Conditions: Leukemia, Myeloid, Acute
Keywords: glasdegib; untreated; Hedgehog Inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 730
Healthy volunteers: no

Brief summary:
Glasdegib is being studied in combination with azacitidine for the treatment of adult patients with previously untreated acute myeloid leukemia (AML) who are not candidates for intensive induction chemotherapy (Non-intensive AML population).

Glasdegib is being studied in combination with cytarabine and daunorubicin for the treatment of adult patients with previously untreated acute myeloid leukemia (Intensive AML population).

Detailed description:
Two separate registration trials conducted under one protocol number are proposed to adequately and independently evaluate the addition of glasdegib in intensive and non-intensive chemotherapy populations. Each study will have an experimental treatment arm and a placebo arm. Endpoints are the same for each study except where specifically indicated.

Assignment to the Intensive Study or the Non-Intensive Study will be made by the Investigator based on the 2017 European LeukemiaNet (ELN) recommendations.

Study B1371019 is a randomized (1:1), double-blind, multi-center, placebo controlled study of chemotherapy in combination with glasdegib versus chemotherapy in combination with placebo in adult patients with previously untreated AML.

Glasdegib is being studied in combination with azacitidine for the treatment of adult patients with previously untreated acute myeloid leukemia (AML) who are not candidates for intensive induction chemotherapy (Non-intensive AML population).

Glasdegib is being studied in combination with cytarabine and daunorubicin for the treatment of adult patients with previously untreated acute myeloid leukemia (Intensive AML population).

Arms:
arm 1: Glasdegib + '7+3' Induction(s) arm 2: Placebo + '7+3' Induction(s) arm 3: Glasdegib + azacitidine arm 4: Placebo + azacitidine

Interventions: intervention 1: glasdegib intervention 2: daunorubicin + cytarabine intervention 3: azacitidine intervention 4: Placebo intervention 5: Placebo intervention 6: glasdegib intervention 7: cytarabine intervention 8: HSCT
Intervention descriptions: intervention 1: Daily Glasdegib (100 mg, PO), beginning on Day 1 and is to continue up to 2 years post randomization.

Following consolidation therapy, glasdegib or placebo will be administered daily for up to 2 years after randomization or until they have minimal residual disease (MRD) negative disease, whichever comes first.

Daily Glasdegib (100 mg, PO) or matching placebo will continue throughout Induction(s) and Consolidation therapies regardless of dose modifications/delays in the chemotherapy. intervention 2: '7+3' (cytarabine 100 mg/m2, IV for 7 days by continuous infusion and daunorubicin 60 mg/m2 for 3 days).

If a second induction is needed, Investigators may choose either a 5 day cytarabine continuous infusion plus daunorubicin for 2 days ('5+2') or a 7 day cytarabine continuous infusion plus daunorubicin for 3 days ('7+3'); intervention 3: Azacitidine (75 mg/m2, SC or IV) daily for 7 days, in 28 day cycles for as long as they do not meet the criteria for disease progression, unacceptable toxicity, consent withdrawal, or death. intervention 4: Matching placebo (PO) given on Day 1 and is to continue up to 2 years post randomization. Following consolidation therapy, placebo will be administered daily for up to 2 years after randomization or until they have MRD negative disease, whichever comes first.

Daily placebo will continue throughout Induction(s) and Consolidation therapies regardless of dose modifications/delays in the chemotherapy. intervention 5: Matching placebo (PO) is to be administered by mouth daily beginning on Day 1 of chemotherapy and will continue if subjects demonstrate reasonable evidence of clinical benefit and do not meet the criteria for progression regardless of any delays/modifications in the chemotherapy treatment. Subjects will continue placebo until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first. intervention 6: Glasdegib 100 mg PO QD is to be administered by mouth daily beginning on Day 1 of chemotherapy and will continue if subjects demonstrate reasonable evidence of clinical benefit and do not meet the criteria for progression regardless of any delays/modifications in the chemotherapy treatment.

Subjects will continue glasdegib until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first. intervention 7: Consolidation with single agent cytarabine 3 g/m2 IV for adults \<60 years and 1 g/m2 for adults 60 years over 3 BID on Days 1, 3, and 5, every 28 days for up to 4 cycles or alternative single agent cytarabine consolidation schedules may be used per local prescribing information. intervention 8: If required, and done per standard of care post Induction(s).

Protocol document:
Prot_000.pdf: 
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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
Investigational Product Number:
PF-04449913
Investigational Product Name:
Glasdegib
United States (US) Investigational New 
Drug (IND) Number:
105453
European Clinical Trials Database 
(EudraCT) Number:
2017-002822-19
Protocol Number:
B1371019
Phase:
Phase 3
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.


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Document History
Document
Version Date
Summary of Changes and Rationale
Original 
protocol
27-July-2017
Not applicable (N/A)
Amendment 
1
19-September
-2017
All changes were made prior to start of the study and made 
per FDA comments except where indicated.  Other minor 
changes were added for clarity.
Schedule of Activities for the Intensive and Non-intensive 
Studies and applied throughout protocol: 

For bone marrow assessments, bone marrow aspirates 
are required; however, we now added preference for 
bone marrow biopsies in addition to aspirates.  In the 
event of an inadequate aspirate, a bone marrow biopsy 
is required.

Baseline genetics edits made for clarification that 
known genetics at the time of randomization will be 
used to stratify subjects.

Red blood cell and platelet transfusion history required 
8 and not 24 weeks prior to randomization for the 
non-intensive study only.

Added windows for follow-up assessments.
Schedule of Activities for the Intensive Study only:

Removed collection of prior transfusions; only collect 
during study.

Changed from every 28 day to weekly chemistries. 

Consolidation with cytarabine changed from 1-3 g/m2
to 3 g/m2 for adults <60 years and 1 g/m2 for adults 
60 years.

Following HSCT, subjects will not be allowed to have 
Grade 2 GVHD before resuming glasdegib/placebo.
PGIC not collected at baseline for non-intensive study, 
updated as a correction


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Table 2: Made a correction by adding the time, 1 hour 
post-dose, for the column labeled “Glasdegib following 
chemotherapy”.
Cycle ≥1, Day 1
Secondary Endpoint (Section 2 and throughout protocol): 
added CR with partial hematologic recovery (CRh) for the 
Non-intensive study only.
 
Inclusion Criterion 5: removed one single dose of Ara C of 
up to 2 grams for control of blasts counts.
Exclusion Criterion 10: clarified that dose equivalent of 
≥550 mg/m2 of daunorubicin is a criterion for the Intensive 
Chemotherapy study only.
Dose Modifications (Section 5.5.5): clarified glasdegib or 
placebo does not be delayed or dose reduced for Grade 
3/Grade 4 non-hematologic, study-treatment-related 
toxicity and should be permanently discontinued if 
interruptions are for more than 28 consecutive days.
Concurrent administration of herbal preparations 
prohibited (Section 5.8.1), added as a clarification since it 
is already an exclusion criterion.
Prophylactic Intrathecal Chemotherapy allowed per 
investigator discretion in Permitted Concomitant 
Medications in Section 5.8.2.
Efficacy Assessments (Section 7.2) now includes 
definition for CR with partial hematologic recovery for the 
Non-intensive study.
Immunophenotying and Genetics (Section 7.2.2) 
clarifications added regarding requirement to stratify based 
on known genetic risk classification at the time of 
randomization.
Section 9.3.2: Added updated definitions for EFS and 
includes CR/CRh as response (in duration of response and 
time to response endpoints) for the non-intensive study.  
CCI
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Appendix 4: Added response definition for CRh and 
clarified CRi requires either criteria for residual 
neutropenia or thrombocytopenia must be met. 
Appendix 14: added ELN Risk Stratification by Genetics
table.
General spelling and grammar issues corrected.
 
 
 
 
 
 
 
Amendment 
2
15-November
-2017
All changes were made prior to start of the study in 
response to FDA request except where indicated.  Other 
minor changes were added for clarity.
Secondary endpoints updated:
•
CR/CRh was added to duration of response assessment 
to match statistical analysis section.
•
CR/CRh was added to time to response assessment to 
match statistical analysis section.
•
Schedule of Activities (Intenstive study):
•
Pregnancy testing added for Day 1 of each 
Consolidation Cycle with single-agent cytarabine 
and Day 1 of each cycle where single-agent 
glasdegib/placebo administered to ensure 
appropriate safety monitoring.
•
Schedule of Activities (Intenstive and Non-intensive 
studies):
•
Immunophenotyping was removed because it is not 
required for any study analysis.  
Immunophenotyping was also removed from 
Sections 7.1 and 7.2.2 for consistency.
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
X’s added to tables so tables now match footnotes 
indicating specified instances AEs and SAEs may 
be collected during the follow-up period.

Table 2 and Table 4 now provide time windows for 
assessments allowing sites flexibility in obtaining 
assessments without jeopardizing data.

Other minor footnote clarifications to ensure 
consistency with tables.

Inclusion Criterion #4: removed bullet indicating 
that the criterion does not apply to subjects with 
bundle branch blocks and is otherwise 
asymptomatic.  This conflicted with an exclusion 
criterion and was confusing.

Exclusion Criterion #4: specified that a subject 
could not participate in other clinical studies 
involving other investigational drugs to clarify that 
this did not apply to glasdegib in this study.

Section 5.4.1.2: Reduced the text describing the 
azacitidine supply to match information supplied 
for other chemotherapy drugs in this study.  Edits 
added for clarity, instructing sites to follow local 
regulations.

Section 5.5.5 updated per FDA request to provide 
more information regarding glasdegib/placebo dose 
modifications.

Corrected typographical error in Section 5.5.5.1 
indicating that glasdegib or placebo does not 
need to be delayed or dose reduced for 
hematologic, study-treatment-related toxicity.

Specified dose escalations will not be allowed 
following glasdegib/placebo dose reductions.

Added Section 5.5.5.2 for dosing interruptions 
for glasdegib/placebo non-hematological 
toxicities.


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•
Section 5.8.1: corrected a typographical error, 
removing word permitted.
Section 7.1.3: Added text specifying that assessment of 
acute GVHD will be graded by standard criteria based on 
the Consensus conference on acute GVHD grading and 
assessment of chronic GVHD will be assessed based on the 
NIH criteria with associated references.  Grading and 
Staging for acute GVHD is summarized in Appendix 15.
•
Section 7.1.4: Clarified that laboratory tests only need 
to be obtained during screening, and there is no need to 
repeat these tests on Day 1 if performed within 3 days 
prior to randomization.
•
Section 7.1.7: specified type of ECGs (supine) for 
clarity.
•
Section 7.4.3 updated per FDA request:  
•
Changed PGIS from 7-point scale to a 4-point scale.  
The FDA recommended that Pfizer revise the PGIS to 
4-response options (eg, absent (no symptoms), mild, 
moderate, and severe) so patients can easily distinguish 
severity.
•
Section 9.2.5: updated for clarity; now specifies 
Intensive and Non-intensive studies. 
•
Section 9.3.2: updated per FDA request, specifying 
type of analysis required for fatigue and to correct 
minor errors. 
 
 
 
•
For the Non-intensive study, Method 2 for the EFS 
definition now specifies CR or CRi will be 
evaluated following up to 6 cycles of therapy.
•
Now specifies the Brookmeyer and Crowley 
method will be used to evaluate EFS for clarity.
C
C
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
PK Parameters now specify Ctrough will be reported 
for glasdegib metabolites, if relevant.  Though there 
is no activity anticipated for the N-desmethyl 
metabolite (M3) that is <10% in circulation; 
possible metabolite measurement is added, if 
applicable as a conservative approach.

Appendix 4 updated to match data analysis section 
for consistency:

Absence of CRh added to SD definition.

Treatment failure definitions added for 
Intensive and Non-intensive studies.

Appendix 11 updated to address FDA comments:

PGIS now includes question regarding leukemia 
symptoms.
General spelling, grammar, and consistency issues 
corrected throughout the protocol.
Amendment 
3
1-March-201
8
All changes were made prior to start of the study in 
response to regulatory requests except where indicated.  
Other minor changes were added for clarity.
Addded BRIGHT AML1019 study logo to cover page.
Endpoints: clarified response definition by defining CRi or 
better to include CR (including CRMRD-negative) or CRi 
for intensive chemotherapy subjects, and CR (including 
CRMRD-negative), CRh, or CRi for non-intensive 
chemotherapy subjects.  CRh or better is only defined for 
non-intensive chemotherapy subjects as CR (including 
CRMRD-negative) or CRh.  Also updated Section 9.3 (and 
subsections) and Appendix 4 with these definitions.
Schedule of Activities:

Clarified that bone marrow assessments for study 
assessments other than disease classification must 
be done after informed consent signed in footnotes, 
as specified in the Protocol Administrative Change 


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Letter, dated 20 Dec 2017.

Added whole blood collection for 
immunophenotyping and molecular profiling on 
Day 1, prior to dosing study drug to provide a
baseline sample to compare to future samples for 
MRD assessment. 

Removed whole blood collection for 
pharmacogenomic analysis from intensive and 
non-intensive chemotherapy studies because 
pharmacogenomic analysis of drug metabolizing 
enzymes and transporters was no longer a priority 
for this study as it was unlikely to provide valuable 
information that would inform either safety or 
efficacy.  Also removed Section in protocol 
defining this analysis.

Added additional times when bone marrow samples 
must be collected post consolidation for the 
Intensive Study so MRD status may be confirmed 
in a timely manner.

Table 3: blood chemistry deleted from follow-up 
visits; added in error.
Section 1.2.3: Edited text for glasdegib nonclinical toxicity 
to align with updated data.
Inclusion criterion #5: specified anti-cancer agents for 
clarity in response to regulatory request.
Exclusion criteria #7: removed right bundle branch blocks 
as this is common and it should not be excluded.
Section 4.3.1: Added a requirement for a backup 
contraception method in response to regulatory request.
Section 5.4.1.3: removed subcutaneous route for cytarabine 
since this will not be an option.
Removed term allogeneic because either autologous or 
allogeneic HSCT is allowed during the Intensive
Chemotherapy Study per regulatory feedback. 


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Section 5.8.1: re-organized CYP3A4/5 inducers so bullet 
appears under proper heading.
Table 11 now specifies that glasdegib/placebo should be 
permanently discontinued for all cases of confirmed 
DILI/Hy’s Law and potential cases require 
glasdegib/placebo dose interruption and potential 
restarting.  Added in response to regulatory request.
Table 14 now includes required bicarbonate testing to 
determine dose reductions per azacitidine label, per 
regulatory request.  Also clarified indication for U/A with 
microscopic evaluation and 24-hour urine protein.
Sections 7.1.7: removed additional QTc monitoring 
requirements if a moderate/strong CYP3A4/5 inhibitor or 
TdP drug administered during study since additional 
monitoring was not required. 
Section 9.3: Changes in the PRO section were made to 
improve clarity regarding planned analyses per regulatory 
request. Other changes clarified method by which response 
will be analyzed.
Removed section specifying end of trial in a member state 
because LSLV will be considered the end of trial in all 
participating countries. Removed due to regulatory request.
Appendix 16 added per country-specific requirement in 
France.
General spelling, grammar, and consistency issues 
corrected throughout the protocol.
Amendment 
4
02-July-2018
Amendment 4 changes will be applicable to subjects 
enrolling in Germany.
German ethics committee requested collection of unrelated 
SAEs during the HSCT period.  This edit was made in 
Section 8.1.
Section 9.5.1: deleted text impacted by update to 
Section 8.1.


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Amendment 
5
12 April 2019
Note that 2 tables have been removed from the 
introduction section, resulting in updated table numbers.
Schedule of Activities (SOA):
Tables 1 and 3, Footnote 1: clarify that assessments 
performed as standard of care within 28 days of 
randomization do not need to be repeated to be used for 
screening.  
Tables 1 and 3, Footnote 4: clarified that Response 
Assessment includes assessment of EMD (eg, disease in 
CSF). 
Table 1, Footnotes 6 and 7: clarified that weekly 
hematology and chemistry tests must continue weekly until 
the next phase of study/treatment begins. 
Table 1, Footnote 14 and Table 3, Footnote 13: Morning 
dosing of blinded therapy is preferred but not mandatory, 
rationale for change added to Section 5.5.1.1.
Tables 1 and 3, Deleted individual rows for each Patient 
Reported Outcome survey since they are administered 
together and are outlined in footnote and Section 7.4. 
Table 1, Footnote 32 and Table 3, Footnote 36: added “if
able” to the PRO collection during HSCT period. 
Table 3 and Section 5.5.1.3: Subjects enrolled in the 
Non-Intensive study may undergo HSCT per local standard 
of care and at the Investigator’s discretion.
Table 1, Footnotes 26, 27, 38 and Table 3, Footnotes 24, 
25, 31: Updated with text related to China samples. 
Table 1, Footnote 19, Table 3, Footnote 16 and 
Section 7.2.3: Bone marrow assessments within 3 weeks of 
growth factor administration are evaluable and do not need 
to be repeated. Original text that these BM assessments 
would not be considered evaluable has been deleted.  
Introduction: Background (Section 1.2) and Rationale 
sections have been separated and updated to reflect current 


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data and Investigator Brochure (IB).

Removed Nonclinical Toxicology text 
(Section 1.2.3).

Clinical Development (Section 1.2.4): Removed 
Table 5 and Table 6. Safety and Efficacy sections 
removed and new section inserted describing 
Glasdegib Clinical Pharmacology.  Updates to 
relevant clinical studies with glasdegib made to 
provide relevant background. Data from thorough 
QTc study included. 
Section 4.2, Inclusion/Exclusion:

Inclusion #1: Clarified that subjects with FLT3+ 
AML not receiving and not intended to receive a 
FLT3 inhibitor during study participation are 
allowed per regulatory agreement. 

Inclusion #5: Removed ATRA since it is meant to 
treat APL and removed anageride.  Text added, 
continuation or resumption of hydroxyurea or 
leukopheresis after described time period must be 
approved by the Sponsor.

Exclusion #1: Clarified that APL is associated with 
t(15;17).

Exclusion #2: Clarified that the mutation must be 
known.

Exclusion #4: QTc exclusion does not apply to 
subjects with cardiac pacemaker. 

Exclusion #14: Removed local radiation as an 
excluded treatment modality during the screening 
period. 
Section 4.3: Text added defining Screen Failures as 
subjects who consent to participate in the clinical study but 
are not subsequently randomized.  Added data collection 
required for Screen Failure subjects. 
Section 4.4.1: Text updated to require one method of birth 


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control, consistent with sponsor requirements. Language 
added to to clarify Investigator responsibility for 
reproductive capability assessment. 
Table 6: Updated to include abstinence.
Section 4.4.2: Added to provide postmenopausal
definition.
Section 5.2 Breaking the Blind: Text now reflects that CRF 
does not collect Break blind data, but that this will be 
documented within the source. Additionally, subjects may 
not continue on study treatment once an investigator breaks 
the blind for that subject.
Section 5.5.1.2: Clarification text added regarding the 
timing and terms of bone marrow assessments.
Section 5.5.2: Adverse events and concomitant 
medications will not be collected during long-term 
follow-up. 
Table 10 Glasdegib/placebo Dose Modifications for mean 
QTcF Prolongation: updated in alignment with the US 
Package Insert (USPI) Also added comment that mQTcF 
dose mods do not apply to subjects with cardiac 
pacemakers. 
Figure 2: Updated for clarity and to align terms with CRF 
fields. 
Figure 3: Updated with addition of option for HSCT. 
Section 5.8.1: Removed requirement of discussion with 
Medical Monitor for the concomitant use of CYP3A4 
inhibitors/inhibitors. 
Section 5.8.2.2: Removed text requiring a repeat BM 
assessment if done within 3 weeks from last dose of 
growth factor. Growth factors may be given per local 
standard of care and local label. 
Section 6.4, Table 1, Footenote 31 and Table 3,
Footnote 29: Text added regarding the use of public 
records for long term survival follow-up as allowed by 


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local law. 
Section 7.2.1: Additional text describing the AML 
response assessment added for clarity.
Section 7.2.2: Text added allowing post baseline genetic 
assessments to be limited to abnormalities noted at baseline 
and molecular assessments to follow standard of care. 
 
 
 
Section 7.4: Updates to account for hospitalized subject 
schedules, subjects with visual problems, and clarification 
that for patients hospitalized or with a timepoint falling on 
a weekend or holiday, PRO questionnaires may be 
performed on the next business day.
Section 7.1.4: Re-screening is allowed. 
Section 9:
•
9.1: clarified percentage of patients censored for 
OS used in the sample size determination.
•
9.2: clarified all analyses of intensive and 
non-intensive chemotherapy subjects will be 
conducted separately and independently of each 
other.
•
9.3.1: added region (rest of world versus China) as 
a stratification factor to the primary and secondary 
analyses for intensive patients due to potentially 
different rates of stem cell transplantation.
•
9.3.2: clarified all secondary PRO and efficacy 
endpoints will be based on the full analysis set 
unless stated otherwise; clarified method for 
calculating confidence intervals for binary efficacy 
endpoints; removed Kaplan-Meier analysis for time 
to response as analysis is for responders only; 
clarified censoring for those without event-free 
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survival events; clarified which event-free survival 
methods are for responders only.

9.4: clarified transfusion conversion rate is 
analyzed in the safety analysis set.

9.5.1: clarified safety analyses are analyzed in both 
intensive and non-intensive studies.

9.7: clarified DMC will convene at least once 
yearly per DMC charter.
Clarified throughout document that restarting 
glasdegib/placebo Post HSCT requires no ongoing
Grade 2 graft-versus-host disease (GVHD).
Section 14: Added text regarding options for 
Non-Intensive subjects to continue treatment at study end. 
Appendix 1: Added abbreviation for HGRAC.
Appendix 4: Updates for clarity and readability.  
Appendices 5, 6, 7, 8 and references updated.
General spelling, grammar, repetitions and formatting 
corrected.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs). 


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................20
LIST OF FIGURES .................................................................................................................21
APPENDICES .........................................................................................................................21
PROTOCOL SUMMARY.......................................................................................................22
SCHEDULE OF ACTIVITIES................................................................................................28
1. INTRODUCTION ...............................................................................................................48
1.1. Indication.................................................................................................................48
1.2. Background .............................................................................................................48
1.2.1. Acute Myeloid Leukemia ...........................................................................48
1.2.2. Hedgehog Signaling Pathway and Glasdegib Mechanism .........................49
1.2.3. Glasdegib Nonclinical Toxicology.............................................................50
1.2.4. Clinical Development.................................................................................50
1.2.4.1. Clinical Pharmacology of Glasdegib.........................................50
1.2.4.2. Relevant Clinical Studies with Glasdegib.................................52
1.3. Rationale for Drug Combinations and Dosing........................................................53
1.3.1. Rationale for Glasdegib in Combination with Azacitidine as 
Non-Intensive Chemotherapy..........................................................................53
1.3.2. Rationale for Glasdegib in Combination with Daunorubicin and 
Cytarabine as Intensive Chemotherapy ...........................................................54
1.3.3. Rationale for Glasdegib Dosing and Schedule...........................................55
1.4. Rationale for Biospecimen Collection ....................................................................55
1.5. Summary of Benefit Risk Assessment....................................................................55
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................56
3. STUDY DESIGN.................................................................................................................58
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................62
4.1. Inclusion Criteria.....................................................................................................62
4.2. Exclusion Criteria....................................................................................................64
4.3. Screen Failures ........................................................................................................65
4.4. Lifestyle Requirements ...........................................................................................66
4.4.1. Contraception..............................................................................................66
4.4.2. Postmenopausal Defined ............................................................................66
4.5. Sunlight Exposure ...................................................................................................67


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4.6. Sponsor’s Qualified Medical Personnel..................................................................67
5. STUDY TREATMENTS.....................................................................................................68
5.1. Allocation to Treatment ..........................................................................................68
5.2. Breaking the Blind ..................................................................................................68
5.3. Subject Compliance.................................................................................................69
5.4. Investigational Product Supplies.............................................................................69
5.4.1. Formulation, Packaging, Preparation, and Dispensing...............................69
5.4.1.1. Glasdegib/Placebo.....................................................................69
5.4.1.2. Azacitidine ................................................................................70
5.4.1.3. Cytarabine .................................................................................70
5.4.1.4. Daunorubicin.............................................................................70
5.5. Administration.........................................................................................................70
5.5.1. General Administration Guidance for Study Drugs ...................................70
5.5.1.1. Glasdegib or Placebo in Subjects Receiving Intensive 
Chemotherapy and Non-Intensive Chemotherapy ............................71
5.5.1.2. Intensive Chemotherapy............................................................71
5.5.1.3. Non-Intensive Chemotherapy ...................................................78
5.5.2. End-of-Treatment Follow-up......................................................................80
5.5.3. Food Requirements.....................................................................................81
5.5.4. Treatment Discontinuation .........................................................................81
5.5.5. Dose Modifications.....................................................................................81
5.5.5.1. Glasdegib or Placebo in Subjects Receiving Intensive 
Chemotherapy and Non-Intensive Chemotherapy ............................81
5.5.5.2. Dosing Interruptions for Glasdegib/placebo 
Non-hematological Toxicities ...........................................................82
5.5.5.3. Intensive Chemotherapy and Non-Intensive 
Chemotherapy....................................................................................86
5.6. Investigational Product Storage ..............................................................................86
5.7. Investigational Product Accountability...................................................................87
5.7.1. Destruction of Investigational Product Supplies ........................................87
5.8. Concomitant Treatment(s).......................................................................................87
5.8.1. Restricted or Prohibited Concomitant Medications....................................88
5.8.2. Permitted Concomitant Medications ..........................................................89


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5.8.2.1. Best Supportive Therapy...........................................................89
5.8.2.2. Hematopoietic Growth Factors .................................................89
5.8.2.3. Anti-Emetic and Anti-Diarrheal Therapy .................................90
5.8.2.4. Prophylactic Intrathecal Chemotherapy....................................90
5.8.2.5. Corticosteroids ..........................................................................90
5.8.2.6. Surgery ......................................................................................90
6. STUDY PROCEDURES .....................................................................................................90
6.1. Screening.................................................................................................................90
6.2. Treatment Period.....................................................................................................90
6.3. End of Treatment Visit............................................................................................91
6.4. Follow-up ................................................................................................................91
6.5. Subject Withdrawal.................................................................................................91
7. ASSESSMENTS..................................................................................................................93
7.1. Safety Assessments .................................................................................................93
7.1.1. Cardiac Testing (MUGA/ECHO)...............................................................93
7.1.2. Pregnancy Testing ......................................................................................94
7.1.3. Adverse Events ...........................................................................................94
7.1.4. Laboratory Safety Assessments..................................................................94
7.1.5. Transfusions................................................................................................97
7.1.6. Vital Signs and Physical Examination........................................................97
7.1.7. Triplicate (12-Lead) ECGs .........................................................................97
7.1.8. HSCT-Related Information ........................................................................98
7.1.9. ANC Engraftment.......................................................................................98
7.1.10. Pharmacokinetics Assessments ................................................................98
7.1.10.1. Glasdegib.................................................................................98
7.2. Efficacy Assessments..............................................................................................99
7.2.1. AML Response Criteria..............................................................................99
7.2.2. Genetics ......................................................................................................99
7.2.3. Bone Marrow Assessments.........................................................................99
100
100
100
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101
101
7.4. Patient Reported Outcomes (PROs)......................................................................102
7.4.1. MDASI-AML/MDS .................................................................................103
7.4.2. EQ-5D-5L.................................................................................................103
7.4.3. Patient Global Impression of Symptoms ..................................................104
7.4.4. Patient Global Impression of Change.......................................................105
105
8. ADVERSE EVENT REPORTING....................................................................................106
8.1. Requirements.........................................................................................................106
8.1.1. Additional Details on Recording Adverse Events on the CRF.................108
8.1.2. Eliciting Adverse Event Information........................................................108
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Subject Withdrawal Section) .........................................................................109
8.1.4. Time Period for Collecting AE/SAE Information....................................109
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................109
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ...............109
8.1.5. Causality Assessment ...............................................................................110
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................110
8.2. Definitions.............................................................................................................110
8.2.1. Adverse Events.........................................................................................110
8.2.2. Abnormal Test Findings ...........................................................................111
8.2.3. Serious Adverse Events ............................................................................112
112
8.3. Severity Assessment..............................................................................................114
8.4. Special Situations ..................................................................................................114
8.4.1. Protocol-Specified Serious Adverse Events.............................................114
8.4.2. Potential Cases of Drug-Induced Liver Injury..........................................114
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................116
8.4.3.1. Exposure During Pregnancy....................................................116
8.4.3.2. Exposure During Breastfeeding ..............................................118
8.4.3.3. Occupational Exposure ...........................................................118
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8.4.4. Medication Errors .....................................................................................118
8.4.4.1. Medication Errors....................................................................118
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................119
9.1. Sample Size Determination...................................................................................119
9.2. Analysis Population...............................................................................................120
9.2.1. Full Analysis Set.......................................................................................120
9.2.2. Safety Analysis Set...................................................................................120
9.2.3. PK Analysis Set ........................................................................................120
121
9.3. Efficacy Analysis ..................................................................................................121
9.3.1. Analysis of the Primary Endpoint.............................................................121
9.3.2. Analysis of Secondary Endpoints.............................................................122
9.4. Analysis of Other Endpoints .................................................................................127
9.5. Safety Analysis......................................................................................................128
9.5.1. Adverse Events.........................................................................................128
9.5.2. Laboratory Test Abnormalities.................................................................129
9.5.3. Baseline Characteristics............................................................................129
9.5.4. Electrocardiogram Analysis......................................................................129
9.5.4.1. Summary and Categorical Analysis of Electrocardiogram 
Findings ...........................................................................................129
9.6. Interim Analyses ...................................................................................................130
9.7. Data Monitoring Committee .................................................................................131
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................131
11. DATA HANDLING AND RECORD KEEPING ...........................................................132
11.1. Case Report Forms/Electronic Data Record .......................................................132
11.2. Record Retention.................................................................................................132
12. ETHICS............................................................................................................................133
12.1. Institutional Review Board (IRB)/Ethics Committee (EC).................................133
12.2. Ethical Conduct of the Study ..............................................................................133
12.3. Subject Information and Consent........................................................................133
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................134
13. DEFINITION OF END OF TRIAL.................................................................................134
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13.1. End of Trial in All Participating Countries .........................................................134
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................134
15. PUBLICATION OF STUDY RESULTS........................................................................135
15.1. Communication of Results by Pfizer ..................................................................135
15.2. Publications by Investigators ..............................................................................135
16. REFERENCES ................................................................................................................137
LIST OF TABLES
Table 1.
Schedule of Activities for Patients Receiving Intensive 
Chemotherapy: Glasdegib/Placebo + Cytarabine/Daunorubicin..............29
Table 2.
Pharmacokinetics & ECG Schedule for Patients Receiving 
Intensive Chemotherapy: Glasdegib/Placebo + 
Daunorubicin/Cytarabine..........................................................................39
Table 3.
Schedule of Activities for Patients Receiving Non-Intensive 
Chemotherapy: Glasdegib/Placebo + Azacitidine....................................40
Table 4.
Pharmacokinetics & ECG Schedule for Patients Receiving Non 
Intensive Chemotherapy: Glasdegib/Placebo + Azacitidine ....................47
Table 5.
Median Overall Survival (mOS) in Patients >60 Years Stratified by 
European Leukemia Net (ELN) Risk Criteria ..........................................52
Table 6.
Contraceptives Allowed During the Trial.................................................67
Table 7.
Intensive Chemotherapy Doses and Dose Frequency: Glasdegib or 
Placebo in Combination with Daunorubicin and Cytarabine ...................74
Table 8.
Non-Intensive Chemotherapy: Glasdegib or Placebo in 
Combination with Azacitidine..................................................................79
Table 9.
Glasdegib or Placebo Dose Modifications for Non Hematologic 
Toxicities (Excluding QTc Prolongation, Muscle Spasms, and 
Myalgia)....................................................................................................83
Table 10.
Glasdegib Dose Modifications for mean QTcF (mQTcF) 
Prolongation..............................................................................................84
Table 11.
Dose Modifications for glasdegib/placebo in Case of Drug Class 
Related AEs ..............................................................................................85
Table 12.
Required Laboratory Tests .......................................................................96
Table 13.
Adverse Event Reporting........................................................................107


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LIST OF FIGURES
Figure 1.
Schematic of Study Design.......................................................................59
Figure 2.
Intensive Chemotherapy Treatment Algorithm: Glasdegib or 
Placebo in combination with Cytarabine and Daunorubicin....................72
Figure 3.
Non- Intensive Chemotherapy Treatment Algorithm: Glasdegib or 
Placebo in combination with Azacitidine.................................................78
APPENDICES
Appendix 1. Abbreviations....................................................................................................141
Appendix 2. 2016 WHO Classification of Myeloid Neoplams and Acute Leukemia...........146
Appendix 3. Eastern Cooperative Oncology Group Performance Status..............................149
Appendix 4. Summary of Response Criteria and Progression Definitions for AML 
Treated with Intensive and Non-Intensive Chemotherapy used in 
BRIGHT AML1019................................................................................150
Appendix 5. Strong and Moderate CYP3A4/5 Inducers .......................................................153
Appendix 6. Strong CYP3A4/5 Inhibitors.............................................................................154
Appendix 7. Moderate CYP3A4/5 Inhibitors ........................................................................155
Appendix 8. List of Drugs with Known Risk of Torsade de Pointes ....................................156
159
161
163
164
165
Appendix 14. 2017 ELN Risk Stratification by Genetics......................................................166
Appendix 15. 2017 Recommended staging and grading of acute GVHD.............................167
Appendix 16. France Appendix.............................................................................................168
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PROTOCOL SUMMARY
Indications
Glasdegib is being studied in combination with azacitidine for the treatment of adult patients 
with previously untreated acute myeloid leukemia (AML) who are not candidates for 
intensive induction chemotherapy (Non-intensive AML population).
Glasdegib is being studied in combination with cytarabine and daunorubicin for the treatment 
of adult patients with previously untreated acute myeloid leukemia (Intensive AML 
population). 
Background and Rationale
Glasdegib is a selective, orally administered inhibitor of smoothened (SMO), which 
demonstrates potent and selective inhibition of Hedgehog (Hh) signaling in vitro and 
significant antitumor efficacy in vivo.  The Hh signaling pathway regulates cell 
differentiation and self-renewal in the developing embryo, and is typically silenced in adult 
tissues.  Aberrant Hh signaling may result from mutations in key pathway genes, 
non-mutational mechanisms related to the secretion of Hh ligands, or from cells in the tumor 
microenvironment.  Aberrant Hh signaling has been identified in a variety of human 
leukemia and leukemic stem cells (LSCs).1-3 Upregulation of Hh pathway components has 
been observed in chemo resistant AML cell lines in vitro, and pharmacological inhibition of 
the Hh pathway resulted in decreased multi-drug resistance 1 (MDR-1) or P-glycoprotein 
(P-gp) expression in these cells.4  The SMO inhibitors, vismodegib (Erivedge®)5 and 
sonidegib (Odomzo®)6 have been demonstrated to be safe and effective in the treatment of 
patients with advanced basal cell carcinoma.  Glasdegib is being developed for indications in 
myeloid malignancies.
Acute Myeloid Leukemia (AML) is a heterogeneous cancer of the hematopoietic system
characterized by increased blast counts, pancytopenias causing infections and bleeding, and 
reduced survival.  AML is characterized by multiple genetic mutations at the time of 
diagnosis that evolve with treatment, resulting in treatment resistance, disease relapse, and
reduced survival.  It is estimated that there will be 21,380 new cases and 10,590 deaths from 
AML in the United States (US) in 2017.7 Incidence rates in Europe are similar to rates in the 
United States.8  AML is a disease of older people and is uncommon before the age of 45.  
The average age of a patient with AML is about 67 years. 
Existing standards of care, such as anthracycline + cytarabine or hypomethylating agents like 
decitabine and azacitidine, can induce complete remissions in 5-70% of patients; however, 
remissions are not durable and disease relapse occurs in up to 60% of patients.9  For AML 
patients unable to receive intensive chemotherapy, existing standard treatments like low-dose 
cytarabine (LDAC) are associated with response rates <20% and median overall survival 
(mOS) times of 5-6.5 months.  Hypomethylating agents, although not approved in the US
specifically for AML, have shown improved overall survival (OS) vs LDAC in AML patients 
not suitable for intensive chemotherapy. Midostaurin (Rydapt®) is indicated for use in 
combination with standard ‘7+3’ cytarabine and daunorubicin induction, and with cytarabine 
consolidation therapy, for the treatment of adult patients with newly diagnosed AML who are 


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FLT3 mutation-positive.  Approval in 2017 was based on the Phase III RATIFY (Cancer and 
Leukemia Group B [CALGB] 10603) clinical trial resulting in a 23% reduction in the risk of 
death compared with chemotherapy alone (hazard ratio [HR] = 0.77, 95% confidence interval 
[CI], 0.63, 0.95; 2 sided p=0.016).10  Event-free survival (EFS) was significantly higher for 
Rydapt plus chemotherapy versus chemotherapy alone (EFS median of 8.2 months compared 
to 3.0 months, HR = 0.78, 95% CI 0.66, 0.93 and 2 sided p=0.004). The most frequent 
adverse events (AEs) were febrile neutropenia, nausea, vomiting, mucositis, headache, 
musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia and upper 
respiratory tract infections. 
Reducing the incidence of disease progression to prolong survival remains the highest unmet 
medical need in the treatment of AML patients.11-13
Glasdegib has shown activity in myelodysplastic syndrome (MDS) and AML with improved 
response rates and improved OS.
In the safety lead-in cohort of the B1371012 study, 12 patients with previously untreated 
intermediate-2 or high-risk MDS (n=7) AML with 20-30% blastsand multi-linage dysplasia 
(n=3), erythroleukemia (n=1) or CMML (n=1) were treated with glasdegib in combination 
with azacitidine. Patients were treated for a median 94.0 days.  One patient had a glasdegib 
dose reduction 98 days after start of treatment.  As of March 2017, 5 out of the 12 patients
responded. 3 patients with CR (all AML) and 2 patients with marrow CR.14 The number of 
CRs observed with glasdegib and azacitidine appears favorable in the context of the 
15-17% CR rate seen with azacitidine alone.
In the randomized Phase 2 cohort of Study B1371003, patients with previously untreated 
AML or high-risk MDS who were not candidates for standard induction chemotherapy using 
established criteria15 were stratified into good/intermediate risk vs poor risk by genetics and 
were randomized 2:1 to receive in an open-label fashion, LDAC + glasdegib vs LDAC alone.  
In AML patients (78 and 38 randomized to LDAC + glasdegib and LDAC, respectively), 
mOS for LDAC + glasdegib was 8.3 vs 4.3 months for LDAC alone (and OS HR=0.463, 
with p-value=0.0002) with 94 observed deaths.  Glasdegib has demonstrated a statistically 
significant and clinically meaningful improvement in OS when combined with LDAC vs 
LDAC alone in elderly AML patients not suitable for intensive chemotherapy, with no new 
significant safety signals identified to date in a prospective randomized trial.
In the ongoing single-arm Phase 2 cohort of Study B1371003, patients with previously 
untreated AML or high-risk MDS received intensive chemotherapy (‘7+3’) in combination 
with glasdegib in an open-label fashion. The ‘7+3’ regimen consists of 7 days of cytarabine 
and 3 days of daunorubicin. Based on investigator’s assessment, CR rate for AML patients 
was 47% (80% CI 38.3-55.6) and Complete Remission/Complete remission with incomplete 
hematologic recovery (CR/CRi) rate was 55% (80% CI 46.7-62.7). The mOS for AML pts 
(n=64) was 16.3 months with 37 observed deaths.


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Based on results from B1371003, 2 prospective randomized (1:1), double-blind, placebo 
controlled registration trials in patients with newly diagnosed AML are proposed: in the first 
study, 400 AML patients suitable for intensive chemotherapy will be randomized to receive 
‘7+3’+ glasdegib (Arm A) or ‘7+3’+ placebo (Arm B).  In the second study, 320 AML 
patients not suitable for intensive chemotherapy per investigator will be randomized to 
receive azacitidine + glasdegib (Arm A) or azacitidine + placebo (Arm B).  The primary 
endpoint for both trials will be OS.  Both studies will be powered, conducted, and analyzed
separately and independently under 1 protocol (B1371019) to maximize efficiency.  
Together, the trials can provide substantial evidence to register glasdegib in AML patients
treated in combination with 7+3 or with azacitidine.
Objectives and Endpoints
Protocol B1371019 consists of 2 independent studies: an intensive chemotherapy study and 
non-intensive chemotherapy study.  Within each study, subjects will be randomized to 
chemotherapy with either glasdegib or matching placebo.  The primary and secondary 
endpoints for each study will be analyzed separately.  Response criteria for AML are defined 
by the 2017 European LeukemiaNet (ELN) recommendations.16
The objectives and endpoints for each study are the same unless otherwise specified and are 
described below:
Primary Objective:
Primary Endpoint:

To demonstrate that glasdegib is superior to 
placebo in combination with azacitidine 
(non-intensive study) or cytarabine and 
daunorubicin (intensive study) in prolonging OS 
in subjects with untreated AML.

Overall survival.
Secondary Objectives:
Secondary Endpoints:

To compare fatigue score post-baseline as 
measured by MDASI-AML/MDS in both 
treatment arms;

To compare glasdegib versus placebo in 
combination with azacitidine (non-intensive 
study) or ‘7+3’ (cytarabine and daunorubicin) in 
improving other clinical efficacy measures;

To estimate the duration of response in both 
treatment arms;

To estimate the time to response in both 
treatment arms in the Non-intensive study only;

To compare Event-free Survival (EFS) in both 
treatment arms;

To compare PRO measurements in both 

Fatigue score measured by the 
MDASI-AML/MDS questionnaire;

Rate of CR (including CRMRD-negative as assessed 
by multiparametric flow cytometry), CRi as 
defined by the ELN recommendations (2017), 
MLFS, PR, and CR with partial hematologic 
recovery (CRh) for the Non-intensive study 
only;

Duration of response (defined as CRi or better
or CRh or better if applicable)*;

Time to response (CRi or better or CRh or 
better)* in the non-intensive study only;

Event-free Survival;

PROs as measured by the M.D. Anderson 
Symptom Inventory AML/MDS Module 


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treatment arms;
•
To evaluate the overall safety profile in both 
treatment arms;
•
To evaluate laboratory abnormalities in both 
treatment arms;
•
To characterize the pharmacokinetics (PK) of 
glasdegib;
•
To characterize treatment effects on the QTc 
interval.
(MDASI-AML/MDS), EuroQoL 5 Dimension 
questionnaire 5-Level version (EQ-5D-5L), 
Patient Global Impression of Symptoms (PGIS) 
and Patient Global Impression of Change 
(PGIC);
•
Adverse events as characterized by type, 
frequency, severity (as graded by NCI CTCAE 
v.4.03), timing, seriousness and relationship to 
study therapy;
•
Laboratory abnormalities as characterized by 
type, frequency, severity (as graded by NCI 
CTCAE v.4.03) and timing;
•
PK of glasdegib;
•
QTc interval.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* CRi or better includes CR (including CRMRD-negative) or CRi for intensive chemotherapy subjects, and CR 
(including CRMRD-negative), CRh, or CRi for non-intensive chemotherapy subjects. CRh or better is only 
defined for non-intensive chemotherapy subjects as CR (including CRMRD-negative) or CRh.
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Study Design and Study Treatment
Intensive Chemotherapy Study: 
A total of 400 subjects eligible to receive intensive chemotherapy per investigator assessment 
will receive treatment as follows: 

Experimental Therapy: Glasdegib 100 mg orally (PO), once a day (QD) or matching 
placebo will be administered PO QD, starting Day 1 of chemotherapy.  Subjects will 
receive daily glasdegib 100 mg PO or matching placebo for up to 2 years after
randomization or until CR with minimal residual disease (MRD)-negative disease
status is documented post consolidation or HSCT based on confirmed central 
laboratory results.  Glasdegib or placebo therapy may continue throughout 
induction(s) and consolidation therapy regardless of any delays/modifications in the 
chemotherapy treatment.

For subjects proceeding to hematopoietic stem cell transplantation (HSCT) post 
remission during the study period, glasdegib or placebo will be interrupted at least
28 days before HSCT Day 0 and resumed 30-60 days post date of stem cell 
infusion, once there is absolute neutrophil count (ANC) engraftment, no ongoing
Grade 2 graft-versus-host disease (GVHD) and no ongoing serious adverse 
events (SAEs) that prevent resuming glasdegib or placebo in the judgement of the 
investigator.

‘7+3’ Induction: cytarabine 100 mg/m2 intravenous (IV) daily by continuous infusion
for 7 days (Days 1-7) plus daunorubicin 60 mg/m2 IV daily × 3 days.

If a second induction is needed, Investigators will select either ‘5+2’ (cytarabine 
100 mg/m2 IV daily by continuous infusion × 5 days plus daunorubicin 60 mg/m2
IV daily × 2 days) or repeat ‘7+3’.

If <5% bone marrow blasts: Consolidation may include either or both of the 
following: 

Consolidation with single-agent cytarabine 3 grams (g)/m2 IV for adults <60 years 
and 1 g/m2 for adults 60 years over 3 hours twice daily (BID) on Days 1, 3, and 
5, every 28 days for up to 4 cycles or alternative single-agent cytarabine dosing 
schedules may be used per local prescribing information.

HSCT administered per local standard of care.
Following Chemotherapy or HSCT, glasdegib or matching placebo may be permanently 
discontinued as described in Section 6.5. Subject will discontinue blinded therapy if disease 
status is MRD-negative post consolidation or HSCT by 2 consecutive timepoints per central 
laboratory results. Subjects will then enter the post treatment follow-up phase for survival 
assessments.


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Non-Intensive Chemotherapy Study
A total of 320 patients who are not considered adequate candidates to receive or who refuse 
intensive chemotherapy will be treated as follows:

Experimental therapy: Glasdegib 100 mg PO QD or matching placebo. Both will be 
administered daily, starting on Day 1 and will continue if subjects demonstrate 
reasonable evidence of clinical benefit and do not meet the criteria for progression 
regardless of any delays/modifications in the chemotherapy treatment.  Subjects will 
continue glasdegib or placebo until disease progression, unacceptable toxicity, 
consent withdrawal, or death, whichever comes first.  If there is HSCT per local 
standard of care, single agent blinded therapy may be administered up to 2 years post 
randomization or until they have 2 consecutive CR MRD negative central laboratory 
results, whichever comes first.

For subjects proceeding to HSCT following CR during the study period, glasdegib 
or placebo will be interrupted at least 28 days before HSCT Day 0 and may be 
resumed 30-60 days post date of stem cell infusion, once there is ANC
engraftment, no ongoing Grade 2 graft-versus-host disease (GVHD), and no 
ongoing SAEs that prevent resuming glasdegib or placebo in the judgement of the 
investigator.

All subjects will receive azacitidine per local label or per the Investigational Product 
Manual (or summary of product characteristics [SPC]).  The dose for azacitidine is 
75 mg/m2 daily for 7 days administered by subcutaneous (SC) injection or 
IV infusion in 28 day cycles.

Alternate dosing schedule to administer the 7 doses may be used to accommodate 
patient and treatment center availability.  Dose adjustments will be made according to 
institutional guidelines or per the SPC for azacitidine.  In addition, each subsequent 
cycle may be delayed for up to 28 days to allow for recovery of blood counts.

Subjects who proceed to HSCT will not receive azacitidine post HSCT. 
Discontinuation of Study Therapy for the Non-Intensive Study
If glasdegib or placebo is permanently discontinued for reasons other than objective disease
progression, patient refusal, or consent withdrawal, single-agent treatment with azacitidine
may be continued if, in the Investigator’s judgment, a clinical benefit has been observed.
In cases of unacceptable toxicity or pregnancy, the patient must be withdrawn from study 
treatment and entered into the follow-up phase of the study.


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Statistical Methods
Sample Size Determination
The interim and final analyses of the intensive chemotherapy and non-intensive 
chemotherapy populations will be conducted separately and independent of each other.
Intensive Chemotherapy Study: 
Approximately 400 subjects are to be enrolled with 33% expected to be censored. A total of 
267 death events among the enrolled subjects would provide 90% power to detect an 
improvement in OS with an HR of 0.67 (translating in mOS from 21 months to 31.5 months 
assuming a composite mOS for the population as follows: young AML [aged 60 years] with 
a mOS of 23.7 months and elderly AML [aged >60 years] with a mOS of 15 months17,18)
using a 1-sided log-rank test at a significance level of 0.025 and a 3-look group-sequential 
design. 
Two interim analyses would be conducted: an early futility-only analysis of OS after 
50% death events occur and an efficacy and futility analysis of OS after 70% deaths occur in 
the Intensive Chemotherapy population or upon completion of enrollment of these patients, 
whichever occurs later.
Non-Intensive Chemotherapy Study:
Approximately 320 subjects are to be enrolled with 31% expected to be censored. A total of 
220 death events among all the enrolled subjects would provide 90% power to detect an 
improvement in OS with an HR=0.64 (translating in mOS from 10.4 months9 to 16.2 months)
using a 1-sided log-rank test at a significance level of 0.025 and a 2-look group-sequential 
design.  One interim efficacy and futility analysis of OS would be planned after 60% death 
events occur in the non-intensive chemotherapy population or upon completion of enrollment 
of these patients, whichever is later. 
SCHEDULE OF ACTIVITIES
The Schedule of Activities tables provide an overview of the protocol visits and procedures.
Refer to Study Procedures (Section 6) and Assessments (Section 7) for detailed information 
on each procedure and assessment required for compliance with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities table, in order to conduct evaluations or assessments required to protect 
the well-being of the subject.


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Table 1.
Schedule of Activities for Patients Receiving Intensive Chemotherapy: Glasdegib/Placebo + 
Cytarabine/Daunorubicin
Screening
Induction
Consolidation Cytarabine and/or post remission 
HSCT17
Following 
Consolid-a
tion(s)36: 
up to 2 
years post 
randomiza
tion
Post Treatment
Induction 1 and Induction 2
Cytarabine16
1-4 Cycles (28-day cycle)
HSCT period34,37
28-day 
cycle
Protocol 
Activity
28 days
prior to 
study 
entry
Day 1 Every 7 
days (2 
days)
Every 
28 
days
(2 
days)
Post first 
Induc-
tion
Remis-
sion 
Assess-
ment
Day
1
Day
5
Day 
10 
(1
days)
Day 21
(7
days)
First day 
of 
condition-i
ng
HSCT 
Day 0
> Day 0, 
monthly
(2 
days)
Day 1
(2 days)
End of 
Treatment
Visit29
(Within 14 
days after 
last dose)
Post 
Treat_
ment 
Follow-U
p Visits
(7 
days)30
Long- Ter
m 
Follow-Up 
Activity 
Log (14 
days)31
Baseline documentation
Informed 
Consent1
X
Medical 
History2
X
ECOG 
Performance 
Status3
X
X
X
X
X
Disease 
Classification4
X
Physical 
Examination5,30
X
X
X
X
X
X
X
X
X
X
HSCT- related 
information34
X
X
Laboratory Studies
Hematology6,30
X
X
X
X
X
X
X
X
X
X
X
X
Blood 
Chemistry7
X
X
X
X
X
X
X
X
X
X
X
Urinalysis8
X
Coagulation9
X
Pregnancy
test10
X
X
X
X
X


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Screening
Induction
Consolidation Cytarabine and/or post remission 
HSCT17
Following 
Consolid-a
tion(s)36: 
up to 2 
years post 
randomiza
tion
Post Treatment
Induction 1 and Induction 2
Cytarabine16
1-4 Cycles (28-day cycle)
HSCT period34,37
28-day 
cycle
Protocol 
Activity
28 days
prior to 
study 
entry
Day 1 Every 7 
days (2 
days)
Every 
28 
days
(2 
days)
Post first 
Induc-
tion
Remis-
sion 
Assess-
ment
Day
1
Day
5
Day 
10 
(1
days)
Day 21
(7
days)
First day 
of 
condition-i
ng
HSCT 
Day 0
> Day 0, 
monthly
(2 
days)
Day 1
(2 days)
End of 
Treatment
Visit29
(Within 14 
days after 
last dose)
Post 
Treat_
ment 
Follow-U
p Visits
(7 
days)30
Long- Ter
m 
Follow-Up 
Activity 
Log (14 
days)31
Triplicate 12 –
lead ECG11
X
X
X
X
X
X
ECHO or 2-D
MUGA12
X
ANC 
engraftment35
X
Registration and Treatment13
Glasdegib or 
Placebo14,37
Oral Once Daily Continuous Dosing.
If post remission HSCT37 interrupt glasdegib/placebo at least 28 days prior to HSCT; may resume following ANC 
engraftment.
Daunorubicin 
Dosing15
Days 1-3
Cytarabine
Dosing16
Days 1-7
Days 1,3 
and 5
Drug 
Compliance18
Continuous
Continuous
Continuous
Disease Assessments
Bone Marrow 
Aspirate/
Biopsy19,30
X-See19
X-See19
X-See
19
X-See19
X-See19,30
X-See19,
30
Bone marrow 
genetics20,30
X
X-See20
X-See
20
X-See20
X-See20
X-See20
Response 
Assessment4
X
X-See19
X-See19
X-See19


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Screening
Induction
Consolidation Cytarabine and/or post remission 
HSCT17
Following 
Consolid-a
tion(s)36: 
up to 2 
years post 
randomiza
tion
Post Treatment
Induction 1 and Induction 2
Cytarabine16
1-4 Cycles (28-day cycle)
HSCT period34,37
28-day 
cycle
Protocol 
Activity
28 days
prior to 
study 
entry
Day 1 Every 7 
days (2 
days)
Every 
28 
days
(2 
days)
Post first 
Induc-
tion
Remis-
sion 
Assess-
ment
Day
1
Day
5
Day 
10 
(1
days)
Day 21
(7
days)
First day 
of 
condition-i
ng
HSCT 
Day 0
> Day 0, 
monthly
(2 
days)
Day 1
(2 days)
End of 
Treatment
Visit29
(Within 14 
days after 
last dose)
Post 
Treat_
ment 
Follow-U
p Visits
(7 
days)30
Long- Ter
m 
Follow-Up 
Activity 
Log (14 
days)31
Other Clinical Assessments
SAE and A E 
Monitoring
21,34,36
X
Continuous Monitoring; See34,36 for HSCT period
X
X21
X21
Review Prior/ 
Concomitant 
Medications 
and Treatments
22,34
X
Continuous Collection; except during HSCT period34
X
Recording of 
red cell and 
platelet 
transfusions23
Continuous Collection; except during HSCT period34
X
Patient 
Reported 
Outcomes24,30,3
1,32,
X
X
X
X
X
X
X
X32
X32
X32
X
X
X
X
Pharmacokinetic Sampling
Blood samples 
for glasdegib 
Pharmacokineti
cs (PK)25
Refer to Table 2 Pharmacokinetics & ECG Schedule for Patients Receiving Intensive Chemotherapy: 
Glasdegib/Placebo + /Cytarabine/Daunorubicin


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Screening
Induction
Consolidation Cytarabine and/or post remission 
HSCT17
Following 
Consolid-a
tion(s)36: 
up to 2 
years post 
randomiza
tion
Post Treatment
Induction 1 and Induction 2
Cytarabine16
1-4 Cycles (28-day cycle)
HSCT period34,37
28-day 
cycle
Protocol 
Activity
≤28 days
prior to 
study 
entry
Day 1 Every 7 
days (±2 
days)
Every 
28 
days
(±2 
days)
Post first 
Induc-
tion
Remis-
sion 
Assess-
ment
Day
1
Day
5
Day 
10 
(±1
days)
Day 21
(±7
days)
First day 
of 
condition-i
ng
HSCT 
Day 0
> Day 0, 
monthly
(±2 
days)
Day 1
(±2 days)
End of 
Treatment
Visit29
(Within 14 
days after 
last dose)
Post 
Treat_
ment 
Follow-U
p Visits
(±7 
days)30
Long- Ter
m 
Follow-Up 
Activity 
Log (±14 
days)31
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Screening
Induction
Consolidation Cytarabine and/or post remission 
HSCT17
Following 
Consolid-a
tion(s)36: 
up to 2 
years post 
randomiza
tion
Post Treatment
Induction 1 and Induction 2
Cytarabine16
1-4 Cycles (28-day cycle)
HSCT period34,37
28-day 
cycle
Protocol 
Activity
28 days
prior to 
study 
entry
Day 1 Every 7 
days (2 
days)
Every 
28 
days
(2 
days)
Post first 
Induc-
tion
Remis-
sion 
Assess-
ment
Day
1
Day
5
Day 
10 
(1
days)
Day 21
(7
days)
First day 
of 
condition-i
ng
HSCT 
Day 0
> Day 0, 
monthly
(2 
days)
Day 1
(2 days)
End of 
Treatment
Visit29
(Within 14 
days after 
last dose)
Post 
Treat_
ment 
Follow-U
p Visits
(7 
days)30
Long- Ter
m 
Follow-Up 
Activity 
Log (14 
days)31
Follow Up Assessments
Disease 
progression 
post 
treatment30,31
X
X
New 
Anti-cancer 
therapies since 
discontinuation 
of study 
treatment30,31
X
X
Survival 
Follow-Up 
Telephone 
contact31
X
* Patients may continue on treatment for up to a maximum of 2 years as long as they demonstrate clinical benefit. 
Abbreviations: ANC: absolute neutrophil count; ECG: electrocardiogram; ECHO: Echocardiogram; ECOG: Eastern Cooperative Oncology Group; HSCT: hematopoietic stem 
cell transplant; MRD: minimum residual disease; MUGA: multigated acquisition scan; PGIC: Patient Global Impression of Change; PK: pharmacokinetics; SoA: Schedule of 
Activities.
1.
Informed Consent: Must be obtained prior to undergoing any study specific procedure. Assessments performed as standard of care within 28 days of 
randomization do not need to be repeated.
2.
Medical History: Includes cancer history and prior illnesses, and concomitant illnesses.
3.
ECOG Performance Status: Appendix 3.


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4.
Disease Classification and Response Assessment: AML classified according to 2016 WHO disease classification in Appendix 2.  Prognostic genetic risk
classification (Appendix 14) and Response Assessments will be done according to 2017 European Leukemia Net (ELN) criteria in Appendix 4. Response 
assessment includes assessment of EMD (eg disease in CSF).
5.
Physical Examination: Examination of major body systems, body weight, height, and vital signs (blood pressure and heart rate to be recorded in sitting 
position).  Weight must be recorded at Screening and Day 1 of Induction(s).  Height need not be recorded after the first measurement at screening.
6.
Hematology: No need to repeat on Induction 1 Day 1 if screening assessment is performed within 3 days prior to randomization.  The list of required 
laboratory tests is provided in the protocol (Table 12).  If weekly hematology is on same day as another hematology assessment (ie, post first induction, 
remission, etc), only one hematology sample may be taken on same day. If Induction(s) are extended, hematology tests should continue every 7 days until 
the next phase begins.
7.
Blood Chemistry: No need to repeat on Induction 1 Day 1 if screening assessment performed within 3 days prior to randomization.  The list of required 
laboratory tests is provided in the protocol (Table 12).  If a weekly chemistry is on same day as another chemistry assessment (ie, post first induction, 
remission, etc), only one chemistry sample may be taken on same day. If Induction(s) are extended, blood chemistry tests should continue every 7 days until 
the next phase begins.
8.
Urinalysis: Should be performed after Screening if clinically indicated.  The list of required laboratory tests is provided in the protocol in Table 12.
9.
Coagulation: Should be performed after Screening if clinically indicated.  The list of required laboratory tests is provided in the protocol Table 12. 
10. Pregnancy Tests: Pregnancy tests (serum/urine) for patients of child-bearing potential only must be performed on two occasions prior to starting study 
therapy (once at the start of screening and once at the baseline visit, immediately prior to initiation of treatment (first dose), start of every Induction (1,2)
during the active treatment period, and at Day 1 of each Consolidation Cycle with single-agent cytarabine, Day 1 of each cycle for single-agent 
glasdegib/placebo following Consolidation up to 2 years post randomization, and the End of Treatment.  Following a negative pregnancy result at screening, 
appropriate contraception (will be defined in the protocol) must be commenced and a further negative pregnancy result will then be required at the baseline 
visit before the patient may receive the investigational product.  It may also be repeated as per request of IRB/ECs (or if required by local regulations), if one 
menstrual cycle is missed or when potential pregnancy is otherwise suspected during the active treatment period or as clinically indicated.
11. ECGs (local): See Table 2 for detailed ECG Schedule.
12. Echocardiogram (ECHO) or Multigated Acquisition Scan (MUGA): Should be repeated before Induction 2 if signs of cardiac toxicity are observed and 
as clinically indicated thereafter. See Section 7.1.1.
13. Subject Registration: Subject registration and assignment of treatment will be obtained from the centralized Interactive Response Technology (IRT).
14. Glasdegib or Placebo Dosing: Treatment will be administered in 28-day cycles.  Glasdegib or placebo will be administered orally once daily, continuously, 
preferably in the morning at approximately the same time each day.  Where possible, glasdegib will be administered together with daunorubicin IV injection 
during induction.  Patients may continue on glasdegib treatment for up to a maximum of 2 years, as long as they demonstrate clinical benefit and do not have 
CR MRD-negative disease post consolidation/HSCT as confirmed at 2 consecutive time points.
15. Daunorubicin Dosing (Induction Only): Daunorubicin will be given at a dose of 60 mg/m2 daily as an IV in combination with cytarabine and glasdegib or 
placebo, on Days 1-3.  Induction chemotherapy may be repeated for one additional induction if an unsatisfactory clinical response is observed and there are 
no signs of cardiac toxicity. If a second induction is needed, Investigators may choose either daunorubicin 60 mg/m2 IV on Days 1-2 or daunorubicin 
60 mg/m2 IV on Days 1-3 with cytarabine and glasdegib or placebo. If clinical signs of cardiac dysfunction are observed, a repeat MUGA/ECHO should be 
performed, and must demonstrate a LVEF 45% to receive a second course of induction chemotherapy.  If a second induction therapy is required, dose must 
be recalculated if the weight changes by >10%. 


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16. Cytarabine Dosing: Separate cytarabine dosing and schedules will be used for Induction and Consolidation and administered using local package inserts (or 
SPC) or Investigational Product Manual. Alternative single-agent cytarabine consolidation schedules may be used per local prescribing information. 
Induction: Cytarabine will be administered (in parallel to daunorubicin) at a dose of 100 mg/m2 daily by continuous IV infusion for 7 days on Days 1-7 of 
induction 1.  For the second induction therapy, Investigators may choose either cytarabine 100 mg/m2 IV on Days 1-5 or on Days 1-7. Dose must be 
recalculated if the weight changes by >10%. 
Consolidation with Cytarabine: Single agent cytarabine will be administered at a dose of 3 g/m2 IV for adults <60 years and 1- g/m2 for adults ≥60 years 
infused over 3 hours, given approximately Q12 hours (morning and evening) on Days 1, 3 and 5 or per local SOC. Alternative single-agent cytarabine 
consolidation schedules may be used per local prescribing information.  Consolidation cytarabine will be repeated every 28 days for up to 4 cycles unless the 
patient relapses, unacceptable toxicity or patient withdrawal.  Dose must be recalculated if the weight changes by >10%. The start of subsequent 
consolidation cycles may be delayed from the end of the previous cycle to allow for recovery from reversible hematologic or non-hematologic drug-related 
toxicities.  If the consolidation cycle(s) extends longer than 28 days, dosing with glasdegib or placebo should continue daily in the absence of 
glasdegib-related toxicity that would prevent dosing.
17. Post remission HSCT: Follow local and institutional standard of care practices for HSCT conditioning and transplant (see footnote 37).
18. Drug Compliance: Dates of all missed doses must be recorded.  All glasdegib or placebo bottles including any unused tablets and patient dosing diaries will 
be returned to the clinic for compliance assessment and drug accountability. 
19. Bone Marrow Assessments for Disease Evaluation.
Baseline Bone Marrow Sample: For all patients, a bone marrow aspirate sample is required at screening plus a bone marrow biopsy is preferred.  Samples 
taken prior to consent but within 28-days of first dose can be used for disease classification only and need not be repeated.  Bone marrow samples required 
for other study assessments must be done after consent is signed. 
 
Response assessments require bone marrow aspirates and bone marrow biopsies are preferred. All samples for disease assessments will be evaluated by a 
local laboratory. In case of an inadequate aspirate (eg dry tap), a bone marrow biopsy is required.
Post-Baseline Time points for Bone Marrow Sampling:
No bone marrow assessments are necessary if non-response or progressive disease can be diagnosed from peripheral blood evaluation or radiological/clinical 
assessment. For instances when bone marrow assessments are done, bone marrow aspirates are required and bone marrow biopsies are preferred. In cases
of an inadequate aspirate (eg dry tap), a bone marrow biopsy is required.
•
Induction: Bone marrow assessments will be collected post Induction to determine if a 2nd Induction is needed and at the end of the Remission
period to confirm remission status.
•
Consolidation (applies to Cytarabine and post remission HSCT): Bone marrow assessments will be collected at the end of the Consolidation 
period with cytarabine to confirm disease status and determine response. A bone marrow assessment must be done prior to HSCT (may be same 
marrow assessment as remission assessment or post consolidation assessment).
•
Glasdegib Therapy following Cytarabine Consolidation or post remission HSCT, up to 2 years: A bone marrow sample should be obtained at 
least every 3 months or sooner if relapse is suspected unless other clinical signs of relapse are present and in the clinical judgement of the 
Investigator aspirate collection is inappropriate.
Please see Footnote 30 for details on the timing for collection of bone marrow assessments during the Post-Treatment Follow Up period visits.
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If an on-treatment BM assessment is scheduled within 3 weeks from the last dose of G-CSF or GM-CSF growth factor, it should be considered “Not 
Evaluable” for response assessment and a BM evaluation should be repeated at least 3 weeks from the last dose of growth factor.
20. Bone Marrow genetics: Genetics (local) will be conducted on all patients using any scheduled or unscheduled bone marrow samples collected during study 
participation.  Please see Footnotes 19 and 30 for details on bone marrow samples collection schedule.  Baseline genetics classification must be completed 
within 28 days of first dose.  Since known baseline genetics classification will be used for stratification, investigators must review the available results and 
stratify subjects into this study. Patients will be stratified according to their 2017 ELN risk category at randomization by the Investigator (Appendix 14).
Post baseline genetic assessments may be limited to the abnormalities identified at baseline.
21. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the NCI CTC AE version 4.03.  Patients must be 
followed for AEs for 28 days after the last treatment administration or until all drug related toxicities have resolved, whichever is later. AEs must be 
collected up until the start of another anticancer therapy if the start of anticancer therapy is earlier than 28 days.  For serious adverse events (SAEs), the 
active reporting period to Pfizer or its designated representative begins from the time that the patient provides informed consent, which is obtained prior to 
the patient’s participation in the study, (ie, prior to undergoing any study related procedure and/or receiving investigational product), through and including 
28 calendar days after the last administration of the investigational product.  Serious adverse events occurring to a patient after the active reporting period 
has ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, all serious adverse events that the investigator 
believes have at least a reasonable possibility of being related to study drug are to be reported to the sponsor.
22. Concomitant Medications and Treatments: All concomitant medications and treatments should be recorded in the CRF. However, for post remission 
HSCT period, no concomitant medications will be recorded during the HSCT period. 
23. Red Blood Cells and Platelets Transfusion Recording: All red blood cell and platelet transfusions, including date of each transfusion and number of red 
blood cell and platelet units transfused will be recorded while on treatment.  Note that number of units not number of bags must be recorded. 
24. PRO surveys (MDASI-AML/MDS, EQ 5D 5L, PGIC, PGIS, 
 refer to Section 7.4): The surveys will be completed by the patient as 
described in the Schedule of Activities for Induction, Consolidation, and Follow-up (footnotes 30, 31). Interviewer administration may be used under 
special ccircumstances (eg, subject is visually impaired, forgot their glasses, feels too ill). PROs are collected every 7 days up to 28 days during Induction. 
There is no PGIC on Day 1 of Induction 1 but it will be administered for Day 1 of Induction 2. See footnote #32 for schedule during HSCT consolidation. 
.  Each PRO will continue to be 
completed at each Post Treatment Follow Up visit and during the Long-Term Follow-up phase by phone.  PROs should never be completed more than once 
on any calendar day.  For subjects hospitalized or with a timepoint falling on weekend or holiday, the PRO may be performed on the next business day.  If 
Consolidation(s) are extended PRO will not continue beyond Day 28.
25. Blood Samples for glasdegib PK: See detailed information in Table 2 for specific time points.
 
 
 
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29. End of Treatment: Obtain these assessments if not completed in the last week (last 3 months for BM assessments, unless the patient is coming off study 
treatment for disease progression). Occurs within 14 days of last dose but may be longer only if dosing was interrupted due to an AE and it led to permanent 
discontinuation.  Subjects continuing to experience toxicity following discontinuation of treatment will be followed at least every 4 weeks by the investigator 
until resolution or determination, in the clinical judgment of the investigator, that no further improvement is expected. 
30. Post Treatment Follow Up Visits (First 2 years): A follow-up contact will be completed at least 28 calendar days, and up to 35 calendar days after the last 
administration of the investigational product (Section 6.4). Subjects will return to site for visits every 3 months starting from the last dose of study 
medication, for the first 2 years only.  During these visits, physical examinations will be performed, hematology samples and information on any new 
anti-cancer therapies initiated will be collected, PRO data will be collected, and bone marrow biopsy and/or aspirate samples will be obtained once yearly 
only from subjects considered to be in clinical remission. Date of post-treatment disease progression recorded in the source notes will be collected. 
31. Long Term Follow up activity log (Years ≥3): Survival Follow-Up Telephone contact, New Anti-cancer therapies since discontinuation of study treatment, 
Disease progression, and PRO: Patients will be contacted by telephone every 3 months starting from the last Post Treatment Follow visit to confirm survival 
status and collect information on any new anti-cancer therapies initiated.  Date of post-treatment hematologic relapse or disease progression recorded in the 
source notes will be collected. During this period, PRO data collection is required and may be collected by phone with data entered by the caller into a Site 
Tablet.  Subjects will be followed up for survival for up to 5 years from the date of randomization of the last patient randomized in the study, or until death, 
or consent withdrawal. See Section 6.4. Public records may be used to find current contact information and/or to document date of death, if permitted by 
local law. 
32. PRO Collection during HSCT Post Remission Period (HSCT Period): PRO will be completed on the day of conditioning regimen administration as 
described in Section 7.4, then on the day of stem cell infusion prior to infusion and any other clinical activities, then once a month after HSCT infusion 
(Day 0) until the subject resumes glasdegib or placebo; then begin PRO assessments on Day 1 in SoA column labeled “Following Consolidation until up to
2 years post randomization). Optimally, subjects will complete electronic PROs (in tablet) themselves.  However, if PRO tablets are not available to the 
subject during this HSCT period, subject if able, will complete the PRO over the phone with a study coordinator so the coordinator may complete the 
electronic tablet.  The study coordinator will make no attempt to clarify, explain, interpret, influence or filter, but simply reading the questions verbatim and 
transcribing patient choice of answers directly onto the site tablet.
 
34. HSCT- related information: Donor details, type of transplant, day of donor stem cell infusion, and conditioning regimen (including radiation) will be 
collected in the CRF.  Presence of GVHD prior to resuming glasdegib/placebo post HSCT will be reported in the CRF. HSCT–related information must be 
made available to the B1371019 study and must be able to be monitored. Post Remission HSCT period (HSCT period) is defined as time from start of 
conditioning until resuming glasdegib/placebo, death, withdrawal of consent, or entering follow up period post HSCT. No concomitant medications 
(including transfusions) will be collected during the HSCT period.  Day 0 is defined as the day of stem cell infusion (HSCT). See Section 7.1.8.
35. ANC engraftment: ANC engraftment is defined as ≥0.5 x 109/L for 3 consecutive days without growth factor support.  ANC engraftment must be 
documented prior to continuing glasdegib or placebo post-HSCT.
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36. SAE Collection post remission HSCT Period from HSCT (Day 0) until resumption of study therapy, death, or withdrawal: All deaths regardless of 
causality, Grade 3 and Grade 4 treatment-related AEs, and SAE events that the investigator believes have at least a reasonable possibility of being related to 
study drug during the HSCT period are to be reported to the sponsor. Once subjects resume glasdegib or placebo following HSCT, events summarized in 
Table 13 will be reported.
37. Interrupt glasdegib/placebo at least 28 days prior to day of hematopoietic stem cell infusion (HSCT). Following HSCT, subjects may continue 
glasdegib or matching placebo 30-60 days post first day of HSCT, once there is ANC engraftment, no ≥Grade 2 ongoing GVHD, and no ongoing SAEs that 
prevent resuming glasdegib or placebo, in the judgement of the investigator.
 
 
 
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Table 2.
Pharmacokinetics & ECG Schedule for Patients Receiving Intensive Chemotherapy: Glasdegib/Placebo + 
Daunorubicin/Cytarabine
Assessment
Screening
Induction 1, and 
Induction 21
Day 1
Induction 1 and 
Induction 21
Day 10 (1 day)
Consolidation2, 5
Cycles 1-4, Day 1
Consolidation2, 5
Cycles 1-4, Day 10 (1 
day)
Glasdegib 
following 
chemotherapy
Cycle 1, Day 1
End of 
Treatment
HOUR post-dose3
03
1
4
03
1
4
03
1
4
03
1
4
1
Glasdegib/placebo PK 
Plasma Samples
X
X
X
X
X
X
X
X
Triplicate 12-lead ECG4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: ECG: electrocardiogram; PK: pharmacokinetics.
1.
Induction Phase: Glasdegib/placebo PK samples to be collected ONLY in Induction 1. 
2.
Consolidation Phase: Glasdegib/placebo PK samples to be collected ONLY in Cycles 1 and 2. 
3.
Glasdegib/Placebo PK sample collection: In all instances, “0 hour” represents a pre-dose collection.  The PK sample should be collected within 
30 minutes prior to dose administration.  Patients should be reminded not to take their study drug prior to arriving at the clinic on protocol scheduled visits.  
All PK time points are in reference to dosing of glasdegib/placebo. There is a 10% window around the nominal timepoints (1 hour timepoint has a 
±6 minute window and the 4 hour timepoint has a ±24 minute window). 
4.
Triplicate 12-lead ECGs (local): At each time point, 3 consecutive supine 12-lead ECGs will be performed approximately 2 minutes apart to determine 
mean QTc interval.  When matched with PK samples, ECGs will be collected: prior to blood sample collection, such that the blood sample is collected at 
the nominal planned time.  All ECG time points are in reference to dosing of glasdegib/placebo. ECGs will be locally read.  A 15-min window for each 
ECG collection is allowed around the nominal ECG time point.
5.
Glasdegib/Placebo sample collection for HSCT Subjects: For subjects who go to HSCT, PK samples will be collected as per PK schedule until 
conditioning therapy is initiated. No consolidation PK samples will be collected once HSCT conditioning begins until the subject resumes glasdegib or 
placebo.


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Table 3.
Schedule of Activities for Patients Receiving Non-Intensive Chemotherapy: Glasdegib/Placebo + Azacitidine
Screening
Treatment
Post Treatment
Cycle 1
(28 –day cycle)
(-3/+3 day time window)
All subsequent cycles 
(28 –day cycles)
(-3/+3 day time 
window)
HSCT Period17
End of 
Treatment
Visit27
Post 
Treatment 
Follow-Up 
Visits (7 
days)28
Long-Term 
Follow-Up 
Activity Log 
(14 days)29
Protocol Activity
(28 days 
prior to 
study entry)
Day 1
Day 7
(3 days)
Day 15 
(3 days)
Day 1
(-3/+28 days)
First day 
of 
condition-
ing
HSCT 
Day 0
> Day 0, 
monthly 
(2 days)
(Within 14 days 
after last dose)
Informed Consent1
X
Medical History2
X
ECOG Performance 
Status3
X
X
X
X
Disease Classification4
X
Physical 
Examination5,28
X
X
X
X
per footnote28
HSCT-related 
information32
X
Laboratory Studies
Hematology6,28
X
X
X
X
X
X
X
Blood Chemistry7
X
X
X
X
X
X
Urinalysis8
X
Coagulation9
X
Pregnancy Test10
X
X
X
X
Triplicate 12 – Lead 
ECG11
X
X
X
X
X
Registration and Treatment12
Glasdegib or 
Placebo13
Oral Once Daily Continuous Dosing
Azacitidine14
SC injection or IV Days 1-7 (3 day time window 
applicable to each dose)14
Drug Compliance15
Continuous
X
Disease Assessments
Bone Marrow Biopsy 
and/or aspirate16,28
X- See 
Footnote16
X-See Footnote16
X16
Bone Marrow 
genetics17,28
X
X-See Footnote17
X-See 
Footnote17
Response Assessment4
X-See Footnote16
per footnote16


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Table 3.
Schedule of Activities for Patients Receiving Non-Intensive Chemotherapy: Glasdegib/Placebo + Azacitidine
Screening
Treatment
Post Treatment
Cycle 1
(28 –day cycle)
(-3/+3 day time window)
All subsequent cycles 
(28 –day cycles)
(-3/+3 day time 
window)
HSCT Period17
End of 
Treatment
Visit27
Post 
Treatment 
Follow-Up 
Visits (±7 
days)28
Long-Term 
Follow-Up 
Activity Log 
(±14 days)29
Protocol Activity
(≤28 days 
prior to 
study entry)
Day 1
Day 7
(±3 days)
Day 15 
(±3 days)
Day 1
(-3/+28 days)
First day 
of 
condition-
ing
HSCT 
Day 0
> Day 0, 
monthly 
(±2 days)
(Within 14 days 
after last dose)
Other Clinical Assessments
Serious and 
non-serious Adverse 
Event Monitoring19
X
Continuous monitoring; except during HSCT period
X19
X19
X19
Review 
Prior/Concomitant 
Treatments20
X
Continuous Monitoring; except during HSCT period
X
Recording of Red 
Blood Cell and 
Platelet Transfusions21
X
Continuous Monitoring except during HSCT period
X
Patient Reported 
Outomes22,28,29,36
X
X
X
X
X
X
X
X
X
X
Pharmacokinetic Sampling
Blood samples for 
Glasdegib PK23
Refer to Table 4 Pharmacokinetics & ECG Schedule for Patients Receiving Non-Intensive Chemotherapy:
Glasdegib/Placebo + Azacitidine
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Table 3.
Schedule of Activities for Patients Receiving Non-Intensive Chemotherapy: Glasdegib/Placebo + Azacitidine
Screening
Treatment
Post Treatment
Cycle 1
(28 –day cycle)
(-3/+3 day time window)
All subsequent cycles 
(28 –day cycles)
(-3/+3 day time 
window)
HSCT Period17
End of 
Treatment
Visit27
Post 
Treatment 
Follow-Up 
Visits (±7 
days)28
Long-Term 
Follow-Up 
Activity Log 
(±14 days)29
Protocol Activity
(≤28 days 
prior to 
study entry)
Day 1
Day 7
(±3 days)
Day 15 
(±3 days)
Day 1
(-3/+28 days)
First day 
of 
condition-
ing
HSCT 
Day 0
> Day 0, 
monthly 
(±2 days)
(Within 14 days 
after last dose)
Follow Up Assessments
Disease progression 
post treatment28,29
X
X
New anti-cancer 
therapies since 
discontinuation of 
study treatment28,29
X
X
Survival Follow-Up 
Telephone contact29
X
Abbreviations: ANC: absolute neutrophil count; BM: Bone Marrow; C#D#: Cycle # Day #; CSF: cerebrospinal fluid; ECG: electrocardiogram; 
ECOG: Eastern Cooperative Oncology Group; EMD: Extra Medulary Disease; GVHD: Graft versus Host Diease; HSCT: hematopoietic stem cell transplant; 
MRD: minimum residual disease; PK: pharmacokinetics WHO: World Health Organization. 
1.
Informed Consent: Must be obtained prior to undergoing any study procedure.  Assessments performed as standard of care within 28 days of randomization 
do not need to be repeated.  
2.
Medical History: Includes cancer history, and prior illnesses, and concomitant illnesses.
3.
ECOG Performance Status: Appendix 3.
4.
Disease Classification and Response Assessment: AML classification according to 2016 WHO classification, Appendix 2.  Prognostic genetic risk 
classification (Appendix 14) and Response Assessments according to 2017 European Leukemia Net (ELN) criteria in Appendix 4.  Response assessment 
includes assessment of EMD (eg disease in CSF).
5.
Physical Examination: Examination of major body systems, body weight, height, and vital signs (blood pressure and heart rate to be recorded in sitting 
position).  Weight must be recorded at Screening and Day 1 of each cycle.  Height need not be recorded after the first measurement at screening.
6.
Hematology: No need to repeat on C1D1 if screening assessment performed within 3 days prior to randomization.  The list of required laboratory tests is 
provided in the protocol (Table 12). 
7.
Blood Chemistry: No need to repeat on C1D1 if screening assessment performed within 3 days prior randomization.  The list of required laboratory tests is 
provided in the protocol (Table 12).
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8.
Urinalysis: Should be performed after Screening if clinically indicated.  The list of required laboratory tests is provided in the protocol in Table 12. 
9.
Coagulation: Should be performed after Screening if clinically indicated.  The list of required laboratory tests is provided in the protocol. 
10. Pregnancy Tests: Pregnancy tests (serum/urine) for patients of child-bearing potential only must be performed on two occasions prior to starting study 
therapy (once at the start of screening and once at the baseline visit, immediately prior to initiation of treatment (first dose), every cycle during the active 
treatment period and at the End of Treatment.  Following a negative pregnancy result at screening, appropriate contraception (will be defined in the protocol) 
must be commenced and a further negative pregnancy result will then be required at the baseline visit before the patient may receive the investigational 
product.  It may also be repeated as per request of IRB/ECs (or if required by local regulations), if one menstrual cycle is missed or when potential 
pregnancy is otherwise suspected during the active treatment period or as clinically indicated. 
11. ECGs (local): See Table 4 for detailed ECG Schedule.
12. Patient Registration: Patient registration and assignment of treatment will be obtained from the centralized Interactive Response Technology (IRT).
13. Glasdegib or Matching Placebo Dosing: Treatment will be administered in 28-day cycles (cycle duration may be extended to allow for toxicity resolution).  
Glasdegib or placebo will be administered oraly once daily, continuously, preferably in the morning at approximately the same time each day.
14. Azacitidine dosing: Treatment can be administered as a SC injection or IV on Days 1-7 (±3 days).  Visit time window added to accommodate varying 
single-agent azacitidine dosing schedules.  The start of subsequent cycles can be delayed to allow for toxicity resolution.  Post HSCT, there will be no further 
azacitidine administration.
15. Drug Compliance: All glasdegib or placebo bottles including any unused tablets and patient dosing diaries will be returned to the clinic for compliance 
assessment and drug accountability. 
16. Bone Marrow Assessments for Disease Evaluation.
Type of Bone Marrow Sample: For all patients, a bone marrow aspirate sample is required at screening; in addition, a bone marrow biopsy is preferred.  
Samples taken prior to consent but within the 28-day window can be used for disease classification only and need not to be repeated.  
 
  Thereafter bone marrow aspirates are required and 
bone marrow biospsies are preferred for disease evaluation by a local laboratory.  Bone marrow aspirates will be required and bone marrow biospies are 
preferred during follow up visits.  In cases of an inadequate aspirate (eg dry tap), a bone marrow biopsy is required.  No bone marrow assessment is 
necessary if non-response or progressive disease can be diagnosed from peripheral blood evaluation or radiological/clinical assessment.
 
Time points for Bone Marrow Sampling:
•
Baseline Bone Marrow must be completed at screening (within 28 days of first dose), Response assessment when CR suspected or after end of Cycle 6; 
whichever, is earlier.  For patients receiving HSCT, a BM aspirate/biopsy must be done prior. Disease assessment will occur when progressive disease 
(PD) is suspected; then when the investigator suspects progression.
•
Please see Footnote 28 for details on collection of bone marrow assessments during the Post-Treatment Follow Up period.
17. Post remission HSCT: Follow local and institutional standard of care practices for HSCT conditioning and transplant. HSCT may occur at any time during 
study treatment, after a confirmed response (See footnote 35).
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18. Bone Marrow genetics: Genetics (local) will be conducted on all patients using any scheduled or unscheduled bone marrow samples collected during study 
participation.  Please see Footnotes 16 and 28 for details on bone marrow samples collection schedule.  Baseline genetics classification must be completed 
within 28 days of first dose.  Since known baseline genetics classification will be used for stratification, investigators must review the available genetics 
results and stratify subjects into this study.  Patients will be stratified according to their genetic risk category at randomization. 
19. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using the NCI CTCAE version 4.03.  Patients must be 
followed for AEs for 28 days after the last treatment administration or until all drug related toxicities have resolved, whichever is later.  AEs must be 
collected up until the start of another anticancer therapy if the start of anticancer therapy is earlier than 28 days.  For serious adverse events (SAEs), the 
active reporting period to Pfizer or its designated representative begins from the time that the patient provides informed consent, which is obtained prior to 
the patient’s participation in the study, (ie, prior to undergoing any study related procedure and/or receiving investigational product), through and including 
28 calendar days after the last administration of the investigational product.  Serious adverse events occurring to a patient after the active reporting period 
has ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, all serious adverse events that the investigator 
believes have at least a reasonable possibility of being related to study drug are to be reported to the sponsor.
20. Concomitant Medications and Treatments: All concomitant medications and treatments should be recorded in the CRF.
21. Red Blood Cells and Platelets Transfusion Recording: Transfusion history up to 8 weeks prior to randomization should be recorded.  All red blood cell 
and platelet transfusions, including date of each transfusion and number of red blood cell and platelet units transfused will be recorded while on treatment.  
Note that number of units not number of bags must be recorded.
22. PRO surveys (MDASI AML/MDS, PGIS, PGIC, EQ 5D 5L, 
 refer to Section 7.4): The surveys will be by the patient on Day 1 
(except there is no PGIC on Day 1 of initial treatment dose – C1D1), 7, 15 of Cycle 1, then Day 1 of each subsequent cycle and at the EOT visit.  
.  See Footnote 28, 29 below for details 
on PRO data collection during the follow up activity period.
23. Blood samples for Glasdegib PK: See detailed information in (Table 4) for specific time points.
 
 
 
 
 
 
 
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27. End of Treatment: Obtain these assessments if not completed in the last week (last 3 months for BM assessments, unless the patient is coming off study 
treatment for disease progression).  Occurs within 14 days of last dose but may be longer only if dosing was interrupted due to an AE and it led to permanent 
discontinuation.  Subjects continuing to experience toxicity following discontinuation of treatment will be followed at least every 4 weeks by the investigator 
until resolution or determination, in the clinical judgment of the investigator, that no further improvement is expected. 
28. Post Treatment Follow Up Visits (First 2 years): Physical Exams, Hematology samples, Yearly Bone Marrow samples for patients in remission, 
Anti-cancer therapies since discontinuation of study treatment, Disease progression post-treatment, and PRO: A follow-up contact will be completed 
at least 28 calendar days, and up to 35 calendar days after the last administration of the investigational product (Section 6.4).  Patients will return to site for 
visits every 3 months starting from the last dose of study medication, for the first 2 years only.  During these visits, physical examinations will be performed, 
hematology samples and information on any new anti-cancer therapies initiated will be collected, PRO data will be collected, and bone marrow assessment 
samples will be obtained once yearly only from patients in remission.  Date of post-treatment disease progression recorded in the source notes will be 
collected. 
29. Long Term Follow up activity log (Years ≥3): Survival Follow-Up Telephone contact, New Anti-cancer therapies since discontinuation of study 
treatment, Disease progression, and PRO: Patients will be contacted by telephone every 3 months starting from the last Post Treatment Follow visit to 
confirm survival status and collect information on any new anti-cancer therapies initiated.  Date of post-treatment hematologic relapse or disease progression 
recorded in the source notes will be collected.  During this period, PRO data collection is required and may be collected by phone with data entered by the 
caller into a Site Tablet.  Patients will be followed up for survival for up to 5 years from the date of randomization of the last patient randomized in the study, 
or until death, or consent withdrawal. Public records may be used to find current contact information and/or to document date of death, if permitted by local 
law. 
 
 
32. HSCT related information: Donor details, type of transplant, day of donor stem cell infusion, and conditioning regimen (including radiation) will be 
collected in the CRF.  Presence of GVHD prior to resuming glasdegib/placebo post HSCT will be reported in the CRF.  HSCT–related information must be 
made available to the B1371019 study and must be able to be monitored.  Post Remission HSCT period (HSCT period) is defined as time from start of 
conditioning until resuming glasdegib/placebo, death, withdrawal of consent, or entering follow up period post HSCT.  No concomitant medications 
(including transfusions) will be collected during the HSCT period.  Day 0 is defined as the day of stem cell infusion (HSCT).  See Section 7.1.8.
33. ANC engraftment: ANC engraftment is defined as ≥0.5 x 109/L for 3 consecutive days without growth factor support.  ANC engraftment must be 
documented prior to continuing glasdegib or placebo post HSCT. 
34. SAE Collection post remission HSCT Period from HSCT (Day 0) until resumption of study therapy, death, or withdrawal: All deaths regardless of 
causality, Grade 3 and Grade 4 treatment related AEs, and SAE events that the investigator believes have at least a reasonable possibility of being related to 
study drug during the HSCT period are to be reported to the sponsor.  Once subjects resume glasdegib or placebo following HSCT, events summarized in 
Table 13 will be reported.
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35. Interrupt glasdegib/placebo at least 28 days prior to day of hematopoietic stem cell infusion (HSCT). Following HSCT, subjects may continue
glasdegib or matching placebo 30 -60 days post first day of HSCT, once there is ANC engraftment, no ongoing ≥Grade 2 GVHD, and no ongoing SAEs that 
prevent resuming glasdegib or placebo, in the judgement of the investigator. Patients may continue on glasdegib treatment following HSCT or up to 2 years 
post randomization or until CR MRD-negative disease is confirmed at 2 consecutive time points post HSCT, whichever comes first. The 2 consecutive time 
points will be done as part of the scheduled marrow assessments.
36. PRO Collection during HSCT Post Remission Period (HSCT Period): PRO will be completed on the day of conditioning regimen administration prior to 
dosing and any other clinical activities, then on the day of stem cell infusion prior to infusion and any other clinical activities, then once a month after HSCT 
infusion (Day 0) until the subject resumes glasdegib or placebo; then begin PRO assessments on Day 1 in SoA column labeled “Following Consolidation 
until up to 2 years post randomization”.  Optimally, subjects will complete electronic PROs (in tablet) themselves.  However, if PRO tablets are not available 
to the subject during this HSCT period, subject if able, will complete the PRO over the phone with a study coordinator so the coordinator may complete the 
electronic tablet.  The study coordinator will make no attempt to clarify, explain, interpret, influence or filter, but simply reading the questions verbatim and 
transcribing patient choice of answers directly onto the site tablet.


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Table 4.
Pharmacokinetics & ECG Schedule for Patients Receiving Non Intensive Chemotherapy: Glasdegib/Placebo + 
Azacitidine
Assessment
Screening
Cycle 1, Day 1
Cycle 1, Day 15
(3 days)
Cycle 2-3, Day 13
(-3/+28 days)
Cycles 4, 
Day 1
(-3/+28 days)
End of treatment
HOUR post-dose1
01
1
4
01
1
4
01
1
4
1
Glasdegib/placebo PK Plasma 
Samples
X
X
X
X
X
X
X
X
Triplicate 12-lead ECG2
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: ECG: electrocardiogram; PK: pharmacokinetics
1.
Glasdegib/Placebo PK Sample Collection: In all instances, “0 hour” represents a pre-dose collection.  The PK sample should be collected within 
30 minutes prior to dose administration.  Patients should be reminded not to take their study drug prior to arriving at the clinic on protocol scheduled visits.  
All PK time points are in reference to dosing of glasdegib/placebo. There is a 10% window around the nominal timepoint, (1 hour timepoint has a ±6 minute 
window and the 4 hour timepoint has a ±24 minute window). 
2.
Triplicate 12-Lead ECGs: At each time point, 3 consecutive supine 12-lead ECGs will be performed approximately 2 minutes apart to determine mean 
QTc interval.  When matched with PK samples, ECGs will be collected: prior to blood sample collection, such that the blood sample is collected at the 
nominal planned time.  All ECG time points are in reference to dosing of glasdegib/placebo.  ECGs will be locally read. A 15-min window for each ECG 
collection is allowed around the nominal ECG time point.
3.
PK samples to be collected only on Cycle 2 Day 1.


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1. INTRODUCTION
1.1. Indication
Glasdegib is being studied in combination with azacitidine for the treatment of adult patients 
with previously untreated acute myeloid leukemia who are not candidates for intensive 
induction chemotherapy (Non-intensive AML population).
Glasdegib is being studied in combination with cytarabine and daunorubicin for the treatment 
of adult patients with previously untreated acute myeloid leukemia (Intensive AML 
population).
1.2. Background 
1.2.1. Acute Myeloid Leukemia 
Acute Myeloid Leukemia (AML) is a heterogeneous cancer of the hematopoietic system
characterized by increased blast counts, pancytopenias causing infections and bleeding, and 
reduced survival.  AML is a genetically heterogeneous malignancy characterized by multiple
genetic mutations at the time of diagnosis that evolve with treatment, resulting in treatment 
resistance, disease relapse, and reduced survival.  It is estimated that there will be 21,380 new 
cases and 10,590 deaths from AML in the United States in 2017.7 Incidence rates in Europe 
are similar to rates in the United States.8  AML is a disease of older people and is uncommon 
before the age of 45.  The average age of a patient with AML is about 67 years. 
Existing standards of care, such as anthracycline + cytarabine or hypomethylating agents like 
decitabine and azacitidine, can induce complete remissions in 5-70% of patients; however, 
remissions are not durable and disease relapse occurs in up to 60% of patients.9 For AML 
patients unable to receive intensive chemotherapy, existing standard treatments like low-dose 
cytarabine (LDAC) are associated with response rates <20% and median overall survival 
(mOS) times of 5-6.5 months.  Hypomethylating agents, azacitidine and decitabine, although 
not approved in the United States (US) specifically for AML, have shown improved overall 
survival (OS) vs LDAC in AML patients not suitable for intensive chemotherapy. 
Midostaurin (Rydapt®) is indicated for use in combination with standard cytarabine and 
daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult 
patients with newly diagnosed AML who are Fms-like tyrosine kinase 3 (FLT3)
mutation-positive.19  Approval in 2017 was based on the Phase III RATIFY
(CALGB 10603 [Alliance]) clinical trial resulting in a 23% reduction in the risk of death 
compared with chemotherapy alone (hazard ratio [HR] = 0.77, 95% confidence interval [CI], 
0.63, 0.95; 2 sided p=0.016)[3].10  Event-free survival was significantly higher for Rydapt 
plus chemotherapy versus chemotherapy alone (median of 8.2 months compared to 
3.0 months, HR = 0.78, 95% CI 0.66, 0.93 and 2 sided p=0.004). 
The most frequent adverse reactions were febrile neutropenia, nausea, vomiting, mucositis, 
headache, musculoskeletal pain, petechiae, device-related infection, epistaxis, hyperglycemia 
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Reducing the incidence of disease progression to prolong survival remains the highest unmet 
medical need in the treatment of AML patients.11-13
Glasdegib has shown activity in myelodysplastic syndrome (MDS) and AML with improved 
response rates and improved OS.
Genetic and functional studies have demonstrated that AML develops as a result of 
acquisition of genetic and epigenetic alternations that result in abnormal differentiation and 
unlimited cellular self-renewal.  The World Health Organization (WHO) 2016 classification 
defines AML as 20% blasts in the marrow or blood. A diagnosis of AML may be made 
with less than 20% in patients with recurrent cytogenetic abnormalities [eg, t(15;17), t(8;21), 
t(6;16), inv(160)].  In 2016, the World Health Organization (WHO) revised their 
classification of myeloid neoplasms and acute leukemia (Appendix 2).20 In this revision, 
acute promyelocytic leukemia (APL) with a t(15:17) gene fusion, was renamed as APL with 
PML-RARA. AML with t(9:22) was renamed AML with BCR-ABL breakpoint cluster 
region-Abelson 1 (BCR-ABL1) to identify the rare cases that may benefit from tyrosine 
kinase inhibitor (TKI) therapy.21,22
1.2.2. Hedgehog Signaling Pathway and Glasdegib Mechanism
Glasdegib is a selective, orally administered inhibitor of the seven-transmembrane protein, 
smoothened (SMO), which demonstrates potent and selective inhibition of Hedgehog (Hh) 
signaling in vitro and significant antitumor efficacy in vivo.  The Hh signaling pathway 
regulates cell differentiation and self-renewal in the developing embryo, and is typically 
silenced in adult tissues.  Aberrant Hh signaling may result from mutations in key pathway 
genes, non-mutational mechanisms related to the secretion of Hh ligands, or from cells in the 
tumor microenvironment.  Aberrant Hh signaling has been identified in a variety of human 
leukemia and leukemic stem cells (LSCs).1  Upregulation of Hh pathway components has 
been observed in chemo resistant AML cell lines in vitro, and pharmacological inhibition of 
the Hh pathway resulted in decreased multi-drug resistance 1 (MDR-1) or P-glycoprotein 
(P-gp) expression in these cells.4 The SMO inhibitors, vismodegib (Erivedge®)5 and 
sonidegib (Odomzo®)6 have been demonstrated to be safe and effective in the treatment of 
patients with advanced basal cell carcinoma.  Glasdegib is being developed for indications in 
myeloid malignancies.
In nonclinical models, SMO, acting via its effector, Glioma-associated oncogene homolog 
2 (GLI2), has been implicated in the maintenance of LSC dormancy and associated resistance 
to chemotherapy and targeted therapy, while inhibition of SMO via glasdegib can cause 
LSCs to re-enter the cell cycle.22-24  Recrudescence of LSCs is prevented in preclinical hosts 
that were pre-treated with Hh pathway inhibitors, including glasdegib.22  Consistent with 
these effects, glasdegib sensitized AML cells to cytosine arabinoside, and abrogated 
resistance to cytosine arabinoside in AML cells co-cultured with stromal cells.22  Thus, Hh 
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Gene profiling analysis showed that treatment with glasdegib modulates self-renewal and 
cell-cycling in AML by encouraging quiescent LSCs into cell cycle. NANOG transcript 
level may be a responsive biomarker during treatment with glasdegib in AML.25 Upon GLI 
binding to the NONOG pluripotency promoter, GLI-NANOG axis promotes stemness and 
growth in several cancers. When NANOG expression was examined in primary AML 
patient bone marrow samples following treatment with glasdegib, NONOG transcript levels 
decreased along with GLI-target genes; such as, GLI1 and patched (PTCH).  Upregulation of 
Hh pathway components has been observed in chemo-resistant AML cell lines in vitro, and 
pharmacological inhibition of the Hh pathway resulted in decreased multi drug resistance 
(MDR-1) or P-glycoprotein (P-gp) expression in these cells.4 Additional evidence for the 
importance of the Hh pathway in leukemia is derived from patients enrolled in the completed
single agent hematology trials. Importantly, these preliminary data suggest the mechanism of 
action of Hh inhibition in leukemia appears to be mobilization of blast cells from the bone 
marrow to the peripheral blood, with subsequent expansion and differentiation of LSCs.23
1.2.3. Glasdegib Nonclinical Toxicology
Details of the nonclinical safety program are provided in the current Investigator’s Brochure, 
Section 5.3.
1.2.4. Clinical Development
In the clinical development program to date, glasdegib has been studied in >300 patients 
across multiple diseases, and >100 healthy participants. 
1.2.4.1. Clinical Pharmacology of Glasdegib
Glasdegib has been orally administered to humans at doses ranging from 5 mg to 640 mg 
QD.  Following daily dosing as a single agent, steady state was usually achieved by Day 8 of 
treatment.  In patients with myeloid malignancies and solid tumors, the time to maximum 
plasma concentration (Tmax) typically ranged from 1-4 hours both after a single dose and at 
steady state. 
The geometric mean (geometric %CV) apparent volume of distribution (Vz/F) of glasdegib 
was 188 (20) L following a single dose of 100 mg glasdegib in patients with hematologic 
malignancies and exceeded the typical plasma volume (3L) suggesting that glasdegib is 
distributed into tissues from plasma.  In nonclinical studies, the fraction unbound in human 
plasma (fu) was 0.0899 at a concentration of 10 µM (3744 ng/mL).  The absolute 
bioavailability of glasdegib was 77.12%.
In the first-in-participant (FIP) study (B1371001), following peak plasma concentrations 
obtained after oral administration, glasdegib plasma concentrations appear to have a 
biexponential decline.  Glasdegib accumulated following repeated dosing with a median 
accumulation ratio (Rac) ranging from 1.2 to 2.5.  Observed Cmax and AUC of glasdegib 
increased in a dose-proportional manner over the dose range of 5 mg to 600 mg QD after 
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CYP3A4 is the enzyme primarily responsible for the metabolism of glasdegib, with minor 
contributions from other pathways.  Renal excretion of unchanged glasdegib is ~17% of the 
total administered dose (100 mg).  
To estimate the impact of a inhibition of CY3A4/5 on glasdegib plasma exposures, an 
interaction study with ketoconazole, a strong CYP3A4/5 inhibitor, was conducted in 
14 healthy volunteers. A single 200-mg oral dose of glasdegib in the presence of 
ketoconazole compared to 200-mg dose of glasdegib alone resulted in higher glasdegib 
exposures, with the mean plasma exposure (AUCinf) ratio of 2.4 (90% CI: 2.15, 2.68) and the 
mean peak plasma concentration (Cmax) ratio of 1.4 (90% CI: 1.24-1.58).   
A second interaction study to estimate the effect of a strong CYP3A4/5 inducer on glasdegib 
PK was conducted using rifampin, a strong inducer of CYP3A4/5, in 12 healthy volunteers.  
In the presence of rifampin, there was a 70% decrease (90% CI: 26, 31) in plasma exposures 
(AUCinf) and a 35% decrease (90% CI: 57,73) in peak plasma concentration (Cmax) of a 
single 100 mg oral dose of glasdegib when compared to glasdegib alone indicating that 
CYP3A4/5 related metabolism is a major pathway for glasdegib biotransformation. 
An evaluation of the effect of food on the maleate salt 100 mg tablet formulation (B1371026) 
showed a reduction in glasdegib Cmax and AUCinf [geometric mean ratio (90% CI): 
76% (65%, 88%) and 86% (81%, 92%) respectively]. Co-administration of glasdegib with a 
pH altering agent (the proton pump inhibitor, rabeprazole) under fasting conditions, resulted 
in no change in glasdegib AUCinf (geometric mean ratio [90% CI]: 100.58% [93.19%, 
108.55%]) and a 19.5% decrease in glasdegib Cmax (geometric mean ratio [90% CI]: 
80.46% [70.68%, 91.59%]) compared with a single dose of glasdegib administered alone. 
This impact of PPI on the PK of glasdegib was not considered to be clinically meaningful. 
A Phase 1, single-center, randomized, 4-period, 4-sequence, 4-treatment (glasdegib at 
therapeutic and supratherapeutic exposure and placebo [blinded]; moxifloxacin [open label]), 
single dose, 4-way crossover thorough QT (TQT) study was conducted that investigated the 
effect of glasdegib on cardiac repolarization in 36 healthy participants. Absence of a large 
effect of glasdegib on the QTcF interval was demonstrated at the therapeutic (100 mg QD 
steady state glasdegib exposures) and supratherapeutic (~2X the steady state glasdegib 
exposures) doses as the upper bound of the 2-sided 90% CIs for all time-matched least 
squares mean differences between glasdegib (150 mg and 300 mg) and placebo was below 
the pre-specified criterion of 20 msec – the threshold of clinical concern in oncology. None 
of the participants had absolute QTcF interval of 480 msec or increase from baseline in 
QTcF interval 30 msec after receiving any treatment. 
Additional clinical pharmacology information for this compound may be found in the single 
reference safety document (SRSD), the Investigator’s Brochure.


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1.2.4.2. Relevant Clinical Studies with Glasdegib
B1371003 Phase 2 Randomized Non-intensive Chemotherapy
AML + MDS patients not eligible for intensive chemotherapy were randomized 2:1 to 
glasdegib + LDAC or LDAC alone. The combination of glasdegib 100 mg QD plus LDAC
resulted in a clinically meaningful and statistically significant improvement in OS in the 
AML subgroup that comprised 88% of all randomized participants (hazard ratio (HR)=0.463 
[95% confidence interval (CI): 0.299, 0.717], p=0.0002), with an mOS of 8.3 months versus 
4.3 months. Improvement in OS was consistent across pre-specified subgroups by
good/intermediate and poor cytogenetic risk. The demonstrated benefits in OS were 
supported by improvements in CR rates, which appeared to be consistent across the clinical 
trial program when glasdegib was combined with standard-of-care chemotherapy for AML or 
MDS such as azacitidine, decitabine, or 7+3 in the context of historical controls.
B1371003 Phase 2 Single-Arm Intensive Chemotherapy
In a single-arm open-label trial in AML + MDS patients who were able to receive intensive
chemotherapy with 7+3, including approximately 25% with adverse or poor cytogenetic risk
disease, there was at least a 1.5-fold increase in mOS in each of the ELN risk stratifications,
including adverse risk, as compared to historical controls, which is supportive of the OS
benefit seen in the randomized Phase 2 part of Study B1371003. This improvement in OS
observed with glasdegib treatment did not appear to be influenced by HSCT given that the
OS results with and without censoring for patients who underwent HSCT were similar.
The mOS for 44 AML patients (29 deaths) age >60 yrs is presented in Table 5, in the context 
of historical control. 
Table 5.
Median Overall Survival (mOS) in Patients >60 Years Stratified by 
European Leukemia Net (ELN) Risk Criteria
Risk Group
7+3 (Historical
Röllig et al, 2011,
N=710)
Months
Glasdegib Plus 7+3
(n=44*)
Months
Increase in mOS 
withAddition of 
Glasdegib
(29 deaths)
Favorable
14.6
Not reached (n=9)
Not estimable
Int-1
9.5
15.7 (n=12)
65.3%
Int-2
9.2
13.4 (n=11)
45.7%
Adverse
4.8
8.5 (n=10)
77.1%
*2 pts were not classifiable by ELN risk.
Although the CR rates do not appear to be higher than those reported historically for older 
AML pts receiving intensive chemotherapy, the mOS stratified by subgroup appears 
improved by adding glasdegib, as may be expected for an agent that targets LSCs. The 
combination of glasdegib with ‘7+3’ was well-tolerated, with a safety profile consistent with 
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B1371012 Phase 1b/2
In Study B1371012, 12 patients with high risk MDS, CMML, or AML were treated with 
glasdegib 100 mg PO QD in combination with azacitidine 75 mg/m2 daily for 7 days 
subcutaneously in a safety lead-in cohort. No evidence of drug-drug interaction (DDI) with 
azacitidine was noted. As of March 2017, 5 of the 12 participants responded: 3 participants 
with CR (all AML) and 2 participants with marrow CR.14
Updated details of the clinical safety program are provided in the current Investigator’s 
Brochure. 
1.3. Rationale for Drug Combinations and Dosing
1.3.1. Rationale for Glasdegib in Combination with Azacitidine as Non-Intensive 
Chemotherapy
In the randomized cohort of Study B1371003, glasdegib (100 mg PO QD) demonstrated a 
statistically significant and clinically meaningful improvement in median overall survival 
(mOS) when combined with LDAC vs LDAC alone in elderly AML patients not suitable for 
intensive chemotherapy, with no new safety signals identified. 
For AML patients who are not expected to tolerate intensive chemotherapy, treatment 
alternatives are limited to best supportive care, low-intensity treatment, or clinical trials with 
investigational drugs. When compared with conventional care regimens, azicitidine 
increased mOS from 6.5 months to 10.4 months.16  In the European Union (EU), azacitidine 
(Vidaza®) has been approved for patients aged 65 years with AML who are not eligible for 
HSCT based on data from the AML-001 study.9 Median OS was 10.4 months. The one year 
survival rate was 46.5%. Grade 3-4 anemia, neutropenia, febrile neutropenia, and 
thrombocytopenia rates, respectively, were 16%, 26%, 28%, and 24% with azacitidine.  
Azacididine is not curative; therefore, continuing glasdegib or placebo until disease 
progression or toxicity is reasonable.
Preclinical data demonstrated synergistic activity when a SMO inhibitor erismodegib, was 
combined with 5-azacitidine, a hypomethylating agent.32 Silencing of chromosomes 5 and 
7 enhances the activity of 5-azacitidine. In a 5-azacitidine ribonucleic acid 
(RNA)-interference sensitizer screen to identify gene targets within the commonly deleted 
regions of chromosomes 5 and 7, drugs that inhibited SMO (erismodegib and vismodegib) 
showed single-agent activity in AML cell lines. Combination of erismodegib with 
5-azacitidine demonstrated synergistic activity in multiple AML cell lines regardless of the 
extent of Hh pathway gene expression. 
In Study B1371012, serial PK samples were collected for both glasdegib and azacitidine 
alone and in combination during the first cycle of treatment, to assess for potential drug-drug 
interaction. The PK parameters for glasdegib and azacitidine were similar when dosed 
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Additional information for glasdegib may be found in the Single Reference Safety Document 
(SRSD), the Investigator Brochure. For the purposes of this trial, the SRSD for azacitidine is 
the EU SPC for Vidaza®.33
1.3.2. Rationale for Glasdegib in Combination with Daunorubicin and Cytarabine as 
Intensive Chemotherapy
When combined with glasdegib (100 mg PO QD), improvements in response rates, 
reductions in disease relapse frequency, and improvements in OS in the context of historical 
controls have been observed both in different populations (MDS, post-allogeneic stem cell 
transplant, elderly AML and suitable for intensive chemotherapy) and with different 
treatment combinations commonly used in the treatment of AML patients (azacitidine, 
decitabine, ‘7+3’, allogeneic stem cell transplant.  AML relapse does not typically occur after 
2 years; therefore, it is reasonable to administer glasdegib or placebo up to 2 years post 
randomization.12,16
CR is achieved in 60%-80% of younger adults and 40%-60% adults (age 60) following 
administration with standard intensive ‘7+3’ chemotherapy consisting of 7 days of cytarabine 
(100-200 mg/m2) and 3 days of an anthracycline (ie, daunorubicin
45-60 mg/m2.12,16  Thus, a ‘7+3’ is a reasonable induction regimen for patients who are 
medically fit.34
The AML14 trial enrolled 1273 patients, predominantly aged >60 years (although younger 
patients were allowed) with AML and High Risk MDS.35 The overall response rate across all 
arms was 62% (CR 54%, CR without platelet/neutrophils recovery 8%); 5-year survival was
12%, and no benefits were observed in either dose escalation schedule. To determine if the 
addition of a Hh inhibitor can increase intensive chemotherapy response rates, glasdegib will 
be administered once daily and continuously starting on Day 1, along with the start of 
cytotoxic therapy. This schedule is consistent with other mobilizing/cytotoxic combination 
studies, and will allow cells time to transit from the marrow to the peripheral blood 
compartment.36
The most common consolidation regimens include single-agent cytarabine at high doses and 
multiagent chemotherapy which lead to similar outcomes. High –dose cytarabine (HIDAC; 
2000-3000 mg/m2) is commonly used.37
Allogeneic HSCT is generally recommended as a standard of care consolidation therapy,
especially in patients who are medically suitable for HSCT and with adverse genetics.16
The relapse incidence without the procedure is expected to be 35% to 40%.
In the Phase 1b portion of Study B1371003 for glasdegib in combination with 7+3, the PK of 
100 mg QD glasdegib at steady state were in line with expected exposures and the exposures 
of 7+3 were in line with historically reported exposure data. 


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Additional information for glasdegib may be found in the SRSD, the Investigator Brochure. 
For the purposes of this trial, the SRSD is the EU Summary of Product Characteristics (SPC)
for cytarabine38 and daunorubicin.39
1.3.3. Rationale for Glasdegib Dosing and Schedule
B1371001 first-in-human study identified the MTD for single-agent glasdegib continuous 
administration as 400 mg QD, and the RP2D as 200 mg QD in patients with select 
hematologic malignancies. Study B1371003 with glasdegib in combination with LDAC and 
intensive chemotherapy (cytarabine/daunorubicin) initially tested both glasdegib 100 mg QD 
and 200 mg QD starting dose levels in the Phase 1b portion of the study.  However the 
clinical dose of 100 mg QD (MTD-4) was selected as the dose for further evaluation in the 
Phase 2 portions of the study on the basis of the observed clinical activity, safety and 
tolerability profile, modulation of hedgehog pathway activity in surrogate tissue, and 
information relating to the possible impact of a CYP3A4 inhibitor. These data provided a 
compelling rationale for the 100 mg QD dose of glasdegib being a safe and clinically 
effective dose in combination with azacitidine or cytarabine/ daunorubicin.
 
 
 
 
 
 
 
 
 
1.5. Summary of Benefit Risk Assessment
Glasdegib is a selective, once daily oral tablet SMO inhibitor with a safety profile that 
appears consistent with other approved, marketed SMO inhibitors based upon data reported 
in the IB (September 2018).  In the ongoing clinical development program, glasdegib 
significantly improved OS in a prospective randomized study in combination with LDAC in 
AML patients not suitable for intensive chemotherapy. 
Data are mature, as median duration of follow-up is longer than mOS.  
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The safety profile of the addition of glasdegib to LDAC was generally tolerable and 
manageable.  Despite the differences in treatment and follow-up duration between the two 
arms, increases in cytopenias were not accompanied by significant increases in sepsis or 
bleeding.  The principle SMO inhibitor toxicities of dysgeusia, alopecia, and muscle spasms 
were mostly Grade 1 or 2 in severity and manageable with continued dosing with or without 
dose modification.
Improvements in response rates, reductions in disease relapse frequency, and improvements 
in OS in the context of historical controls have been observed both in different populations 
(MDS, post-allogeneic stem cell transplant (SCT), and elderly patients with AML suitable for 
intensive chemotherapy) and with different AML treatment regimens commonly used in the 
treatment of AML patients (azacitidine, decitabine, ‘7+3’, allogeneic SCT). 
The clinical safety database of glasdegib contains over 300 patients with hematologic 
malignancies who received the glasdegib recommended daily dose of at least 100 mg.  The 
safety profile observed so far appears consistent with that reported for the SMO inhibitor 
class and the underlying chemotherapy backbones. 
Based on the results from B1371003, 2 prospective randomized (1:1), double-blind, 
placebo-controlled registration trials in patients with newly diagnosed AML are proposed: in 
the first study, 400 AML patients suitable for intensive chemotherapy will be randomized to 
receive ‘7+3’+ glasdegib (Arm A) or ‘7+3’+ placebo (Arm B).  In the second study, 
320 AML patients not suitable for intensive chemotherapy per investigator will be 
randomized to receive azacitidine + glasdegib (Arm A) or azacitidine + placebo (Arm B).  
The primary endpoint for both trials will be OS.  Both studies will be powered, conducted, 
and analyzed separately and independently under 1 protocol (B1371019) to maximize 
efficiency.  Together, the trials can provide substantial evidence to register glasdegib in AML 
patients treated in combination with 7+3 or with azacitidine.
2. STUDY OBJECTIVES AND ENDPOINTS
Protocol B1371019 consists of 2 independent studies: an intensive chemotherapy study and 
non-intensive chemotherapy study.  Within each study, subjects will be randomized to 
chemotherapy with either glasdegib or matching placebo. The primary and secondary 
endpoints for each study will be analyzed separately.  Response criteria for AML are defined 
by the 2017 ELN recommendations.16
The objectives and endpoints for each study are the same unless otherwise specified and are 
described below:
Primary Objective:
Primary Endpoint:

To demonstrate that glasdegib is superior to 
placebo in combination with azacitidine
(non-intensive study) or cytarabine and 
daunorubicin (intensive study) in prolonging OS 
in subjects with untreated AML.

Overall survival.


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Secondary Objectives:
Secondary Endpoints:
•
To compare fatigue score post-baseline as 
measured by MDASI-AML/MDS in both 
treatment arms;
•
To compare glasdegib versus placebo in 
combination with azacitidine (non-intensive
study) or ‘7+3’ (cytarabine and daunorubicin) in 
improving other clinical efficacy measures;
•
To estimate the duration of response in both 
treatment arms;
•
To estimate the time to response in both 
treatment arms in the Non-intensive study only;
•
To compare Event-free Survival (EFS) in both 
treatment arms;
•
To compare PRO measurements in both 
treatment arms;
•
To evaluate the overall safety profile in both 
treatment arms;
•
To evaluate laboratory abnormalities in both 
treatment arms;
•
To characterize the PK of glasdegib;
•
To characterize treatment effects on the QTc 
interval.
•
Fatigue score measured by the 
MDASI-AML/MDS questionnaire;
•
Rate of CR (including CRMRD-negative as assessed 
by multiparametric flow cytometry), CRi as 
defined by the ELN recommendations (2017), 
MLFS, PR, and CR with partial hematologic 
recovery (CRh) for the Non-intensive study 
only;
•
Duration of response (defined as CRi or better
or CRh or better if applicable):*
•
Time to response (CRi or better -or CRh or 
better)* in the non-intensive study only;
•
Event-free Survival;
•
PROs as measured by the M.D. Anderson 
Symptom Inventory AML/MDS Module 
(MDASI-AML/MDS), EuroQoL 5 Dimension 
questionnaire 5-Level version (EQ-5D-5L), 
Patient Global Impression of Symptoms (PGIS)
and Patient Global Impression of Change 
(PGIC);
•
Adverse events as characterized by type, 
frequency, severity (as graded by NCI CTCAE 
v.4.03), timing, seriousness and relationship to 
study therapy;
•
Laboratory abnormalities as characterized by 
type, frequency, severity (as graded by NCI 
CTCAE v.4.03) and timing;
•
PK of glasdegib;
•
QTc interval.
 
 
 
 
 
 
 
 
 
 
 
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* CRi or better includes CR (including CRMRD-negative ) or CRi for intensive chemotherapy subjects, and CR 
(including CRMRD-negative), CRh, or CRi for non-intensive chemotherapy subjects.  CRh or better is only 
defined for non-intensive chemotherapy subjects as CR (including CRMRD-negative) or CRh. 
The Intensive and Non-Intensive Chemotherapy studies will use the same external data 
monitoring committee (E-DMC).
3. STUDY DESIGN
Two separate registration trials conducted under one protocol number are proposed to 
adequately and independently evaluate the addition of glasdegib in intensive and 
non-intensive chemotherapy populations. Each study will have an experimental treatment 
arm and a placebo arm.
Study B1371019 (Figure 1) is a randomized (1:1), double-blind, multi-center, placebo 
controlled study of chemotherapy in combination with glasdegib versus chemotherapy in 
combination with placebo in adult patients with previously untreated AML (excluding APL 
with PML-RARA, AML with BCR-ABL1 and active central nervous system [CNS]
leukemia) to support the proposed indication statements: 
•
Intensive Study: Glasdegib is being studied in combination with cytarabine and 
daunorubicin for the treatment of adult patients with untreated AML.
•
Non-intensive Study: Glasdegib is being studied in combination with azacitidine for
the treatment of adult patients with untreated AML who are not candidates for 
intensive induction chemotherapy.
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Figure 1.
Schematic of Study Design
* Section 5.5 describes dosing details for the intensive chemotherapy regimen(s) [including ‘7+3’ or ‘5+2’ 
option for Induction 2], non-intensive chemotherapy regimen, and experimental study drugs.
Assignment to the Intensive Study or the Non-Intensive Study will be made by the 
Investigator based on the 2017 ELN recommendations.16  
The treatment arm allocation for Arm A or Arm B within each study will be operated by the 
sponsor following the rules defined in Section 5.1.
In each study, the primary endpoint will be OS, and the secondary endpoints would include 
response, duration of response, time to response, EFS, safety, 
, PROs, 
and PK.  Study visits would occur on the first day of each cycle during the treatment period, 
and after end of treatment per the Schedule of Events (Table 1, Table 2 and Table 3, Table 4) 
to evaluate safety, disease progression, further anti-cancer therapy, or death. 
Intensive Chemotherapy Study: 
Subjects will be stratified at randomization by genetic risk (favorable vs intermediate vs 
adverse by ELN genetic risk categories)16 and age (≤60 years vs >60 years).
A total of 400 subjects eligible to receive intensive chemotherapy per investigator assessment 
will receive treatment as follows: 
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
Experimental Therapy: Glasdegib 100 mg PO or matching placebo will be 
administered by mouth daily beginning on Day 1 and is to continue up to 2 years post 
randomization.  Following consolidation therapy, glasdegib or placebo will be 
administered daily for up to 2 years after randomization or until they have 
2 consecutive CR MRD-negative central laboratory results, whichever comes first.  
Daily Glasdegib 100 mg PO or matching placebo will continue throughout 
Induction(s) and Consolidation therapies regardless of dose modifications/delays in 
the chemotherapy.

For HSCT consolidation, glasdegib or placebo will be interrupted at least 28 days
before HSCT Day 0 (day of HSCT) and resumed 30-60 days post HSCT, once 
there is ANC engraftment (≥0.5 x 109/L for 3 consecutive days without growth 
factor support), no ongoing Grade 2 graft-versus-host disease (GVHD), and no 
ongoing SAEs that prevent resumption of glasdegib or placebo in the judgement 
of the investigator.

Induction chemotherapy: ‘7+3’ (cytarabine 100 mg/m2 IV for 7 days by continuous 
infusion and daunorubicin 60 mg/m2 for 3 days).  If a second induction is needed, 
Investigators may choose either a 5 day cytarabine continuous infusion plus 
daunorubicin for 2 days (‘5+2’) or a 7 day cytarabine continuous infusion plus 
daunorubicin for 3 days (‘7+3’);

If <5% bone marrow blasts and per investigator judgement: consolidation cytarabine 
or post remission HSCT with either or both of the following: 

Consolidation with single-agent cytarabine 3 g/m2 IV for adults <60 years and 
1 g/m2 for adults 60 years over 3 hours twice daily (BID) on Days 1, 3, and 5, 
every 28 days for up to 4 cycles or alternative single-agent cytarabine 
consolidation schedules may be used per local prescribing information.

HSCT per standard of care.
A total of 267 death events would provide 90% power to detect an improvement in overall 
survival from 21 months to 31.5 months assuming a composite mOS for the population as 
follows: young AML (aged 60 years) with a mOS of 23.7 months and elderly AML (aged 
>60 years) with a mOS of 15 months17,18 and with an HR=0.67 using a 1-sided log-rank test 
at a significance level of 0.025 and a 3-look group-sequential design. 
Two interim analyses will be conducted: an early interim analysis of OS after 50% death 
events occur (no plan to stop for efficacy even if the efficacy boundary is crossed) and an 
efficacy and futility analysis of OS after 70% death events occur in the Intensive 
Chemotherapy population or upon completion of enrollment, whichever is later.
Non-Intensive Chemotherapy Study:
Subjects will be stratified at randomization by genetic risk (favorable vs intermediate vs 
adverse by ELN genetic risk categories)16 and age (<75 years vs ≥75 years).9,40


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A total of 320 subjects who are not candidates to receive Intensive Chemotherapy will 
receive treatment as follows:

Experimental Therapy: Glasdegib 100 mg PO QD or matching placebo is to be 
administered by mouth daily beginning on Day 1 of chemotherapy and will continue 
if subjects demonstrate reasonable evidence of clinical benefit and do not meet the 
criteria for progression regardless of any delays/modifications in the chemotherapy 
treatment.  Subjects will continue glasdegib or placebo until disease progression, 
unacceptable toxicity, consent withdrawal, or death, whichever comes first. 

Azacitidine will be administered by subcutaneous injection (SC) or intravenous (IV) 
infusion daily for 7 days, in 28 day cycles for as long as they do not meet the criteria 
for disease progression, unacceptable toxicity, consent withdrawal, or death, 
whichever comes first. 

Alternate dosing schedules to administer the 7 doses of azacitidine to accommodate 
patient and treatment center availability is allowed.  Dose adjustments will be made 
according to local approved label for azacitidine.  In addition, each subsequent cycle 
may be delayed for up to 28 days to allow for recovery of blood counts.  Patients 
should continue to receive treatment as long as they do not meet the criteria for 
progression.

Per Investigator discretion, HSCT may be performed.  Glasdegib or placebo will be 
interrupted at least 28 days before HSCT Day 0 (day of stem cell infusion), and 
resumed 30-60 days post HSCT after documentation of ANC engraftment 
(≥0.5 x 109/L for 3 consecutive days without growth factor support), no ongoing 
≥Grade 2 GVHD, and no ongoing SAEs that prevent resumption of 
glasdegib/placebo in the judgement of the Investigator.  If therapy is resumed, 
glasdegib/placebo may continue up until 2 consecutive CR MRD-negative results, 
death or consent withdrawal.

For patients undergoing HSCT, azacitidine may continue prior to HSCT, per the 
investigator discretion.  Following HSCT, azacitidine will not be resumed.
A total of 220 death events would provide 90% power to detect an improvement in overall 
survival from 10.4 months9 to 16.2 months with an HR=0.64 using a 1-sided log-rank test at 
a significance level of 0.025 and a 2-look group-sequential design.  One interim efficacy and 
futility analysis of OS would be planned after 60% death events occur in the non-intensive 
chemotherapy population or upon completion of enrollment of these subjects, whichever is 
later. 
The interim and final analyses of the intensive chemotherapy and non-intensive 
chemotherapy populations will be conducted separately and independent of each other.


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4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol. 
These criteria must also be met prior to dosing on Day 1. No exceptions will be granted.
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study. 
Assignment to the Intensive Study or the Non-Intensive Study will be made by the 
Investigator based the 2017 ELN recommendations.16  
The following eligibility criteria applies to subjects assigned to both the intensive study and 
the non-intensive study unless otherwise indication.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
Intensive and Non-Intensive study (unless where indicated):
1. Subjects with untreated AML according to the World Health Organization (WHO) 
2016 Classification,20 including those with:

AML arising from MDS or another antecedent hematologic disease (AHD).

AML after previous cytotoxic therapy or radiation (secondary AML).

FLT3+ AML, assuming the patient is not receiving and is not intended to receive 
FLT3 inhibitor therapy during study participation.
2. 18 years of age (In Japan, 20 years of age).
3. Adequate Organ Function as defined by the following:

Serum aspartate aminotransferase (AST) and serum alanine aminotransferase 
(ALT) 3 x upper limit of normal (ULN), excluding subjects with liver function 
abnormalities due to underlying malignancy.

Total serum bilirubin 2 x ULN (except subjects with documented Gilbert’s 
syndrome).

Estimated creatinine clearance 30 mL/min as calculated using the standard 
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4. QTc interval 470 msec using the Fridericia correction (QTcF).

QTc criteria for eligibility does not apply to subjects with a functioning 
pacemaker, whether the rhythm is paced or not.
5. All anti-cancer treatments (unless specified) should be discontinued 2 weeks from 
study entry, for example: targeted chemotherapy, radiotherapy, investigational
anti-cancer agents, hormones, or cytokines.

For control of rapidly progressing leukemia, hydroxyurea, and/or leukopheresis
may be used before and for up to 1 week after the first dose of glasdegib.  
Continuation or resumption of hydroxyurea or leukopheresis after that time period 
must be approved by the Sponsor. 
6. Serum or urine pregnancy test (for female subjects of childbearing potential) with a 
minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin 
(hCG) negative at screening.
7. Male and female subjects of childbearing potential and at risk for pregnancy must 
agree to use at least one highly effective method of contraception throughout the 
study and for 180 days after the last dose of azacitidine, cytarabine, or daunorubicin;
and the last dose of glasdegib or placebo, whichever occurs later.
8. Female subjects of non-childbearing potential must meet at least 1 of the following 
criteria:
a.
Have undergone a documented hysterectomy and/or bilateral oophorectomy;
b. Have medically confirmed ovarian failure; or 
c.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum follicle 
stimulating hormone (FSH) level confirming the postmenopausal state. 
All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential.
9. Consent to a saliva sample collection for a germline comparator, unless prohibited by 
local regulations or ethics committee (EC) decision.
10. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
11. Subjects who are willing and able to comply with the study scheduled visits, 
treatment plans, laboratory tests and other procedures (including bone marrow [BM]
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4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Acute Promyelocytic Leukemia (APL) and APLwith PML-RARA subjects (WHO 
2016 classification).1 This disease is associated with t(15;17).
2. AML with known BCR-ABL1 mutation or known t(9;22)(q34;q11.2) as a sole 
abnormality.

Complex genetics may include t(9;22) cytogenetic translocation.
3. Subjects with known active CNS leukemia. 
4. Participation in other clinical studies involving investigational drug(s) other than 
anti-cancer agents (Phases 1-4) within 4 weeks prior study entry and/or during study 
participation.
5. Subjects known to be refractory to platelet or packed blood red cell transfusions per 
Institutional Guidelines, or a patient who refuses blood product support.
6. Subjects with another active malignancy on treatment with the exception of basal cell 
carcinoma, non-melanoma skin cancer, cervical carcinoma-in-situ.  Other prior or 
concurrent malignancies will be considered on a case-by-case basis.
7. Any one of the following ongoing or in the previous 6 months: myocardial infarction, 
congenital long QT syndrome, Torsades de pointes, symptomatic arrhythmias 
(including sustained ventricular tachyarrhythmia), left bundle branch block or
bifascicular block, unstable angina, coronary/peripheral artery bypass graft, 
symptomatic congestive heart failure (CHF New York Heart Association class III or 
IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary 
embolism; as well as bradycardia defined as <50 bpm.
8. Subjects with an active, life threatening or clinically significant uncontrolled systemic 
infection not related to AML.
9. Subjects with left ventricular ejection fraction (LVEF) <50% are excluded from the 
Intensive Chemotherapy Study only.
10. Cumulative anthracycline dose equivalent of 550 mg/m2 of daunorubicin for the 
Intensive Chemotherapy Study only.
11. Known malabsorption syndrome or other condition that may significantly impair 
absorption of study medication in the investigator’s judgment (eg, gastrectomy, lap 
band, Crohn’s disease) and inability or unwillingness to swallow tablets or capsules.


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12. Current use or anticipated requirement for drugs that are known strong 
CYP3A4/5 inducers (Appendix 5).
13. Concurrent administration of herbal preparations.
14. Major surgery within 4 weeks of starting study treatment.
15. Documented or suspected hypersensitivity to any one of the following:

For subjects assigned to intensive chemotherapy, documented or suspected 
hypersensitivity to cytarabine (not including drug fever or exanthema, including 
known cerebellar side-effects) or daunorubicin.

For subjects assigned to non-intensive chemotherapy, documented or suspected 
hypersensitivity to azacitidine or mannitol.
16. Known active drug or alcohol abuse.
17. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
18. Pregnant females or breastfeeding female subjects.
19. Known recent or active suicidal ideation or behavior.
20. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
subjects who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
4.3. Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not randomized.  A minimum set of screen failure subject data, should be collected to ensure 
transparent reporting of screen failure subjects. 


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4.4. Lifestyle Requirements
4.4.1. Contraception
In this study, male subjects who are able to father children and female subjects who are of 
childbearing potential will receive glasdegib, a compound which has been associated with 
teratogenic risk. Subjects treated with the non-intensive therapy will receive azacitidine, a 
compound that has been shown to cause congenital malformations in animals. Subject’s 
ability to father or bear children must be assessed by the investigator at the time of screening 
and documented in the subject’s chart. Subjects who are, in the opinion of the investigator, 
sexually active and at risk for pregnancy with their partner(s) must agree to use at least
1 highly effective form of contraception throughout the study and for at least 180 days after 
the last dose of investigational product as defined in Table 6.  
The investigator or his or her designee, in consultation with the subject, will confirm that the 
subject has selected at least 1 appropriate method of contraception for the individual subject
and his/her partner(s) from the list of permitted contraception methods (see below) and will 
confirm that the subject has been instructed in their consistent and correct use.  At time 
points indicated in the Schedule of Activities, the investigator or designee will inform the 
subject of the need to use at least 1 highly effective method of contraception consistently and 
correctly and document the conversation, and the subject’s affirmation, in the subject’s chart.  
In addition, the investigator or designee will instruct the subject to call immediately if the 
selected contraception method is discontinued or if pregnancy is known or suspected in the 
subject or partner(s). 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the methods described in Table 6.
4.4.2. Postmenopausal Defined
Postmenopausal female
A postmenopausal state is defined as age 60 or older or no menses for 12 months without an 
alternative medical cause.

A high follicle stimulating hormone (FSH) level in the postmenopausal range (as per
the reference range used by the laboratory) may be used to confirm a postmenopausal
state in women under 60 years old and not using hormonal contraception or hormonal
replacement therapy (HRT).

Females on HRT and whose menopausal status is in doubt will be required to use one
of the non-estrogen hormonal highly effective contraception methods if they wish to
continue their HRT during the trial. Otherwise, they must discontinue HRT to allow
confirmation of postmenopausal status before trial enrollment.


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Table 6.
Contraceptives Allowed During the Trial 
Highly effective (failure rate <1% if used 
consistently and correctly) low user dependency
Highly Effective (Failure rate <1% if used 
consistently and correctly) high user dependency
1.
Implantable progestogen only contraceptive implant 
associated with inhibition of ovulation.
2.
Intrauterine hormone releasing system (IUS).
3.
Intrauterine device (IUD).
4.
Bilateral tubal occlusion.
5.
Vasectomized partner:
A vasectomized partner is a highly effective form of 
contraception provided they are the sole male partner 
of the WOCBP and the absence of sperm has been 
confirmed.  If not an additional highly effective 
method of contraception should be used.
1.
Combined hormonal contraception (estrogen and 
progestogen).

Oral.

Intravaginal.

Transdermal. 

Injectable.
2.
Progestogen only hormonal contraception.

Oral; or 

Injectable.
3.
Sexual abstinence.
Sexual abstinence is considered a highly effective 
method only if defined as refraining from heterosexual
intercourse during the entire period of risk associated 
with the trial intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the 
duration of the trial and the preferred and usual 
lifestyle of the participant.
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this trial. 
Male condom and female condom should not be used together (due to risk of failure with friction).
4.5. Sunlight Exposure
Patients will be advised to report any reaction to sun exposed skin. In addition, special
precautions will be taken to limit any potential photo irritation effect, by minimizing the
subjects’ exposure to light including high intensity ultraviolet B light (UVB) sources such as
tanning beds, tanning booths and sunlamps. Subjects should be encouraged to apply
sunscreen/sunblock daily.
4.6. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the
study is documented in the study contact list located in the investigator file.
To facilitate access to appropriately qualified medical personnel on study-related medical
questions or problems, subjects are provided with a contact card. The contact card contains,
at a minimum, protocol and investigational product identifiers, subject study numbers,
contact information for the investigator site, and contact details for a help desk in the event 
that the investigator site staff cannot be reached to provide advice on a medical question or 
problem originating from another healthcare professional not involved in the subject’s 


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participation in the study. The contact number can also be used by investigator staff if they 
are seeking advice on medical questions or problems; however, it should only be used in the 
event that the established communication pathways between the investigator site and the 
study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The help desk
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this protocol, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).

For this study, the investigational products are glasdegib, azacitidine, daunorubicin, 
and cytarabine. 
5.1. Allocation to Treatment
Allocation of subjects to treatment groups will proceed through the use of an interactive 
response technology (IRT) System [Interactive Web Response (IWR)/Interactive Voice 
Response (IVR)]. The site personnel (study coordinator or specified designee) will be 
required to enter or select information including but not limited to the user’s identification 
(ID) and password, protocol number and the date of birth of the subject. The site personnel 
will then be provided with a treatment assignment and dispensable units (DU) or container 
number(s) when drug is being supplied via the IRT. The IRT system will provide a 
confirmation report containing the subject identification number and DU(s) or container 
number(s) assigned. The confirmation report must be stored in the site’s files.
The study-specific IRT reference manual will provide the contact information and further
details on the use of the IRT system. 
Glasdegib or matching placebo treatment allocation will be blinded to the subject, 
investigator, and the study team. Randomization will be stratified according the stratification 
factors described in Section 9.3.1.
5.2. Breaking the Blind
The study will be subject and investigator blinded.


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At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be an electronic process. Blinding codes should be 
broken only in exceptional circumstances when knowledge of the actual treatment code is 
absolutely essential for further management of the subject. Investigators should make every 
effort to contact the sponsor prior to unblinding a participant’s treatment assignment are 
encouraged to discuss with a member of the study team if they believe that unblinding is 
necessary, unless this could delay further management of the participant. The date and 
reason that the blind was broken must be recorded in the source documentation. 
Treatment allocation will be subject, investigator and sponsor blinded. There is no plan to 
break the blind upon subject progression or permanent discontinuation from study treatment.  
Blinding codes may be broken in emergency situations for reasons of subject safety.
NOTE: Once the blind is broken for a given patient, the patient will no longer be able to 
receive additional study treatment, follow-up and long-term follow-up are expected. 
5.3. Subject Compliance
For glasdegib/placebo, all subjects will maintain subject dosing diaries throughout the study 
which will record the date of administration and all regular, missed, changed, or delayed 
doses. 
Subjects are required to return all bottles, unused study drug and the subject dosing diary, at 
each cycle (or Day 1 of Induction(s)) and at End of Treatment visit for compliance 
assessment and drug accountability. 
The number of tablets returned by the subject at the end of the cycle or Induction(s) will be 
counted, documented and recorded.
For azacitidine, daunorubicin, and cytarabine, the site should complete the required dosage 
Preparation Record located in the Investigational Product Manual.  The use of the 
Preparation Record is preferred but it does not preclude the use of an existing appropriate 
clinical site documentation system.  The existing clinical site's documentation system should 
capture all pertinent/required information on the preparation and administration of the dose 
including the methodology used to calculate the subject body surface area (BSA).  This may 
be used in place of the Preparation Record after approval from the Sponsor.
5.4. Investigational Product Supplies
5.4.1. Formulation, Packaging, Preparation, and Dispensing
5.4.1.1. Glasdegib/Placebo
Glasdegib will be supplied by Pfizer Worldwide Research and Development as 25 mg and 
100 mg tablets for oral administration.  Matching placebo tablets will also be provided.  
Supplies will be labeled according to local regulatory requirements.


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Glasdegib and the matching placebo will be packaged in high-density polyethylene (HDPE) 
bottles and should be handled with care.  Each bottle will contain enough medication for a 
28-day cycle of daily dosing, plus an additional amount to cover the time between site visits.  
Subjects should be instructed to keep their medication in the bottles provided and not transfer 
it to any other containers and return the bottles to the site at the next study visit.  Site 
personnel must ensure that subjects clearly understand the directions for self-medication.
Investigational product should be dispensed by an appropriately qualified and experienced 
member of the study staff (eg, physician, nurse, physician’s assistant, practitioner, or 
pharmacist) as allowed by local, state, and institutional guidance.
5.4.1.2. Azacitidine
Central supply (provided by Pfizer) or locally obtained commercial supplies of azacitidine
will be used in accordance with local regulations. Azacitidine is available as a vial 
containing 100 mg of powder for suspension for injection.  Please refer to the local package 
insert (or SPC) or the Investigational Product Manual for detailed formulation information as 
well as SC or IV preparation and administration instructions. 
5.4.1.3. Cytarabine
Central supply (provided by Pfizer) or locally obtained commercial supplies of cytarabine
will be used in accordance with local regulations. Please refer to the local package insert (or 
SPC) or the Investigational Product Manual for detailed formulation, preparation for IV 
administration instructions. 
5.4.1.4. Daunorubicin
Central supply (provided by Pfizer) or locally obtained commercial supplies of daunorubicin
will be used in accordance with local regulations. Please refer to the local package insert (or 
SPC) or the Investigational Product Manual for detailed formulation, preparation and IV
administration. 
5.5. Administration
5.5.1. General Administration Guidance for Study Drugs
Bone marrow evaluations are performed at specific times to determine clinical response and 
treatment progression decisions within the trial. Bone marrow assessments are described in 
the Schedule of Activities for Intensive Chemotherapy (Table 1, Table 2) and for 
Non-Intensive Chemotherapy (Table 3, Table 4).
For subjects receiving chemotherapy, all subjects should be weighed within 72 hours prior to 
dosing for every cycle (or start of Induction 1, 2) to ensure they did not experience either a 
weight loss or gain >10% from the prior weight used to calculate the amount of azacitidine, 
cytarabine, or daunorubicin required for dose preparation. Decision to recalculate 
chemotherapy dose based on the weight obtained at each cycle (or start of Induction 1, 2) can 
be in accordance with institutional practice for changes in weight of 10% or less; however if 
the subject experienced either a weight loss or gain of >10%, the amount of chemotherapy


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required for study drug preparation and administration must be recalculated using this most 
recent weight/BSA obtained.
5.5.1.1. Glasdegib or Placebo in Subjects Receiving Intensive Chemotherapy and 
Non-Intensive Chemotherapy
Study treatment (glasdegib or placebo) will be administered by mouth at a starting dose of 
100 mg daily at approximately the same time each day, preferably in the morning with 
approximately 8 ounces (240 ml) of water.  Study treatment can be administered with or 
without food.  Tablets must not be crushed or cut; they must be swallowed whole and not 
chewed.
A cycle is defined as 28 days, in the Non-Intensive Chemotherapy study. There is up to a 
28 day window to coincide with azacitidine administration; dose delays due to toxicity will 
not impact the cycle duration or planned protocol assessments. 
If a subject forgets to take their dose at the regularly scheduled time, and if less than 10 hours 
have passed since the scheduled dosing time, that dose should be taken as soon as possible.  
If more than 10 hours have passed since the scheduled dosing time, the dose should be 
skipped and the subject should continue on their normal dosing schedule.  If a subject misses 
a day’s dose entirely, they must be instructed not to “make it up” the next day.  Missed doses 
will NOT be made up at any time.  If a subject vomits any time after taking a dose, they must 
be instructed not to “make it up,” but to resume subsequent doses the next day as prescribed.
If a subject inadvertently takes one extra dose during a day, the subject should not take the 
next day’s dose of glasdegib or placebo.
During the intensive chemotherapy study, glasdegib/placebo dosing will begin on Day 1 and 
be given once daily continuously in combination with Induction and Consolidation 
chemotherapy.  Glasdegib or placebo will continue to be administered for a maximum of 
2 years (starting from randomization until 2 years) or until subject discontinues per 
Section 6.5, or until confirmed CR MRD negative with two consecutive central laboratory 
results post consolidation. 
During the non-intensive chemotherapy study, glasdegib or placebo dosing will begin on 
Day 1 and will be given once daily with azacitidine in 28 day cycles or until subject 
discontinues per Section 6.5, or is confirmed CR MRD negative by two consecutive central 
lab results post HSCT. 
5.5.1.2. Intensive Chemotherapy
Refer to the local package inserts (or SPC) or Investigational Product Manual for detailed 
formulation, preparation and dispensing information for cytarabine and daunorubicin.38,39 An 
overview of the treatment algorithm is shown in Figure 2 and specific doses and dosing 
frequencies are provided in Table 7.


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Figure 2.
Intensive Chemotherapy Treatment Algorithm: Glasdegib or Placebo in 
combination with Cytarabine and Daunorubicin
Figure footnotes:
a. If <5% bone marrow blasts, the investigator may either treat with a second Induction therapy or proceed to Consolidation 
therapy with single-agent cytarabine and/or post remission HSCT. 


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b. Consolidation with cytarabine 3 g/m2 IV for adults <60 years and 1 g/m2 for adults 60 years over 3 hours twice daily 
(BID) on Days 1, 3, and 5, every 28 days for up to 4 cycles. Alternative single-agent cytarabine consolidation schedules 
may be used per local prescribing information.
c. Resume glasdegib or placebo 30-60 days post day of stem cell infusion, once there is confirmed ANC engraftment 
(≥0.5 x 109/L) for 3 consecutive days with no growth factor support, no Grade 2 ongoing GVHD, and no ongoing SAEs 
that prevent resuming glasdegib or placebo in the judgment of the investigator. Following Post Consolidation or Post
Remission HSCT, modify treatment based on 2 matching and consecutive MRD negative results (by central laboratory) 
when they are available.
d. Post consolidation bone marrow assessment should be conducted after chemotherapy-based consolidation period. For 
patients proceeding to HSCT, post-HSCT bone marrow assessment will be conducted approximately 3 months after 
HSCT. This post-HSCT bone marrow assessment may be later than the resumption of glasdegib/placebo 30-60 days post 
HSCT. 
Glasdegib or Placebo
Experimental Therapy: Glasdegib 100 mg PO QD or matching placebo will be administered 
by mouth daily beginning on Day 1 and is to continue up to 2 years post randomization until 
treatment failure, hematologic relapse, objective disease progression, patient refusal, 
unacceptable toxicity, unexpected pregnancy, death, or consent withdrawal.

Subjects will receive daily glasdegib 100 mg PO or matching placebo up to 2 years 
after randomization or until they have CR MRD-negative disease post consolidation.  
Glasdegib or placebo therapy will continue throughout Induction(s) and 
Consolidation Therapy regardless of any delays/modifications in the chemotherapy 
treatment.
Cytarabine

Separate cytarabine dosing and schedules will be used for Induction and 
Consolidation per the local package insert (or SPC) or Investigational Product 
Manual (or SPC).

Induction 1: Cytarabine will be administered (in parallel to daunorubicin) at a 
dose of 100 mg/m2 daily by continuous IV infusion for 7 days (Days 1-7).

Induction 2, if indicated based on 5% marrow blasts (or investigator judgment 
if <5% bone marrow blasts), The Investigator may choose either cytarabine 
100 mg/m2 IV daily on Days 1-5 or Days 1-7. Dose must be recalculated if the 
weight changes by >10%.
Daunorubicin Dosing (Induction Only): 

During Induction 1, daunorubicin 60 mg/m2 daily IV on Days 1-3. 


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
Induction 2, if indicated based on 5% bone marrow blasts (or investigator judgment 
if <5% bone marrow blasts), the Investigator will choose either daunorubicin 
60 mg/m2 IV daily on Days 1-2 or Days 1-3 with cytarabine. If clinical signs or 
symptoms of cardiac dysfunction are observed, multigated acquisition 
scan/echocardiogram (MUGA/ECHO) must demonstrate a LVEF 45% before 
initiation of Induction 2.  Dose must be recalculated if the weight changes by >10%.

If <5% bone marrow blasts: treatment with either or both of the following if a second 
Induction is not selected (per investigator judgment):  

Consolidation with single-agent cytarabine 3 g/m2 IV for adults <60 years and 1 g/m2
for adults 60 years over 3 hours twice daily (BID) on Days 1, 3, and 5, every 
28 days for up to 4 cycles or alternative single-agent cytarabine consolidation 
schedules may be used per local prescribing information.

HSCT per local standard of care.
A detailed dosing schedule is found in Table 7.
Table 7.
Intensive Chemotherapy Doses and Dose Frequency: Glasdegib or 
Placebo in Combination with Daunorubicin and Cytarabine
Induction Therapy
Days
Backbone Chemotherapya
Experimental Therapya,b,c
1-3
Administer Daunorubicin 60 mg/m2 IV 
Administer cytarabine 100 mg/m2 IV 
Administer glasdegib 100 mg PO or 
placebo PO
4-7
Administer cytarabine 100 mg/m2 IV 
8d
Days
Second Induction if ≥5% bone marrow blasts or investigator judgement for 
<5% bone marrow blasts (Option 1: ‘5+2’)
Backbone Chemotherapya
Experimental Therapya,b,c
1-2
Administer Daunorubicin 60 mg/m2 IV 
Administer cytarabine 100 mg/m2 IV
Administer glasdegib 100 mg PO or 
placebo PO
3-5
Administer cytarabine 100 mg/m2 IV 
6d
Days
Second Induction if ≥5% bone marrow blasts or investigator judgement for 
<5% bone marrow blasts (Option 2: ‘7+3’)
Backbone Chemotherapya
Experimental Therapya,b,c
1-3
Administer Daunorubicin 60 mg/m2 IV 
Administer cytarabine 100 mg/m2 IV 
Administer glasdegib 100 mg PO or 
placebo PO
4-7
Administer cytarabine 100 mg/m2 IV 
8d
Days
If <5% bone marrow blasts, Consolidation (Option 1): 1-4 Cycles of Consolidation 
(28 day cycles)
Backbone Chemotherapya
Experimental Therapya,b
1
Administer cytarabine 1or 3 g/m2 IV twice 
daily (BID)
Administer glasdegib 100 mg PO or 
placebo PO
2


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Table 7.
Intensive Chemotherapy Doses and Dose Frequency: Glasdegib or 
Placebo in Combination with Daunorubicin and Cytarabine
3
Administer cytarabine 1or 3 g/m2 IV twice 
daily (BID)
4
5
Administer cytarabine 1or 3 g/m2 IV twice 
daily (BID)
6d
Up to 2 years 
after 
randomizationd
Timing
If <5% bone marrow blasts, 
Consolidation (and/or Option 2): HSCT
Chemotherapy containing regimen
Experimental Therapya,b
At least 28 days
before HSCT 
(Day 0)
Interrupt all study therapy.
Confirmed 
ANC 
engraftment, 
30-60 days post 
HSCTe
Administer glasdegib 100 mg PO or 
placebo PO
a.
Instructions for glasdegib/placebo dose modifications and Intensive chemotherapy are in Section 5.5.5.
Consolidation with cytarabine 3 g/m2 IV for adults <60 years and 1 g/m2 for adults 60 years over 3 hours twice 
daily (BID) on Days 1, 3, and 5, every 28 days for up to 4 cycles. Alternative single-agent cytarabine consolidation 
schedules may be used per local prescribing information.
b.
Treatment with glasdegib should continue during any delay before the start of another cycle or Induction in the 
absence of glasdegib-related toxicity that would prevent dosing.
c.
Where possible, glasdegib will be administered together with daunorubicin IV injection during induction.
d.
Glasdegib or placebo is administered up to 2 years after randomization unless there is progression, unmanageable 
toxicity, withdrawal of consent, or CR MRD-negative disease confirmed at 2 consecutive time points post 
consolidation.
e.
Confirmed ANC engraftment is defined by ANC ≥0.5 x 109/L for 3 consecutive days with no growth factor support 
following HSCT using myeloablative or non-myeloablative conditioning regimen. 30-60 days post HSCT, 
glasdegib or placebo may be resumed with ANC engraftment, no ≥Grade 2 ongoing GVHD, and no ongoing SAEs 
that prevent resuming glasdegib or placebo maybe present, in the judgement of the investigator. 
Induction for Intensive Chemotherapy Study
Subjects will participate in their first induction therapy for a total of 28 days. However, if a 
subject requires a second Induction therapy due to residual leukemia or investigator opinion, 
this second course may start as soon as possible following Induction 1 bone marrow 
evaluation. 
If the induction cycle(s) extends longer than 28 days, dosing with glasdegib or placebo 
should continue daily in the absence of glasdegib-related toxicity that would prevent dosing.


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The second induction may be delayed up to an additional 28 days from Day 28 of the first 
induction to allow for the subject to recover from any severe reversible hematologic or 
non-hematologic drug related toxicity. Treatment with glasdegib or placebo should continue 
during any delay before the start of the second induction in the absence of glasdegib-related 
toxicity that would prevent dosing. The second induction should not be performed if the 
subject has clinically significant cardiotoxicity (LVEF <45%) and the subject should be 
discontinued from treatment.
Bone marrow may be repeated at Investigator discretion as required for clinical staging any 
time prior to next Induction chemotherapy.
The following rules apply for progression from induction to consolidation (Table 7):
a.
Subjects who successfully obtain a <5% bone marrow blasts after induction are 
eligible to enter the consolidation phase of the trial 28-days from the start of the last 
induction.  These subjects may also proceed to a second Induction per investigator 
judgment;
b. Subjects with residual leukemia at the end of induction 1 may be treated with a 
second induction therapy;
c.
If after the second induction, the subject still shows residual or resistant leukemia, 
they must be discontinued from treatment and followed as described in Section 5.5.2. 
Subjects with resistant leukemia after the first or second course of induction will be 
discontinued from treatment and followed as described in Section 5.5.2.
Precise timings for the post first induction bone marrow assessment and remission 
assessment will depend on investigator judgement. In general:

The post first induction bone marrow assessment will occur approximately 
14-15 days after initiation of first induction therapy; however, the precise timing will 
be according to investigator judgment.  The post first induction bone marrow 
assessment is generally done to assess marrow hypoplasia and determine if/when a 
second Induction is needed. Following the post first induction bone marrow 
assessment, subjects may complete Induction 1 therapy, start Induction 2 before 
finishing Induction 1, or end treatment and go to follow-up.

The remission bone marrow assessment usually occurs approximately 36-48 days 
after initiation of induction therapy.  However, these timings will depend on 
investigator judgement.  The remission bone marrow assessment is generally done to 
assess hematologic response following Induction therapy. Hematological response 
will be assessed using the bone marrow results from the remission bone marrow 
assessment.


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Consolidation Therapy with a Chemotherapy-containing regimen
Subjects achieving <5% bone marrow blasts, after the completion of induction therapy are 
eligible to begin consolidation. Glasdegib will continue to be given at the dose given during 
induction (unless dose modification due to toxicity is required) once daily in the morning 
continuously in 28-day cycles, where possible at the same with chemotherapy infusion start.
Subjects can remain on study for a minimum of one but not more than four courses of 
consolidation if they do not progress during consolidation treatment. If a subject enters 
consolidation with a CRi (post induction) assessment but then achieves hematologic recovery 
in the peripheral blood (defined as ANC >1000/μL and platelets 100,000/µL), the bone 
marrow evaluation should be repeated within 14 days of the hematologic recovered blood 
counts observation. Bone marrow examinations may be performed at any time throughout 
consolidation as clinically indicated to confirm the subject has not relapsed. At a minimum a 
bone marrow evaluation is required following the final consolidation cycle before any 
subsequent therapy.
The start of subsequent consolidation cycles may be delayed from the end of the previous 
cycle to allow for recovery from reversible hematologic or non-hematologic drug-related 
toxicities. If the consolidation cycle(s) extends longer than 28 days, dosing with glasdegib or 
placebo should continue daily in the absence of glasdegib-related toxicity that would prevent 
dosing.
Post Remission HSCT
Subjects who are eligible for Post Remission HSCT will undergo HSCT per local standard of 
care. For HSCT, Day 0 is the first day of HSCT; this is the day when stem cells are infused. 
For post remission HSCT, glasdegib or placebo will be interrupted at least 28 days before 
HSCT and resumed 30-60 days post date of stem cell infusion, once there is ANC 
engraftment, no Grade 2 ongoing GVHD, and no ongoing SAEs that prevent resuming 
glasdegib/placebo in the judgement of the investigator. Confirmed ANC engraftment is 
defined by ANC 0.5 x 109/L for 3 consecutive days without growth factor support following 
HSCT using myeloablative or non-myeloablative conditioning regimen.
Post Consolidation or Post HSCT treatment
Daily glasdegib (100 mg) PO or placebo PO may continue up to 2 years following 
randomization unless AML is confirmed MRD negative post Consolidation or post HSCT 
MRD at 2 consecutive time points per central laboratory analysis.  These 2 consecutive time 
points may be approximately 3 months apart as part of the already scheduled marrow 
assessments. 


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5.5.1.3. Non-Intensive Chemotherapy
For subjects in the Non-Intensive Chemotherapy study, central supply (provided by Pfizer) or 
locally obtained commercial supplies of azacitidine will be used. Refer to the local package 
insert (or SPC) or Investigational Product Manual (or SPC) for detailed formulation, 
preparation and dispensing information.33
The general treatment algorithm for the Non-Intensive study is described in Figure 3.
Figure 3.
Non- Intensive Chemotherapy Treatment Algorithm: Glasdegib or Placebo 
in combination with Azacitidine
1. Details for azacitidine administration with glasdegib or placebo are described in Table 8.
2. A bone marrow assessment is required when CR is suspected or after end of Cycle 6; whichever, is earlier. 
BM aspirate is required, and biopsy is preferred. Following Cycle 6, BM assessments will occur when there is 
an intention for patient to receive HSCT, progressive disease (PD) suspected.


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Table 8.
Non-Intensive Chemotherapy: Glasdegib or Placebo in Combination with 
Azacitidine
Days
Study Treatmenta
Chemotherapy
Experimental Therapy
1-7
(3 day 
window for 
each dose)
Administer azacitidine 75 mg/m2 SC 
or IV 
Administer glasdegib 100 mg PO or placebo PO
8-28
Administer glasdegib 100 mg PO or placebo PO
Repeatb
Repeat administration of azacitidine 
75 mg/m2 SC or IV for 7 days as 
28 day cyclesa
Administer glasdegib 100 mg PO or placebo PO
Timing
If proceeding to HSCT per local Standard of Care
At least 28 
days before 
HSCT 
(Day 0)
Interrupt Glasdegib/placebo. 
30-60 days 
post HSCTc
Resume administration of Glasdegib 100mg PO or Placebo POd
a.
See Section 5.5.5 for recommended dose modifications/delays/reductions. Since responses to azacitidine may 
require 4-6 cycles of administration to emerge, treatment with the study drug combination should be continued for at 
least 6 cycles, or until unacceptable toxicity, patient refusal or death, whichever occurs first. Treatment will be 
administered in a 28 day cycle, but cycle duration may be extended to allow for toxicity resolution.
b.
Treatment with the study drug combination should be continued beyond 6 cycles of treatment until objective disease 
progression or relapse, unacceptable toxicity, patient refusal or death, whichever occurs first.
c.
Confirmed ANC engraftment is defined by ANC ≥0.5 x 109/L for 3 consecutive days with no growth factor support 
following HSCT using myeloablative or non-myeloablative conditioning regimen.  30-60 days post HSCT, 
glasdegib or placebo may be resumed with ANC engraftment, no ≥Grade 2 ongoing GVHD, and no ongoing SAEs 
that prevent resuming glasdegib or placebo may be present, in the judgement of the investigator.
d.
Glasdegib or placebo is administered up to 2 years after randomization unless there is progression, unmanageable 
toxicity, withdrawal of consent, or CR MRD-negative disease confirmed at 2 consecutive time points post 
consolidation.
Subjects will receive either glasdegib 100 mg PO once daily or matching placebo starting on 
Day 1 and continuing beyond 6 cycles of treatment until objective disease progression or 
relapse, unacceptable toxicity, patient refusal or death, whichever occurs first.
Azacitidine will be administered per local label or per the Investigational Product Manual (or 
SPC).  The dose for azacitidine is 75 mg/m2 daily for 7 days to be administered by SC 
injection or IV infusion in 28 day cycles.  Alternate dosing schedule to administer the 7 doses 
to accommodate subject and treatment center availability is allowed.  Dose adjustments will 
be made according to local approved label or per the Investigational Product Manual (or 
SPC) for azacitidine. 
Since responses to azacitidine may require 4-6 cycles of administration to emerge, treatment 
with the study drug combination will be continued for at least 6 cycles, or until unacceptable 
toxicity, patient refusal or death, whichever occurs first.  In addition, each subsequent cycle 
may be delayed for up to 28 days to allow for recovery of blood counts.  Subjects should 
continue to receive treatment beyond the Cycle 6, as long as they do not have uncontrollable 
toxicity, withdrawal consent, and do not meet the criteria for progression.


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HSCT following CR
Subjects who are eligible HSCT will undergo HSCT per local standard of care. For HSCT, 
Day 0 is the first day of HSCT; this is the day when stem cells are infused. 
For post remission HSCT, glasdegib or placebo will be interrupted at least 28 days before 
HSCT and resumed 30-60 days post date of stem cell infusion, once there is ANC 
engraftment, no Grade 2 ongoing GVHD, and no ongoing SAEs that prevent resuming 
glasdegib/placebo in the judgement of the investigator.  Confirmed ANC engraftment is 
defined by ANC 0.5 x 109/L for 3 consecutive days without growth factor support following 
HSCT using myeloablative or non-myeloablative conditioning regimen.
Transplant-related information; such as, donor source, type of transplant, and conditioning 
regimen, must be entered into the CRF. 
The HSCT Post Remission Period (HSCT period) is defined as time from the start of the 
conditioning regimen until the subject restarts glasdegib or placebo, death, post study 
follow-up, or withdrawal. During the HSCT Consolidation Period, AE collection during the 
HSCT period is defined in Section 8.
Post Consolidation or Post HSCT treatment
Daily glasdegib (100 mg) PO or placebo PO may continue up to 2 years following 
randomization unless AML is confirmed MRD negative post HSCT at 2 consecutive time 
points per central laboratory analysis. These 2 consecutive time points will be approximately 
3 months apart as part of the already scheduled marrow assessments. 
5.5.2. End-of-Treatment Follow-up
After discontinuation of study treatment (all arms), post-treatment survival status, response 
assessments (for those in remission), and hematologic relapse/disease progression will be 
collected as described in Table 1 and Table 2 for subjects receiving Intensive Chemotherapy 
and in Table 3 and Table 4 for subjects receiving Non-Intensive Chemotherapy until death or 
until termination of the study by the Sponsor. 
Post treatment follow up visits will occur for the first 2 years.  Subjects will return to the site 
for visits every 3 months starting from the last dose of study medication, for the first 2 years 
only.
A post treatment long-term follow-up will be completed ≥3 years starting from the last post 
treatment follow up visit.  A telephone log will include the date of contact and survival data 
(including date and cause of death) and where possible, subsequent anticancer therapies, 
including HSCT. 
The study will be considered complete once all subjects have been followed for survival for 
up to 5 years from the first dose of the last subject enrolled in the study, or until death, or 
consent withdrawal.


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5.5.3. Food Requirements
Glasdegib will be administered with a glass of water, with or without food.
5.5.4. Treatment Discontinuation
If a subject demonstrates unequivocal clinically significant disease progression or 
unacceptable toxicity, they must be discontinued from treatment and followed as described in
Section 6.4.
If glasdegib/placebo is permanently discontinued for reasons other than treatment failure, 
hematologic relapse, objective disease progression, subject refusal, or consent withdrawal, 
single-agent treatment with azacitidine, or combination daunorubicin and cytarabine may be 
continued if, in the Investigator’s judgment, a clinical benefit has been observed and 
following discussion between the Investigator and Sponsor.
In cases of unacceptable toxicity or pregnancy, the subject must be withdrawn from study 
drug combination and entered into the follow-up phase of the study.
When study treatment with both drugs of the study combination (glasdegib/placebo and 
azacitidine, or cytarabine and daunorubicin) is permanently discontinued, subjects will enter 
into the follow-up phase.
5.5.5. Dose Modifications
Every effort should be made to administer the study treatments at the planned dose and 
schedule.
5.5.5.1. Glasdegib or Placebo in Subjects Receiving Intensive Chemotherapy and 
Non-Intensive Chemotherapy
In the event of Grade 3 or Grade 4 non-hematologic, study-treatment-related toxicity, dosing 
may be delayed and/or dose reduced. The glasdegib dose should be reduced 1 dose level at a 
time, in increments of 25 mg (75 mg QD, 50 mg QD, in the form of 3 or 2 x 25 mg tablets 
respectively).
Glasdegib or placebo does not need to be delayed or dose reduced for hematologic, 
study-treatment-related toxicity. 
Glasdegib or placebo may be interrupted or permanently discontinued for any reason as per 
good clinical practice. Glasdegib or placebo should be permanently discontinued if 
interruptions are for more than 28 consecutive days when not required by the protocol (ie,
HSCT period).
Dose escalations will not be allowed following glasdegib/placebo dose reductions.
Dose modifications may occur in three ways:


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
Within a cycle or within Induction 1, 2: Dosing interruption until adequate recovery 
followed by dose reduction (if required) of glasdegib during a given treatment cycle. 

Between cycles or between Induction 1, 2: The next treatment cycle may be delayed 
if toxicity from the preceding cycle persists.

In the next cycle or within the next Induction: Dose reduction may be required 
based on toxicities experienced in the previous cycle.
When chemotherapy is given, a Cycle is determined by chemotherapy administration 
schedule.  A Cycle is 28 days, but will be extended if there are dose delays or modifications 
in the chemotherapy backbone.  For Induction, there is no cycle and this therapy is referred to 
as Induction 1 and Induction 2. 
When glasdegib or placebo is given alone, it is always in a 28 day Cycle.
No crossover between treatment arms will be permitted as crossover could significantly 
impact the primary endpoint of overall survival. Investigators are discouraged from 
prescribing glasdegib after discontinuation of study therapy. 
5.5.5.2. Dosing Interruptions for Glasdegib/placebo Non-hematological Toxicities
Subjects experiencing Grade 3 or 4 non-hematological toxicities potentially attributable to 
glasdegib or placebo should have their glasdegib or placebo treatment interrupted regardless 
of when it occurs in the cycle until the toxicity resolves or returns to baseline or Grade 1, as 
described in Table 9. 
If these parameters have not been met following >28 consecutive days of dose interruption, 
glasdegib or placebo should be permanently discontinued.  If glasdegib or placebo treatment 
is permanently discontinued, patients may continue single-agent treatment with 
daunorubicin, cytarabine, or azacitidine, if according to the investigator’s judgment a clinical 
benefit has been observed, and following discussion between the investigator and the 
sponsor.


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Table 9.
Glasdegib or Placebo Dose Modifications for Non Hematologic Toxicities 
(Excluding QTc Prolongation, Muscle Spasms, and Myalgia)
Toxicity
(NCI CTCAE version 4.03)
Glasdegib or Placebo
≥ Grade 3 toxicity (Nausea, vomiting, and/or 
diarrhea must persist at ≥ Grade 3 (despite maximal 
appropriate medical therapy) to require dose 
modification).
Potential DILI/Hy’s Law (as defined in 
Section 8.4.2).
Confirmed DILI/Hy’s Law (as defined in 
Section 8.4.2).
Hold study drug until toxicity has recovered to 
baseline or Grade 1.
First episode: Decrease by 1 dose level.
Second episode: Decrease by 1 dose level.
Third episode: Permanently discontinue.
Interrupt glasdegib/placebo dosing.  If an alternative 
cause is found, restarting of glasdegib/placebo at the 
same dose may be considered.
Glasdegib/placebo should be permanently 
discontinued.
Appropriate follow-up assessments should be implemented until adequate recovery (toxicity
resolves or returns to baseline) occurs.
Depending on when the adverse event resolved, treatment interruption may lead to the patient 
missing all subsequent planned doses of glasdegib or placebo within the cycle. If the AE 
leading to treatment interruption recovers within the same cycle, re-commencement of dosing 
in that cycle is allowed. Glasdegib or placebo doses omitted for toxicity will not be replaced 
within that cycle (eg, cycles will not be prolonged beyond the 28 days in order to make up 
for any missed glasdegib or placebo doses during that cycle). 
The need for a dose reduction at the time of treatment resumption should be based on the 
criteria outlined in Table 9, unless specifically agreed otherwise following discussion 
between the investigator and the sponsor. If a dose reduction for glasdegib or placebo is 
applied in the same cycle, the patient must return to the clinic to receive a new supply of 
drug.
In the event of glasdegib or placebo treatment interruption for reasons other than 
treatment-related toxicity (eg, elective surgery) for a duration >28 days, the details of 
treatment resumption will be determined in consultation with the sponsor.Glasdegib/placebo 
dose modifications for mean QTcF (mQTcF) prolongation are outlined in Table 10.


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Table 10.
Glasdegib Dose Modifications for mean QTcF (mQTcF) Prolongation
CTCAE v 4.03
Electrocardiogram 
QT corrected 
(QTc) 
interval 
prolonged*
Grade 1
Grade 2
Grade 3**
Grade 4**
450-480 msec
481-500 msec
≥501 msec on at 
least two separate 
ECGs
QTc >501 msec or 
>60 msec change 
from baseline and 
Torsade de pointes 
or polymorphic 
ventricular 
tachycardia or 
signs/symptoms of 
serious arrhythmia
*The severity of QTc prolongation assessment is to be determined by calculating a mean QT of 3 consecutive 
ECGs performed approximately 2 minutes (but no longer than 5 minutes) apart using the Frederica correction 
method (mQTcF).
**Please see Section 8.4.1 for protocol specified SAE reporting requirement of Grade 3 or 4 mQTcF 
prolongation. 
Grade
Category
Action
1
2
3
4
General 
management
Assess electrolyte levels and supplement as clinically 
indicated
X
X
X
Review and adjust concomitant medications with 
known QTc interval-prolonging effects
X
X
X
ECG monitoring
Monitor ECGs at least weekly for 2 weeks following 
resolution of mQTcF prolongation to ≤480 msec
X
X
X
Initial glasdegib 
action
Discontinue and do not re-challenge
X
Interrupt treatment
X
Continue treatment at same dose 
X
X
Resume glasdegib 
dosing
If no prior glasdegib dose interruption related to 
QTcF 
prolongation has occurred, resume at a reduced dose 
of 75 mg once daily when mQTcF interval returns to 
within 30 msec of baseline or ≤480 msec
X
If one prior glasdegib dose interruption related to 
QTcF prolongation has occurred, resume at a reduced 
dose of 50 mg once daily when mQTcF interval 
returns to within 30 msec of baseline or ≤480 msec
X
Discontinue 
glasdegib 
permanently
If two prior glasdegib dose interruptions related to 
QTcF prolongation have occurred
X
QTc criteria for dose modifications does not apply to subjects with a functioning pacemaker, 
whether the rhythm is paced or not.  Dose modifications for glasdegib/placebo in case of 
drug class related AEs (muscle spasms, myalgia) are outlined in Table 11.


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Table 11.
Dose Modifications for glasdegib/placebo in Case of Drug Class Related 
AEs
Muscle Spasms 
or Myalgia
Grade 1
Grade 2
Grade 3
Glasdegib/
Placebo
Continue at same dose 
level.
Administer oral 
rehydration solutions 
containing electrolytes.a
Consider other appropriate 
interventions (eg, 
anti-spasmodics) as per 
institutional guidelines.
Evaluate levels of: CK, Vit 
B6, Vit D, ferritin, 
transferin and electrolytes 
(Na, K, Mg, Ca and P).b
If CK is elevated, evaluate 
urine and serum 
myoglobin, CK 
isoenzymes, and plasma 
creatinine.
Continue at same dose 
level.
Administer oral 
re-hydration salts 
containing electrolytes.a
Consider other appropriate 
interventions (eg, 
anti-spasmodics) as per 
institutional guidelines.
Evaluate levels of: CK, Vit 
B6, Vit D, ferritin, 
transferin and electrolytes 
(Na, K, Mg, Ca and P).b
If CK is elevated, evaluate 
urine and serum 
myoglobin, CK 
isoenzymes, and plasma 
creatinine.
If event persists, hold dose 
until resolution to 
Grade ≤1.
Upon resolution, restart at 
prior dose, or for 
prolonged muscle spasms, 
consider reducing dose by 
one dose level.
Hold dose.
Administer oral re-hydration 
salts containing 
electrolytes.a
Consider other appropriate 
interventions (eg, 
anti-spasmodics) as per 
institutional guidelines.
Evaluate levels of: CK, Vit 
B6, Vit D, ferritin, 
transferin and electrolytes 
(Na, K, Mg, Ca and P).b
If CK is elevated, evaluate 
urine and serum myoglobin, 
CK isoenzymes, and plasma 
creatinine.
Upon resolution to 
Grade ≤1, restart study 
treatment at next lower dose 
level.
If the event does not resolve 
within 3 weeks to Grade ≤1, 
at the discretion of the 
Investigator the dose may be 
restarted at the next lower 
dose level or the subject
may be permanently 
discontinued from study 
treatment. 
Abbreviations: CK creatinine kinase; Vit vitamin; Na sodium; K potassium; Mg magnesium; Ca calcium; 
P phosphorous.
a. Electrolyte replacement drinks should include Na, K, Mg, Ca and P. Consideration should be given to ensuring 
adequate hydration prior to bedtime, and whenever fluid intake is decreased for a prolonged duration.
b. Labs may be drawn as unscheduled assessments between protocol visits.
In the event of alopecia or dysgeusia, investigator discretion should be applied with respect to dose interruption and/or 
dose reduction of glasdegib/placebo as preliminary analysis of available clinical data suggests that these events are not 
dose dependent. 


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5.5.5.3. Intensive Chemotherapy and Non-Intensive Chemotherapy
For subjects in the Intensive Chemotherapy study, Central supply (provided by Pfizer) or
locally obtained commercial supplies of daunorubicin and cytarabine will be used. Refer to 
the local package insert (or SPC) or Investigational Product Manual for dose modification 
criteria.
For subjects in the Non-Intensive Chemotherapy study, Central supply (provided by Pfizer) 
or commercially available azacitidine will be used (Section 5.4.1.2). Refer to the local 
package insert (or SPC) or Investigational Product Manual for dose modification criteria.
5.6. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparator and/or marketed products, are stored in a 
secured area with controlled access under required storage conditions and in accordance with 
applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
Any storage conditions stated in the SRSD (IB for PF-04449913 and EU SPC for Vidaza®,33
EU SPC for Cytarabine,38 and EU SPC for Daunorubicin)39 will be superseded by the storage 
conditions stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 


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Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
Site staff will instruct subjects on the proper storage requirements for take home 
investigational products and how to report excursions.
5.7. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. At each dispensing visit 
(Cycle 2 Day 1, Cycle 3 Day 1, Induction 1, Induction 2, etc. or when there is a dose 
reduction), all unused or partially used bottles of glasdegib/placebo must be returned by 
patients to the Investigator.  The number of tablets returned by the patient at the end of the 
cycle (or induction 1, 2) will be counted, documented and recorded.
5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.8. Concomitant Treatment(s)
All concomitant medications and treatments must be recorded in the CRF except during the 
HSCT period from the first day of conditioning until a subject resumes glasdegib or placebo 
post HSCT.  During this HSCT period, no concomitant medications (other than transplant 
conditioning regimen) will be collected. If a patient resumes glasdegib or placebo following 
HSCT, HSCT-related Medical History must be provided.  This will include information 
regarding ongoing medical conditions and their associated concomitant medications that 
started from the first day of conditioning until the time of re-starting glasdegib or placebo 
therapy.
Any prior treatment received within 28 days prior to study entry (including hematopoietic 
growth factor receptor agonists: erythropoietin, granulocyte colony stimulating factor 
(G-CSF), romiplostim, eltrombopag) will be recorded in the CRF. 


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In addition, any transfusion (red blood cells or platelets) within 8 weeks prior to 
randomization should be recorded in the CRF for the non-intensive study only.  Transfusions 
(red blood cells or platelets) will not be recorded during the HSCT period unless part of 
ongoing Medical History once they resume glasdegib/placebo.
All prior therapies used to treat AML will be recorded regardless of when they were received 
by the subject.  Information collected will include dates of use, best treatment response and 
the reasons for stopping therapy. 
Every concomitant treatment, blood products, growth factors, as well as interventions, 
required by the subjects during the active study treatment (and up to 28 days following last 
study drug administration or until initiation of another anti-cancer treatment) and the reason 
for its administration must be recorded on the CRF.
5.8.1. Restricted or Prohibited Concomitant Medications
The following medications are not allowed during the active study treatment period:

Agents used to treat AML;

Investigational agents;

Concurrent administration of herbal preparations;

CYP3A4/5 Inducers: A drug-drug interaction study in health subjects with the strong 
CYP3A4 inducer, rifampin, resulted in a 70% decrease in plasma exposures (AUCinf) 
and a 35% decrease in peak plasma concentration (Cmax) of a single 100-mg oral dose 
of glasdegib.  Therefore co-administration of glasdegib and moderate/strong 
CYP3A4/5 inducers is not permitted.  A comprehensive list of moderate/strong 
CYP3A4/5 inducers is provided in Appendix 5.  However, if you are uncertain 
whether a concomitant medication is contraindicated, you should contact the Sponsor 
study team.
The following medications have use restrictions during the active study treatment period:

CYP3A4/5 Inhibitors: In a healthy volunteer study, ketoconazole, a potent 
CYP3A4/5 inhibitor, produced a 2.4-fold increase in plasma exposure and a 1.4-fold 
increase in peak plasma concentration of glasdegib.  Therefore a potential exists for 
drug-drug interactions with CYP3A4/5 inhibitors, and co-administration of 
glasdegib/placebo in combination with moderate/strong CYP3A4/5 inhibitors is not 
recommended.  Selection of concomitant medication with no or minimal 
CYP3A4/5 inhibition potential is recommended.  Moderate/strong 
CYP3A4/5 inhibitors (Appendix 6 and Appendix 7) should be used with caution and 
only if considered medically necessary.  If a moderate/strong CYP3A4/5 inhibitor is 
to be initiated in addition to glasdegib/placebo, the guidance provided in Section 7.1.7
and dose modifications for QT prolongation per Table 10 must be followed. If you 


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are uncertain whether a concomitant medication is a CYP3A4 inhibitor, you should 
contact the Sponsor study team.

Drugs with a known risk of Torsade de pointes (TdP): Glasdegib has been shown 
to have the potential to prolong the QTc interval in pre-clinical studies. In the 
first-in-subject study as single agent, Grade 3 QTcF prolongation was observed at 
the highest doses tested (400 mg and 600 mg).  While the glasdegib dose 
evaluated in this study is 100 mg, the concomitant administration of glasdegib and 
drugs with a known risk of Torsade de pointes should be avoided whenever 
possible.  A list of such drugs is provided in Appendix 8.  Use of these drugs is 
not recommended unless there are no alternatives. If a TdP drug is to be initiated 
in addition to glasdegib/placebo the guidance provided in Section 7.1.7 and dose 
modifications for QT prolongation per Table 10 must be followed. 

QT prolonging medications (without a risk of TdP) should be avoided whenever 
possible. 

Concomitant administration of multiple moderate/strong CYP3A4/5 inhibitors, TdP 
drugs, and/or QT prolonging medications (without a risk of TdP) is not 
recommended.
5.8.2. Permitted Concomitant Medications
5.8.2.1. Best Supportive Therapy
Best Supportive Therapy (BST) administration is permitted and encouraged according to 
Institutional guidelines for all subjects on study.  BST will be provided by the site and may 
vary depending on the subject’s signs and symptoms, site current practice, and country 
practice.  It includes medications and supportive measures that may palliate disease-related 
symptoms, improve quality of life, prevent and treat bacterial, fungal or viral infections.  
BST may include:

Blood transfusions;

Platelet transfusions;

Prophylactic antimicrobials (recommended particularly for intensive chemotherapy 
arm according to institutional guidelines);

Antibiotics (Section 5.8.1);

Anti-fungal agents (Section 5.8.1);

Anti-viral agents (Section 5.8.1).
5.8.2.2. Hematopoietic Growth Factors
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5.8.2.3. Anti-Emetic and Anti-Diarrheal Therapy
Subjects should be pre-medicated with anti-emetics for nausea and vomiting before each 
dose of chemotherapy according to local practice and guidelines.
Primary prophylaxis of diarrhea is permitted at the Investigator’s discretion.  The choice of 
the prophylactic drug is up to the investigator.
5.8.2.4. Prophylactic Intrathecal Chemotherapy
Prophylactic intrathecal chemotherapy is allowed, per investigator discretion.
5.8.2.5. Corticosteroids
Chronic and acute administration of systemic and non-systemic corticosteroids (topical 
applications, inhaled sprays, eye drops or local injections) is allowed.
5.8.2.6. Surgery
Caution is advised for any surgical procedures during the study.  The appropriate interval of 
time between surgery and glasdegib required to minimize the risk of wound healing and 
bleeding has not been determined.  Stopping glasdegib is recommended at least 7 days prior 
to surgery.  Post-operatively, the decision to reinitiate glasdegib treatment is up to the 
Investigator with Sponsor approval and should be based on a clinical assessment of 
satisfactory wound healing and recovery from surgery.
6. STUDY PROCEDURES 
6.1. Screening
Screening can be accomplished over one or multiple visits over a 4-week period (28 days), 
unless specifically noted otherwise (ie, bone marrow sample collection).  Protocol specific 
tests or procedures not considered standard of care can only be done after the subject has 
signed the Informed Consent document.  The Informed Consent document may be signed up 
to 60 days prior to study entry.
See the Schedule of Activities for a complete list of assessments and procedures to be 
collected during the screening period.
6.2. Treatment Period
See the Schedule of Activities for a detailed list of the assessments and procedures to be 
collected.  Study entry is defined as when the subject is randomized into the IRT system.  
Subjects must be randomized into the IRT system prior to receiving first dose of study drug. 
All assessments on Day 1 of each cycle should be collected pre-dose, unless documented
otherwise.
 
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In cases of unacceptable toxicity or pregnancy, the subject must be withdrawn from study 
drugs, have an end of treatment visit (Section 6.3), and be entered into the post-treatment 
follow-up phase (Section 6.4).
Subjects who permanently discontinue both study drugs (azacitidine or daunorubicin and 
cytarabine or glasdegib/placebo) for any reason (except death, or withdrawal of subject
consent for follow-up) will enter into the follow-up phase of the study. 
6.3. End of Treatment Visit
The End of Treatment Visit should be scheduled as soon as possible once a patient has been 
withdrawn from study drug.  For a detailed list of assessments and procedures to be 
completed please refer to the Schedule of Activities.
Patients continuing to experience toxicity following discontinuation of treatment will be 
followed by the Investigator at least every 4 weeks until resolution or determination, in the
Clinical judgment of the investigator, that no further improvement is expected.
6.4. Follow-up
Follow-up contact will be completed at least 28 calendar days, and up to 35 calendar days 
after the last administration of the investigational product to capture any potential adverse 
events (see the Time Period for Collecting AE/SAE Information section) and to confirm 
appropriate contraception usage (see the Contraception section).  Contact with the subject 
may be done via a phone call.
Please refer to the Schedule of Activities for details on assessments to be completed during 
the 2 types of follow-up visits: post treatment follow-up visits (first 2 years following last 
dose of study medication) and long-term follow-up (3 years).
Subjects will be followed for survival for up to 5 years from the first visit of the last subject
randomized in the study, or until death, or consent withdrawal. Public records may be used 
for contact information and/or to document date of death, as permitted by local law.
6.5. Subject Withdrawal
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal from the Study Due to Adverse Events (see also the Subject Withdrawal Section)
section) or behavioral reasons, or the inability of the subject to comply with the 
protocol-required schedule of study visits or procedures at a given study site. 
Reasons for withdrawal of study treatment may include: 

Objective disease progression in the Intensive and Non-Intensive Chemotherapy 
Study or Treatment Failure or Hematologic relapse (Lack of Efficacy) in the Intensive 
Chemotherapy Study according to the 2017 ELN Recommendations (Appendix 4):16

Global deterioration of health status requiring discontinuation;


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
Unacceptable toxicity (of either study treatment);

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Subject refused further treatment;

Study terminated by sponsor;

Death.
Reasons for withdrawal from study follow-up may include:

Study terminated by Sponsor;

Lost to follow-up;

Withdrawal of subject consent for any further contact;

Death.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The Investigator should inquire 
about the reason for withdrawal, request that the subject return all unused investigational 
product(s), request that the subject return for a final visit, if applicable, and follow up with 
the subject regarding any unresolved AEs.
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Withdrawal of consent:
Subjects who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures.  The only 
exception to this is when a subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information.  
Subjects should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or post-treatment 
study follow-up, and entered on the appropriate CRF page.  In the event that vital status 


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(whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to follow-up: 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails. All attempts should be documented in the subject’s medical 
records.  If it is determined that the subject has died, the site will use locally permissible 
methods to obtain the date and cause of death.  If, after all attempts, the subject remains lost 
to follow-up, then the last-known-alive date as determined by the investigator should be 
reported and documented in the subject’s medical records.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Safety Assessments
Safety assessments will include collection of AEs, SAEs, vital signs, physical examinations, 
triplicate ECGs (12-lead), laboratory assessments (including genetics), transfusions, 
HSCT-related information, and verification of concurrent medications and interventions.
7.1.1. Cardiac Testing (MUGA/ECHO)
For subjects to be enrolled in the Intensive Study, an ECHO or MUGA scan is required at 
screening. If the LVEF is 50%, the subject may proceed to their first induction therapy. If 
the LVEF is <50%%, the subject may not be included in the Intensive Chemotherapy Study, 
per Section 4.2 and may be eligible for the treatment in the Non-intensive Chemotherapy
Study.
If a second cycle of induction chemotherapy is indicated, a second MUGA or ECHO is 
required prior to initiating the second cycle if clinically indicated (eg, subject exhibiting signs 
of cardiac failure). If the second MUGA or ECHO demonstrates a LVEF <45%, the subject 
is not eligible to receive additional induction chemotherapy and will be removed from the 
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7.1.2. Pregnancy Testing
For female subjects of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed on 2 occasions prior to starting study 
treatment - once at the start of screening and once at the baseline visit andimmediately before 
investigational product administration (first dose).  In addition, for the Intensive Study, a 
pregnancy test must also be done at the start of every Induction (1,2) during the active 
treatment period, and at Day 1 of each Consolidation Cycle with single-agent cytarabine, 
Day 1 of each cycle for single-agent glasdegib/placebo following the period labeled as
“Consolidation up to 2 years post randomization” (as labeled in Table 1), and the end of 
treatment.  For the Non-intensive Study, a pregnancy test must be done every cycle during 
the active treatment period and at the end of treatment. 
Following a negative pregnancy result at screening, appropriate contraception (defined in
Section 5.3) must be commenced and a further negative pregnancy result will then be 
required at the baseline visit before the subject may receive the study treatment.  Pregnancy 
tests will be repeated at every treatment cycle or start of each induction(s) during the active 
treatment period, at the end of study treatment, and additionally whenever 1 menstrual cycle 
is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests 
may also be undertaken if requested by Institutional Review Boards (IRBs)/Ethic 
Committees (ECs) or if required by local regulations. In the case of a positive confirmed 
pregnancy, the subject will be withdrawn from administration of study treatment and enter 
into the Follow-up phase of the study. 
7.1.3. Adverse Events
Assessment of AEs will include the type, incidence, severity (graded by the NCI CTCAE 
version 4.03) timing, seriousness, and relatedness.  Additional information regarding AE and 
Serious AE (SAE) reporting is provided in Section 8.  Assessment of acute GVHD will be 
graded by standard criteria based on the Consensus Conference on acute GVHD Grading 
(Appendix 15).46  Assessment of chronic GVHD will be assessed based on the National 
Institutes of Health (NIH) Diagnosis and Staging Working Group Report.47,48
7.1.4. Laboratory Safety Assessments
Hematology, blood chemistry, coagulation and urinalysis assessments will be drawn at the 
time points described in the Schedule of Activities and will be analyzed by the 
site/Investigator at local laboratories.  Laboratory certifications and normal ranges with units 
must be provided to the Sponsor.
Laboratory assessments should be obtained during the 28-day screening period as described 
in the Schedule of Activities and as defined in Table 12.  There is no need to repeat on 
Day 1 if these assessments are performed within 3 days prior to randomization. From 
Cycle 2 Day 1 (C2D1) onwards (or Induction 2 onward), if a hematology (complete blood 
count [CBC] with differentials) sample is obtained within 3 days of a scheduled blood draw, 
the collection need not be repeated.  For those subjects achieving a CR or PR, a CBC should 
be done at least 4 weeks after the BM assessment in order to confirm response.  Hematology 
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If blood chemistry or coagulations are obtained within 3 days of scheduled blood draw, the 
collection need not be repeated. 
Urinalysis is required during the screening period, and may be repeaated on study as 
clinically indicated. 
For laboratory evaluations used to determine eligibility, a repeated evaluation is permitted for
screening results out of the defined range. If the repeated laboratory result meets the criteria, 
that result may be used to determine eligibility. If the repeated laboratory result does not 
meet the criteria, the subject will be considered a screening failure. Re-screening is allowed 
in this study.
See Table 12 for a list of required laboratory tests. 


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Table 12.
Required Laboratory Tests
Hematology
Blood Chemistry
Urinalysis 
(microscopic analysis)
Coagulation Tests
Pregnancy 
Tests
Hemoglobin
ALT2
aPTT
For female 
subjects of 
childbearing 
potential, 
serum or 
urine
Platelets
AST2
INR
WBC
Alkaline Phosphatase
Specific Gravity
Absolute 
Neutrophils1
Sodium
PH
Absolute 
Lymphocytes1
Potassium
Protein
Absolute 
Monocytes1
Magnesium
Glucose
Absolute 
Eosinophils1
Chloride
RBC
Absolute Basophils1
Total Calcium
WBC
Blast Count
Total Bilirubin2
Ketones
BUN or Urea
Leukocyte Esterase
Creatinine
Uric Acid
Glucose (non-fasting)
Nitrate
Albumin
Total Protein
Phosphorus
LDH
CPK
Bicarbonate3
1 The database allows differential counts as both percent and absolute values for these analytes, the 
preference is absolute if both are available. If only percents are available, thee values may be entered. 
2. For potential Hy's law cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, 
prothrombin time (PT)/INR, and alkaline phosphatase. AEs of Hy’s law must be reported as an SAE.
Refer to Section 8.4.2 for detailed instructions. 
3. Required for Non-Intensive subjects, optional for Intensive subjects. 
ALT= alanine aminotransferase, aPTT= activated partial thromboplastin time, AST= aspartate 
aminotransferase, BUN=blood urea nitrogen, CPK= creatinine phosphokinase, INR=international 
normalization ratio, LDH=lactate dehydrogenase, RBC=red blood cell count, U/A= urinalysis, WBC= white 
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7.1.5. Transfusions
All red blood cell and platelet transfusions, including the date of each transfusion and 
number of red blood cell or platelet units transfused must be recorded while the subject is on 
treatment in the Intensive and Non-intensive studies.  Transfusion histories for the 
8 weeks prior to randomization must also be recorded in the CRF for the Non-intensive 
study only.  Note that the number of units (not the number of bags) must be recorded. 
Transfusions will not be collected during the HSCT period (Day 1 of conditioning until 
resuming glasdegib or placebo, death, withdrawal, or post therapy follow up).
7.1.6. Vital Signs and Physical Examination
Vital signs will include blood pressure and heart rate (to be recorded in sitting position).  
Subjects will have a physical exam (PE) including an examination of major body systems,
measurement by palpation of spleen and liver, weight, height and assessment of Eastern 
Cooperative Oncology Group (ECOG) performance status (Appendix 3).  If PE obtained 
within 48 hours of previous assessments, the evaluation need not be repeated.  Height need 
not be recorded after the first measurement at screening.  Weight must be recorded at 
Screening and Day 1 of each cycle or Day 1 of Induction(s).
7.1.7. Triplicate (12-Lead) ECGs
See the Schedule of Activities for the specific time points of local Electrocardiogram (ECG)
collection and Table 10 for dose modifications related to management of QTcF prolongation.
Triplicate 12-lead (with a 10-second rhythm strip) tracing will be performed for ECGs at
every time point. It is preferable that the machine used has a capacity to calculate the
standard intervals automatically. The acceptable mean on treatment upper limit of QTc
interval will be using the Fridericia (QTcF) correction method. At each time point
3 consecutive supine ECGs will be performed approximately 2 minutes (but no longer than
5 minutes) apart, to determine the mean QTcF interval. The sites will be provided with a
simple calculation tool that will allow for real-time assessment of mean QTcF values from
the triplicate QT and heart rate measurements.
The acceptable mean on-treatment upper limit of QTcF interval is 480 msec. If any subject
has a mean pre- or post-dose QTcF value >480 msec, please refer to Table 10 of the protocol
for detailed instructions on management of QTcF prolongation and handling dose delays and
dose modifications for glasdegib/placebo.
When matched with PK sampling, every effort should be made to perform the ECGs before
each PK sample drawing such that the PK sample is collected at the nominal time (ie, the
timing of the PK collections over rides the timing of the ECG collections). A 15-min
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7.1.8. HSCT-Related Information
Donor details, type of transplant (myeloablative, non-myeloablative, or reduced intensity), 
day of donor stem cell infusion, and conditioning regimen (including radiation) will be 
collected in the CRF.  Presence of GVHD prior to resuming glasdegib/placebo post HSCT 
will be reported in the CRF.  HSCT–related information must be made available to the 
B1371019 study staff and must be able to be monitored. 
Post Remission HSCT period (HSCT period) is defined as time from start of conditioning 
until resuming glasdegib/placebo, death, withdrawal of consent, or entering follow up period 
post HSCT.  No concomitant medications (including transfusions) will be collected during 
the HSCT period.  Day 0 is defined as the day of stem cell infusion (HSCT).
Post HSCT, any ongoing AEs and concomitant medications to treat ongoing AEs from the 
HSCT period must be collected in the CRF.
7.1.9. ANC Engraftment
Following post remission HSCT, ANC engraftment must be confirmed before resuming 
glasdegib or placebo.  Confirmed ANC engraftment is defined by ANC ≥0.5 x 109/L for 
3 consecutive days without growth factor support following HSCT using myeloablative or 
non-myeloablative conditioning regimen.
7.1.10. Pharmacokinetics Assessments
Every effort must be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, PK samples obtained within 10% of the nominal time (eg, within 
6 minutes of a 60 minute sample) will be considered protocol compliant, and the exact time 
of the sample collection should be noted on the CRF.  The pre-dose PK sample should be 
collected within 30 minutes prior to administration of the drug.  If a scheduled blood sample 
collection cannot be completed for any reason, the missed sample time may be rescheduled 
with agreement of clinical investigators, subject and sponsor.
PK samples will be assayed using a validated analytical method in compliance with Pfizer 
standard operating procedures.  Details regarding the collection, processing, storage and 
shipping of the blood samples will be provided in the laboratory manual.
7.1.10.1. Glasdegib
Blood samples (1.5 mL whole blood sufficient to provide a minimum of 0.6 mL of plasma) 
will be collected for PK analysis of glasdegib as outlined in the PK flowchart (see Table 2
and Table 4).


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7.2. Efficacy Assessments
7.2.1. AML Response Criteria
Disease response, measured from baseline through the End of Treatment will be evaluated 
using a modified version of the European LeukemiaNet (ELN) recommendations for 
diagnosis and management of AML in adults (Appendix 4).16 ELN response assessments 
include evaluation of bone marrow, peripheral blood neutrophils, platelets, and blast %, 
assessment for EMD, and results from central lab MRD assessment. Every subject must 
have an Investigator determined Response Assessment documented per Appendix 4 or 
response should be marked as indeterminate if the evaluation does not meet a specific ELN
response criterion. 
All subject files and bone marrow assessment slides/samples must be available for source 
verification.
CR with partial hematologic recovery (CRh) will be assessed for the Non-intensive 
chemotherapy study.  CRh is defined as ANC >0.5x109/L and platelets >50x109/L without 
qualifying for CR.
7.2.2. Genetics 
For all subjects, genetics must be performed using any scheduled or unscheduled bone 
marrow biopsy and/or aspirate samples collected during study participation.
Baseline genetics classification must be completed within 28 days of first dose. Genetic risk 
will be classified according to the the ELN recommendations for diagnosis and management 
of AML in adults (Appendix 14).16  
Baseline genetics classification known at the time of randomization will be used to stratify 
subjects; therefore, the Investigator must review available, baseline genetic and molecular 
reports and stratify each subject.
Following baseline assessments, subsequent analysis of genetic abnormalities may be 
restricted to abnormalities identified at baseline.  Molecular abnormalities will be repeated at 
each none marrow assessment per standard of care.  
7.2.3. Bone Marrow Assessments
Please see the Schedule of Activities for specific assessment time points for BM biopsy
and/or aspirate collection.  Bone marrow samples should be prepared according to the study 
Laboratory Manual. Results of all bone marrow evaluations performed during the study 
participation will be reported in the CRF.
The importance of timely and complete disease assessments (including BM assessments) at 
screening and during the study cannot be understated.  Failure to perform any of the required 
disease assessments will result in the inability to determine disease status for that time point 
and have the potential to weaken the conclusions of this study.


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The two samples that are collected for MRD analysis, the bone marrow aspirate sample and 
the whole blood sample should be collected as they are not exploratory research biomarker 
samples.  Both of these samples for MRD analysis are part of the response assessments in the 
main study; therefore, these samples are a required part of the study and should always be 
collected.  Following MRD analysis on the whole blood sample, any remaining sample will 
be discarded rather than being used for molecular profiling.
 
 
 
 
 
 
 
 
 
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7.4. Patient Reported Outcomes (PROs)
Patient reported outcomes will be assessed using the MD Anderson Symptom Inventory 
AML/MDS Module (MDASI-AML/MDS), EuroQol 5-Dimension questionnaire 5-Level 
version (EQ-5D-5L), Patient Global Impression of Symptoms (PGIS), and Patient Global 
Impression of Change (PGIC).  
 
 
PROs are completed at the same interval as drug dosing, clinical visits, and post-treatment 
follow-up are conducted.  Refer to Table 1 and Table 3 for specific timepoint requirements.
PGIC is completed at all post baseline time points, without the initial baseline assessment.
PRO responses will be obtained directly from patients while on treatment and during the first 
two years of post-treatment follow-up.  During the long term follow up phase, PRO 
responses may betranscribed and entered by site staff.  PROs should never be completed 
more than once on any calendar day.  For subjects hospitalized or with a timepoint falling on 
a weekend or holiday, the PRO may be performed on the next business day.
Site staff role must be strictly limited to transcription and data entry of patient responses, 
without any attempt to interpret, lead, or influence.  Interviewer administration may be used 
under special circumstances (eg, patient is visually impaired, forgot their glasses, or feels too 
ill). If interviewer administration is required, every effort should be made to have the same 
interviewer administer the PRO surveys to the patient.  In addition, the interviewer will stay 
true to the patient’s response and not alter it.
Patients must complete these PRO surveys prior to any discussion of the patient’s health or 
treatment with their physician or other healthcare personnel at the site.  While every effort 
should be made to have patients complete these PRO surveys prior to dosing with any study 
drugs and other clinical procedures, flexibility is allowed to accommodate for site-specific 
operating procedures.
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The data entered into the device will be considered the source documents and sent 
electronically to the vendor when completed.  Patient responses will be captured in a 
database and maintained by the vendor and transferred to the Pfizer database.
7.4.1. MDASI-AML/MDS
The MDASI-AML/MDS is a validated modulized patient reported outcome measure for 
AML and MDS.49-51
It consists of a 19-item core cancer module and a four-item AML/MDS specific module 
[Appendix 9].  The 23 items are designed to measure 13 core cancer symptoms (pain, fatigue, 
nausea, disturbed sleep, distress, shortness of breath, problem remembering, lack of appetite, 
drowsiness, dry mouth, sadness, vomiting, and numbness), 4 AML/MDS-specific symptoms 
(malaise, diarrhea, muscle weakness, and skin problems), and 6 areas of interference (general 
activity, mood, work, walking, relations with other people, and enjoyment of life) The core 
module’s 13 core symptoms and 6 core interference items, are found to have the highest 
frequency and/or severity in patients with various cancers and treatment types.  The four-item 
AML/MDS-module includes additional symptoms that are uniquely relevant to patients with 
AML and MDS. 
It measures at the severity of symptoms and related interference at their WORST level in the 
last 24 hours by asking patients to respond to each item on an 0-10 numeric rating scale 
(NRS), where 0 = “not present” or “did not interfere” and 10 = “as bad as you can imagine” 
or “interfered completely”. 
The instrument is brief, simple, and easy to use. Its 24 hour recall period and 0-10 numerical 
rating scale are easy for patients to understand and complete.  The burden to the patient is 
minimal, as it takes a few minutes to complete the questionnaire.
For this study, the response for the single item “Fatigue” (one of the 13 MDASI core cancer 
symptoms) will be analyzed separately as the key secondary efficacy endpoint.
7.4.2. EQ-5D-5L
The EQ-5D-5L (Appendix 10) is a brief, self-administered, validated and reliable generic 
health status instrument developed by the EuroQoL Group. It consists of the EQ-5D 
descriptive system and a visual analogue scale (VAS), the EuroQoL visual analogue scale 
(EQ-VAS). 
The EQ-5D descriptive system measures a patient’s health state on 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression.  The patient is asked to 
indicate his/her health state by rating each dimension on a five-level scale (1=no problem, 
5=extreme problem).  This rating resulted in a 1-digit number expressing the level selected 
for that dimension.  The digits for the 5 dimensions were combined in a 5-digit number 
describing the respondent’s health state.  It should be noted that the numerals 1-5 have no 
arithmetic properties and should not be used as a cardinal score.


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EQ-5D-5L health states, defined by the EQ-5D-5L descriptive system, can be converted into 
a single index value (the EQ-5D Index or “utility") between 0 to 1 by applying a formula that 
essentially attaches country-specific values (also called weights) to each of the levels in each 
dimension. The index can be calculated by deducting the appropriate weights from 1, the 
value for full health (ie, state 11111). 
Currently, EQ-5D-5L value sets are available for each country that performed a valuation 
study for the EQ-5D-3L. By using the crosswalk link function and the individual responses 
to the EQ-5D-5L descriptive system, index values for the EQ-5D-5L can be calculated. 
Documents containing tables of values for all 3125 health states and the ‘EQ-5D-5L 
Crosswalk Index Value Calculator’ can be downloaded from the EuroQol website.
The EQ-5D Index scores range generally from 0 to 1, with 0 representing the worst health 
state and 1 as perfect health.  The index values, presented in country specific value sets, are a 
major feature of the EQ-5D instrument, facilitating the calculation of quality-adjusted life 
years (QALYs) that are used to inform economic evaluations of health care interventions.
The EuroQoL visual analogue scale (EQ VAS) records the respondent’s self-rated health on 
a 20-cm vertical, visual analogue scale from 0 (worst imaginable health state) to 100 (best 
imaginable health state). This information could then be used as a quantitative measure of 
health as judged by the individual respondents.
A score difference of 0.08 for the EQ-5D Index score and of 7 for the EQ-VAS are 
recommended as estimates of minimally important differences for the EQ-5D.
7.4.3. Patient Global Impression of Symptoms
The Patient Global Impression of Symptoms (PGIS) (Appendix 11) and the Patient Global 
Impression of Change (PGIC) (Appendix 12) are employed as anchors in responder analyses 
for MDASI-AML/MDS, especially the fatigue item, which is a key secondary endpoint. 
PGIS is generally the preferred anchor over PGIC because PGIC may be subject to recall 
bias. As recommended by the Food and Drug Administration (FDA), for this protocol, both 
anchor scales will be used to provide an accumulation of evidence to help interpret a 
clinically meaningful score change in MDASI-AML/MDS.
The PGIS (Appendix 11) is a single1-item questionnaire designed to assess patient’s overall 
impression of disease severity at a given point in time. It uses a 4-point Likert scale as 
follows: In the last 24 hours, my leukemia symptoms are: 1-“Absent (no symptoms)”, 
2-“mild”, 3-“ moderate”,  4=”severe”,  .
It will be used as an anchor for defining a “responder threshold”, on MDASI-AML/MDS and 
can also be used to create severity categorization for this PRO to enhance interpretation.
Patients complete this questionnaire at baseline, and repeatedly at the same time points as the 
MDASI-AML/MDS is collected.


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7.4.4. Patient Global Impression of Change 
The Patient Global Impression of Change (PGIC) (Appendix 12) is a single-item 
questionnaire designed to assess the patient’s overall sense of whether there has been a 
change since starting treatment as rated on a 7 point Likert scale anchored by (1) ‘very much 
improved’ to (7) ‘very much worse’, with (4) =’ no change’.  The PGIC is a measure of 
“participant rating of global improvement and satisfaction with treatment”.
1. This instrument is used to determine global improvement as assessed by the patient 
and as an anchor to define a responder definition for MDASI-AML/MDS and as a 
sensitivity analysis for defining a ‘clinical important difference’ on this PRO. 
2. Patients complete this questionnaire repeatedly at the same post baseline time points 
as the MDASI-AML/MDS.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
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Table 13.
Adverse Event Reporting
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer Safety 
Within 24 Hours of Awareness
SAE
All
All
HSCT Day 0 until resume study 
therapy, death, withdrawal or 
post-treatment follow up: 
All deaths, Grade 3/Grade 4 
treatment-related AEs, and 
treatment related SAEs
Related to glasdegib or placebo 
and deaths regardless of causalitya
Serious and related to glasdegib 
or placebo and deaths regardless 
of causality
Non-serious AE
All
None
Exposure to the investigational 
product under study during 
pregnancy or breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), except 
occupational exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure (regardless 
of whether associated with an AE)
Note: Serious adverse events occurring to a patient after the active reporting period has ended should be reported to the 
sponsor if the investigator becomes aware of them; at a minimum, all serious adverse events that the investigator 
believes have at least a reasonable possibility of being related to study drug are to be reported to the sponsor.
a.
In Germany only: All SAEs, regardless of causality, will be recorded on the CRF.
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Subjects must be followed for AEs for 28 days after the last treatment administration or until 
all drug-related toxicities have resolved, whichever is later; or earlier than 28 days should the 
patient commence another anticancer therapy in the meantime.  For serious adverse events 
(SAEs), the active reporting period to Pfizer or its designated representative begins from the 
time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, (ie, prior to undergoing any study related procedure and/or 
receiving investigational product), through and including 28 calendar days after the last 
administration of the investigational product.  Serious adverse events occurring to a patient 
after the active reporting period has ended should be reported to the sponsor if the 
investigator becomes aware of them; at a minimum, all serious adverse events that the 
investigator believes have at least a reasonable possibility of being related to study drug are 
to be reported to the sponsor.

The HSCT Post Remission Period (HSCT Period) is defined as time from the start of 
the conditioning regimen until the subject restarts glasdegib or placebo, death, post 
study follow up, or withdrawal. For subjects being treated with HSCT, subjects must 
be followed for AEs for at least 28 days after the last investigational treatment 
administration prior to HSCT. Following HSCT Day 0, all deaths regardless of 
causality, Grade 3/Grade 4 treatment-related AEs, and SAE events that the 
investigator believes have at least a reasonable possibility of being related to study 
drug during the HSCT period are to be reported to the sponsor. In Germany 
only: All SAEs, regardless of causality, will be recorded on the CRF. 


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
Once subjects resume glasdegib or placebo following HSCT, events summarized in 
Table 13 will be reported. 
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.


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8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Subject
Withdrawal Section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
If a subject begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.


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If a subject begins a new anticancer therapy, the recording period for non-serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.


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Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
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8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:
•
Results in death;
•
Is life-threatening (immediate risk of death);
•
Requires inpatient hospitalization or prolongation of existing hospitalization;
•
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);
•
Results in congenital anomaly/birth defect.
Or that is considered to be:
•
An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section).
 
 
 
 
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8.3. Severity Assessment
AEs will be reported using concise medical terminology (verbatim) as well as the Common 
Terminology Criteria (CTC) term for Adverse Events (Version 4.03, Publish Date:
June 14, 2010, http://ctep.cancer.gov/reporting/ctc.html)) listed in the Cancer Therapy 
Evaluation Program.
The investigator may use the following definitions of Severity in accordance with CTCAE 
Version 4.03 to describe the maximum intensity of the adverse event:
GRADE
Clinical Description of Severity
0
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
All cases of Grade >2 mQTcF prolongation regardless of causality and treatment arm must 
be reported as an SAE for up to 28 calendar days after the last dose of study drug 
administered. All SAEs will be reported to Pfizer Safety by the investigator as described in 
previous sections, and will be handled as SAEs in the safety database.
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
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In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller);

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 


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anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 


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regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.


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
If the dose administered is >120% of the scheduled dose, <80% of the scheduled 
dose, or dosed outside a 28 day window. If the drug is administered as incorrect 
formulation (ie, pills cut in half instead of administering a lower dosage tablet, pills 
crushed and administered via feeding tube without direction from Sponsor).
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
Medication errors will NOT include:

Cases where commercial backbone drug was used instead of supplied stock;

Cases where the wrong lot number of drug was dispensed;

Dose modifications outlined in Section 5.5.5.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
For the intensive chemotherapy population, a total of 267 death events will be required to 
provide 90% power to detect an HR=0.67 (translating in median OS of 31.5 vs 21 months, 
assuming a composite median OS of 21 months for intensive AML subjects: young intensive 
(aged ≤60 years) with a median OS of 23.7 months and elderly intensive (aged >60 years) 
with a median OS of 15 months17,18 using a 1-sided log-rank test at a significance level of 
0.025 and a 3-look group sequential design.  A first interim analysis for efficacy and futility 
is planned when 50% of death events have occurred.  However, no efficacy stopping will be 
made even if the endpoint crosses the efficacy boundary.  A second interim analysis for 
efficacy and futility is planned when 70% of death events have occurred or upon completion 
of enrollment of intensive chemotherapy subjects, whichever is later.  An O’Brien-Fleming 
boundary with Lan-DeMets spending function will be used for efficacy and a Rho(3) 
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10-month ramp-up of subject enrollment up to 18 subjects per month then plateauing at that 
level and expecting approximately one third of all enrolled subjects to be censored, the 
desired number of death events will accrue within 58 months after randomization of the first 
intensive chemotherapy subjects with a total of 400 intensive chemotherapy subjects using a 
1:1 randomization.  The actual time needed to accrue the desired number of events will be 
impacted by actual subject enrollment and drop-out rates. 
For the non-intensive chemotherapy population, a total of 220 death events will be required 
to provide 90% power to detect an HR=0.64 (translating in median OS of 16.2 vs 
10.4 months9 using a 1-sided log-rank test at a significance level of 0.025 and a 2-look group 
sequential design.  An interim analysis for efficacy and futility is planned when 60% of death 
events have occurred or upon completion of enrollment of non-intensive chemotherapy 
subjects, whichever is later. An O’Brien-Fleming boundary with Lan-DeMets spending 
function will be used for efficacy and a Rho(3) β-spending function will be used for the 
non-binding futility boundary.  Assuming a 10-month ramp-up of subject enrollment up to 
18 subjects per month then plateauing at that level and expecting approximately 31% of all 
enrolled subjects to be censored, the desired number of death events will accrue within 
37 months after randomization of the first non-intensive chemotherapy subjects with a total 
of 320 non-intensive chemotherapy subjects using a 1:1 randomization.  The actual time 
needed to accrue the desired number of events will be impacted by actual subject enrollment 
and drop-out rates. 
9.2. Analysis Population
The primary, secondary, 
 analyses of intensive and non-intensive 
chemotherapy subjects will be conducted separately and independently of each other.
9.2.1. Full Analysis Set
The Full Analysis set (FAS) will include all randomized subjects.  Subjects will be classified 
according to the treatment assigned at randomization.
9.2.2. Safety Analysis Set
The safety analysis set will include all subjects who receive at least one dose of study drug.  
Subjects will be classified according to the treatment assigned at randomization unless the 
incorrect treatment(s) was/were received throughout the dosing period in which case subjects 
will be classified according to the first study treatment received.
9.2.3. PK Analysis Set
The PK concentration analysis set is defined as all subjects who are treated and who have at 
least 1 value of analyte concentration of glasdegib available.  The PK parameter analysis set 
is defined as all subjects who are treated and who have at least 1 of the PK parameters of 
interest.
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9.3. Efficacy Analysis
9.3.1. Analysis of the Primary Endpoint 
OS is defined as the time from the date of randomization to the date of death due to any 
cause.  Subjects last known to be alive will be censored at date of last contact. 
For the intensive chemotherapy population, the primary analysis of OS will be performed 
based on the FAS when about 267 death events have occurred in the intensive chemotherapy 
population.  A 1-sided stratified log-rank test (stratified by ELN genetic risk, ≤60 vs 
>60 years, and region [rest of world {ROW} vs China]) will be used at the interim and final 
analyses with the overall significance level preserved at 1-sided ≤0.025.  The rate of stem 
cell transplantation is expected to be much lower for sites in China versus the ROW thus 
region is being added as a stratification factor in the primary analysis. Should 
over-stratification prevent model convergence or there exists large imbalance in the 
distribution (eg, 90% or more subjects from one strata level), the intermediate and poor 
cytogenetic risk groups may be pooled in the analysis.  OS time associated with each 
treatment arm will be summarized using the Kaplan-Meier method and displayed graphically 
where appropriate CIs for the 25th, 50th (median), and 75th percentiles of OS will be reported 
using Brookmeyer and Crowley method.45 In addition, the median OS and its two-sided 
95% CI using the same method will be provided for each stratum within each treatment arm 
separately.  The Cox proportional hazards model will be fitted to compute the treatment HR 
and the corresponding 95% CI.  The HR and its two-sided 95% CI will be provided for each 
stratum as well.  Additional covariates may be added in the Cox proportional hazard model to 
explore the potential influence of other baseline factors on OS (including but not limited to 
age, race, gender, and secondary AML). 
 
 
The Schoenfeld residuals for the 
stratified Cox PH regression model will be plotted to investigate graphically violations from 
the PH assumption; a non-zero slope is evidence of departure from PH.  The PH assumption 
will be formally tested using Schoenfeld’s residual test.  Large departures from PH will be 
evidenced by a p-value <0.05. 
 
 
 
For the non-intensive chemotherapy population, the primary analysis of OS will be 
performed based on the FAS when about 220 death events have occurred in the non-intensive 
chemotherapy population.  A 1-sided stratified log-rank test (stratified by ELN cytogenetic 
risk and age <75 vs ≥75 years) will be used at the interim and final analyses with the overall 
significance level preserved at 1-sided ≤0.025.  The rate of stem cell transplantation is 
expected to be low in all regions in the non-intensive study.  Should over-stratification 
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prevent model convergence or there exists large imbalance in the distribution (eg, 90% or 
more subjects from one strata level), the intermediate and poor genetic risk groups may be 
pooled in the analysis.  OS time associated with each treatment arm will be summarized 
using the Kaplan-Meier method and displayed graphically where appropriate.  CIs for the 
25th, 50th (median), and 75th percentiles of OS will be reported using Brookmeye and 
Crowley method.45 In addition, the median OS and its two-sided 95% CI using the same
method will be provided for each stratum within each treatment arm separately.  The Cox 
proportional hazards model will be fitted to compute the treatment HRs and the 
corresponding 95% CI.  The HR and its 2-sided 95% CI will be provided for each stratum as 
well.  Additional covariates may be added in the Cox proportional hazard model to explore 
the potential influence of other baseline factors on OS (including but not limited to age, race, 
gender, and ECOG performance status).  
 
 The 
Schoenfeld residuals for the stratified Cox PH regression model will be plotted to investigate 
graphically violations from the PH assumption; a non-zero slope is evidence of departure 
from PH.  The PH assumption will be formally tested using Schoenfeld’s residual test.  Large 
departures from PH will be evidenced by a p-value <0.05. 
 
 
 
 
 
 
 
 
9.3.2. Analysis of Secondary Endpoints
All secondary PRO and efficacy endpoints will be based on the FAS unless stated otherwise.
Fatigue 
The key secondary PRO endpoint based on the Fatigue single-item from the 
MDASI-AML/MDS questionnaire will be analyzed for proportion of responders (defined 
below) at week 12 for non-intensive patients and week 8 for intensive chemotherapy patients. 
The proportion of responders will be estimated with a 2-sided 95% CI (using normal 
approximation). The proportion and 2-sided 95% CI (using exact method) of responders for 
each stratum will also be provided. A hierarchical testing procedure will be followed, 
namely, a formal testing of proportion of responders (using a 1-sided Cochran Mantel 
Haenszel [CMH] test, stratified by ELN genetic risk, age [age ≤60 vs >60 years for the 
intensive patients, and age <75 vs ≥75 years for the non-intensive patients]), and region 
[ROW vs China for intensive patients only]) will only be conducted in one population if the 
primary OS endpoint is met in that population (intensive or non-intensive treatment).  The 
risk ratio and 2-sided 95% CI will also be summarized.
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Responder definition will be determined via anchor-based methods using PGIS (primary) and 
PGIC (supportive), which will be supplemented with cumulative distribution functions 
(CDF) and probability density functions (PDF). Detailed description of the methodology 
will be in the statistical analysis plan. 
CDF and PDF will be created using individual change from baseline for the fatigue item 
score from the MDASI-AML/MDS at week 8 for intensive chemotherapy patients and at 
week 12 for non-intensive patients. 
Disease Specific Efficacy Endpoints 
Disease specific efficacy endpoints include CR, CRMRD-neg (a subgroup of CR), Complete 
remission with incomplete hematologic recovery (CRi), Complete remission with partial 
hematologic recovery (CRh, only defined for Non-intensive patients), Morphological 
Leukemia Free State (MLFS), and Partial Remission, as defined according to the 2017 ELN 
recommendations.16 Note that CR (including CRMRD-neg) is always a deeper response than 
CRi.  CR (including CRMRD-neg) is a deeper response than CRh (if applicable), and CRh (if 
applicable) is a deeper response than CRi.
The proportion of subjects achieving each endpoint will be estimated with 2-sided 95% CI 
(using the normal approximation) respectively. The proportion and 2-sided 95% CI of 
subjects achieving each of the endpoint for each stratum will also be provided. The 
proportion of subjects achieving each endpoint will be compared between the treatment arms 
using a 1-sided CMH stratified test (stratified as described in Section 9.3.1) and an 
unstratified chi-square test.
Duration of Response
For the Intensive chemotherapy subjects, Duration of Response (DoRi) is only defined for 
subjects who have ever achieved CRi or better on study as the time from date of first 
achieving CRi or better to the date of disease progression, or relapse after CRi or better, or 
death due to any cause.  Subjects last known to be alive who are free from disease 
progression or relapse after CRi or better are censored at the date of last disease assessment 
that verifies their status.  Note that CRi or better includes CR and CRi for the intensive 
chemotherapy subjects.  
For non-Intensive chemotherapy subjects, DoRi is only defined for subjects who have ever 
achieved CRi or better on study as the time from date of first achieving CRi or better to the 
date of disease progression, or relapse after CRi or better, or death due to any cause. We also 
define DoRh for subjects who have ever achieved CRh or better on study as the time from 
date of first achieving CRh or better to the date of disease progression, or relapse after CRh
or better, or death due to any cause. Note that CRi or better includes CR, CRh, and CRi for 
the non-intensive chemotherapy subjects. CRh or better includes only CR and CRh for the 
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As DoRi/DoRh are not defined for all subjects, no formal statistical comparison will be made 
between treatment arms.  DoRi/DoRh will be analyzed and displayed graphically for each 
arm separately using the Kaplan-Meier method.  The median DoRi/DoRh for each treatment 
arm and corresponding two-sided 95% CI will be provided. 
Time to Response (Non-Intensive Study only)
Time to Response (TTRi) is only defined for subjects who have ever achieved CRi or better 
on study as the time from date of randomization to date of first achieving CRi or better.  
Similarly, TTRh is only defined for subjects who have ever achieved CRh or better on study 
as the time from date of randomization to date of first achieving CRh or better. 
As TTRi/TTRh are not defined for all subjects, no formal statistical comparison will be made 
between treatment arms.  The minimum, median, and maximum TTRi/TTRh for each 
treatment arm will be provided. 
Event Free Survival
Intensive Study
For the Intensive chemotherapy patients, EFS is defined as the time from the date of 
randomization to the date of treatment failure (TF), relapse from CR, or death from any 
cause, whichever comes first. TF is defined as failure to achieve CR during the induction 
cycle (including the re-induction cycle if there is one) and the event date for TF is the day of 
randomization. Responders last known to be alive who are free from disease progression or 
relapse are censored at the date of last disease assessment that verifies their status.
 
 
 
 
 
 
 
 
 
 
 
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Non-intensive Study
For Non-intensive chemotherapy patients, EFS is defined as the time from the date of 
randomization to the date of TF, relapse from CRh or better, or death from any cause, 
whichever comes first. TF is defined as failure to achieve CRh or better following up to 
6 cycles of study treatment and the event date for TF is the day of randomization. Patients 
who discontinue either study treatment without achieving CRh or better prior to completing 
6 cycles of study treatment are considered treatment failures. Responders last known to be 
alive who are free from disease progression or relapse are censored at the date of last disease 
assessment that verifies their status.
 
 
 
 
 
 
 
 
 
 
 
 
 
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A 1-sided stratified log-rank test (stratified by ELN genetic risk, age [age ≤60 vs >60 years 
for the intensive patients, and age <75 vs ≥75 years for the non-intensive patients], and 
region [ROW vs China for intensive patients only]) will be used.  Should over-stratification 
prevent model convergence or there exists large imbalance in the distribution (eg, 90% or 
more subjects from one strata level), the intermediate and poor cytogenetic risk groups may 
be pooled in the analysis.  EFS time associated with each treatment arm will be summarized 
using the Kaplan-Meier method and displayed graphically where appropriate CIs for the 25th, 
50th, and 75th percentiles of EFS probabilities will be reported (using Brookmeyer and 
Crowley method).44  In addition, the median EFS and its two-sided 95% CI using the 
Brookmeyer and Crowley method45 will be provided for each stratum within each treatment 
arm separately.  The Cox proportional hazards model will be fitted to compute the treatment 
HR and the corresponding 95% CI.  The HR and its two-sided 95% CI will be provided for 
each stratum as well. 
Patient Reported Outcomes
Analysis of patient-reported outcomes will be based on the MDASI-AML/MDS, EQ-5D-5L, 
PGIS, PGIC, 
 
 
 For MDASI-AML/MDS and EQ-5D-5L, a 
completion table will be constructed showing the number and percentage of subjects at each 
time point for each treatment group by each domain. Analysis of MDASI-AML/MDS and 
EQ-5D-5L will be based on their respective subscales as defined in the guidance document 
for each of these instruments.
Particularly, although fatigue is the most commonly experienced symptom among AML 
patients, other symptoms also may be relevant for patients.  Accordingly, analysis of 
MDASI-AML/MDS will be based on the core cancer symptom score, the 
AML/MDS-specific symptom score, the interference areas score, and also the 5 individual 
items of fatigue, disturbed sleep, dry mouth, muscle weakness, and lack of appetite.  Note 
that Fatigue also appears earlier in Section 9.3.2 (as a key secondary endpoint) using a 
responder analysis. 
A display of descriptive statistics including means, medians, standard deviations, and 
95% confidence intervals at each assessment point will be provided. This will be done based 
on the observed values as well as on change from baseline values.  Statistical comparison of 
the 2 treatment groups will be based on a longitudinal repeated measures mixed effects 
model using baseline as a covariate.
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Pharmacokinetic Analysis
PK Parameters:
For intensive and non-intensive studies, the plasma trough concentration (Ctrough) will be 
reported for glasdegib (and metabolite, if relevant). Descriptive statistics will be provided 
for these PK parameters in tabular form (n, mean, standard deviation (Stdev), CV, median, 
minimum, maximum, geometric mean and its associated CV) by cycle (or induction 1,2) and 
day.
PK Concentrations:
For drug concentrations, individual values and descriptive statistics (n, mean, Stdev, CV, 
median, minimum, maximum, geometric mean and its associated CV) will be presented by 
cycle (or induction 1, 2), day of assessment, and nominal time in tabular form. 
Population Pharmacokinetic Analysis or PK/PDx Modeling
PK and pharmacodynamics (PDx) data from this study may be analyzed using modeling 
approaches and may also be pooled with data from other studies to investigate any causal 
relationship between study treatment exposure and biomarkers or significant safety 
endpoints.  The results of these analyses, if performed, may be reported separately.
 
 
 
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9.5. Safety Analysis
9.5.1. Adverse Events
All subjects who receive any study treatment (safety analysis set) will be included in the 
summaries and listings of safety data.  Overall safety profile and tolerability of the 
glasdegib + other study treatment and the placebo + other study treatment arm will be 
characterized by type, frequency, severity, timing, and relationship to study therapy of 
adverse events and laboratory abnormalities.
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE version 4.03. 
In all summaries, emphasis will be placed on treatment emergent adverse events (TEAEs).  
Adverse events will be summarized by the frequency of subjects experiencing treatment 
emergent adverse events corresponding to body systems and MedDRA preferred term and by 
worst NCI CTCAE (version 4.03) grade.  Summaries will also be provided of treatment 
related TEAEs, namely, those judged by the investigator to be related or likely related to 
study drug. 
Adverse events leading to death or discontinuation of study treatment, events classified as 
NCI CTCAE version 4.03 Grade 3 or higher, study drug related events, and serious adverse 
events will be considered with special attention.  Adverse events reporting, including 
suspected unexpected serious adverse reactions, will be carried out in accordance with 
applicable local regulations.
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9.5.2. Laboratory Test Abnormalities
The number and percentage of subjects who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each lab assay, graded according 
to NCI CTCAE version 4.03.  The analyses will summarize laboratory tests both on the 
entire study period and by cycle and/or Induction (Cycle 1 and Cycles beyond 1 or 
Induction 1,2).  Shift tables will be provided to examine the distribution of laboratory 
toxicities.
For laboratory tests without CTC grade definitions, results will be categorized as normal, 
abnormal or not done. 
9.5.3. Baseline Characteristics
Subject characteristics at the time of study entry will be summarized in frequency tables and 
descriptive statistics will be provided for quantitative variables for the full analysis set (see
Section 9.2.1 for definitions of study populations).  Imbalances in subject characteristics in 
the treated populations will be assessed.
9.5.4. Electrocardiogram Analysis
The QT measurements corrected by heart rate (QTc) will be used for the data analysis and 
interpretation.  QTcF is planned to be the primary analysis method for the QTc endpoint.  In 
addition a study-specific correction method (QTcS) and QTcB may also be evaluated for the 
QTc evaluable subjects.  The most appropriate correction method that eliminates any QT vs. 
RR relationship may be chosen after review of the data.
9.5.4.1. Summary and Categorical Analysis of Electrocardiogram Findings
The analysis of ECG results will be based on subjects with both baseline and on-treatment 
ECG data.  All ECGs obtained during the study will be evaluated for safety.  ECG collected 
prior to the first day of dosing will be considered the baseline ECG.
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis as individual values obtained at unscheduled time points.
Data will be summarized and listed for QT, HR, RR, PR, QRS, QTcF and QTcB.  Individual 
QTc (all evaluated corrections) intervals will be listed by time.  The most appropriate 
correction factor will be selected and used for the following analyses of central tendency and 
outliers and used for the study conclusions.
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute QTc value and changes from baseline in QTc after treatment, 
and by treatment and time point.  For each subject by treatment the maximum change from 
baseline will be calculated as well as the maximum post-baseline value across time-points.  
Outlier analysis of the QTc data will be conducted and summarized as follows:


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
The number of subjects with maximum change from baseline in QTc 
(<30, 30-<60, and ≥60 msec);

The number of subjects with maximum post-dose (post-baseline) QTc 
(≤450, >450-≤480, >480- ≤500, and >500 msec);

PR changes from baseline 25% and absolute values >200 msec;

QRS changes from baseline 25% and absolute values >110 msec;

Number and percentage of individuals with abnormal ECG findings.
Shift tables will be provided for baseline versus worst on study QTc (one or more correction 
method will be used). Tables of ECG abnormality at baseline (yes, no, not done: (n, %)) will 
also be provided.  Subjects experiencing clinically-relevant morphological ECG changes will 
be summarized (including frequency and percentage).
9.6. Interim Analyses 
The interim analyses will be performed based on the FAS for the intensive and non-intensive 
chemotherapy population separately and independently of each other.
For the intensive chemotherapy population, two interim analyses are planned.  One efficacy 
and futility interim analysis is planned when 50% of death events have occurred in the 
intensive chemotherapy population.  However, no efficacy stopping will be made even if the 
endpoint crosses the efficacy boundary.  A second interim analysis of efficacy and futility is 
planned when 70% of death events have occurred or upon completion of enrollment of the 
intensive chemotherapy population, whichever is later.  An O’Brien-Fleming boundary with 
Lan-DeMets spending function will be used for efficacy and a Rho(3) -spending function 
will be used for the non-binding futility boundary.  If exactly 50% of the events is accrued at 
the first interim analysis, the futility boundary will be crossed when 1-sided p>0.461.  If 
exactly 70% of the events is accrued at the second interim analysis, the futility boundary will 
be crossed when 1-sided p>0.186 and the efficacy boundary will be crossed when 1-sided 
p<0.007.  If the actual number of events at the interim analyses is different, the 
corresponding spending function will be used to calculate the actual stopping boundaries. 
For the non-intensive chemotherapy population, one interim analysis is planned.  An interim 
analysis of efficacy and futility is planned when 60% of death events have occurred or upon 
completion of enrollment of the non-intensive chemotherapy population, whichever is later.  
An O’Brien-Fleming boundary with Lan-DeMets spending function will be used for efficacy 
and a Rho(3) -spending function will be used for the non-binding futility boundary.  If 
exactly 60% of the events is accrued at the interim analysis, the futility boundary will be 
crossed when 1-sided p>0.302 and the efficacy boundary will be crossed when 1-sided 
p<0.004. If the actual number of events at the interim analyses is different, the 
corresponding spending function will be used to calculate the actual stopping boundaries.


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9.7. Data Monitoring Committee 
This study will use an external data monitoring committee (E-DMC). The study team will 
remain blinded. An unblinded reporting team (separate from the study team) will work with 
E-DMC for the on-going monitoring.
The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the charter.  The recommendations made by the E-DMC to alter the conduct of 
the study will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data
that are not endpoints, to regulatory authorities, as appropriate.  An E-DMC will be convened 
to monitor safety in the study at least once yearly.  The E-DMC will also evaluate the results 
of all interim analyses.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician’s subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects.  The investigator 
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH Good Clinical Practice (GCP), local regulatory requirements, and legal 
requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process and any subject
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.


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The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed. The investigator 
will retain the original of each subject's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in All Participating Countries 
End of Study in all other participating countries is defined as Last Subject Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
glasdegib at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 14 days.  As directed by Pfizer, all study materials must be collected 
and all CRFs completed to the greatest extent possible.
After the end of the trial, the continuation of treatment; such as in an extension study, for 
those patients who are still receiving benefit in the non-intensive study may be decided based 
upon availability of alternative treatment options.  An extension study would not be 
available for patients who receive HSCT within the non-intensive study. Non-intensive 
study subjects who receive HSCT would continue blinded therapy for up to 2 years post 
randomization, upon PD, relapse, consent withdrawal, or upon conversion to MRD-negative 
disease at 2 consecutive timepoints; whichever comes first. 


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15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in subjects) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual subjects has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.


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The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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Kalbfleisch JaP, RL.  The statistical analysis of failure time data. New York: John 
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Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute 
GVHD Grading. Bone marrow transplantation 1995; 15(6): 825-8.
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Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host 
Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow 
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Shulman HM, Cardona DM, Greenson JK, et al. NIH Consensus development project 
on criteria for clinical trials in chronic graft-versus-host disease: II. The 2014 
Pathology Working Group Report. Biol Blood Marrow Transplant 2015; 21(4): 
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for symptoms and symptom burden of acute myeloid leukemia (AML) and 
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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
AE
adverse event
AHD
antecedent haematologc disease
ALT
alanine aminotransferase
ALL
Acute Lymphoblastic Leukemia
AML
Acute Myelogenous Leukemia
ANC
absolute neutrophil count
APL
Acute Promyelocytic Leukemia
Ara-C
Cytarabine
ASCO
American Society for Clinical Oncology
AST
aspartate aminotransferase
ATRA
all-trans retinoic acid
AUC
area under the curve
AUCinf
area under the plasma concentration-time profile from time 0 to 
infinity
AZA
azacitidine
BCR-ABL1
BCR-ABL breakpoint cluster region-Abelson 1
BID
twice a day
BM
bone marrow
BSA
body surface area
BST
best supportive therapy
Ca
calcium
Cavg ss
steady state average concentration
CALGB
Cancer and Leukemia Group B
CBC
complete blood count
C#D#
Cycle # Day #
CD
cluster of differentiation
CDF
cumulative distribution functions
CI
confidence interval
CID
clinically important difference
CK
creatine kinase
Cmax
maximum plasma concentration
CMH
Cochran Mantel Haenszel
CMML
Chronic myelomonocytic leukemia
CNS
central nervous system
CR
complete remission
CRh
complete remission with partial hematologic recovery
CRi
complete remission with incomplete hematologic recovery
CCI
CCI


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Abbreviation
Term
CRMRD-neg
complete remission with negative minimal residual disease
CRF
case report form
CSA
clinical study agreement
CT
clinical trial
CTC
common terminology criteria
CTCAE
common terminology criteria for adverse events
Ctrough
plasma trough concentration
CV
coefficient of variation
DDI
Drug-drug interaction
DILI
drug-induced liver injury
DLT
dose limiting toxicity
DoR
duration of response
DoRi
duration of response (response is defined as CRi or better)
DoRh
duration of response (response is defined as CRh or better)
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EFS
event-free survival
ELN
European Leukemia Net
EQ-VAS
EQ-5D visual analogue scale
EU
European Union
EudraCT
European Clinical Trials Database
EQ-5D-5L
EuroQol 5-Dimension questionnaire 5-Level version
FAS
full analysis set
FDA
Food and Drug Administration
FIP
first-in-participant
FLT3-ITD
fms-like tyrosine kinase internal tandem duplication
FSH
follicle-stimulating hormone
fu
fraction unbound
GCP
good clinical practice
G-CSF
granulocyte-colony stimulating factor
GGT
gamma-glutamyl transferase
GLI
glioma-associated oncogene homolog 1
GLP
good laboratory practice
GM-CSF
granulocyte-macrophage colony stimulating factor
GVHD
graft-versus-host disease
hCG
human chorionic gonadotropin
CCI


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Abbreviation
Term
HDPE
high density polyethylene
HGRAC
Human Genetics Resources Administration of China
Hh
hedgehog
HIDAC
high dose Ara-C
HIV
human immunodeficiency virus
HR
Hazard ratio
HRQL
health-related quality of life
HRT
hormone replacement therapy
HSCT
hematopoietic stem cell transplant
IB
Investigator Brochure
ICH
International Conference on Harmonisation
ID
identification
IIR
investigator-initiated research
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous
IVR
interactive Voice Response
IWR
interactive web response
JAK
janus kinase
K
potassium
LDAC
low-dose cytarabine
LFT
liver function test
LIC
lead-in cohort
LSC
leukemia stem cells
LSLV
last subject last visit 
LVEF
left ventricular ejection fraction
MD
medical doctor
MDASI
MD Anderson Symptom Inventory 
MDR-1
multi-drug resistance-1
MDS
myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MF
myelofibrosis
Mg
magnesium
MLFS
morphologic leukemia-free state
MnB
meningitidis serogroup B
MRD
minimal residual disease
MTD
maximum tolerated dose
MUGA
multigated acquisition scan
CCI


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Abbreviation
Term
mCR
marrow complete remission
mOS
median overall survival
n
number
NCI
National Cancer Institute
NIH
National Institutes of Health
N/A
not applicable
NOAEL
no observed adverse effect level
NPM1
nucleophosmin 1
NRS
numeric rating scale
OS
overall survival
PCD
primary completion date
PD
progressive disease
PDx
pharmacodynamics(s)
PE
physical examination
PEG
pegylated
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Symptoms
P-gp
p-glycoprotein
PGx
pharmacogenomics(s)
PH
potential of hydrogen
PK
pharmacokinetic
PML-RARA
Promyelocytic leukemia – retinoic acid receptor alpha
PO
by mouth, orally
PR
partial remission
PRO
patient reported outcomes
PT
prothrombin time
PTCH
patched
QALY
quality-adjusted life years
QD
once a day
QTc
QT interval corrected for rate
QTcF
QT interval corrected by the Fridericia Correction Formula
Rac
accumulation ratio
RMST
restricted mean survival time
RNA
ribonucleic acid
ROW
rest of world
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SCT
stem cell transplant
SD
stable disease
CCI


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Abbreviation
Term
SMO
smoothened
SoA
schedule of activities
SOP
standard operating procedure
SPC
summary of product characteristics
SRSD
single reference safety document
Stdev
standard deviation
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TdP
torsades de pointes
TEAE
treatment emergent adverse events
TESAE
treatment emergent serious adverse events
TF
treatment failure
TKI
tyrosine kinase inhibitor
Tmax
time to maximum plasma concentration
TTR
time to response
TTRi
time to response (response is defined as CRi or better)
TTRh
time to response (response is defined as CRh or better)
U/A
urinalysis
ULN
upper limit of normal
US
United States
UVB
ultraviolet B light
Vz/F
Apparent volume of distribution
WHO
World Health Organization
CCI


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Appendix 2. 2016 WHO Classification of Myeloid Neoplams and Acute Leukemia


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Arber DA, Orazi A, Robert, H, et.al. The 2016 revision to the World Health Organization classification of 
myeloid neoplasms and acute leukemia. Blood.  2016; 127 (20): 2391-2405.


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Appendix 3. Eastern Cooperative Oncology Group Performance Status
ECOG PERFORMANCE STATUS*
Grade ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities.  
Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or chair
5
Dead
* Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group.  Am J Clin Oncol 5:649-655, 1982.
By the Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.


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Appendix 4. Summary of Response Criteria and Progression Definitions for AML Treated with Intensive and Non-Intensive 
Chemotherapy used in BRIGHT AML1019
Response Criteria1
Minimal 
residual 
disease1
(per central 
lab report 
only)
Peripheral Blood
Bone Marrow 
Blasts (%)
Other
Neutrophils
Platelets 
Peripheral 
Blasts (%)
Treatment Response
Complete Remission 
without minimal 
residual disease 
(CRMRD-)
MRD 
Negative
1 x 109 /L
(1000µL)
100 x 109/L 
(100 000µL)
0
<5
Complete Remission 
(CR)
MRD 
positive or 
unknown
1 x 109 /L
(1000µL)
100 x 109/L 
(100 000µL)
0
<5

Absence of extramedullary disease.

Absence of blasts with Auer rods.
Complete Remission 
with partial 
hematologic 
recovery (CRh)2
APPLIES ONLY FOR THE 
NON-INTENSIVE STUDY
MRD 
positive or 
unknown
0.5 x 109/L
(500µL)
50 x 109/L
(50 000µL)
0
<5

Assess in non-intensive chemotherapy study only, 
not qualifying for CR, ie, both neutrophil 
≥0.5 x 109/L and platelets ≥50 x 109/L must be met, 
but does not satisfy both Neutrophils ≥1 x 109/L 
and Platelets 100 x 109/L at the same time.

Absence of extramedullary disease.

Absence of blasts with Auer rods.
Complete Remission 
with incomplete 
hematologic 
recovery (CRi)
MRD 
positive or 
unknown
< 1 x 109/L
(<1000µL)
<100 x 109/L 
(<100 000µL)
0
<5

Not qualifying for CR or CRh (if applicable), ie,

For intensive chemotherapy study: either 
neutropenia (<1 x 109 /L) or platelets 
(<100 x 109 /L) must be met.

For non-intensive chemotherapy study, either 
neutrophil <0.5 x 109/L or platelets <50 x 109/L) 
must be met.

Absence of extramedullary disease.

Absence of blasts with Auer rods.
Morphologic 
leukemia-free state 
(MLFS)
MRD 
positive or 
unknown
< 5

Absence of extramedullary disease.

Absence of blasts with Auer rods.

No hematologic recovery required; marrow should 
not be aplastic; at least 200 cells enumerated or 
cellularity 10%.
Partial Remission 
MRD 
1 x 109/L
100 x 109/L 
0
Decrease to 


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(PR)
positive or 
unknown
(1000µL)
(<100 000µL)
5 – 25% AND 
Decrease of pre 
treatment bone 
marrow blast 
percentage by at 
least 50%.
Response criteria for clinical trials
Stable Disease (SD)

Absence of CRMRD-, CR, CRh (if applicable), CRi, PR, MLFS, and criteria for PD not met.

Period of stable disease should be at least 3 months in the non-intensive only. The 3 month criteria does not apply to the intensive study.
Progressive Disease 
(PD)

Evidence for an increase in bone marrow blast percentage and/or increase of absolute blast counts in blood:

>50% increase over baseline (a minimum 15% point increase in cases with <30% blasts at baseline); or persistent marrow blast percentage of 
>70% over at least 3 months; without at least a 100% improvement in ANC to an absolute level (>0.5x109/L [500/µL], and/or platelet count to 
>50x109/L [50 000/µL] non-transfused); OR

>50% increase in peripheral blasts (WBC x %blasts) to >25x109/L (>25 000/µL) OR New extramedullary disease.
Indeterminate
A response that does not fit the criteria for SD or PD. For example, when peripheral blood blast count assessed and no bone marrow assessment, or 
when a technical issue prevents the ability to make a response assessment (ie dry tap or insufficient sample), or when an SD is not maintained for 
3 months in the non-intensive study. 
Other Responses referenced in ELN 20173
Relapse
Hematologic relapse 
(after CRMRD-, CR, 
CRi)
Reappearance of blasts in peripheral blood; OR
5% bone marrow blasts; OR
Development of extramedullary disease.
Molecular Relapse 
(after CRMRD-)
Reoccurrence of MRD positive status. 
Treatment Failure
Primary refractory 
disease
For Intensive study: No CR or CRi after 2 courses of induction treatment; excluding patients with death in aplasia or death due 
to indeterminate cause.
For Non-Intensive study: failure to achieve CR or CRh following up to 6 cycles of study treatment, excluding patients with 
death in aplasia or death due to indeterminate cause.
Death in aplasia
Deaths occurring ≥7 days following completion of initial treatment while cytopenic; with an aplastic or hypoplastic bone 
marrow obtained within 7 days of death, without evidence of persistent leukemia.
Death from 
indeterminate cause
Deaths occurring before completion of therapy, or <7 days following its completion or deaths occurring ≥7 days following 
completion of initial therapy with no blasts in the blood, but no bone marrow examination available.


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1.
This study uses modified 2017 ELN recommendations. The definitions used in this study are shown in this table. Original ELN recommendations are found in: Dohner H, 
Etstey E, Grimwade D, et.al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017; 129 (4): 424-447.
2.
CRh is not part of the 2017 ELN recommendations, but is a required assessment for the non-intensive chemotherapy study.
3.
2017 ELN recommendations are found in: Dohner H, Etstey E, Grimwade D, et.al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an 
international expert panel. Blood. 2017; 129 (4):424-447.


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Appendix 8. List of Drugs with Known Risk of Torsade de Pointes
The following drugs are known to have the risk of Torsade de Pointes due to QTc 
prolongation and their current use in combination with glasdegib is not recommended.  If any 
of these drugs are considered to be medically necessary, then they should be used with 
caution in combination with glasdegib.
Generic Name
Drug Class
Therapeutic Use
Route
Aclarubicin (Only 
on Non US Market)
Anti-cancer
Cancer
injection
Amiodarone
Anti-arrhythmic
Abnormal heart rhythm
oral, injection
Anagrelide
Phosphodiesterase 
3 inhibitor
Thrombocythemia
oral
Arsenic trioxide
Anti-cancer
Leukemia
injection
Astemizole 
(Removed from 
Market)
Antihistamine
Allergic rhinitis
oral
Azithromycin
Antibiotic
Bacterial infection
oral, injection
Bepridil 
(Removed from 
Market)
Anti-anginal
Heart pain
oral
Chloroquine
Anti-malarial
Malaria infection
oral
Chlorpromazine
Anti-psychotic/
Anti-emetic
Schizophrenia/nausea
Many others
oral, injection,
suppository
Cilostazol
Phosphodiesterase 
3 inhibitor
Intermittent claudication
oral
Ciprofloxacin
Antibiotic
Bacterial Infection
oral, injection
Cisapride 
(Removed from 
Market)
GI stimulant
Increase GI motility
oral
Citalopram
Anti-depressant, SSRI
Depression
oral
Clarithromycin
Antibiotic
Bacterial infection
oral, inhaled
Cocaine
Local anesthetic
Anesthesia (topical)
oral, nasal
Disopyramide
Anti-arrhythmic
Abnormal heart rhythm
Oral, injection
Dofetilide
Anti-arrhythmic
Abnormal heart rhythm
oral
Domperidone Only 
on Non US market
Anti-emetic
Nausea, vomiting
oral, injection,
suppository
Donepezil
Cholinesterase 
inhibitor
Dementia (Alzheimer’s 
Disease)
oral
Dronedarone
Anti-arrhythmic
Atrial Fibrillation
oral
Droperidol
Anti-psychotic/
Anti-emetic
Anesthesia adjunct, 
nausea
injection
Erythromycin
Antibiotic
Bacterial infection; 
increase GI motility
oral, injection


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Generic Name
Drug Class
Therapeutic Use
Route
Escitalopram
Anti-depressant, SSRI
Major depression/ 
Anxiety disorders
oral
Flecainide
Anti-arrhythmic
Abnormal heart rhythm
oral
Fluconazole
Anti-fungal 
Fungal infection
oral, injection
Gatifloxacin 
(Removed from 
Market)
Antibiotic
Bacterial infection
oral, injection
Grepafloxacin 
(Removed from 
Market)
Antibiotic
Bacterial infection
oral
Halofantrine (Only 
on Non US market)
Anti-malarial
Malaria infection
oral
Haloperidol
Anti-psychotic
Schizophrenia, agitation
oral, injection
Ibogaine (Only on 
Non US market)
Psychedelic
Narcotic addiction, 
unproven
oral
Ibutilide
Anti-arrhythmic
Abnormal heart rhythm
injection
Levofloxacin
Antibiotic
Bacterial infection
oral, injection
Levomepromazine 
(methotrimeprazine) 
(Only on Non US 
Market)
Anti-psychotic
Schizophrenia
oral, injection
Levomethadyl 
(Removed from 
Market)
Opiate
Narcotic dependence
oral
Mesoridazine 
(Removed from 
Market)
Anti-psychotic
Schizophrenia
oral
Methadone
Opiate
Pain control, narcotic 
dependence
oral, injection
Moxifloxacin
Antibiotic
Bacterial infection
oral, injection
Ondansetron
Anti-emetic
Nausea, vomiting
oral, injection
Oxaliplatin
Anti-cancer
Cancer
injection
Papaverine HCl 
(Intra-coronary)
Vasodilator, Coronary
Diagnostic adjunct
injection
Pentamidine
Anti-fungal
Pneumocystis 
pneumonia
injection, 
inhaled
Pimozide
Anti-psychotic
Tourette's tics
oral
Probucol 
(Removed from 
Market)
Antilipemic
Hypercholesterolemia
oral
Procainamide 
Anti-arrhythmic
Abnormal heart rhythm
injection
Propofol
Anesthetic, general
Anesthesia
injection
Quinidine
Anti-arrhythmic
Abnormal heart rhythm
oral, injection


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Generic Name
Drug Class
Therapeutic Use
Route
Roxithromycin 
(Only on Non US 
market)
Antibiotic
Bacterial infection
oral
Sevoflurane
Anesthetic, general
Anesthesia
inhaled
Sotalol
Anti-arrhythmic
Abnormal heart rhythm
oral
Sparfloxacin 
(Removed from 
market)
Antibiotic
Bacterial infection
oral
Sulpiride 
(Only on Non US 
market).
Anti-psychotic, 
atypical
Schizophrenia
Oral, inhaled
Terfenadine 
(Removed from 
market)
Antihistamine
Allergic rhinitis
oral
Terlipressin (Only 
on Non US market)
Vacoconstrictor
Septic shock
injection
Terodiline (Only on 
Non US market)
Muscle relaxant
Bladder spasm
oral
Thioridazine
Anti-psychotic
Schizophrenia
oral
Vandetanib
Anti-cancer
Thyroid cancer
oral
US = United States.
Source: Credible Meds.org (http://crediblemeds.org/healthcare-providers/drug-list/?rf=All). TdP risk category 
filtered on Drugs with known TdP risk. Accessed 26 October 2018.


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Appendix 14. 2017 ELN Risk Stratification by Genetics


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Appendix 15. 2017 Recommended staging and grading of acute GVHD
Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone 
marrow transplantation 1995; 15(6): 825-8.


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Appendix 16. France Appendix
This appendix applies to study sites located in France.
1. GCP Training.
Prior to enrollment of any subjects, the investigator and any sub-investigators will complete 
the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP Training”) or 
training deemed equivalent by Pfizer.  Any investigators who later join the study will 
complete the Pfizer GCP Training or equivalent before performing study-related duties.  For 
studies of applicable duration, the investigator and sub-investigators will complete Pfizer 
GCP Training or equivalent every three years during the term of the study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials.
2. Investigational Product.
No subjects or third-party payers will be charged for investigational product.
3. Inspections.
The investigator(s) will notify Pfizer or its service provider immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with Pfizer or its service provider to prepare the study site for the inspection and will allow 
Pfizer or its service provider (if not prohibited by law) to be present during the inspection.  
The study site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the subject's medical records.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its service provider.  Before response 
submission to the regulatory authorities, the investigator will provide Pfizer or its service 
provider with an opportunity to review and comment on responses to any such findings.
4. Record Retention.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.  The 
investigator must obtain Pfizer’s written permission before disposing of any records, even if 
retention requirements have been met.
5. Urgent Safety Measures.
The investigator will inform Pfizer immediately of any urgent safety measures taken by the 
investigator to protect the study subjects against any immediate hazard, and of any serious 
breaches of this protocol or of ICH GCP that the investigator becomes aware of.


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6. Termination Rights.
7. Pfizer retains the right to discontinue development of <investigational product> at 
any time.
8. Studies Involving Human Cell, Tissue, and/or Organ Transplants.
9. The investigator agrees to abide by the ethical principles set forth in the World Health 
Organization’s Guiding Principles for Human Cell, Tissue and Organ Transplantation 
(WHA63.22), http://www.who.int/transplantation/en/ with regard to the study.

SAP_001.pdf: 
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Protocol B1371019  
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
Statistical Analysis Plan 
(SAP)
Version:
5.0
Date:
14-Apr-2020


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TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
LIST OF TABLES.....................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................6
2.1. Study Objectives .......................................................................................................6
2.2. Study Design .............................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9
3.1. Primary Endpoint ......................................................................................................9
3.2. Secondary Endpoints.................................................................................................9
3.2.1. Efficacy Endpoints........................................................................................9
3.2.2. Safety Endpoints.........................................................................................13
3.2.3. PRO Endpoints ...........................................................................................13
3.2.4. Other Endpoints..........................................................................................15
15
3.4. Baseline Variables...................................................................................................16
3.4.1. Stratification ...............................................................................................16
3.5. Safety Endpoints .....................................................................................................17
3.5.1. Adverse Events...........................................................................................17
3.5.2. Laboratory Data..........................................................................................18
4. ANALYSIS SETS ...............................................................................................................18
4.1. Full Analysis Set .....................................................................................................18
4.2. Per Protocol Analysis Set........................................................................................18
4.3. Safety Analysis Set..................................................................................................18
4.4. Other Analysis Sets .................................................................................................19
4.4.1. Pharmacokinetics Analysis Set...................................................................19
19
4.4.3. China Sub-Population Analysis Sets ..........................................................19
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................19
5.1. Hypotheses and Decision Rules ..............................................................................19
5.1.1. Hypotheses and Sample Size Section.........................................................19
5.1.2. Decision Rules............................................................................................21
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5.2. General Methods .....................................................................................................22
5.2.1. Pooling of Data by Center ..........................................................................22
5.2.2. Definition of Study Day..............................................................................22
5.2.3. Definition of Cycle and Cycle Day ............................................................23
5.2.4. Date of Last Contact ...................................................................................24
5.2.5. Disease Assessment Date ...........................................................................25
5.2.6. Unscheduled Assessments..........................................................................25
5.2.7. Standard Derivations and Reporting Conventions .....................................25
5.2.8. Analyses for Continuous Data....................................................................26
5.2.9. Analyses for Categorical Data....................................................................26
5.2.10. Analyses for Time to Event Data..............................................................26
5.3. Methods to Manage Missing Data ..........................................................................26
5.3.1. Missing Dates .............................................................................................27
5.3.2. Missing Toxicity Grade of Adverse Events................................................30
5.3.3. Missing Pharmacokinetic (PK) Data ..........................................................30
5.3.4. Missing ECG Data......................................................................................31
31
6. ANALYSES AND SUMMARIES ......................................................................................31
6.1. Primary Endpoint - Overall Survival ......................................................................31
33
6.2. Secondary Endpoints...............................................................................................34
6.2.1. Fatigue ........................................................................................................34
6.2.2. Responses ...................................................................................................36
6.2.3. Duration of Response .................................................................................36
6.2.4. Time to Response (Non-intensive Only) ....................................................37
6.2.5. Event-free Survival.....................................................................................37
6.2.6. Patient-Reported Outcomes........................................................................37
6.3. Other Endpoints.......................................................................................................39
39
39
6.3.3. Pharmacokinetic Analysis ..........................................................................40
6.3.4. Population Pharmacokinetic Analysis or PK/PDx Modeling.....................41
41
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6.5. Baseline and Other Summaries and Analyses.........................................................42
6.5.1. Baseline Summaries....................................................................................42
6.5.2. Study Conduct and Patient Disposition......................................................44
6.5.3. Study Treatment Exposure .........................................................................45
6.5.4. Concomitant Medications and Non-Drug Treatments................................49
6.5.5. Prior and Subsequent Anti-Cancer Therapies/Procedures..........................50
6.6. Safety Summaries and Analyses .............................................................................50
6.6.1. Adverse Events...........................................................................................50
6.6.2. Deaths .........................................................................................................53
6.6.3. Laboratory Data..........................................................................................54
6.6.4. Vital Signs ..................................................................................................56
6.6.5. Electrocardiogram.......................................................................................57
6.6.6. Physical Examination .................................................................................59
6.6.7. Left Ventricular Ejection Fraction (LVEF) ................................................59
6.6.8. Performance Status.....................................................................................59
59
7. INTERIM ANALYSES.......................................................................................................59
7.1. Introduction .............................................................................................................59
7.2. Interim Analyses and Summaries............................................................................60
8. REFERENCES ....................................................................................................................61
9. APPENDIX..........................................................................................................................63
9.1. Note on Defining CIR for “Fatigue” Single-item from the MDASI 
AML/MDS Questionnaire.........................................................................................63
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................5
Table 2.
Planned Stopping Boundaries for Overall Survival at Interim 
Analyses and Final Analysis for the Intensive Chemotherapy Study.......21
Table 3.
Planned Stopping Boundaries for Overall Survival at Interim 
Analyses and Final Analysis for the Non-Intensive Chemotherapy 
Study.........................................................................................................22
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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B1371019 is based on Protocol Amendment
#5 dated 12Apr2019 and the Type B supplemental new drug application (sNDA) meeting 
with the Food and Drug Administration (FDA) on 23Mar2020. 
Table 1.
Summary of Major Changes in SAP Amendments
SAP 
Version
Change
Rationale
1
Not Applicable
Not Applicable
2
The PRO sections were 
revised following 
comments from FDA.
Minor clarifications were 
made in other sections.
Following protocol Amendment #2
3
The Pharmacogenomics 
Analysis Set was 
removed. 
Clarification regarding 
select endpoints were 
made (CRi or better, and 
CRh or better).
Add analysis method for 
China subset patients.
Following Protocol Amendment #3 and 
satisfying CFDA requirement
4
Region (rest of world 
versus China) added as a 
stratification factor to the 
applicable efficacy 
analyses for the intensive 
study.
Updated the definition of 
“on-treatment” for 
assessments and 
treatment-emergent 
adverse events.
Following Protocol Amendment #5
5
Add OS subgroup
analysis.
Following FDA feedback


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Add sensitivity analyses 
for handling potential 
missing or unclean data
due to COVID-19.
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data
collected in study B1371019.  This analysis plan is meant to supplement the study protocol. 
Any deviations from this analysis plan will be described in the Clinical Study Report.
The analyses of this study will include all data up to a data cutoff date which will be 
determined by the number of overall survival (OS) events.  All summaries and analyses will 
include all data pertaining to visits/assessments performed up to and including the data cutoff 
date.
Due to cleaning activities, the final number of events might deviate from the planned 
number. The data cut-off date will not be adjusted retrospectively in this case. 
2.1. Study Objectives
Primary Objective

To demonstrate that glasdegib is superior to placebo in combination with azacitidine 
(non-intensive study) or cytarabine and daunorubicin (intensive study) in prolonging 
OS in subjects with untreated AML.
Secondary Objectives:

To compare fatigue score post baseline as measured by MDASI AML/MDS in both 
treatment arms;

To compare glasdegib versus placebo in combination with azacitidine (non-intensive 
study) or ‘7+3’ (cytarabine and daunorubicin) in improving other clinical efficacy 
measures;

To estimate the duration of response in both treatment arms;

To estimate the time to response in both treatment arms in the Non-intensive study 
only;

To compare Event-free Survival (EFS) in both treatment arms;

To compare PRO measurements in both treatment arms;

To evaluate the overall safety profile in both treatment arms;

To evaluate laboratory abnormalities in both treatment arms;


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•
To characterize the PK of glasdegib;
•
To characterize treatment effects on the QTc interval.
 
 
2.2. Study Design
Two separate registration trials conducted under one protocol number are proposed to 
adequately and independently evaluate the addition of glasdegib in intensive and
non-intensive chemotherapy populations.  Each study will have an experimental treatment 
arm and a placebo arm.
Study B1371019 (Figure 1) is a randomized (1:1), double-blind, multi-center, placebo 
controlled study of chemotherapy in combination with glasdegib versus chemotherapy in 
combination with placebo in adult patients with previously untreated AML (excluding APL 
with PML-RARA, AML with BCR-ABL1 and active central nervous system [CNS] 
leukemia) to support the proposed indication statements: 
•
Intensive Study: Glasdegib is being studied in combination with cytarabine and 
daunorubicin for the treatment of adult patients with untreated AML. 
•
Non-intensive Study: Glasdegib is being studied in combination with azacitidine for 
the treatment of adult patients with untreated AML who are not candidates for 
intensive induction chemotherapy.
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Figure 1.
Schematic of Study Design
* Protocol Section 5.5 describes dosing details for the intensive chemotherapy regimen(s) [including ‘7+3’ or 
‘5+2’ option for Induction 2], non-intensive chemotherapy regimen, and experimental study drugs.
Assignment to the Intensive Study or the Non-Intensive Study will be made by the 
Investigator based on the 2017 ELN recommendations.
The treatment arm allocation for Arm A or Arm B within each study will be operated by the 
sponsor following the rules defined in Protocol Section 5.1. 
Intensive Chemotherapy Study: 
A total of 400 subjects eligible to receive intensive chemotherapy per investigator assessment 
will receive treatment. Subjects will be stratified by genetic risk (favorable vs intermediate 
vs adverse by ELN genetic risk categories) and age (≤60 years vs >60 years) at 
randomization.  
A total of 267 death events would provide 90% power to detect an improvement in overall 
survival (translated in median OS [mOS] from 21 months to 31.5 months) assuming a 
composite mOS for the population as follows: young AML (aged ≤60 years) with a mOS of 
23.7 months and elderly AML (aged >60 years) with a mOS of 15 months assuming a 
70% young and 30% elderly AML split12,13 and with an HR=0.67 using a 1-sided log-rank 
test at a significance level of 0.025 and a 3-look group-sequential design.  
Two interim analyses will be conducted: an early efficacy and futility interim analysis of OS 
after 50% death events occur (no plan to stop for efficacy even if the efficacy boundary is 
crossed) and an efficacy and futility analysis of OS after 70% death events occur in the 
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Non-Intensive Chemotherapy Study:
A total of 320 subjects who are not candidates to receive Intensive Chemotherapy will 
receive treatment. Subjects will be stratified by genetic risk (favorable vs intermediate vs 
adverse by ELN genetic risk categories) and age (<75 years vs ≥75 years) at randomization.
A total of 220 death events would provide 90% power to detect an improvement in overall 
survival (translated in mOS from 10.4 months14 to 16.2 months) with an HR=0.64 using a 
1-sided log-rank test at a significance level of 0.025 and a 2-look group-sequential design.  
One interim efficacy and futility analysis of OS would be planned after 60% death events 
occur in the non-intensive chemotherapy population or upon completion of enrollment of 
these subjects, whichever is later.  
The interim and final analyses of the intensive chemotherapy and non-intensive 
chemotherapy populations will be conducted separately and independently of each other.  
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
Of note, the primary endpoint of OS is assessed based on all available data in the database 
and other secondary response endpoints are assessed by the investigator using local 
hematology, chemistry, bone marrow assessments, etc.  Patients will complete PRO
questionnaires in site tablets that will be collected by a central vendor.  MRD results are
determined by a central laboratory.  Time to event and duration endpoints will be derived 
programmatically.
3.1. Primary Endpoint
OS is defined as the time from the date of randomization to the date of death due to any 
cause.  Subjects last known to be alive will be censored at date of last contact.
3.2. Secondary Endpoints
3.2.1. Efficacy Endpoints
Secondary efficacy endpoints will be summarized based on data up to initiation of a new 
anti-cancer drug therapy, if applicable.
Fatigue 
The response for the single item “Fatigue (tiredness)” (one of the 13 MDASI core cancer 
symptoms) will be analyzed as a key secondary efficacy endpoint.  This specific item is 
measured at the patient’s WORST level in the last 24 hours and asks a patient to respond on a 
0-10 numeric rating scale (NRS), where 0 = “not present” and 10 = “as bad as you can 
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Disease specific efficacy endpoints
CR, CRMRD-neg (a subgroup of CR), CRi, Morphological Leukemia Free State, and Partial 
Remission, as defined according to the 2017 ELN recommendations, and CR with partial 
hematologic recovery (CRh) for the Non-intensive study only. Note that CR (including 
CRMRD-neg) is a deeper response than CRh, and CRh is a deeper response than CRi. CR 
(including CRMRD-neg) is always a deeper response than CRi.
Note that patients whose MRD status cannot be determined (eg, due to lack of proper 
identification of a baseline immunophenotype from aspirate or peripheral blood) will not be 
allowed to resume single-agent therapy post HSCT or post consolidation. An MRD status 
will not be determined and the best response possible will be CR with no MRD status 
associated with the response.
Following Consolidation or following HSCT, the MRD result must be confirmed by 
2 consecutive central laboratory results. Once confirmed, this will be used as the MRD 
result. 
Duration of Response 
Intensive Chemotherapy Study
Duration of Response (DoRi) is only defined for subjects who have ever achieved CRi or 
better on study as the time from date of first achieving CRi or better to the date of relapse 
after CRi or better or death due to any cause.  Subjects last known to be alive who are free 
from relapse after CRi or better are censored at the date of last disease assessment that 
verifies their status.  Note that in this study CRi or better includes CR and CRi. 
Non-Intensive Chemotherapy Study
DoRi is only defined for subjects who have ever achieved CRi or better on study as the time 
from date of first achieving CRi or better to the date of relapse after CRi or better or death 
due to any cause.  We also define DoRh for subjects who have ever achieved CRh or better
on study as the time from date of first achieving CRh or better to the date of relapse after 
CRh or better or death due to any cause.  Note that in this study, CRi or better includes CR, 
CRh, and CRi, and CRh or better only includes CR and CRh.   
Time to Response (Non-Intensive Study only)
Time to Response (TTRi) is only defined for subjects who have ever achieved CRi or better
on study as the time from date of randomization to date of first achieving CRi or better. 
Similarly, TTRh is only defined for subjects who have ever achieved CRh or better on study 
as the time from date of randomization to date of first achieving CRh or better. 


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Event Free Survival
Intensive Chemotherapy Study
For the Intensive chemotherapy patients, Event Free Survival (EFS) is defined as the time 
from the date of randomization to the date of treatment failure (TF), relapse from CR, or 
death from any cause, whichever comes first. TF is defined as failure to achieve CR during 
the induction cycle (including the re-induction cycle if there is one) and the event date for 
TF is the day of randomization (ie, EFS of 1 day). Responders last known to be alive who 
are free from disease progression or relapse are censored at the date of last disease 
assessment that verifies their status.
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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Non-Intensive Chemotherapy Study
For Non-intensive chemotherapy patients, EFS is defined as the time from the date of 
randomization to the date of TF, relapse from CRh or better, or death from any cause, 
whichever comes first. TF is defined as failure to achieve CRh or better following up to 
6 cycles of study treatment and the event date for TF is the day of randomization.  Patients 
who discontinue either study treatment without achieving CRh or better prior to completing 
6 cycles of study treatment are considered treatment failures. Responders last known to be 
alive who are free from disease progression or relapse are censored at the date of last disease
assessment that verifies their status.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.2.2. Safety Endpoints
AEs (graded by NCI CTCAE v.4.03 as provided by the investigator on the AE CRF page); 
laboratory abnormalities (graded by NCI CTCAE v.4.03 as programmatically derived based 
on laboratory values); vital signs (blood pressure, pulse rate) and body weight; 
electrocardiograms (ECGs); echocardiogram or multigated acquisition (MUGA) scan; 
ophthalmologic data.
3.2.3. PRO Endpoints
Patient reported outcomes will be assessed using the MD Anderson Symptom Inventory 
AML/MDS Module (MDASI-AML/MDS), EuroQol 5-Dimension questionnaire 5-Level 
version (EQ-5D-5L), Patient Global Impression of Symptoms (PGIS), and Patient Global 
Impression of Change (PGIC).  
MDASI-AML/MDS
The MDASI-AML/MDS is a validated modulized patient reported outcome measure for 
AML and MDS. It consists of a 19-item core cancer module and a 4-item AML/MDS 
specific module.  The 23 items are designed to measure 13 core cancer symptoms (pain, 
fatigue, nausea, disturbed sleep, distress, shortness of breath, problem remembering, lack of 
appetite, drowsiness, dry mouth, sadness, vomiting, and numbness), 4 AML/MDS-specific 
symptoms (malaise, diarrhea, muscle weakness, and skin problems), and 6 areas of
interference (general activity, mood, work, walking, relations with other people, and 
enjoyment of life).
Patients are asked to rate the severity of symptoms and related interference at their WORST 
level in the last 24 hours by responding to each item on an 0-10 numeric rating scale (NRS), 
where 0 = “not present” or “did not interfere” and 10 = “as bad as you can imagine” or 
“interfered completely”.  
For this study, the response for the single item “Fatigue” (one of the 13 MDASI core cancer 
symptoms) will be analyzed separately as the key secondary efficacy endpoint.
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Note that the electronic system capturing PRO data is set up in such a way that no questions 
on a questionnaire can be skipped. Hence, the questionnaires are either 100% or 
0% completed. 
EQ-5D-5L
The EQ-5D-5L is a brief, self-administered, validated and reliable generic health status 
instrument developed by the EuroQoL Group.  It consists of the EQ-5D descriptive system 
and a visual analogue scale (VAS), the EuroQoL visual analogue scale (EQ-VAS).  
The EQ-5D descriptive system measures a patient’s health state on 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression.  The patient is asked to 
indicate his/her health state by rating each dimension on a five-level scale (1=no problem, 
5=extreme problem).  This rating resulted in a 5-digit number describing the respondent’s 
health state.  It should be noted that the numerals 1-5 have no arithmetic properties and 
should not be used as a cardinal score. 
The EQ-5D Index scores are country specific and range generally from 0 to 1, with 0 
representing the worst health state and 1 as perfect health.  The index values, presented in 
country specific value sets, are a major feature of the EQ-5D instrument, facilitating the 
calculation of quality-adjusted life years (QALYs) that are used to inform economic 
evaluations of health care interventions.
The EuroQoL visual analogue scale (EQ VAS) records the respondent’s self-rated health on 
a 20-cm vertical, visual analogue scale from 0 (worst imaginable health state) to 100 (best 
imaginable health state).  This information could then be used as a quantitative measure of 
health as judged by the individual respondents.
PGIS
PGIS and PGIC are employed as anchors for defining a “responder threshold” for 
MDASI-AML/MDS item Fatigue. PGIS is generally the preferred anchor over PGIC 
because PGIC may be subject to recall bias.  As recommended by the FDA, for this protocol, 
both anchor scales will be used to provide an accumulation of evidence to help interpret a
clinically meaningful score change in MDASI-AML/MDS.
The PGIS is a single-item questionnaire designed to assess patient’s overall impression of 
disease severity at a given point in time.  It uses a 4-point Likert scale as follows: In the last 
24 hours, my leukemia symptoms are: 1-“Absent (no symptoms)”, 2-“mild”,  3-“ moderate”, 
4-”severe”.
It will be used as an anchor for defining a “responder threshold”, on MDASI-AML/MDS and 
can also be used to create severity categorization for this PRO to enhance interpretation.


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PGIC
PGIC is a single-item questionnaire designed to assess the patient’s overall sense of whether 
there has been a change since starting treatment as rated on a 7 point Likert scale anchored 
by (1) “very much improved” to (7) “very much worse”, with (4)-“no change”. The PGIC is 
a measure of “participant rating of global improvement and satisfaction with treatment”.
This instrument is used to determine global improvement as assessed by the patient and as an 
anchor to define a responder definition for MDASI-AML/MDS and as a sensitivity analysis 
for defining a “clinical important difference” on this PRO. 
3.2.4. Other Endpoints
•
PK of glasdegib;
•
QTc interval.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
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3.4. Baseline Variables
The date of first dose (start date) of study treatment is the earliest date of non-zero dosing of 
any study drug. The date of last dose of study treatment is the latest date of non-zero dosing 
of any study drug.
No windowing will be applied when defining baseline. Any deviations from the protocol 
specified window will be documented as protocol deviations. 
For efficacy endpoints (except Fatigue) and baseline characteristics the last non-missing 
assessment prior to randomization will serve as the baseline assessment.  For fatigue, similar 
to other PRO endpoints, the last non-missing measurement on the day of the first dose of 
study treatment will serve as baseline (note that PRO endpoints are collected prior to study 
drug dosing on the same day).
For safety (including Eastern Cooperative Oncology Group (ECOG) performance status) the 
last non-missing assessment performed on or prior to date of the first dose of study treatment 
(or prior to randomization for patients randomized but not dosed) will serve as the baseline 
assessment.  If there are no observations meeting these criteria, then baseline is considered 
missing.  
For PRO, the measurement, the day of the first dose of study treatment will be used as the 
baseline measurement. If there are no observations meeting this criteria, then baseline is 
considered missing.
Triplicate ECGs are collected; therefore the baseline for each ECG measurement is the 
average of the pre-dose measurements on the baseline day.  Unscheduled assessments will 
not be included in the calculation of the average.  The average of the replicate measurements 
will be determined after the derivation of the individual parameters at each timepoint.
3.4.1. Stratification
Randomization is stratified by the following factors:
Intensive Chemotherapy Study: 
•
genetic risk (favorable vs intermediate vs adverse by ELN genetic risk categories) and 
age (≤60 years vs >60 years).  
Non-Intensive Chemotherapy Study:
•
genetic risk (favorable vs intermediate vs adverse by ELN genetic risk categories) and 
age (<75 years vs ≥75 years).
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The primary analysis will utilize strata as defined in the IVRS system. In addition,
sensitivity analysis may be conducted with baseline age and ELN genetic risk category 
collected in the CRF.
3.5. Safety Endpoints
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.
On-treatment is defined as the time from the first dose of study treatment to last dose prior to 
HSCT + 28 days and if applicable, from first dose post-HSCT to last dose + 28 days or start 
of new anti-cancer drug therapy (minus 1 day), whichever occurs first. Note that
conditioning regimens for HSCT (regardless of whether glasdegib is resumed after HSCT)
are not considered “new anti-cancer drug therapy”. Adverse events occurring on the same 
day as the first dose of study treatment will be considered to have occurred during the 
on-treatment period. All other assessments which occur on the same day as the first dose of 
study treatment will be considered baseline assessments (see Section 3.4 for the definition of 
baseline).
Safety data collected outside the on-treatment period as described above will be listed but not 
summarized.
3.5.1. Adverse Events
An adverse event is considered treatment emergent (TEAE) relative to a given treatment if:
•
the event occurs during the on-treatment period (regardless if it was seen prior to the 
start of treatment)
 
 
 
 
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Adverse Events of Special Interest (AEoSI)
The current full list of AEoSI and MedDRA high level terms (HLT), standardized MedDRA 
queries (SMQ), and/or preferred terms (PTs) included in each event are listed in a separate 
AEoSI cluster document.  These events will be defined based on a list of MedDRA Preferred 
Terms specified in the Safety Review Plan for glasdegib. A final list will be provided to 
programming prior to database release.
3.5.2. Laboratory Data
Hematology, chemistry, lipid and coagulation tests results will be programmatically graded 
according to the NCI CTCAE version 4.03 for relevant parameters. Parameters which cannot 
be graded will be summarized relative to the normal range (ie, normal range high or normal 
range low).  Additional details are provided in Section 6.6.3.
4. ANALYSIS SETS
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to unblinding and releasing the database and classifications 
will be documented per standard operating procedures. The intensive and non-intensive 
chemotherapy patients are always analyzed separately.
4.1. Full Analysis Set
The Full Analysis (FA) set will include all randomized subjects.  Subjects will be classified 
according to the treatment assigned at randomization.
Randomized but not treated patients will be reported under their randomized treatment group 
for the full analysis set. The FA set will be the primary population for evaluating all efficacy 
and PRO endpoints
 
and patient characteristics.
4.2. Per Protocol Analysis Set 
Not applicable.
4.3. Safety Analysis Set
The Safety Analysis (SA) set will include all subjects who receive at least one dose of study 
drug. 
A randomized but not treated patient will be excluded from this safety analysis set. Subjects 
will be classified according to the treatment assigned at randomization unless the incorrect 
treatment(s) was/were received throughout the dosing period in which case subjects will be
classified according to the first study treatment received. The SA set will be the primary 
population for evaluating treatment administration/compliance and safety, 
 
. Efficacy endpoints may be assessed in this population as well. 
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4.4. Other Analysis Sets
4.4.1. Pharmacokinetics Analysis Set
The PK concentration analysis set is defined as all subjects who are treated and who have at 
least 1 value of analyte concentration of glasdegib available.  The PK parameter analysis set 
is defined as all subjects who are treated and who have at least 1 of the PK parameters of
interest. Subjects will be classified according to the treatment assigned at randomization 
unless the incorrect treatment(s) was/were received throughout the dosing period in which 
case subjects will be classified according to the first study treatment received.
 
 
 
 
 
 
 
4.4.3. China Sub-Population Analysis Sets
For each efficacy, safety, 
and pharmacokinetics analysis set defined above, the 
corresponding China subset analysis set is the subset of patients consisting of patients 
enrolled in mainland China. 
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
5.1.1. Hypotheses and Sample Size Section
The hypotheses and sample size calculation were done independently and separately for the 
patients in the two studies.
Intensive Chemotherapy Study: 
The primary objective of the study is to demonstrate that glasdegib in combination with 
7+3 (Arm A) is superior to placebo in combination with 7+3 (Arm B) in prolonging OS. 
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The study is designed to test H0: HR ≥1 vs. HA: HR <1, where HR is the hazard ratio 
(Arm A/Arm B) of OS.
A total of 400 subjects eligible to receive intensive chemotherapy per investigator assessment 
will be enrolled into the study. A total of 267 death events to be observed in the study would 
provide 90% power to detect an improvement in overall survival translated in mOS from 
21 months to 31.5 months assuming a composite mOS for the population as follows: young 
AML (aged ≤60 years) with a mOS of 23.7 months and elderly AML (aged >60 years) with a 
mOS of 15 months assuming a 70% young and 30% elderly AML split12,13 and with an 
HR=0.67 using a 1-sided log-rank test at a significance level of 0.025 and a 3-look 
group-sequential design.  
The sample size of 400 subjects is determined based on the assumption of a HR of 0.67 under 
the alternative hypothesis (under an exponential model, translating in median OS of 
31.5 months in the treatment arm and 21 months in the control arm) expecting approximately 
one third of all enrolled subjects to be censored. It is assumed a ramping enrollment of 
10 months to reach a maximum enrollment of 18 patients/month. An accrual duration of 
28 months to randomize 400 patients and an overall trial duration of 58 months is expected.
For the China subset, no formal statistical testing will be conducted. 
Non-Intensive Chemotherapy Study:
The primary objective of the study is to demonstrate that glasdegib in combination with 
azacitidine (Arm A) is superior to placebo in combination with azacitidine (Arm B) in 
prolonging OS. 
The study is designed to test H0: HR ≥1 vs. HA: HR <1, where HR is the hazard ratio 
(Arm A/Arm B) of OS.
A total of 320 subjects who are not candidates to receive Intensive Chemotherapy will be 
enrolled into the study. A total of 220 death events to be observed in the study would 
provide 90% power to detect an improvement in overall survival translated in mOS from 
10.4 months14 to 16.2 months with an HR=0.64 using a 1-sided log-rank test at a significance 
level of 0.025 and a 2-look group-sequential design.  One interim efficacy and futility 
analysis of OS would be planned after 60% death events occur in the non-intensive 
chemotherapy population or upon completion of enrollment of these subjects, whichever is 
later.  
The sample size of 320 subjects is determined based on the assumption of a HR of 0.64 under 
the alternative hypothesis (under an exponential model, translating in median OS of 
16.2 months in the treatment arm and 10.4 months in the control arm) expecting 
approximately 31% of all enrolled subjects to be censored. It is assumed a ramping 
enrollment of 10 months to reach a maximum enrollment of 18 patients/month. An accrual 
duration of 23 months to randomize 320 patients and an overall trial duration of 37 months is 
expected.
For the China subset, no formal statistical testing will be conducted. 


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5.1.2. Decision Rules
The interim analyses will be performed based on the FA set for the intensive and 
non-intensive chemotherapy populations separately and independently of each other as 
described in the following. The key secondary Fatigue endpoint will be analyzed using a 
hierarchical testing procedure, provided the primary OS endpoint is statistically significant 
favoring the experimental arm within each patient population (intensive and/or 
non-intensive). 
An interim analysis will not be performed for the China subset. Full analysis following early 
stopping at an interim analysis or following final analysis will be carried out for the China 
subset based on the specifications in other sections. 
Non-binding for the futility implies that the futility boundary will be constructed in such a 
way that it can be overruled if desired by the external data monitoring committee (E-DMC) 
without inflating the type-1 error rate and without decreasing the power.
Intensive Chemotherapy Study: 
Two interim analyses are planned.  One efficacy and futility interim analysis is planned when 
50% of death events have occurred in the intensive chemotherapy population.  However, no 
efficacy stopping will be made even if the interim analysis result crosses the efficacy 
boundary.  A second interim analysis of efficacy and futility is planned when 70% of death 
events have occurred or upon completion of enrollment of the intensive chemotherapy 
population, whichever is later.  An O’Brien-Fleming boundary with Lan-DeMets spending 
function will be used for efficacy and a Rho(3) -spending function will be used for the 
non-binding futility boundary.  If exactly 50% of the events is accrued at the first interim 
analysis, the futility boundary will be crossed when 1-sided p>0.461.  If exactly 70% of the 
events is accrued at the second interim analysis, the futility boundary will be crossed when 
1-sided p>0.186 and the efficacy boundary will be crossed when 1-sided p<0.007.  If the 
actual number of events at the interim analyses is different, the corresponding spending 
function will be used to calculate the actual stopping boundaries. A 1-sided p<0.023 at the 
final analysis suggests the null hypothesis is to be rejected. 
Table 2.
Planned Stopping Boundaries for Overall Survival at Interim Analyses and 
Final Analysis for the Intensive Chemotherapy Study
Analysis
Number of 
Events (%)
Cumulative 
Alpha Spent
Cumulative 
Beta Spent
Futility 
Boundary 
p-value
Efficacy Boundary
p-value
First IA
134 (50%)
0.002
0.013
0.461
*
Second IA
187 (70%)
0.007
0.034
0.186
0.007
FA
267 (100%)
0.025
0.100
0.023
0.023
Abbreviations: IA=interim analysis; FA=final analysis
The cumulative alpha spent, cumulative beta spent, and boundaries were calculated using software EAST 
(version 6.4).
* No stopping for efficacy regardless whether the efficacy boundary is crossed or not.


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Non-intensive Chemotherapy Study: 
One interim analysis is planned.  An interim analysis of efficacy and futility is planned when 
60% of death events have occurred or upon completion of enrollment of the non-intensive 
chemotherapy population, whichever is later.  An O’Brien-Fleming boundary with 
Lan-DeMets spending function will be used for efficacy and a Rho(3) -spending function 
will be used for the non-binding futility boundary.  If exactly 60% of the events is accrued at 
the interim analysis, the futility boundary will be crossed when 1-sided p>0.302 and the 
efficacy boundary will be crossed when 1-sided p<0.004. If the actual number of events at 
the interim analyses is different, the corresponding spending function will be used to 
calculate the actual stopping boundaries. A 1-sided p<0.024 at the final analysis suggests the 
null hypothesis is to be rejected.
Table 3.
Planned Stopping Boundaries for Overall Survival at Interim Analyses and 
Final Analysis for the Non-Intensive Chemotherapy Study
Analysis
Number of 
Events (%)
Cumulative 
Alpha Spent
Cumulative 
Beta Spent
Futility 
Boundary 
p-value
Efficacy Boundary
p-value
IA
132 (60%)
0.004
0.021
0.302
0.004
FA
220 (100%)
0.025
0.100
0.024
0.024
Abbreviations: IA=interim analysis; FA=final analysis
The cumulative alpha spent, cumulative beta spent, and boundaries were calculated using software EAST 
(version 6.4). 
5.2. General Methods 
Unless otherwise specified, baseline data will be summarized by treatment arm and for both 
treatment arms combined.  Disposition, efficacy, exposure (including concomitant therapies), 
and safety data will be summarized by treatment arm only. The intensive and non-intensive 
chemotherapy patients will be analyzed separately.
5.2.1. Pooling of Data by Center
Each study is expected to enrol in more than 20 countries and more than 100 sites. In order 
to provide overall estimates of treatment effects, data will be pooled across centers.  The 
‘center’ factor will not be considered in statistical models or for subset analyses due to the 
high number of participating centers in contrast to the anticipated small number of patients 
randomized/treated at each center.
No pooling across centers will be done for the China subset analysis. 
5.2.2. Definition of Study Day
Start day of study treatment is the day of the first dose of study treatment.
The study day for assessments occurring on or after the first dose of study treatment 
(eg, adverse event onset, laboratory date) will be calculated as:
Study day = Date of the assessment/event - start date of study treatment + 1. 


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The study day for assessments occurring prior to the first dose of study treatment 
(eg, baseline characteristics, medical history) will be negative and calculated as:
Study day = Date of the assessment/event –start date of study treatment.
The study day will be displayed in all relevant data listings.
5.2.3. Definition of Cycle and Cycle Day
Non-intensive Chemotherapy Study
Cycle start and end dates are derived per patient and not per study treatment. 

For Cycle X, the actual cycle start date for each subject is the earliest start date of 
dosing (dose>0 at that visit ) in Cycle X visit CRF exposure page.

For all but the last cycle.

actual cycle end date is calculated as the start date of the next cycle minus one 
day. 

actual cycle duration is calculated from Day 1 of a cycle to the day prior to 
Day 1 of the next cycle, as follows: 
Actual Cycle Duration = cycle end date – cycle start date + 1.

For the last cycle, actual cycle duration is calculated as follows:

Actual Cycle Duration = last date of non-zero study treatment– cycle start 
date + 1.
The cycle day will be calculated as:
Cycle day = Date of the assessment/event – cycle start date + 1. 
Intensive Chemotherapy Study
Study day in association with study period will be displayed for intensive chemotherapy 
patients, ie, Induction 1, Induction 2 (optional), Cytarabine Consolidation Cycle 1 through 
4 (optional), HSCT period (optional), Post-consolidation Cycle 1, 2, 3, etc (optional). Note 
that a patient who undergoes consolidation therapy can either go on Cytarabine 
Consolidation and/or HSCT.
Cycle start and end dates are derived per patient and not per study treatment. 
For all cycles other than the HSCT period.

For any cycle, the actual cycle start date for each subject is the earliest start date of 
dosing (dose >0 at that visit ) in that cycle CRF exposure page.


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
For all but the last cycle.

actual cycle end date is calculated as the start date of the next cycle minus one 
day. 

actual cycle duration is calculated from Day 1 of a cycle to the day prior to Day 1 
of the next cycle, as follows: 
Actual Cycle Duration = cycle end date – cycle start date + 1.

For the last cycle, actual cycle duration is calculated as follows:

Actual Cycle Duration = last date of non-zero study treatment– cycle start 
date + 1.
The cycle day will be calculated as:
Cycle day = Date of the assessment/event – cycle start date + 1. 
HSCT Period
The HSCT period is defined as time from the start of the HSCT conditioning regimen until 
the subject re-starts glasdegib/placebo or cytarabine, death, post study follow-up, or 
withdrawal. Day 1 is the day of the HSCT. Note that in the Protocol this was referred to as 
Day 0 per common clinical practice. Per Protocol Section 8, there are limited data collection 
during the HSCT period beyond 28 days after the last investigational treatment 
administration prior to HSCT.
The cycle day for assessments occurring on or after the day of HSCT will be calculated as:
Cycle day = Date of the assessment/event – date of HSCT + 1. 
The cycle day for HSCT conditioning regimen(s) will be negative as they occur prior to 
HSCT and calculated as:
Cycle day = Date of the assessment/event – date of HSCT.
5.2.4. Date of Last Contact
The date of last contact will be derived for patients not known to have died at the data cutoff 
date using the latest complete date (ie, imputed dates will not be used in the derivation) 
among the following:

All patient assessment dates (eg, blood draws (laboratory, Pharmacokinetics (PK)), 
vital signs, physical exam, performance status, ECG, Echocardiograms 
(ECHO)/MUGA scans, disease assessments).

Start and stop dates of concomitant therapies including non-drug treatments or 
procedures.


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
Completion dates for PRO Questionnaires.

Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation including systemic therapy, radiation, and surgeries.

AE start and end dates.

Last date known to be alive on the ‘Survival Follow-up’ CRF.

Study treatment start and end dates.

Hospitalization admission and discharge dates.

Randomization date, and

Date of discontinuation on disposition CRF pages (do not use if reason for 
discontinuation is lost to follow-up or death).
Only dates associated with actual examinations of the patient will be used in the derivation.  
Dates associated with a technical operation unrelated to patient status such as the date a 
blood sample was processed or dates data were entered into the CRF will not be used. 
Assessment dates after the data cutoff date will not be applied to derive the last contact date.
5.2.5. Disease Assessment Date
Date of assessment from the hematologic response CRF will be used as the date of response.  
Date of hematologic relapse will be derived as the earliest date from the peripheral blood 
blasts, bone marrow blasts, or EMD assessment where the criteria for relapse is met.  For 
hematologic relapse occurring during long-term follow-up, the date of assessment from the 
hematologic response CRF will be used.
5.2.6. Unscheduled Assessments
Unless otherwise specified, unscheduled assessments will not be displayed in summary tables 
by nominal visit/timepoint. Unscheduled assessments will be used when deriving baseline 
and worst case on-treatment for safety and PRO analyses (except where noted for baseline 
ECGs). Additionally, unscheduled disease assessments will be used for efficacy analyses 
(eg, defining date of relapse/censoring, CRi or better, date of last contact).
5.2.7. Standard Derivations and Reporting Conventions
The following conversion factors will be used to convert days into weeks, months or years: 
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Percentages will be reported to one decimal place. The rounding will be performed to closest 
integer/first decimal using the common mid-point between the two consecutive values, 
eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 to 5.9 will be rounded to an 
integer of 6.


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5.2.8. Analyses for Continuous Data
Continuous variables will be summarized using descriptive statistics ie, number of 
non-missing values and number of missing values [ie, n (missing)], mean, median, standard 
deviation (SD), minimum, maximum and first and third quartile (Q1 and Q3). 
 
 PK summaries will also include coefficient of variation percent (%CV).
In case the analysis refers only to certain visits, estimates will be based on the number of 
patients with an assessment at that visit, unless otherwise specified.
5.2.9. Analyses for Categorical Data
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore counts of missing observations will be included in the denominator and presented 
as a separate category.
In case the analysis refers only to certain visits, percentages will be based on the number of 
patients with an assessment at that visit, unless otherwise specified.
5.2.10. Analyses for Time to Event Data
The stratified log-rank test will be used for comparing treatments.  Hazard ratios and the 
associated 95% two-sided confidence intervals are estimated by Cox proportional hazards
(PH) model.  Repeated confidence interval will also be provided, to account for alpha 
spending, when appropriate. 
Time to event endpoints will be summarized using the Kaplan-Meier method and estimated 
survival curves will be displayed graphically when appropriate.  Graphs will describe the 
number of patients at risk over time.  The median, first and third quartiles, and probabilities 
of an event at particular points in time will be estimated by the Kaplan-Meier method.  
Confidence intervals for medians and quartiles are based on the Brookmeyer-Crowley2
method.  Confidence intervals for the estimated probability of an event at a particular 
timepoint will be generated using the log(-log) method with back transformation to a 
confidence interval on the untransformed scale. Summaries of the number and percentages 
of patients with an event and reason for censoring will also be provided on summary tables 
and/or figures.
If a cumulative incidence analysis is performed, the stratified Gray’s test17 will be used for 
comparing treatments.  Hazard ratios and the associated 95% two-sided confidence intervals 
are estimated by a proportional subdistribution hazards model.  The 25th, 50th, and 75th
percentiles and probabilities of an event at particular points in time will be estimated from 
the cumulative incidence curve.  Confidence intervals for the estimated probability of an 
event at a particular timepoint will be generated using the delta method with a log(-log)
transformation for the standard error.  
5.3. Methods to Manage Missing Data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.
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Any imputations will occur at the analysis dataset level.  Additionally, in all patient data 
listings imputed values will be presented and flagged as imputed.
Missing statistics, eg, when they cannot be calculated, should be presented as ‘ND’ for not 
done, ‘NR’ for not reached or ‘NA’ for not applicable.  For example, if N=1, the measure of 
variability cannot be computed and should be presented as ‘ND’ or ‘NA’. 
CDISC  Safety Rulebook will be followed when handling the missing/partial dates, treatment 
emergent AE algorithm, missing AE grades, etc. 
5.3.1. Missing Dates
For purposes of data listings, dates will reflect only the information provided by the
investigator on the CRF.
If start dates for adverse events or concomitant medications are completely missing a worst 
case approach will be taken whereby the events will be considered treatment emergent and 
the medications will be considered concomitant.  If only partial information are available 
(eg, only a month and year or only a year) and the partial information provide sufficient 
information to indicate the dates are prior to the start of study treatment (eg, month/year less 
than month/year of first dose) then these will be considered to have started prior to treatment; 
otherwise a similar worst case approach will apply and these will be considered to have 
started after treatment.
Date of Last Dose of Study Treatment
No imputation will be done for first dose date.  Date of last dose of study treatment, if 
unknown or partially unknown, will be imputed as follows:

If the last date of study treatment is completely missing and there is no Disposition 
CRF page for the treatment phase and no death date, the patient should be considered 
to be ongoing and use the data cutoff date for the analysis as the last dosing date; or

If the last date of study treatment is completely or partially missing and there is 
EITHER a Disposition CRF page for the treatment phase OR a death date available 
(on or prior to the data cutoff date), then impute this date as the last dose date:
= 31DECYYYY, if only Year is available and Year < Year of min (Date of 
Completion/Discontinuation from the Disposition CRF page for the treatment phase, 
death date),
= Last day of the month, if both Year and Month are available and Year = Year of 
min (Date of Completion/Discontinuation from the Disposition CRF page for the 
treatment phase, death date) and Month < the month of min (EOT date, death date), or
= min (Date of Completion/Discontinuation from the Disposition CRF page for the
treatment phase, death date), for all other cases.


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Missing or Partial Death Dates
Missing or partial death dates will be imputed based on the last contact date:

If the entire date is missing it will be imputed as the day after the date of last contact 
(see derivation of date of last contact in Section 5.2.4); or

If the day or month is missing, death will be imputed to the maximum of the full 
(non-imputed) day after the date of last contact and the following:
- Missing day: 1st day of the month and year of death, or
- Missing day and month: January 1st of the year of death.
Date of Start of New Anti-cancer Therapy
Incomplete dates for new anti-cancer therapy will be imputed as follows and will be used to 
determine censoring dates for efficacy analyses. Note that HSCT before the end of the 
treatment phase or its conditioning regimen(s) are not considered new anti-cancer therapies.

The end date of new anti-cancer therapy will be included in the imputation for start 
date of new anti-cancer therapy.  If the end data of new anti-cancer therapy is:

completely missing then it will be ignored in the imputations below, 

partially missing with only year available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy, or

partially missing with only month and year available then the imputations below 
will consider the last day of the month for MMMYYYY as the end date of the 
new anti-cancer therapy.

For patients who have not discontinued study treatment at the time of the data cutoff 
date, last dose of study treatment is set to the data cutoff date in the imputations 
below.

If the start date of new anti-cancer therapy is completely or partially missing then the 
imputed start date of new anti-cancer therapy is:
= 31DECYYYY, if only Year is available and Year < Year of min 
[max (PD/relapse date + 1, last dose of study treatment + 1), end date of new 
anti-cancer therapy]
= Last day of the month, if both Year and Month are available and 
Year = Year of min [max (PD/relapse date + 1, last dose of study 
treatment + 1), end date of new anti-cancer therapy] 


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Month < Month of min [max (PD/relapse date + 1 day, last dose of study 
treatment + 1 day), end date of new anti-cancer therapy]
= min [max (PD/relapse date + 1, last dose of study treatment + 1), end date of 
new anti-cancer therapy], for all other cases.
AE Onset Date:
The following imputation rules apply if the event is unique for a patient or it is the first of a 
series of similar events; otherwise, the AE Onset Date will not be imputed:

If the AE Collection Date is not missing, is less than the Date of First Exposure to 
Treatment, and is less than the AE Stop Date, then AE Onset Date is set to the Date of 
AE Collection.

If the Previous Visit Date is greater than the Date of First Exposure to Treatment and 
less than the AE Stop Date, the AE Start Date is set to the previous visit date.

If the Date of First Exposure to Treatment is greater than the previous visit date and 
less than the AE Stop Date, the AE Onset Date is set to the Date of First Exposure to 
Treatment.

Otherwise AE Onset date is set to the AE Stop date.
AE Stop Date:
Ongoing events will have the AE Stop Date set to one of the following values:

Date of Death, if the patient died and a date of death exists.

Maximum of (Patient Withdraw date, AE Onset Date, AE Collection Date) if the 
patient withdrew from the study and a date of withdraw exists.

Maximum of (AE Onset Date, Subject Summary Collection Date, AE Collection 
Date) if the Disposition CRF page for the long-term follow-up phase exists but a date 
of completion/discontinuation does not exist.

Maximum of (Last Treatment Date, AE Onset Date) if no Disposition CRF page for 
the long-term follow-up phase exists.
Imputation will only occur if event is unique for the patient, or it is the last of a series of 
similar events; otherwise the Stop Date will not be imputed.  Adverse Events are deemed 
similar if they have the same verbatim term.
Resolved events will have the AE Stop Date set to the maximum of the AE collection date 
and the AE Onset date.


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Other Missing or Partial Dates
Imputation methods for other partial dates are as follows: 

If the day of the month is missing for a start date used in a calculation, the first day of 
the month will be used to replace the missing date. 

If both the day and month are missing for a start date, the first day of the year is used. 

For stop dates, the last day of the month, or last day of the year is used if the day or 
day and month are missing, respectively. 

If the date is completely missing, no imputation will be performed.
5.3.2. Missing Toxicity Grade of Adverse Events
During Study Treatment: If no toxicity grade is available or the grade is reported as unknown 
for an adverse event during the study treatment, then the event will be considered treatment 
emergent.
In summaries which present maximum toxicity grade, the maximum of non-missing grades 
will be displayed.  Missing grade will only be displayed for cases where a patient reported 
only one event and the grade is missing. 
5.3.3. Missing Pharmacokinetic (PK) Data
Concentrations below the limit of quantification
For all calculations, figures, and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero. In 
log-linear plots these values will not be represented.  The BLQ values will be excluded from 
calculations of geometric means and their confidence intervals. A statement similar to ‘All 
values reported as BLQ have been replaced with zero’ should be included as a footnote to the
appropriate tables and figures.  In listings BLQ values will be reported as below limit of 
quantification (“<LLOQ”), where LLOQ will be replaced with the corresponding value from 
the analytical assay used.
Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, concentrations will be set to missing if one
of the following cases is true:

A concentration has been reported as ND (ie, not done) or NS (ie, no sample);

A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the clinical pharmacologist.


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Summary statistics will not be presented at a particular timepoint if more than 50% of the 
data are missing.  For analysis of pharmacokinetic concentrations, no values will be imputed 
for missing data.
5.3.4. Missing ECG Data
For ECG analyses, no values will be imputed for missing data (except HR values that can be 
derived from RR values, if present. If both RR and HR values are missing, QTcB and QTcF 
will not be determined). In case of missing HR value, HR (bpm) will be derived as 
(60/RR [sec]), if RR is collected. 
If one or two of the triplicate measurements for an ECG parameter are missed, the average of 
the remaining two measurements or the single measurement can be used in the analyses. If 
all triplicate measurements are missing at a timepoint for an ECG parameter, no values will 
be imputed for this timepoint.  If the triplicate needs to be repeated because of an artifact, 
then the repeated triplicate will be reported on an unscheduled CRF page.  Based on a review 
of the data these unscheduled assessments may be used in place of the assessments at the 
nominal time. Data review and consultation with the study team is required to flag these 
cases.
6. ANALYSES AND SUMMARIES
Analyses for the intensive and non-intensive chemotherapy studies will be conducted 
separately and independently. Unless otherwise stated, stratified analysis will be stratified
based on ELN genetic risk, age ≤60 vs >60 years, and region (rest of world [ROW] vs China)
for the intensive patients, and ELN genetic risk and age <75 vs ≥75 years for the 
non-intensive patients.  The rate of stem cell transplantation is expected to be much lower for 
sites in China versus the ROW thus region is being added as a stratification factor for the 
intensive study analyses.  The rate of stem cell transplantation is expected to be low in all 
regions in the non-intensive study.  
6.1. Primary Endpoint - Overall Survival 
The primary efficacy analysis will compare OS between the experimental arm and the 
control arm, and will be performed using a one-sided stratified log-rank test. The primary 
population for the analysis will be the FA set. Strata will be based on those specified in the 
randomization system including region for the intensive study.   
OS is defined as the time from randomization to the date of death due to any cause. Patients 
last known to be alive will be censored at date of last contact (see Section 5.2.4). OS will be 
summarized in months:
OS (months) = [date of death or censoring–randomization+1]/30.4375.
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The treatment effect will be estimated using a Cox’s PH model stratified by the 
randomization strata and region for the intensive study to calculate the hazard ratio. Each 
stratum will define a separate baseline hazard function (using the 'STRATA' statement in 
SAS PROC PHREG), ie, for the i-th stratum the hazard function is expressed as: 
h(i;t) = h(i,0;t) exp(x), where h(i,0;t) defines the baseline hazard function for the i-th 
stratum and x defines the treatment arm (0=control arm, 1= experimental arm) and is the 
unknown regression parameter. Ties will be handled using the Efron method as an 
approximation to the exact method (Ties=EFRON option in SAS PROC PHREG).
OS time associated with each treatment arm will be summarized using the Kaplan-Meier 
method (product-limit estimates) and displayed graphically where appropriate. CIs for the 
25th, 50th, and 75th percentiles will be reported. Repeated confidence interval will also be 
provided, to account for alpha spending. The Cox PH model will be fitted to compute the 
treatment HRs and the corresponding 95% CIs. In addition, the median OS and its two-sided 
95% CI using the Brookmeyer and Crowley method will be provided for each stratum within
each treatment arm separately.  The HR and its two-sided 95% CI will be provided for each 
stratum as well.  
The OS rate at 12, 24 and 36 months will be estimated with corresponding two-sided 
95% CIs for the intensive chemotherapy patients. The OS rate at 6, 12, and 18 months will 
be estimated with corresponding two-sided 95% CI for the non-intensive chemotherapy 
patients.  The CIs for the median will be calculated according to Brookmeyer and Crowley2
and the CIs for the survival function estimates at the timepoints defined above will be 
derived using the log(-log) method according to Kalbfleisch and Prentice3 (conftype=loglog 
default option in SAS Proc LIFETEST). The estimate of the standard error will be computed 
using Greenwood’s formula.
Frequency (number and percentage) of patients with an event (death) and censoring reasons
will be presented by treatment arm. Censoring reasons are as follows:

Alive;

Withdrawal of consent;

Lost to follow-up.
The OS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Should over-stratification prevent model convergence or there exists large imbalance in the 
distribution (eg, 90% or more subjects from one strata level), the intermediate and adverse 
ELN risk groups may be pooled in the analysis.  
Time of Follow-Up for OS
A Kaplan-Meier summary table for OS follow-up duration will also be generated to assess 
the follow-up time in the treatment arms reversing the OS censoring and event indicators.15


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6.2. Secondary Endpoints
6.2.1. Fatigue
The “Fatigue” single-item from the MDASI-AML/MDS questionnaire is the key secondary 
endpoint. Similar to analysis of the primary endpoint, the analysis of Fatigue will be 
conducted separately and independently across the two patient populations (intensive or 
non-intensive patients). There are two steps of the analysis of Fatigue. If the primary 
endpoint of OS is met in one population, the hypothesis testing described in Step 2 of this 
section will be carried out in that population. The overall Type I error is preserved by 
following this pre-specified hierarchical testing sequence (ie, OS followed by Fatigue). 
Step 1: A repeated measures model will be used to determine Clinically Important 
Responder (CIR) within each patient population. We use the change in Fatigue from 
baseline as the outcome and SGIC-S (Subject Global Impression of Change using PGIS) 
score (defined below) as the anchor. Note that Fatigue and PGIS are collected following the 
same schedule and treatment assignment is not a covariate in the model. All available 
post-baseline data up to Week X will be used (X=8 for intensive patients, X=12 for 
non-intensive patients). A window of +/-3 days will be applied. If more than one assessment 
are available in a week, the average value will be used.
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A SGIC-S score with three possible values (-1, 0, and 1, treated as continuous variable) will
be derived for each subject at each week post-baseline, from Week 1 through Week X, as 
follows:
a.
SGIC-S = -1, if post-baseline PGIS minus PGIS at baseline is positive (this means 
worse);
b. SGIC-S = 0, if post-baseline PGIS minus PGIS at baseline is zero (ie, no change, this
means the same);
c.
SGIC-S = 1, if post-baseline PGIS minus PGIS at baseline is negative (this means
better).
The predicted change in Fatigue score corresponding to one unit difference on SGIC-S is the 
threshold for “responder” vs “non-responder”. All patients with change in Fatigue at 
Week X (X=8 for intensive patients, X=12 for non-intensive patients) at or below the 
threshold (note that lower values suggest lessening of Fatigue) will be defined as responders.  
As a supportive analysis, a SGIC-C (Subject Global Impression of Change using PGIC) score 
with three possible values (-1, 0, and 1, treated as continuous variable), derived below, will 
be used in place of SGIC-S in the repeated measures model. Note that PGIC is collected on 
the same schedule as Fatigue other than there is no assessment of PGIC at baseline.
a.
SGIC-C = -1, if PGIC is 5 or more (this means worse);
b. SGIC-C = 0, if PGIC is 4 (ie, no change, this means the same);
c.
SGIC-C = 1, if PGIC is 3 or less (this means better).
Additional details of the CIR can be found in the Appendix, where potential sensitivity 
analyses treating SGIC-S and SGIC-C as categorical variables are also described.
Step 2: A formal testing of proportion of responders at Week X (using a 1-sided Cochran 
Mantel Haenszel [CMH] test, stratified by ELN risk, age [age ≤60 vs >60 years for the 
intensive patients, and age <75 vs ≥75 years for the non-intensive patients], and region 
[ROW vs China for intensive patients only) will only be conducted in one population if the 
primary OS endpoint is met in that population (intensive or non-intensive patients). The risk 
ratio and 2-sided 95% CI will be summarized. 
The proportion of responders by treatment arm will be estimated with a 2-sided 95% CI 
(using normal approximation). The proportion and 2-sided 95% CI (using exact method) of 
responders for each stratum by treatment arm will also be provided. 
In addition to the above responder analyses, analysis of Fatigue will also be supplemented 
with cumulative distribution function (CDF) and probability density function (PDF) of
change in Fatigue score from baseline to Week X. The change in Fatigue at Week X will be 
plotted on the X-axis while its CDF or PDF will be plotted on the Y-axis.


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If the Week X PRO assessment is missing, then the next available completed PRO 
assessment will be used.
6.2.2. Responses
The proportion of patients achieving CRMRD-negative, CR (including CRMRD-negative), CRi, CRh 
(non-intensive only), MLFS, and PR as their best overall response will be estimated with 
two-sided 95% CI (using normal approximation).  The proportion and two-sided 95% CI 
(using exact method) of patients achieving each response category for each stratum will also 
be provided.  The proportion of patients with CRMRD-negative, CR (including CRMRD-negative), 
CRi or better and CRh or better (non-intensive only) respectively will be compared between 
the 2 treatment arms using a 1-sided CMH stratified test and an unstratified chi-square test. 
The risk ratio and difference in proportions and their 95% CIs will be provided overall and 
within each stratum as well.  The proportion of patients experiencing stable disease, 
indeterminate response (eg, those that met the criteria for stable disease but for <3 months in 
the non-intensive study or those where response could never be assessed due to missing 
information such as peripheral or bone marrow blasts) and disease progression as their best 
response or ever experiencing disease progression will also be summarized.  For those 
patients not assessed for response, the reason for treatment discontinuation will be 
summarized.  Patients with indeterminate as their best response will be categorized into one 
of the following groups: no post-baseline bone marrow blasts available, post-baseline bone 
marrow blasts available but missing peripheral blood data, stable disease for <3 months in 
the non-intensive study, or other.  Patients without a response CRF will be classified as Not 
Evaluated and the overall reason for discontinuation from treatment will be summarized.
6.2.3. Duration of Response
Duration of Response (DoRi or DoRh [non-intensive only]) is defined, for patients from the 
FA set with a best overall response of CRi or better or CRh or better, as the time from first 
documentation of response (CRi or better or CRh or better) to the date of first documentation 
of objective disease relapse or death due to any cause.  The censoring rules for DoRi/DoRh
are discussed Section 3.2.1.
DoRi (months) = [date of event or censoring– first date of CRi or better +1]/30.4375.
DoRh (months) = [date of event or censoring– first date of CRh or better +1]/30.4375.
Depending on the number of subjects who achieve a best overall response of CRi or better or 
CRh or better and subsequently have an event in each arm, Kaplan-Meier estimates 
(product-limit estimates) will be presented by treatment arm together with a summary of 
associated statistics including the median DoRi or DoRh (non-intensive only) time with 
two-sided 95% CIs.  Inferential analyses (eg, a hazard ratio and p-value) will not be provided 
for duration of response.
Duration of response for the subset of patients with a best overall response of CR or better 
will also be analyzed.


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An alternative definition of DoRi defined for all FA patients, may be explored for the 
intensive chemotherapy patients, where patients who have never achieved CRi or better will 
be considered having an event on Day 1.16
6.2.4. Time to Response (Non-intensive Only)
Time to Response (TTRi or TTRh) is defined, for patients achieved CRi or better or CRh or 
better, as the time from the date of randomization to the first documentation of response 
(CRi or better or CRh or better).
The minimum, median, and maximum TTRi/TTRh for each treatment arm will be provided.  
6.2.5. Event-free Survival
A 1-sided stratified log-rank test (stratified by ELN genetic risk, age [age ≤60 vs >60 years, 
and region [ROW vs China] for the intensive patients, and genetic risk and age <75 vs 
≥75 years for the non-intensive patients]) will be used. Analyses will be performed using 
various EFS definitions as specified in Section 3.2.1. Should over-stratification prevent 
model convergence or there exists a large imbalance in the distribution (eg, 90% or more 
subjects from one strata level), the intermediate and adverse ELN risk groups may be pooled 
in the analysis.  EFS time associated with each treatment arm will be summarized using the 
Kaplan-Meier method and displayed graphically where appropriate. CIs for the 25th, 50th, 
and 75th percentiles of EFS probabilities will be reported (using Brookmeyer and Crowley 
method).  In addition, the median EFS and its two-sided 95% CI using the same method will 
be provided for each stratum within each treatment arm separately.  The Cox PH model will 
be fitted to compute the treatment HR and the corresponding 95% CI.  The HR and its 
two-sided 95% CI will be provided for each stratum as well.  The proportion of patients 
experiencing each type of EFS event (eg, TF, hematologic relapse, death) will also be 
summarized.  
6.2.6. Patient-Reported Outcomes
All PRO analyses will be based on the FA
 
.
6.2.6.1. MDASI-AML/MDS
A MDASI-AML/MDS completion table will be constructed showing for each treatment 
group at each time point the number and percentage of subjects who completed and who had 
not completed the questionnaires, and also the reasons for non-completion.
Analysis of MDASI-AML/MDS will be based on the core cancer symptom score, the 
AML/MDS-specific symptoms score, the interference areas score, and also the 5 individual 
items of fatigue, disturbed sleep, dry mouth, muscle weakness, and lack of appetite. Note 
that Fatigue also appears in Section 6.2.1 (as a key secondary endpoint) using a responder 
analysis. 
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A display of descriptive statistics including means, medians, standard deviations, and 
95% confidence intervals at each assessment point will be provided.  This will be done based 
on the observed values as well as on change from baseline values.  Statistical comparison of 
the 2 treatment groups will be based on a longitudinal repeated measures mixed effects 
model using baseline as a covariate. 
A graphical representation of observed mean and standard error over time and change from 
baseline over time by treatment arms will also be provided for the core cancer symptom 
score, the AML/MDS-specific symptom score, the interference area score, and also the 
5 individual items of fatigue, disturbed sleep, dry mouth, muscle weakness, and lack of 
appetite.
6.2.6.2. EQ-5D-5L
An EQ-5D completion table will be constructed showing for each treatment group at each 
time point the number and percentage of subjects who completed and who had not completed 
the questionnaires, and also the reasons for non-completion.
Analysis of EQ-5D-5L and EQ-VAS will follow similar methodology as for the MDASI 
endpoints described above.  It will include a display of descriptive statistics including means, 
medians, standard deviations, and 95% confidence intervals at each assessment point.  This 
will be done based on the observed values as well as on change from baseline values.  
Statistical comparison of the 2 treatment groups on EQ-5D and EQ-VAS will be carried out 
using a longitudinal repeated measures mixed effects model with baseline as a covariate. 
In addition to the above analyses, a health status profile table showing the number of patients 
responding at each level on each dimension at each timepoint will also be constructed. 
Finally as with the MDASI variables, a graphical representation of observed mean and 
standard error over time and change from baseline over time by treatment arms for EQ-5D 
and EQ-VAS will also be provided.
6.2.6.3. PGIS
PGIS will be used as an anchor for defining “responder” versus “non-responder” for 
MDASI-AML/MDS individual item Fatigue. Analysis method for anchoring is given in 
Section 6.2.1 under analysis for Fatigue.  A frequency distribution of PGIS categories at each 
time point by treatment arm will also be provided.
6.2.6.4. PGIC
As with PGIS, a frequency distribution of PGIC categories by treatment arm will be provided 
and PGIC will also serve as a secondary anchor to define a responder definition for 
MDASI-AML/MDS individual item Fatigue and as a sensitivity analysis for defining a 
“clinically important responder” on this endpoint. 


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6.3. Other Endpoints
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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6.3.3. Pharmacokinetic Analysis
PK Parameters:
For intensive and non-intensive studies, the plasma trough concentration (Ctrough) will be 
reported.  Descriptive statistics will be provided for these PK parameters in tabular form 
(n, mean, standard deviation (Stdev), CV, median, minimum, maximum, geometric mean and 
its associated CV) by cycle (or Induction 1, 2) and day.
PK Concentrations:
For drug concentrations, individual values and descriptive statistics (n, mean, Stdev, CV, 
median, minimum, maximum, geometric mean and its associated CV) will be presented by 
cycle (or Induction 1, 2), day of assessment, and nominal time in tabular form. 
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6.3.4. Population Pharmacokinetic Analysis or PK/PDx Modeling
PK and pharmacodynamics (PDx) data from this study may be analyzed using modeling 
approaches and may also be pooled with data from other studies to investigate any causal 
relationship between study treatment exposure and biomarkers or significant safety 
endpoints.  The results of these analyses, if performed, may be reported separately.
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
The following analyses will be based on the FA set overall and separately by treatment arm.
Descriptive baseline summaries by race will not be performed for the China subset.
•
Demographic and Physical Characteristics 
The following demographic and baseline characteristics will be summarized by number 
and percentage:
•
Gender (male, female).
•
Age (18-<45; 45- <65; 65-<75; ≥75), additionally ≤60 years vs >60 years for 
intensive patients and <75 years vs ≥75 years for non-intensive patients.
•
Race (White, Black, Asian, Other), Racial designation for Asian (Japanese, Korean, 
Chinese, other), ethnicity (Hispanic/Latino, non-Hispanic/Latino).
•
Eastern Cooperative Oncology Group (ECOG) Performance status.
Age (continuous), height (cm), weight (kg), will be summarized with descriptive statistics 
(mean, median, standard deviation, minimum, and maximum).  
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
Disease Characteristics 
The following baseline disease characteristics will be summarized by number and 
percentage:

ELN risk category at randomization.

Reasons for choosing non-intensive study.

Bone marrow blasts (<30, ≥30%).

White blood cell (WBC) count (<10, ≥10x109/L).

Platelet count (<50, ≥50x109/L).

Hemoglobin (<100, ≥100 g/L).

Genetic Abnormality (eg, NPM1 MUTATION WITHOUT FLT3-ITD, etc).

Hematological Disease History (de novo, secondary).
Time from initial diagnosis to screening, peripheral blood blasts and bone marrow 
blasts (%), WBC (109/L), platelet count (109/L), and hemoglobin (g/L) will be 
summarized with descriptive statistics (mean, median, standard deviation, minimum, and 
maximum).

Stratification Factors 
The number of patients per strata will be summarized based on strata reported in the 
randomization system as well as on the CRF including a summary of any discordance.  
The following categories will be considered:
Intensive Chemotherapy Study

age ≤60 years, favorable ELN risk category, and ROW.

age ≤60 years, intermediate ELN risk category, and ROW.

age ≤60 years, adverse ELN risk category, and ROW.

age >60 years, favorable ELN risk category, and ROW.

age >60 years, intermediate ELN risk category, and ROW.

age >60 years, adverse ELN risk category, and ROW.

age ≤60 years, favorable ELN risk category, and Chinese site.


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
age ≤60 years, intermediate ELN risk category, and Chinese site.

age ≤60 years, adverse ELN risk category, and Chinese site.

age >60 years, favorable ELN risk category, and Chinese site.

age >60 years, intermediate ELN risk category, and Chinese site.

age >60 years, adverse ELN risk category, and Chinese site.
Non-intensive Chemotherapy Study

age <75 years and favorable ELN risk category.

age <75 years and intermediate ELN risk category.

age <75 years and adverse ELN risk category.

age ≥75 years and favorable ELN risk category.

age ≥75 years and intermediate ELN risk category.

age ≥75 years and adverse ELN risk category.

Medical History 

Medical history will be coded using the most current version of MedDRA and 
summarized by MedDRA’s System Organ Class (SOC) and PT.  Each patient will be 
counted only once within each PT or SOC.  Summaries will be ordered by primary 
SOC and PT in descending order of frequency by the experimental treatment arm.  
Separate summaries will be provided for past and present conditions. 
6.5.2. Study Conduct and Patient Disposition
The following analyses will be based on the FA set overall and separately by treatment arm.
6.5.2.1. Patient Disposition
A summary of the number of patients screened and enrolled overall and by country and site 
will be provided.
Discontinuation of treatment overall and for each study drug, discontinuation of 
post-treatment follow-up, and discontinuation of study will be summarized separately and by 
reason for discontinuation.  Discontinuations from study treatment and post-treatment 
follow-up will be summarized using the safety analysis set and discontinuations from the 
study will be summarized using the FA set.  Once a patient discontinues all study drugs they 
will be considered discontinued overall from study treatment.  The reason and date 
corresponding to the last drug discontinued should be used for the overall summary.  If 


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multiple drugs were discontinued on the same date with different reasons then the reason for 
discontinuing blinded therapy will be used.
Patients completing blinded therapy will be identified as either those who were confirmed 
MRD negative and were treated for less than 2 years or those who were treated for 2 years.
Discontinuations from study treatment due to adverse events will be identified as either 
related or not related to study treatment. If causality is missing the event will be considered 
related to treatment.  If multiple events lead to study treatment discontinuation and at least 
one was considered related, discontinuation will be reported as related to study treatment. 
An additional summary to meet European Union Disclosure requirements will categorize 
discontinuations due to adverse events based on the following categories:

Adverse Event, not serious.

Adverse event, serious non-fatal.

Adverse event, serious fatal.
6.5.2.2. Protocol Deviations
Protocol deviations will be compiled prior to database closure and will be summarized by 
category (n(%)) for the FA set by treatment arm.  Categories will be assigned by the study 
Clinician.
6.5.3. Study Treatment Exposure
The following analyses will be based on the SA set.
6.5.3.1. Exposure to Glasdegib
The summary of treatment exposure for glasdegib will include the following information:

Treatment duration (weeks);

Cumulative dose (mg);

Dose intensity (mg/day);

Relative dose intensity (%). 
The duration of glasdegib (in weeks) is defined as:
Treatment duration (weeks) = (last dose date – first dose date + 1)/7.
The cumulative dose (mg) of glasdegib is the sum of the actual dose levels that the patient 
received (ie, total dose administered (mg)). 


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The dose intensity (DI) and the relative dose intensity (RDI) of glasdegib will be calculated 
for each patient during the study. The DI (mg/day) of glasdegib during the study is defined 
as:
DI (mg/day) = [cumulative dose (mg)]/[treatment duration (days) including any dose 
interruption period prior to permanent treatment discontinuation and excluding the 
HSCT period, if applicable].
The RDI of glasdegib is defined as the ratio of the DI and planned dose intensity and 
expressed in %
RDI (%) = 100× [DI (mg/day]/[100 (mg/day)].
6.5.3.2. Exposure to Cytarabine (Induction, Intensive Study Only)
The summary of treatment exposure for cytarabine in the induction cycles will include the 
following information:

Treatment duration (weeks);

Total number of infusions received;

Cumulative dose (mg/m2);

Dose intensity (mg/m2/day);

Relative dose intensity (%). 
Cytarabine is administered by intravenous (IV) infusion daily for 7 days, in 28 day cycles
(5 days allowed in re-induction cycle).
The dose level for cytarabine captured on the CRF is calculated as actual dose 
administered/body surface area (BSA) (mg/m2). The last available weight of the patient on 
or prior to the day of dosing will be used.
The duration of cytarabine (in weeks) during the study for a patient is defined as:
Treatment duration (weeks) = (last dose date – first dose date + 1)/7.
The cumulative dose (mg/m2) of cytarabine per cycle is the sum of the actual dose levels that 
the patient received within that cycle (ie, total dose administered (mg)/BSA (m2)).  
Cumulative dose (mg/m2) of cytarabine is the sum of the actual dose levels that the patient 
received throughout induction.
Since the planned cytarabine dose may be 5 (Option 1: ‘5+2’) or 7 (Option 2: ‘7+3’) days in 
the re-induction cycle, the dose intensity (DI) and the relative dose intensity (RDI) of 
cytarabine will be calculated for each patient by cycle and across all cycles based on the 
actual treatment received. The DI (mg/m2/day) of cytarabine is defined as:
DI (mg/m2/day) = [cumulative dose (mg/m2)]/[number of days with a non-zero dose].


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The RDI of cytarabine is defined as the actual DI divided by the planned dose per day and 
expressed in %:
RDI (%) = 100× [DI (mg/m2/day)]/[100× (mg/m2/day)].
6.5.3.3. Exposure to Cytarabine (Consolidation, Intensive Study Only)
The summary of treatment exposure for cytarabine in the consolidation cycles will include 
the following information:

Total number of infusions received;

Cumulative dose (g/m2);

Dose intensity (g/m2/day).
Cytarabine is administered by intravenous (IV) infusion twice daily for 3 days or follow local 
prescribing information, in 28 day cycles.
The dose level for cytarabine captured on the CRF is calculated as actual dose 
administered/BSA (g/m2). The last available weight of the patient on or prior to the day of 
dosing will be used.
The cumulative dose (g/m2) of cytarabine per cycle is the sum of the actual dose levels that 
the patient received within that cycle (ie, total dose administered (g)/BSA (m2)).  Cumulative 
dose (g/m2) of cytarabine is the sum of the actual dose levels that the patient received 
throughout consolidation.
Since the planned cytarabine dose in consolidation cycles can be 1 or 3 g/m2 BID according 
to patient age or different following local clinical practice (eg, Japan will use 2 g/m2 BID for 
5 days in a 28 days cycle), the DI of cytarabine will be calculated for each patient by cycle 
and across all cycles based on the actual treatment received. The DI (g/m2) of cytarabine is 
defined as:
DI (g/m2/day) = [cumulative dose (g/m2)]/[number of days with a non-zero dose].
The RDI of cytarabine will not be calculated for consolidation since the intended dose is not 
captured on the CRF.
6.5.3.4. Exposure to Daunorubicin (Induction Only, Intensive Study Only)
The summary of treatment exposure for daunorubicin will include the following information:

Treatment duration (weeks);

Total number of infusions received;

Cumulative dose (mg/m2);

Dose intensity (mg/m2/day);


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
Relative dose intensity (%). 
Daunorubicin is administered by intravenous (IV) infusion daily for 3 days, in 28 day cycles
(2 days allowed in re-induction cycle).
The dose level for daunorubicin captured on the CRF is calculated as actual dose 
administered/BSA (mg/m2). The last available weight of the patient on or prior to the day of 
dosing will be used.
The duration of daunorubicin (in weeks) during the study for a patient is defined as:
Treatment duration (weeks) = (last dose date – first dose date + 1)/7.
The cumulative dose (mg/m2) of daunorubicin per cycle is the sum of the actual dose levels 
that the patient received within that cycle (ie, total dose administered (mg)/BSA (m2)).  
Cumulative dose (mg/m2) of daunorubicin is the sum of the actual dose levels that the patient 
received throughout induction.
Since the planned daunorubicin dose is 2 (Option 1: ‘5+2’) or 3 (Option 2: ‘7+3’) days in the 
re-induction cycle, the DI and RDI of daunorubicin will be calculated for each patient by 
cycle and across all cycles based on the actual treatment received. The DI (mg/m2/day) of 
daunorubicin is defined as:
DI (mg/m2/day) = [cumulative dose (mg/m2)]/[number of days with a non-zero 
dose].
The RDI of daunorubicin is defined as the actual DI divided by the planned dose per day and 
expressed in %:
RDI (%) = 100× [DI (mg/ m2/day]/[60× (mg/m2/day)].
6.5.3.5. Exposure to Azacitidine (Non-intensive Study Only)
The summary of treatment exposure for azacitidine will include the following information:

Treatment duration (weeks);

Total number of injections/infusions received;

Cumulative dose (mg/m2);

Dose intensity (mg/m2/day);

Relative dose intensity (%). 
Azacitidine is administered by subcutaneous injection (SC) or intravenous (IV) infusion 
75 mg/m2 daily for 7 days, in 28 day cycles.


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The dose level for azacitidine captured in the CRF is calculated as actual dose 
administered/BSA (mg/m2). The last available weight of the patient on or prior to the day of 
dosing will be used.
The duration of azacitidine (in weeks) during the study for a patient is defined as:
Treatment duration (weeks) = (last dose date – first dose date + 1)/7.
The cumulative dose (mg/m2) of azacitidine per cycle is the sum of the actual dose levels that 
the patient received within that cycle (ie, total dose administered (mg)/BSA (m2)).  
Cumulative dose (mg/m2) of azacitidine is the sum of the actual dose levels that the patient 
received throughout the study.
The DI) and RDI of azacitidine will be calculated for each patient by cycle and across all 
cycles. The DI per day (mg/m2/day) of azacitidine is defined as:
DI (mg/m2/day) = [cumulative dose (mg/m2)]/[7 days x number of cycles with a 
non-zero dose].
The RDI of azacitidine is defined as the actual DI divided by the planned dose per day and 
expressed in %:
RDI (%) = 100× [DI (mg/ m2/day]/[75 (mg/m2/day)].
6.5.3.6. Dose Reductions and Interruptions due to Adverse Events
A dose reduction due to an AE is defined as a non-zero dose where reason for adjustment on 
the dosing CRF is AE.
The number and percentage of patients with at least one dose reduction as well as a 
breakdown of dose reductions (1 / 2 / ≥3) and/or the dosage administered will be summarized 
by treatment and by treatment arm.  
An interruption due to an AE is defined as a 0 mg dose administered where reason for 
adjustment on the dosing CRF is AE. The number and percentage of patients with dose 
interruptions will be summarized by treatment and by treatment arm.  Percentages will be 
calculated based on the total number of patients in the safety analysis set.
6.5.4. Concomitant Medications and Non-Drug Treatments
Concomitant medications and non-drug treatments received by patients during the study will 
be summarized for the safety analysis population by treatment arm.  
Concomitant medications refer to all medications which started prior to first dose of study 
treatment and continued during the on-treatment period (see Section 3.5) as well as those 
started during the on-treatment period.  Concomitant medications will be coded in the WHO 
Drug coding dictionary and will be tabulated by Anatomical Therapeutic Chemical (ATC) 
Classification level 2 and preferred term in descending order of frequency in the glasdegib
arm. In case of equal frequency regarding drug class (respectively drug name), alphabetical 


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order will be used.  A patient will be counted only once within a given drug class and within 
a given drug name, even if he/she received the same medication at different times.  Preferred 
Terms will be reported under each ATC class that it is included under within WHO Drug (no 
primary path is available in WHO Drug). 
Concomitant non-drug treatments refer to all non-drug treatments administered during the 
on-treatment period.  Non-drug treatments will be coded with the most current version of 
MedDRA and will be summarized by MedDRA’s SOC and PT in descending order of 
frequency in the glasdegib arm.  Patients will be counted only once per PT even if he/she 
received the same treatment multiple times.
Any medications or non-drug treatments which were only administered prior to treatment 
start will be listed but not summarized.
6.5.5. Prior and Subsequent Anti-Cancer Therapies/Procedures
Prior and subsequent Anti-Cancer Therapies and Procedures are defined as therapies entered 
on the ‘Prior Cancer Therapy’ and ‘Follow-up Cancer Therapy’ CRF pages, respectively.  
The number and percentage of patients within each category (medication therapy, radiation 
therapy, and surgeries) will be provided by treatment arm.  
Medications will be coded using the WHO Drug coding dictionary and will be tabulated by 
preferred term in descending order of frequency on the glasdegib arm.  
Analyses will be based on the FA set by treatment arm.
6.6. Safety Summaries and Analyses
Unless otherwise specified, summaries of AEs and other safety parameters will be based on 
the safety analysis population by treatment arm.
6.6.1. Adverse Events
All analyses will be based on treatment emergent events unless otherwise specified.  
Treatment emergent is defined in Section 3.5.1.
A high level summary of adverse events will include the number and percent of patients 
with:

Any Adverse Event;

Serious AE;

Adverse Events with maximum CTCAE Grade 3-4;

Grade 5 events;

AEs leading to dose interruptions separately for each study drug, for chemotherapy, 
and for any study treatment;


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
AEs leading to dose reductions separately for each study drug, for chemotherapy, and
for any study treatment;

AEs leading to withdrawal separately for each study drug, for chemotherapy, and for 
any study treatment.
Additionally, the number of events reported for each of the categories above will be 
provided.  Each unique adverse event at the PT level in each treatment arm of the study for a 
patient is included in the count. 
Seriousness, toxicity grade, action taken (interruption, reduction, and withdraw) are as 
reported by the investigator on the adverse event CRF.
Summaries by treatment arm, SOC and PT in decreasing frequency based on the frequencies 
observed in the glasdegib arm will be provided for:

Treatment Emergent Events by Maximum Toxicity Grade (All Causality);

Treatment Emergent Events by Maximum Toxicity Grade (Treatment Related);

Serious Treatment Emergent Events by Maximum Toxicity Grade (All Causality);

Serious Treatment Emergent Events by Maximum Toxicity Grade (Treatment 
Related).
An event will be considered treatment related if the investigator considered the event related 
to the study drug or this information is unknown.
The above four summaries will also be provided separately for (1) treatment emergent events 
prior to HSCT, (2) non-treatment emergent events during HSCT, and (3) treatment emergent 
events after HSCT.
The following summaries will be provided by treatment arm and PT (ie, summaries will not 
include SOC) in decreasing frequency based on the frequencies observed in the glasdegib
arm for:

Treatment Emergent Events (All Causality) Experienced by ≥10% of patients in 
either treatment arm; 

Treatment Emergent Events (All Causality) by Preferred Term and Maximum 
Toxicity Grade;

Treatment Emergent Grade 3-5 Events (All Causality) by Preferred Term and 
Maximum Toxicity Grade;

Treatment Emergent Adverse Events Leading to Dose Interruptions by Maximum 
Toxicity Grade (All Causality) separately for each study drug, for chemotherapy, and 
for any study treatment;


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•
Treatment Emergent Adverse Events Leading to Dose Reductions by Maximum 
Toxicity Grade (All Causality) separately for each study drug, for chemotherapy, and 
for any study treatment;
•
Treatment Emergent Adverse Events Leading to Permanent Withdrawal by 
Maximum Toxicity Grade (All Causality) separately for each study drug, for 
chemotherapy, and for any study treatment;
•
Serious Treatment Emergent Events (All Causality).
Each patient will be counted only once within each PT.  
As described in Section 5.3.2, in case a patient has events with missing and non-missing 
toxicity grades, the maximum of the non-missing grade will be displayed.  Missing grade will 
only be displayed in the event that only one event has been reported for a patient and the 
grade is missing.
6.6.1.1. Basic Results
For basic results disclosures in the US and EU the following additional summaries will be 
provided:
•
Treatment Emergent Non Serious Adverse Events by SOC and PT in >5% of patients 
in either treatment arm;
•
Treatment Emergent Serious Adverse Events by SOC and PT; and 
•
Fatal Adverse Events by SOC and PT.
Each of the above summaries will include a count of the number of patients with all causality 
events and the number of patients with treatment related events.
 
 
 
 
 
 
 
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6.6.1.3. Adverse Events of Special Interest
These analyses will be performed for treatment emergent AEs of special interest as specified 
in 3.5.1.
•
Time to AE Onset (in days) is defined as the time from the date of the first dose to 
the onset date of the AE, regardless of grade.  If a patient has multiple episodes of an 
AE, the date of the first occurrence is used.  Time to AE onset (in days) will be 
calculated as (AE start date – first dose date +1). Time to onset is calculated for the 
subgroup of patients who had the specific AE.
•
Time to Grade 3 or 4 AE Onset (in days) is defined similarly as time to AE onset 
for Grade 3 or 4 AEs.
•
Duration of AE (in days) is defined as the cumulative duration across episodes of the 
AE, regardless of grade, where duration for each episode is the time from the AE start 
date to the AE end date.  For one episode, duration (in days) = AE end date – AE start 
date + 1. If a patient has multiple episodes of an AE, cumulative duration across all 
episodes will be used adjusting for any overlap.  If a patient has an AE that was 
ongoing at the time of analysis, the time is censored at the last available on treatment 
visit date.  Duration is calculated for the subgroup of patients who had the specified 
AE.
Descriptive statistics will be presented for time to AE onset (days), time to Grade 3 or 4 AE 
onset, and duration of AEs for the subgroup of patients with the AE.
Person-year exposure analyses may also be considered in case of relevant difference in 
treatment duration between treatment arms.
6.6.2. Deaths
The frequency (number and percentage) of patients in the safety analysis set who died during 
the study and who died within 28 days after last dose of study treatment as well as the 
primary reason for death, will be tabulated based on information from the ‘Notice of Death’ 
CRF, by treatment arm.  
The frequency (number and percentage) of patients in the safety analysis set who died within 
30 days of first dose of study treatment will also be provided.
Date and cause of death will be provided in individual patient data listing together with 
selected dosing information (study treatment received, date of first/last administration, dose).
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6.6.3. Laboratory Data
Laboratory results will be converted to International System of Units (Système International 
d'unités, SI) units which will be used for applying toxicity grades and for all summaries. 
As described in Section 3.4, baseline will be defined as the last non-missing assessment 
performed on or prior to date of the first dose of study treatment (or prior to randomization 
for patients randomized but not dosed).  If there are multiple assessments that meet the 
baseline definition on the same day without the ability to determine which was truly last, then 
the worst grade will be assigned as the baseline grade.  Since a few CTCAE terms (including 
Hypo/Hypercalcemia and Activated Partial Thromboplastin) can be derived using several 
laboratory tests (analytes) refer to the section 2.3.7 of the “Pfizer Oncology CTCAE Grading 
Implementation Guidance for Laboratory Data” for determination of baseline CTCAE grade 
in this situation.
Laboratory results will be programmatically classified according to NCI-CTCAE version 
4.03 grade.  Non-numerical qualifiers will not be taken into consideration in the derivation of 
grade (eg, hypokalemia Grade 1 and Grade 2 are only distinguished by a non-numerical 
qualifier and therefore Grade 2 will not be derived). In summary statistics the number and 
percentage of patients corresponding to grades that only include non-quantitative criteria will 
be displayed as a blank or NA (not assessed) rather than 0.  If there is any overlap between 
grade criteria (eg, CTCAE grading criteria for Creatinine Increased – a value can fall into one 
range based on comparison to ULN and another range based on comparison to baseline), the 
highest (worst) grade would be assigned to that record. Grade 5 is defined in the CTCAE 
criteria guidance as an event with an outcome of death. Since laboratory data does not 
collect an outcome, Grade 5 is not used when programmatically grading laboratory data.
Grade 0 or Outside Toxicity Reference (OTR) is not defined specifically in the CTCAE 
guidance. However, programmatically this is used as a category to represent those patients 
who did not meet any of the Grades 1 to 4 criteria.  If the laboratory value is evaluable for 
CTCAE criteria grading (numeric value is present, valid units and ranges are present as 
required to allow conversion to standard units and grading), and does not qualify for any of 
the Grade 1-4 criteria for a given lab test, then the value is assigned as Grade 0 or OTR.
Abnormalities will be described using the worst grade post-baseline. When determining the 
maximum post-baseline grade for a given patient and CTCAE test, the maximum across all 
analytes and assessments contributing to that CTCAE test will be used. Several laboratory 
tests have bi-directional grading criteria defined so that both low (hypo) and high (hyper) 
values can be graded separately.  Each criterion will be summarized separately.  In the cases 
where a value is graded as a Grade 1, 2, 3, or 4 for one of the directions, that value will also 
be assigned as a Grade 0 for the opposite direction for that test.  For example, a value 
meeting the criteria for Grade 3 Hypercalcemia will be classified as a Grade 0 Hypocalcemia.
For CTCAE terms that can be derived using one of several laboratory tests, the maximum 
post-baseline grade for a given patient and CTCAE term will be the maximum across all 
possible laboratory tests.


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For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported by the lab.  
When only percentages are available (this is mainly applicable for neutrophils and 
lymphocytes, because the CTCAE grading is based on the absolute counts), the absolute 
value is derived as follows: 
Derived differential absolute count = (WBC count) × (Differential %value/100).
If the investigator reports both the absolute and % value for Neutrophils or Lymphocytes 
from the same laboratory sample date and patient, ONLY the absolute value will be graded.  
The % value will not be graded in this scenario. 
If the % value is converted to the differential absolute count for grading and the LLN for the 
differential absolute count is not available (only LLN for % is available) then Grade 1 will be 
assigned if the following conditions are met: 

Lymphocyte count decreased:  
- derived absolute count does not meet Grade 2-4 criteria, and
- % value < % LLN value, and
- derived absolute count ≥800/mm3.

Neutrophil count decreased 
- derived absolute count does not meet Grade 2-4 criteria, and
- % value < % LLN value, and
- derived absolute count ≥1500/mm3.
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium. 
Corrected Calcium is calculated from Albumin and Calcium as follows:

Corrected Calcium (mmol/L) = Calcium (mmol/L) + 0.02 [40 - Albumin (g/L)].
Laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages):

Summary of laboratory parameters by worst CTCAE grade post-baseline table will 
include number and percentage of patients with Grade 0, 1, 2, 3, 4, and 
Grade 1-4 laboratory abnormalities.

Shift table will summarize baseline CTCAE grade versus the worst post-baseline 
CTCAE grade.

Patients who developed toxicities of grade ≥3 will also be listed.


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Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the following categories overall: below normal limit, within normal limits, and above normal 
limits. In the unlikely event that for a given patient, clinically significant abnormalities are 
noted in both directions (eg, > Upper Limit of Normal (ULN) and < Lower Limit of Normal 
(LLN)), then both abnormalities are counted. 
Drug Induced Liver Toxicity
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), Alkaline Phosphatase 
(ALP), and total bilirubin (TBILI) are used to assess possible drug induced liver toxicity. 
The ratios of test result over the ULN will be calculated and classified for these three 
parameters during the on-treatment period. 
Summary of liver function tests will include the following categories.  The number and 
percentage of patients with each of the following during the on-treatment period will be 
summarized by treatment arm:

For patients with normal ALT, AST, and TBILI at baseline, (ALT or AST) > 3×ULN 
and TBILI > 2×ULN and ALP < 2×ULN or missing.

For patients with ALT, AST, or TBILI above the ULN at baseline:

Preexisting AST or ALT baseline values above ULN: AST or ALT values 
>2 times the baseline values AND >3×ULN; or >8×ULN (whichever is smaller).

Preexisting values of TBILI above the normal range: TBILI level increased from
baseline value by an amount of at least 1×ULN or if the value reaches >3×ULN 
(whichever is smaller).
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment arms, by graphically displaying:

peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
ALT=3×ULN and total bilirubin=2×ULN. 

peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at  
AST=3×ULN and total bilirubin=2×ULN. 
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a post-
baseline TBILI > 2×ULN, ALT > 3×ULN or AST > 3×ULN will be provided.
6.6.4. Vital Signs
Vital signs data includes weight, pulse, systolic blood pressure, and diastolic blood pressure.  
Measurements were only to be provided once per timepoint.  If multiple assessments are 
provided per timepoint, the maximum value will be used for reporting.  


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Vital signs data will be summarized using simple descriptive statistics (mean, standard 
deviation, median, quartiles, minimum, and maximum) of actual values and change from 
baseline for each nominal visit over time (ie, unscheduled assessments will be excluded). 
The total number of patients for change from baseline will include all patients in the 
treatment arm who have both a baseline value and a value at the nominal visit. Baseline will 
be selected as defined in Section 3.4.
The number and percent of patients in each of the following minimum and maximum blood 
pressure, body weight, and pulse categories will be presented:

Increase in Systolic Blood Pressure ≥40 mmHg.

Decrease in Systolic Blood Pressure ≥40 mmHg.

Decrease in Systolic Blood Pressure ≥60 mmHg.

Increase in Diastolic Blood Pressure ≥20 mmHg.

Decrease in Diastolic Blood Pressure ≥20 mmHg.

Decrease in Diastolic Blood Pressure ≥40 mmHg.

Decrease in Body Weight ≥10%.

Maximum Pulse Rate >120 bpm.

Minimum Pulse Rate <50 bpm.

Maximum increase in pulse rate ≥30 bpm.

Maximum decrease in pulse rate ≥30 bpm.
All assessments, including unscheduled assessments will be considered.  A patient can be 
included in multiple categories if different criteria are met at different timepoints. 
6.6.5. Electrocardiogram
Triplicate ECGs assessments are required at each specified nominal visit and time-point as 
specified in the Schedule of Activities in the Protocol (Table 2 for Intensive and Table 4 for 
Non-intensive). A mean value is calculated for any replicate measurements having the same 
nominal visit. The mean measurement is reported. 
QTcF and QTcB (both Fridericia and Bazett’s correction) will be programmatically derived 
using the following formula:
QTcF(msec) = QT(msec)/(60/HR[bpm])1/3
QTcB(msec) = QT(msec)/(60/HR[bpm])1/2


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QT, RR, HR, PR, QRS, QTcF, and QTcB will be summarized using simple descriptive 
statistics (mean, standard deviation, median, quartiles, minimum, and maximum) of actual 
values and change from baseline for each nominal visit over time (ie, unscheduled 
assessments will be excluded). The total number of patients for change from baseline will 
include all patients in the treatment arm who have both a baseline and a value at the nominal 
visit. Baseline will be selected as defined in Section 3.4.
The mean absolute value will be presented with two-sided 95% confidence intervals and the 
baseline adjusted mean QT, RR, HR, PR, QRS, QTcF and QTcB will be presented with 
two-sided 90% confidence intervals.
Additionally QTcF and QTcB will be summarized by maximum post-baseline values using 
the following categories.

≤450 msec;

>450 msec but 480 msec; 

>480 msec but ≤500 msec; 

>500 msec.
Unscheduled assessments will be utilized in addition to planned assessments.  
And maximum increases from baseline in QTcF and QTcB (including scheduled and 
unscheduled assessments) will be also summarized based on the following categories:

Change ≥60 msec;

Change ≥30 msec but <60 msec;

Change <30 msec.
In the event that neither Fridericia’s nor Bazett’s correction adequately adjusts for heart rate, 
an additional correction such as a population or patient-specific baseline correction could be 
used and should be fully justified. 
For PR and QRS maximum increases from baseline, the following categories will be applied:

PR changes from baseline ≥25% and absolute values >200 msec; 

QRS changes from baseline ≥25% and absolute values >110 msec.
Shift tables will be provided for baseline versus worst on study QTc (one or more correction
method will be used) using categories ≤450 msec, >450 msec but ≤480 msec, >480 msec but 
≤500 msec, and >500 msec. Tables of ECG abnormality at baseline (yes, no, not done: 
(n, %)) will also be provided. Subjects experiencing abnormal and clinically-relevant 
morphological ECG changes will be summarized (including frequency and percentage).


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If more than one ECG is measured at a nominal time post-dose (eg, triplicate ECGs within 
2-4 minutes), the mean will be used to represent a single observation per patient and time 
post-dose. If any of the three individual ECGs results in a QTc >500 msec and the mean is 
not >500 msec, then that patient’s data will be described in the safety section in the study 
report in order to place the >500 msec value in appropriate clinical context. On the other 
hand, such individual >500 msec value within a triplicate will not be included in the 
categorical analysis unless the average from that triplicate is also >500 msec. Data listings 
will contain the means from a triplicate as well as the parameters from each of the three 
ECGs. Note that using the mean value may result in a patient having a measurement that is 
not represented by an actual ECG. 
6.6.6. Physical Examination
Physical examination findings will only be listed.
6.6.7. Left Ventricular Ejection Fraction (LVEF)
LVEF% will be summarized using simple descriptive statistics (mean, SD, median, Q1, Q3,
minimum, and maximum) of actual values and changes from baseline for each nominal visit
over time. In addition, a shift table will be provided for baseline versus worst on-treatment 
LVEF% per NCI CTCAE version 4.03. 
A patient will be included in the categories above if any post-baseline assessment (including 
unscheduled assessments) meet the criteria; however only post-baseline assessments which 
use the same method of assessment (ECHO or MUGA) as baseline will be considered.
6.6.8. Performance Status
The ECOG shift from baseline to the highest score during the post-baseline period will be 
summarized by treatment arm.
 
 
 
  
7. INTERIM ANALYSES
7.1. Introduction
The goals of the interim analyses are to allow early stopping of the study for futility or 
efficacy. The interim analysis of OS will be performed as described in Section 5.1.1 and
5.1.2 using the methodology described in Section 6.2.1 for OS. 
CCI


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The interim analysis will be performed by an independent statistician. Unblinded results 
from the interim analysis will not be communicated to the Sponsor’s clinical team or to any 
party involved in the study conduct (apart from the independent statistician and E-DMC 
members) until the E-DMC has determined that (i) OS analysis has crossed the prespecified 
boundary (except for the efficacy boundary at the first planned interim analysis for the 
intensive chemotherapy study when there is no plan to stop for efficacy regardless of whether 
the boundary is crossed) and the Sponsor has decided to terminate the study or (ii) the study 
needs to be terminated due to any other cause, including safety reasons. Further details will 
be described in the E-DMC charter.
The final OS analysis will be performed by the Sponsor's clinical team.
7.2. Interim Analyses and Summaries
At each analysis timepoint, the critical boundaries for the group sequential test will be 
derived from the predefined spending function(s) as described in Section 5.1. The 
calculations of boundaries will be performed using EAST. For the intensive chemotherapy 
study, there will not be any efficacy stopping at the first planned interim analysis even if the 
efficacy stopping boundary is crossed.
Let l(t1) and u(tF) denote the lower critical boundaries for futility at the interim analysis and 
the upper critical boundaries for efficacy at the final analysis based on the test statistics 
Z1 and ZF, respectively. 
The critical values l(t1) for the interim analysis of OS are determined such that 
)
(
))
(
(
1
1
1
t
t
l
Z
Pa



where Pa denote the probabilities under the alternative hypothesis and 
)
( 1t

denote the 
spent, based on the predefined spending functions at information fraction t1 (t1 is calculated 
as the ratio of the number of deaths observed at the time of the data cutoff for the interim 
analysis and the total number of deaths targeted for the final analysis). 
The boundary for the final efficacy analysis is derived such that
025
.0
))
(
(
0


F
F
t
u
Z
P


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8. REFERENCES
1.
Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 
2017 ELN recommendations from an international expert panel. Blood 2017; 
129(4): 424-47.
2.
Brookmeyer R and Crowley J.  A confidence interval for the median survival time. 
Biometrics 38:29-41, 1982.
3.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition.
Hoboken, Wiley Interscience.
4.
Schoenfeld, D. A. (1982), “Partial Residuals for the Proportional Hazards Regression 
Model,” Biometrika, 69, 239–241.
5.
Therneau, T. M. and Grambsch, P. M. (2000). Modeling Survival Data: Extending the 
Cox Model, Springer-Verlag, New York.
6.
Zhang X. Comparison of restricted mean survival times between treatments based on a 
stratified Cox model. DOI 10.1515/bams-2013-0101 Bio-Algorithms and Med-Systems 
2013; 9(4): 183–9.
7.
Fayers P et al. EORTC QLQ-C30 Scoring Manual. 2001. EORTC, Brussels.
8.
The EuroQol Group. EQ-5D-5L: User Guide. V 2.1, April 2015. EuroQol Research 
Foundation, Rotterdam.
9.
Osoba D et al, Interpreting the significance of changes in health-related quality of life 
scores. 3. Cin Oncology. 1998. 16:139-144.
10.
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. 1997. Biometrics, 53, 983-997.
11.
Santner TJ and Snell MK. Small-Smple Confidence Interval for p1 – p2 and p1/ p2 in 2x2 
Contingency Tables. Journal of the American Statistical Association 75: 386-394, 1980.
12.
Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid 
leukemia. The New England journal of medicine 2009; 361(13): 1249-59.
13.
Lowenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older 
patients with acute myeloid leukemia. The New England journal of medicine 2009; 
361(13): 1235-48.
14.
Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs 
conventional care regimens in older patients with newly diagnosed AML with >30% 
blasts. Blood 2015; 126(3): 291-9.
15.
Schemper M and Smith TL, A Note on Quantifying Follow-up in Studies of Failure 
Time, Controlled Clinical Trials 1996, 17:343-346.


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16.
Morgan TM, Analysis of uration of rResponse: A Problem of Oncology Trials, 
Controlled Clinical Trials 1988, 9:11-18.
17.
Gray RJ, A class of k-sample tests for comparing the cumulative incidence of a 
competing risk, Annals of Statistics 1988, 16: 1141-1154.


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9. APPENDIX
9.1. Note on Defining CIR for “Fatigue” Single-item from the MDASI AML/MDS 
Questionnaire
(Note this description is for the cohort of intensive patients. The analysis for non-intensive 
patients can easily be inferred by extending Week 8 to Week 12 throughout).
FDA document “Guidance for Industry. Patient-Reported Outcome Measures: Use in 
Medical Product Development to Support Labeling Claims” gives following definition for 
Clinically Important Responder (CIR) Definition: 
“Responder definition — A score change in a measure, experienced by an individual 
patient over a predetermined time period that has been demonstrated in the target 
population to have a significant treatment benefit.”
In the guidance the following algorithm is proposed to define responder definition: 
“…anchor-based approach to defining responders makes use of patient ratings of change 
administered at different periods of time or upon exit from a clinical trial. These numerical 
ratings range from worse to the same and better. The difference in the PRO score for 
persons who rate their condition the same and better or worse can be used to define 
responders to treatment. Patient ratings of change are less useful as anchors when patients 
are not blinded to treatment assignment.…”
First ,we do not have simple numerical rating scale with just 3 categories – that is, 
"numerical ratings range from worse to the same and better." PGIS is used to create 
a simplified numerical rating with 3 categories worse, the same, and better. 
Specifically, we create a new anchor Subject Global Impression of Change using 
PGIS (SGIC-S) by using the following algorithm (note that Y in below represents 
“Week 1”, “Week 2”,… “Week 8”): 
a.
SGIC-S = -1, if PGIS at Week Y minus PGIS at baseline (day 1) is positive (this 
means worse);
b. SGIC-S = 0, if PGIS at Week Y minus PGIS at baseline (day 1) is zero (ie, no 
change, this means the same);
c.
SGIC-S = 1, if PGIS at Week Y minus PGIS at baseline (day 1) is negative (this 
means better).
A repeated measures model will be used to determine CIR. Figure 1 represents the SAS 
implementation of the model. We use the change in the “Fatigue” single-item (from 
baseline) as the outcome (variable changeFatigue) and SGIC-S score as the anchor variable 
(note that variable SGICS has only 3 categories worse [value of -1], the same [value of 0], 
and better [value of 1]). It is important to note that we treat SGIC-S in this model as a 
continuous variable – by doing so we impose a linear relationship between change in a 
“Fatigue” single-item and SGIC-S. As a sensitivity analysis we may also perform modeling 
using SGIC-S as a categorical variable – this approach does not impose any functional 


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relationship between outcome and anchor (see figure 2 for SAS implementation). In this 
case, the larger difference between two contiguous categories (no change vs. worse, or better 
vs. no change) will be used as the CIR. We should note that all available post-baseline data 
will be used (starting with Week 1 and up to Week 8 from the cohort of intensive patients).
Figure 1. SAS Proc Mixed code (SGIC-S as a continuous anchor)
Proc mixed data=_mixed_;
    Class PID Week ;
    Model changeFatigue = SGICS / ddfm=kr s;
    Repeated Week / Type=SP(POW)(cVisit)  Subject=PID;
    Estimate "CIR (One Category Change)"  SGICS 1 /cl;
   Estimate "worse    SGIC=-1" Intercept 1 SGICS -1 /cl;
    Estimate "the same SGIC=0 " Intercept 1 SGICS 0 /cl;
    Estimate "better   SGIC=1 " Intercept 1 SGICS 1 /cl;
    Run;
Figure 2. SAS Proc Mixed code (SGIC as a categorical anchor)
Title "Experience Domain Score";
Proc mixed data=_mixed_;
    Class PID Week SGICS;
    Model changeFatigue = SGICS / ddfm=kr s;
    Repeated Week / Type=SP(POW)(cVisit)  Subject=PID;
    LSMeans  SGICS / diff cl;
Run;
In addition, sensitivity analyses the above approach is augmented by using PGIC. 
Specifically, we create another anchor Subject Global Impression of Change using PGIC 
(SGIC-C) by using following algorithm (note that Y in below represents “Week 1”, 
“Week 2”,… “Week 8”): 
a.
SGIC-C = -1, if PGIC at Week Y represents worsening (PGIC scores of 5, 6, and 7; 
this means worse);
b. SGIC-C = 0, if PGIC at Week Y is 4 (ie, no change, this means the same);
c.
SGIC-C = 1, if PGIC at Week Y represents improvement  (PGIC scores of 1, 2, 
and 3; this means better). 
The same models represented by figures 1 and 2 will be used (the variable SGICS will be 
replaced by variable SGICC representing SGIC-C).