Orange
Film Coated Tablet (DC)Glasdegib 25 mg Round Yellow Film
Coated Tablet (DC)Glasdegib 100 mg Round Pale Orange
Film Coated Tablet (DC)Glasdegib 100 mg Round Pale Orange
Film Coated Tablet (DC)Glasdegib 100 mg Round Pale Orange
Film Coated Tablet (DC)Glasdegib 25 mg Round Yellow Film
Coated Tablet (DC)Glasdegib 25 mg Round Yellow Film
Coated Tablet (DC)Glasdegib 25 mg Round Yellow Film
Coated Tablet (DC)
Azacitidine 100 mg powder for
25 mg/mL suspension for injection vial
Azacitidine 100 mg powder for
25 mg/mL suspension for injection vial
Azacitidine 100 mg powder for
25 mg/mL suspension for injection vial
Azacitidine 100 mg powder for
25 mg/mL suspension for injection vial
in 1×1 pack
Azacitidine 100 mg powder for
25 mg/mL suspension for injection vial
in 1×1 pack
Azacitidine 100 mg powder for
25 mg/mL suspension for injection vial
in 1×1 pack
Azacitidine 100 mg powder for
25 mg/mL suspension for injection vial
in 1×1 pack
Azacitidine 100 mg powder for
25 mg/mL suspension for injection vial
Azacitidine 100 mg powder for
25 mg/mL suspension for injection vial
in 1×1 pack
Placebo for Glasdegib 25 mg RoundYellow Film Coated Tablet
Placebo for Glasdegib 100 mg Round
Pale Orange Film Coated Tablet
Placebo for Glasdegib 25 mg RoundYellow Film Coated Tablet

Vendor Lot
Number
Not
Applicable(N/A)
19-DP-00032

Pfizer Lot
Number18-000163

Strength/Potency
100 mgDosageForm
Tablet19-001635

100 mgTablet19-DP-00031

19-001634

25 mg

Tablet19-DP-00033

19-001636

100 mgTablet17-001948

17-003503

100 mgTabletN/A

17-000224

100 mgTabletN/A

17-000222

25 mg

TabletN/A

18-000162

25 mg

TabletN/A

17-001947

25 mg

Tablet

9A146A

19-004070

100 mg 25 mg/mL

9A146A

19-004071

100 mg 25 mg/mL

9E200A

19-004474

100 mg 25 mg/mL

7A961A

17-004252

100 mg 25 mg/mL

Commercial
Product
Commercial
Product
Commercial
Product
Commercial
Product

6I920A

17-003002

100 mg 25 mg/mL

Commercial
Product

8H100A

19-002518

100 mg 25 mg/mL

Commercial
Product

8H100A

19-000728

100 mg 25 mg/mL

Commercial
Product

8I114A

19-001767

100 mg 25 mg/mL

6H912A

17-001253

100 mg 25 mg/mL

Commercial
Product
Commercial
Product

N/A

17-000217

0 mg

TabletN/A

17-000218

0 mg

Tablet19-DP-00029

19-001454

0 mg

TabletPFIZER CONFIDENTIAL
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Table S2. Manufacturing Lot Numbers for Study Drugs Administered
Investigational Product Description
Placebo for Glasdegib 100 mg Round
Pale Orange Film Coated Tablet

Vendor Lot
Number
19-DP-00030

Pfizer Lot
Number19-001633

Strength/Potency
0 mg

DosageForm
TabletDuration of Study Intervention:
Daily glasdegib (100 mg) PO or placebo PO could continue up to 2 years following
randomization unless AML was confirmed MRD negative post hematopoietic stem celltransplant (HSCT) at 2 consecutive time points per central laboratory analysis. These
2 consecutive time points were approximately 3 months apart as part of the already scheduled
marrow assessments.
The median duration of treatment was similar between the 2 treatment arms: 22.2 weeks(range: 0.4, 156.6) in the glasdegib arm and 24.2 weeks (range: 0.4, 127.3) in theplacebo arm.
Summary of Results:
Demographic and Other Baseline Characteristics:
Of the 325 randomized participants, 186 (57.2%) were male and 139 (42.8%) were female;the majority of participants were White (60.3%); mean (standard deviation [SD]) age was
73.17 (6.99) years.
The distribution of disease characteristics (white blood cell [WBC], platelets, hemoglobin,
peripheral blasts, bone marrow [BM] blasts, Eastern Cooperative Oncology Group [ECOG]
performance status, age group, ELN risk group) was similar between the 2 treatment arms.


The majority of participants had BM blasts ≥30%: 108 (66.3%) and
106 (65.4%) participants in the glasdegib and placebo arms, respectively.

For the classification from Interactive Voice Response System (IVRS), the majority ofparticipants had intermediate ELN risk, specifically 123 participants in the glasdegib arm
and 124 participants in the placebo arm.



As derived from case report form (CRF), the majority of participants had intermediate or
adverse ELN risk, specifically 134 participants in the glasdegib arm and 140 participantsin the placebo arm.



Advanced age was the most common reason for enrollment of participants in the
non-intensive chemotherapy in both the glasdegib arm (136 [83.4%] participants) and in
the placebo arm (125 [77.2%] participants).
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Exposure:
Exposure to Glasdegib/Placebo
Both the median and mean study treatment exposures to glasdegib/placebo were similar
between the 2 treatment arms.


The median treatment exposure time was 21.8 weeks for the glasdegib arm and24.1 weeks for the placebo arm.



The median relative dose intensity was 95.0% for the glasdegib arm and 96.9% for theplacebo arm.

Exposure to Azacitidine
Both the median and mean study treatment exposures to azacitidine were similar between the
2 treatment arms.


The median treatment exposure time was 21.0 weeks for the glasdegib arm and21.5 weeks for the placebo arm.



The median relative dose intensity for azacitidine was 100% in both treatment arms.

Efficacy Results:
Primary Endpoint - Overall Survival
The non-intensive study did not meet its primary objective of demonstrating that glasdegib +azacitidine was superior to placebo + azacitidine in prolonging OS in all randomized
participants with untreated AML.


A total of 117 (71.8%) and 113 (69.8%) participants died in the glasdegib and placeboarms, respectively.

Glasdegib did not extend OS with hazard ratio = 1.02 (95% CI: 0.787, 1.326) and 1-sided
p-value = 0.5622.

The estimated median OS for the glasdegib arm was 10.3 (95% CI: 7.6, 12.2) months
while for the placebo arm was 10.9 (95% CI: 7.9, 12.9) months.



The OS at 6, 12 and 18 months were comparable between the 2 treatment arms.

An analysis of OS by baseline characteristics showed that the glasdegib arm performed
better than the placebo arm in subgroups of Favorable and Intermediate ELN risk
categories, females, ECOG performance status ≥2, de novo hematological diseasehistory, and participants with baseline WBC ≥10 × 109/L, but the OS benefit was notstatistically significant. In contrast, the placebo arm performed better in subgroups of
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adverse ELN risk category, males, Asian population, EGOG performance status 0 and 1,
and Secondary hematological disease history, but the OS benefit was not statisticallydifferent. All these subgroup analyses are considered exploratory.
The estimated median duration of follow-up for OS by reversed Kaplan-Meier method
for the glasdegib arm was 22.0 (95% CI: 18.2, 23.7) months and for the placebo arm was
19.4 (95% CI: 16.4, 21.2) months.

Key Secondary Endpoint - Fatigue by MDASI-AML/MDS
At Week 12, the percentage of participants with improvement in fatigue was numericallylower in the glasdegib arm compared to that in the placebo arm with the CMH unstratified
1-sided p-value of 0.8397 and CMH stratified 1-sided p-value of 0.8359.
The estimated mean change in fatigue score anchored on PGI-S among clinically important
responders was -1.35 (95% CI: -1.61, -1.09).
Other Secondary Endpoints
Rate of CR, CRi, MLFS, PR and CRh
The percentages of participants achieving CR (including CRMRD-), CRi and MLFS werenumerically greater in the glasdegib arm as compared to the placebo arm.


A total of 32 (19.6%) participants in the glasdegib arm and 21 (13.0%) participants in theplacebo arm had CR.

A total of 4 (2.5%) participants in the glasdegib arm and 1 (0.6%) participant in theplacebo arm had CRi.



A total of 5 (3.1%) participants in the glasdegib arm and 1 (0.6%) participant in theplacebo arm had MLFS.

The percentage of participants achieving PR was numerically lower in the glasdegib arm(4 [2.5%] participants) as compared to the placebo arm (8 [4.9%] participants). The numberof participants achieving CRh was same between the 2 treatment arms (5 [3.1%] participantseach).
The odds ratio (95% CI) of glasdegib arm vs placebo arm in objective response was
1.624 (0.941, 2.804) for CRMRD-+CR+CRh and 1.767 (1.037, 3.013) for CRMRD+CR+CRh+CRi.

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Time to Response
For participants who responded, the time to response was comparable between the
2 treatment arms (median TTRi of 3.76 months in both treatment arms; median TTRh of
3.88 months in the glasdegib arm, and 3.75 months in the placebo arm).
Safety Results:
AEs
The incidence of treatment-emergent adverse events (TEAEs) was comparable between the
2 treatment arms.


161 (99.4%) participants and 158 (98.8%) participants in the glasdegib arm and placeboarm, respectively, experienced 1923 and 1836 all-causality TEAEs. A total of
133 (82.1%) participants and 123 (76.9%) participants in the 2 arms, respectively, had
748 and 562 treatment-related TEAEs.

All-causality TEAEs occurring in ≥10% participants were reported in 161 (99.4%)
participants in the glasdegib arm and 158 (98.8%) participants in the placebo arm.
Treatment-related TEAEs occurring in ≥10% participants were reported in 121 (74.7%)
participants in the glasdegib arm and 107 (66.9%) participants in the placebo arm.


The most frequently reported all-causality TEAEs (in the glasdegib arm and placebo arm)
were anaemia (75 [46.3%] and 73 [45.6%] participants), constipation (59 [36.4%] and52 [32.5%] participants), nausea (58 [35.8%] and 44 [27.5%] participants), pneumonia(43 [26.5%] and 48 [30.0%] participants), and pyrexia (48 [29.6%] and 42 [26.3%]
participants).



The most frequently reported treatment-related TEAEs (in the glasdegib arm and placeboarm) were anaemia (45 [27.8%] and 48 [30.0%] participants) and nausea (44 [27.2%] and37 [23.1%] participants).

There were more participants with all-causality TEAEs of dysgeusia (38 [23.5%] participantsvs 8 [5.0%] participants) and muscle spasms (31 [19.1%] participants vs 4 [2.5%]
participants) in the glasdegib arm vs placebo arm. Consistently, there were more participants
with treatment-related TEAEs of dysgeusia (34 [21.0%] participants vs 7 [4.4%] participants)
and muscle spasms (30 [18.5%] participants vs 2 [1.3%] participants) in the glasdegib arm vsplacebo arm. These TEAEs were expected as part of the glasdegib-specific AEs.
Deaths
The incidence of TEAEs leading to death was comparable between the glasdegib arm(50 [30.9%] participants) and placebo arm (52 [32.5%] participants).

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The most frequently reported TEAEs leading to death were disease progression(14 [8.6%] participants in the glasdegib arm and 22 [13.8%] participants in the placeboarm) and pneumonia (11 [6.8%] participants in the glasdegib arm and7 [4.4%] participants in the placebo arm).

A total of 117 (71.8%) and 113 (69.8%) participants in the glasdegib and placebo arms,
respectively, died in this non-intensive study. The most common cause of death was diseaseprogression, which was reported in 69 (42.3%) and 68 (42.0%) participants in the glasdegib
and placebo arms, respectively.
A total of 108 (33.2%) participants died within 28 days after last dose of study treatment,with the most common reasons of disease progression (50 [15.4%] participants) and AEs not
related to study treatment (47 [14.5%] participants).
Two deaths were considered as associated with COVID-19 in this non-intensive study.
Serious TEAEs
The incidence of serious TEAEs was comparable between the 2 treatment arms (117 [72.2%]
participants in the glasdegib arm and 124 [77.5%] participants in the placebo arm).


The most frequently reported all-causality serious TEAEs in the glasdegib and placeboarms were pneumonia (29 [17.9%] and 36 [22.5%] participants, respectively) and febrileneutropenia (24 [14.8%] and 20 [12.5%] participants, respectively).



The most frequently reported treatment-related serious TEAEs in the glasdegib andplacebo arms were febrile neutropenia (12 [7.4%] and 6 [3.8%] participants, respectively)
and pneumonia (9 [5.6%] and 8 [5.0%] participants, respectively).

Discontinuations From Study Intervention or Dose Modifications Due to AEs
The percentage of participants discontinued any study drug due to AEs was comparable
between the glasdegib arm (67 [41.4%] participants) and placebo arm (63 [39.4%]
participants).
The incidence of TEAEs leading to glasdegib/placebo permanent withdrawal was slightly
higher in the glasdegib arm (64 [39.5%] participants) compared to the placebo arm(58 [36.3%] participants).
The incidence of TEAEs leading to any dose interruptions was comparable between the
2 treatment arms: 104 (64.2%) and 102 (63.8%) participants in the glasdegib and placeboarms, respectively.
The incidence of TEAEs leading to any dose reductions was higher in the glasdegib arm(25 [15.4%] participants) compared to the placebo arm (13 [8.1%] participants).
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Adverse Events of Special Interest (AEoSI)
The incidence of treatment-emergent AEoSI was comparable between the glasdegib arm(133 [82.1%] participants) and the placebo arm (134 [83.8%] participants).


Most AEoSI in the glasdegib and placebo arms were at CTCAE Grades 3-4(74 [45.7%] participants and 81 [50.6%] participants, respectively) or Grades 3-5(101 [62.3%] participants and 103 [64.4%] participants, respectively). The highest
frequency of AEoSI in the glasdegib and placebo arms was observed in the cluster ofcytopenic events (122 [75.3%] participants and 124 [77.5%] participants, respectively).

A total of 4 (2.5%) participants in the glasdegib arm and 7 (4.4%) participants in the placebo
arm experienced treatment-emergent COVID-19-related AEoSI, and the maximum CTCAE
Grades of these events were at Grades 3-5.
Clinical Laboratory and Other Safety Evaluations
There were no clinically meaningful findings in the laboratory safety assessments. The
assessments and observations were comparable between the 2 treatment arms.
Categorized absolute value and change from baseline in vital sign data were comparable
between the 2 treatment arms. Based on TEAEs reported, there was no evidence of aclinically significant effect of glasdegib on vital signs.
The change from baseline in QTcF was similar between the 2 treatment arms. Percentages ofparticipants with QTcF changes meeting pre-specified criteria in the 2 treatment arms,
respectively, are summarized below:


QTcF change from baseline <30 msec (glasdegib: 53.1%, placebo: 70.0%);



QTcF change from baseline ≥30 msec to <60 msec (glasdegib: 35.2%, placebo:
23.1%);



QTcF change from baseline ≥60 msec (glasdegib: 11.7%, placebo: 6.9%).

The shift results in QTcF category were similar between the 2 treatment arms. Percentagesof participants with QTcF ≤450 msec at baseline and had QTcF abnormality category shifts
in the 2 treatment arms, respectively, are summarized below:

Shift from ≤450 msec at baseline to >450 - ≤480 msec post baseline (glasdegib:
25.2%, placebo: 23.2%);

Shift from ≤450 msec at baseline to >480 - ≤500 msec post baseline (glasdegib: 4.5%,
placebo: 0);
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Final Abbreviated Clinical Study Report – Non-intensive
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CLINICAL STUDY REPORT SYNOPSIS

Shift from ≤450 msec at baseline to >500 msec post baseline (glasdegib: 0.6%,
placebo: 0.6%).

There were no clinically significant differences between the 2 treatment arms in TEAEs ofelectrocardiogram QT prolonged, which was reported in 21 (13.0%) participants in theglasdegib arm and 20 (12.5%) participants in the placebo arm.
Pharmacokinetic Results:
For glasdegib plasma PK in this blinded study, only samples from the glasdegib treatment
arm were analyzed and results reported. The samples collected from the placebo arm were
not analyzed.
For the dose compliant participants, the geometric mean (geometric % coefficient ofvariation [CV]) value for glasdegib plasma Ctrough on Cycle 1 Day 15 and Cycle 2 Day 1 was
565.4 ng/mL (126%) and 472.4 ng/mL (122%), respectively.
Conclusions:
Efficacy:The non-intensive study did not meet its primary objective of demonstrating thatglasdegib + azacitidine was superior to placebo + azacitidine in prolonging OS in all
randomized participants with previously untreated AML.

The non-intensive study did not demonstrate that glasdegib was superior to placebo in
combination with azacitidine in percentage of participants with improvement in fatigue.

The rates of CR, CRi and MLFS were numerically greater in the glasdegib arm ascompared to the placebo arm. The percentage of participants achieving PR wasnumerically lower in the glasdegib arm as compared to the placebo arm. The number ofparticipants achieving CRh was same between the 2 treatment arms.

PK:The plasma Ctrough exposures in participants on the non-intensive study were consistent
with previously reported plasma exposures for glasdegib.

Safety:The evaluation of the safety of glasdegib plus azacitidine demonstrated a manageable
safety profile in adult participants with previously untreated AML who were notcandidates for intensive induction chemotherapy, and the overall safety profile wasconsistent with the known safety profiles of glasdegib as single agent.

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CLINICAL STUDY REPORT SYNOPSIS

There were no unexpected AEs with glasdegib + azacitidine non-intensive chemotherapy.
The rates of TEAEs, CTCAE Grade 3 or 4 AEs, and serious TEAEs were similar
between the glasdegib arm and the placebo arm.



There were more participants with TEAEs of dysgeusia and muscle spasms in theglasdegib arm compared to the placebo arm. These TEAEs were expected as part of theglasdegib-specific AEs.



Treatment with glasdegib was tolerable and AEs were manageable by temporary
discontinuation, dose reduction, and/or standard medical therapy.

There was no increase in treatment-related deaths in participants randomized to glasdegib
compared to participants randomized to placebo.

No new safety signals were identified in the combination of glasdegib and azacitidine,compared to glasdegib alone.

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Final Abbreviated Clinical Study Report – Intensive
Protocol B1371019

CLINICAL STUDY REPORT SYNOPSISSYNOPSIS
Study Title: A Randomized (1:1), Double-Blind, Multi-Center, Placebo Controlled Study
Evaluating Intensive Chemotherapy With or Without Glasdegib (PF-04449913) or
Azacitidine (AZA) With or Without Glasdegib in Patients With Previously Untreated Acute
Myeloid Leukemia
Study Number: B1371019
Regulatory Agency or Public Disclosure Identifier Number:
EudraCT Number: 2017-002822-19
ClinicalTrials.gov ID: NCT03416179
Study Phase: Phase 3
Name of Study Intervention: Glasdegib (PF-04449913)
Trade Name: DAURISMO™
Name of Sponsor/Company: Pfizer Inc.
CSR Version and Report Date: Final CSR Version 1.0, 03 June 2022
Number of Study Center(s) and Investigator(s):A total of 404 participants were randomized at 94 centers in 20 countries. No sites were
terminated from the study.
A list of study centers and investigators involved in this study is provided inAppendix 16.1.4.1.
Publications: None
Study Period:
Study Initiation Date (First Participant First Visit [FPFV]): 20 April 2018
Primary Completion Date (PCD): 05 June 2020
Study Completion Date (Last Participant Last Visit [LPLV]) - Intensive Cohort:
01 February 2021
This study was neither discontinued nor interrupted.

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Final Abbreviated Clinical Study Report – Intensive
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CLINICAL STUDY REPORT SYNOPSIS
Rationale:
The intensive B1371019 study was designed to investigate if glasdegib in combination withcytarabine and daunorubicin chemotherapy is superior to placebo in combination withcytarabine and daunorubicin chemotherapy in prolonging overall survival (OS) in
participants with untreated acute myeloid leukemia (AML).
Objectives, Endpoints, and Statistical Methods:
Table S1. Study Objectives and Endpoints – Intensive Chemotherapy StudyType
Primary
Efficacy

Objectives

Endpoints

Analyzed/Not
Analyzed

To demonstrate thatglasdegib was superior toplacebo in combination withcytarabine and daunorubicinin prolonging OS inparticipants with untreated
AML.

OS

Analyzed

To compare fatigue scorepost-baseline as measured by
MDASI-AML/MDS
To compare glasdegib versus
placebo in combination withcytarabine and daunorubicinin improving other clinicalefficacy measures.
To estimate the DoRb

Fatigue score measured by the
MDASI-AML/MDS questionnaire

Analyzed

Rate of CR (including CRMRD- as
assessed by multiparametric flow
cytometry), CRi as defined by the
ELN recommendations (2017),
MLFS, PR, and CR with CRha
DoR (defined as CRi or better or
CRh or better if applicable)
TTR (CRi or better or CRh or
better)Analyzed

To compare EFSb

EFS

Not Analyzed

PRO

To compare PRO
measurementsb

Not Analyzed

SafetyTo evaluate the overall safety
profilePROs as measured by the
MDASI-AML/MDS, EQ-5D-5L,
PGI-S and PGI-C
AEs as characterized by type,
frequency, severity (as graded by
NCI CTCAE version 4.03), timing,
seriousness, and relationship to
study therapy
Laboratory abnormalities ascharacterized by type, frequency,
severity (as graded by NCI CTCAE
v.4.03) and timing
QTc interval
PK of glasdegib

Analyzed

Secondary
Efficacy

To estimate the TTRb

To evaluate laboratory
abnormalities

Pharmacokinetics

To characterize treatment
effects on the QTc interval
To characterize the PK ofglasdegib

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Not Analyzed
Not Analyzed

Analyzed

Analyzed

AnalyzedFinal Abbreviated Clinical Study Report – Intensive
Protocol B1371019

CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and Endpoints – Intensive Chemotherapy StudyType
Exploratory
Biomarker

Objectives

Endpoints

Analyzed/Not
Analyzed

Bone marrow and bloodbiomarkers of response
and/or resistance to glasdegib
in combination withcytarabine and daunorubicinb

Molecular, cellular, and soluble
Not Analyzed
markers in peripheral blood and/or
bone marrow which might include,
but were not limited to: Hh pathway
and/or AML gene and protein
expression, epigenetic status andchanges, and gene mutation
profilingPRO
PROs for symptomatic AEsb
As measured by a questionnaire
Not Analyzed
containing 2 items from the
PRO-CTCAE item library version
1.0 and an add-on item on muscle
spasm
a: CRi or better included CR (including CRMRD-), CRh, or CRi for non-intensive chemotherapy participants.
CRh or better was only defined for non-intensive chemotherapy participants as CR (including CRMRD-) or
CRh.
b: Not analyzed as the intensive cohort ended in futility. Participants ended study intervention early and were
not followed for the remainder of the study.
Abbreviations: AE = adverse event; CR = complete remission; CRh = complete remission with partial
hematologic recovery; CRi = complete remission with incomplete hematologic recovery; CRMRD- = complete
remission with negative minimal residual disease; CTCAE = Common Terminology Criteria for Adverse
Events; DoR = duration of response; EFS = event-free survival; ELN = European Leukemia Net; EQ-5D-5L= EuroQoL 5-dimension questionnaire 5-level version; Hh = Hedgehog; MDASI-AML/MDS = M.D.
Anderson Symptom Inventory AML/MDS Module; MLFS = morphological leukemia free state; NCI =National Cancer Institute; PGI-C = patient global impression of change; PGI-S = patient global impression ofsymptoms; PK = pharmacokinetics; PRO = patient reported outcome; QTc = QT interval corrected for heart
rate; TTR = time to response.

Because the intensive cohort was terminated for futility, data for several endpoints were notcollected as per the protocol, so analysis was not done for these endpoints.
Methodology:
Study Design: The B1371019 study was a randomized (1:1) double-blind, multicenter,
placebo-controlled study of ‘7+3’ intensive chemotherapy (cytarabine and daunorubicin) in
combination with glasdegib versus ‘7+3’ chemotherapy in combination with placebo in adultparticipants with previously untreated AML (Figure S1).

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CLINICAL STUDY REPORT SYNOPSIS
Figure S1. Intensive Cohort Study Design

The intensive cohort was stopped by the sponsor for futility.
Number of Participants (planned and analyzed):A total of 400 participants eligible to receive intensive chemotherapy per investigatorassessment were planned to receive the treatment.

404 participants were randomized; 399 received treatment (198 in the glasdegib +intensive chemotherapy arm [glasdegib + ‘7+3’] and 201 in the placebo + intensive
chemotherapy [placebo + ‘7+3’] arm).

All randomized participants (404 participants) were included in the efficacy analysis (fullanalysis set), 399 were included in the safety analysis (safety analysis set), 196 in the PKconcentration analysis, and 123 in the PK parameter analysis.

Diagnosis and Main Criteria for Inclusion and Exclusion:
Adult participants with previously untreated AML who were candidates for intensive
induction chemotherapy.
Study Interventions, Dose, Mode of Administration, and Batch Number(s):Glasdegib 100 mg by mouth (PO) or matching placebo PO began on Day 1 and was given
once daily (QD) continuously in combination with Induction and Consolidation
chemotherapy.
Study intervention information is provided in Table S2.
Table S2. Manufacturing Lot Numbers for Study Intervention(s) Administered
Investigational Product Description

Vendor Lot
No.
CT31704A

Pfizer Lot
No.
18-000111

Cytarabine 100 mg/ml solution for
injection or infusion single dose 20 ml vial
Cytarabine 100 mg/ml solution for
CT31804A
18-002585
injection or infusion single dose 20 ml vial
Cytarabine 100 mg/ml solution for
CT31801B
18-001352
injection or infusion single dose 20 ml vial
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Strength/
Potency2 g 100 mg/mL
2 g 100 mg/mL
2 g 100 mg/mL

DosageForm
Commercial
Product
Commercial
Product
Commercial
Product

Final Abbreviated Clinical Study Report – Intensive
Protocol B1371019

CLINICAL STUDY REPORT SYNOPSIS
Table S2. Manufacturing Lot Numbers for Study Intervention(s) Administered
Investigational Product Description

Vendor Lot
No.
CT31901B

Cytarabine 100 mg/ml solution for
injection or infusion single dose 20 ml vial
Cytarabine 100 mg/ml solution for
CT31901C
injection or infusion single dose 20 ml vial
Cytarabine 100 mg/ml solution for
CT31905A
injection or infusion single dose 20 ml vial
Cytarabine 100mg (20mg/ml) solution for
7L366C8
injection or infusion single dose vial
Cytarabine 100mg (20mg/ml) solution for
8D377H8
injection or infusion single dose vial
Cytarabine 100mg (20mg/ml) solution for
8M391F9
injection or infusion single dose vial
Daunorubicin 20mg Powder for I.V.
28233
Injection vial
Daunorubicin 20mg Powder for I.V.
28474
Injection vial
Daunorubicin 20mg Powder for I.V.
28584
Injection vial
Daunorubicin 20mg Powder for I.V.
28643
Injection vial
Glasdegib 100 mg Round Pale Orange
N/A
Film Coated Tablet (DC)Glasdegib 100 mg Round Pale Orange
19-DP-00032
Film Coated Tablet (DC)Glasdegib 100 mg Round Pale Orange
17-001948
Film Coated Tablet (DC)Glasdegib 100 mg Round Pale Orange
N/A
Film Coated Tablet (DC)Glasdegib 100 mg Round Pale Orange
19-DP-00033
Film Coated Tablet (DC)Glasdegib 25 mg Round Yellow Film
N/A
Coated Tablet (DC)Glasdegib 25 mg Round Yellow Film
19-DP-00031
Coated Tablet (DC)Glasdegib 25 mg Round Yellow Film
N/A
Coated Tablet (DC)Glasdegib 25 mg Round Yellow Film
N/A
Coated Tablet (DC)
Placebo for Glasdegib 100 mg Round Pale N/AOrange Film Coated Tablet
Placebo for Glasdegib 100 mg Round Pale 19-DP-00030
Orange Film Coated Tablet
Placebo for Glasdegib 25 mg Round
N/A
Yellow Film Coated Tablet
Placebo for Glasdegib 25 mg Round
19-DP-00029
Yellow Film Coated Tablet
Abbreviations: DC = Drug Count; N/A = not applicable.

Pfizer Lot
No.
19-000810

Strength/
Potency2 g 100 mg/mL

19-002314

2 g 100 mg/mL

19-004424

2 g 100 mg/mL

18-000055

17-003001

100 mg 20
mg/ml
100 mg 20
mg/ml
100 mg 20
mg/ml
20 mg

18-001693

20 mg

19-000449

20 mg

19-001749

20 mg

18-000163

100 mgDosageForm
Commercial
Product
Commercial
Product
Commercial
Product
Commercial
Product
Commercial
Product
Commercial
Product
Commercial
Product
Commercial
Product
Commercial
Product
Commercial
Product
Tablet19-001635

100 mgTablet17-003503

100 mgTablet17-000224

100 mgTablet19-001636

100 mgTablet18-000162

25 mg

Tablet19-001634

25 mg

Tablet17-001947

25 mg

Tablet17-000222

25 mg

Tablet17-000218

0 mg

Tablet19-001633

0 mg

Tablet17-000217

0 mg

Tablet19-001454

0 mg

Tablet18-001986
19-000989

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CLINICAL STUDY REPORT SYNOPSIS
Duration of Study Intervention:
Glasdegib or placebo was to be continued for a maximum of 2 years (starting fromrandomization until 2 years) or until participant discontinued, or until confirmed CRMRD- with
2 consecutive central laboratory results post consolidation. Glasdegib or placebo therapy
continued throughout Induction(s) and Consolidation Therapy regardless of any
delays/modifications in the chemotherapy treatment.
Summary of Results:
Demographic and Other Baseline Characteristics:


58.4% of the participants were male, and 41.6% were female.

The majority of the participants were White (57.7%) and non-Hispanic or Latino(83.4%); 30.4% were Asian.

The mean (range) age was 56.55 (19-78) and 55.38 (19-86) years in the glasdegib + ‘7+3’
and placebo + ‘7+3’ arms, respectively.

Median (range) of bone marrow blasts (%) was 51.5% (0-100.0%) and 50.0%(4.0%-98.0%) in the 2 arms, respectively.

Exposure:
Exposure to Glasdegib/Placebo
Both the median and mean study treatment exposure to glasdegib/placebo were similar
between the treatment arms.


The median treatment exposure time to glasdegib/placebo was 10.4 weeks in theglasdegib + ‘7+3’ arm and 9.9 weeks in the placebo + ‘7+3’ arm.



The median relative dose intensity of glasdegib/placebo was 94.3% and 99.7%,
respectively in the 2 arms.

Exposure to Cytarabine (Induction)
Both the median and mean study treatment exposure to cytarabine as part of the induction
therapy (induction overall) were similar between the treatment arms.


The median treatment exposure time of cytarabine (induction overall) was 1.1 weeks
each in the glasdegib + ‘7+3’ and placebo + ‘7+3’ arms.



The median dose intensity of cytarabine (induction overall) was 100.0 mg/m2/day in eacharm.

Exposure to Cytarabine (Consolidation)
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Final Abbreviated Clinical Study Report – Intensive
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The median and mean study treatment exposure to cytarabine as part of the consolidation
therapy (consolidation overall) were higher in the glasdegib + ‘7+3’ arm than the placebo +‘7+3’ arm.


The median treatment exposure time of cytarabine (consolidation overall) was 9.4 and5.6 weeks, respectively, in the 2 arms.



The median dose intensity of cytarabine (consolidation overall) was 3.0 g/m2/day in eacharm.

Exposure to Daunorubicin (Induction)
Both the median and mean study treatment exposure to daunorubicin as part of the induction
therapy (induction overall) were similar between the treatment arms.


The median treatment exposure time of daunorubicin (induction overall) was 0.4 week
each in the glasdegib + ‘7+3’ and placebo + ‘7+3’ arms.



The median dose intensity of daunorubicin (induction overall) was 60.0 mg/m2/day ineach arm.

Efficacy Results:
Primary Endpoint Analysis: Overall Survival
The intensive study did not meet its primary objective of demonstrating that glasdegib +‘7+3’ is superior to placebo + ‘7+3’ in prolonging OS in all randomized participants withuntreated AML.


A total of 90 (44.8%) and 88 (43.3%) events were observed in the 2 arms, respectively.

The median OS estimated by Kaplan-Meier method was 17.2 (95% confidence interval[CI]: 15.3, 18.5) and 20.0 (95% CI: 14.0, Not Estimable) months in the 2 arms,
respectively.

The observed stratified hazard ratio comparing the 2 arms was 0.97 (95% CI: 0.725,
1.309) with 1-sided p-value of 0.4321.



The median time of follow-up for OS was 12.65 and 12.19 months in the 2 arms,
respectively.

The median duration of follow-up estimated by reversed Kaplan-Meier method was 15.2
and 15.8 months in the 2 arms, respectively.

An analysis of OS by baseline characteristics showed the control arm (placebo + ‘7+3’)
had an OS survival advantage in participants with intermediate ELN risk, and in the
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CLINICAL STUDY REPORT SYNOPSIS
Asian population. The experimental arm (glasdegib + ‘7+3’) performed better than thecontrol arm in the Favorable ELN risk category, and in the White population. All thesesubgroup analyses are considered exploratory.
Key Secondary Endpoint Analysis: Fatigue MDASI-AML/MDS

A total of 17.41% and 17.24% of participants in the 2 arms, respectively, had
improvement in fatigue.

Other Secondary Endpoints: Overall ResponseThe proportion of participants achieving CRMRD-, CR, PR, MLFS was similar between
the 2 arms.

The proportion of CRi responders was 3 (1.5%) and 11 (5.4%) in the 2 arms,
respectively.

Safety Results:
All-Causality Treatment-Emergent AEs (TEAE) and Serious AEs (SAEs):

99.0% and 98.5% of participants in the glasdegib + ‘7+3’ and placebo + ‘7+3’ arms,
respectively, experienced all-causality TEAEs, and 43.4% and 45.8% of participants,
respectively, experienced all-causality SAEs.



The most frequently reported all-causality TEAEs (≥30% of participants in any treatmentarm) in the 2 arms, respectively, were: nausea (55.6%, 53.7%), febrile neutropenia(53.5%, 53.2%), anaemia (53.5%, 50.2%), diarrhoea (49.5%, 43.8%), pyrexia (41.9%,
43.3%), hypokalaemia (38.4%, 41.8%), platelet count decreased (40.4%, 37.8%),
constipation (35.9%, 30.3%), and white blood cell count decreased (32.8%, 26.9%).

The most frequently reported all-causality SAEs (≥5% of participants in any treatmentarm) in the 2 arms, respectively, were febrile neutropenia (9.1%, 8.5%), sepsis (7.6%,
6.5%), pneumonia (7.6%, 5.5%), and electrocardiogram (ECG) QT prolonged (6.6%,
4.0%).

Treatment-related AEs and SAEs:


91.4% and 93.5% of participants in the glasdegib + ‘7+3’ and placebo + ‘7+3’ arms,
respectively, experienced treatment-related TEAEs, and 24.2% and 29.9% of participants,
respectively, experienced treatment-related SAEs.



The most frequently reported treatment-related TEAEs (≥30% of participants in any
treatment arm) in the 2 arms, respectively, were anaemia (46.5%, 43.8%), febrileneutropenia (35.4%, 37.8%), nausea (46.0%, 45.3%), diarrhoea (31.8%, 26.4%), platelet
count decreased (38.4%, 32.3%), and white blood cell count decreased (32.3%, 25.9%).
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CLINICAL STUDY REPORT SYNOPSIS

The most frequently reported treatment-related SAEs (≥3% of participants in any
treatment arm) in the 2 arms, respectively, were: febrile neutropenia (6.6%, 8.0%), sepsis(4.5%, 4.5%), and ECG QT prolonged (4.5%, 4.0%).

Deaths:

A total of 44.8% and 43.3% of participants in the glasdegib + ‘7+3’ and placebo + ‘7+3’
arms, respectively, in the intensive cohort died. The primary reason for death was diseaseprogression, with 25.9% and 24.1% of participants in the 2 arms, respectively.

AEs of Special Interest

The most frequently reported AEs of Special Interest for glasdegib + ‘7+3’and placebo +‘7+3’ arms, respectively, were: cytopenic events: 75.8% and 81.1%; QT interval
prolongation: 21.2% and 17.9%; and renal toxicity: 13.6% and 12.4%.

Study Discontinuation:


A total of 10.6% and 10.0% of participants in the glasdegib + ‘7+3’ and placebo + ‘7+3’
arms, respectively, discontinued from study due to all-causality TEAEs. A total of 6.6%
and 4.5% of participants in the 2 arms, respectively, discontinued from study due totreatment-related AEs.

Treatment Discontinuation, Dose Modification or Reduction:


A total of 13.1% and 14.4% of participants in the glasdegib + ‘7+3’ and placebo + ‘7+3’
arms, respectively, discontinued any study intervention due to all-causality TEAEs.



A total of 31.3% and 27.9% of participants in the 2 arms, respectively, had TEAEs
leading to any study intervention dose interruptions.



A total of 14.6% and 11.9% of participants in the 2 arms, respectively, had TEAEs
leading to any study intervention dose reductions.

Clinical Laboratory and Other Safety Evaluation
No clinically meaningful findings in the laboratory, vital signs measurements, ECGs,
physical examination assessments, or other observations related to safety were observedin this study.

Pharmacokinetic Results:
For the dose compliant participants, the geometric mean (geometric percent coefficient ofvariation [%CV]) value for glasdegib plasma trough concentration (Ctrough) on Day 10 of theinduction cycle was 413.5 ng/mL (125%). Overall, the range of Ctrough observed across
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CLINICAL STUDY REPORT SYNOPSIS
Induction and Consolidation 1 and 2 ranged from 245.5-413.5 ng/mL for geometric mean
and 80-125% for geometric %CV.
CONCLUSIONS:
Efficacy

The intensive study did not meet its primary objective of demonstrating that glasdegib +‘7+3’ is superior to placebo + ‘7+3’ in prolonging OS in all randomized participants withuntreated AML.

At Week 8, the proportion of MDASI-AML/MDS responders was similar between the
2 arms.



The proportion of participants achieving CR was similar between the 2 arms.

SafetyThe safety profile of glasdegib + ‘7+3’ was consistent with the known safety profiles ofglasdegib and of the combination of daunorubicin and cytarabine.



There were no unexpected AEs with glasdegib + ‘7+3’ intensive chemotherapy. The
frequency of all-causality TEAEs and treatment-related AEs was generally similar
between the treatment arms.



There were more participants with TEAEs of dysgeusia (19.7% and 10.0%, respectively,in the 2 arms) and muscle spasms (12.6%, 1.5%) in the glasdegib + ‘7+3’ arm. These
TEAEs were expected as part of the glasdegib-specific AEs. There were moreparticipants with TEAEs of hypertension (5.1%, and 12.4%, respectively in the 2 arms)
reported in the placebo + ‘7+3’ arm.

PK

The plasma Ctrough exposures in participants on study were consistent with previously
reported plasma exposures for glasdegib.

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