Clinical trial NCT02367456
Conditions: Myelodysplastic Syndrome Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia
Keywords: MDS AML CMML
Sponsor: Pfizer
Start date: 2015-04-28; Completion date: 2022-03-07
Enrollment: 73 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multi center open label Phase 1b study is designed to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of glasdegib (PF-04449913) when combined with azacitidine in patients with previously untreated Higher Risk Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), or Chronic Myelomonocytic Leukemia (CMML). This clinical study includes two components: (a) a safety lead in cohort (LIC) and (b) an expansion phase with an AML cohort and an MDS cohort.

Detailed description:

Arms: arm 1: MDS patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2 arm 2: AML patients: PF-04449913 (Glasdegib) 100 mg + Azacitidine 75 mg/m2
Interventions: intervention 1: PF-04449913 (Glasdegib) intervention 2: Azacitidine
Intervention descriptions: intervention 1: Daily dose of PF-04449913 100mg tablet in a continuous regimen of 28 day cycles intervention 2: 75mg/m2 on Days 1-7 (+/- 3 days for each dose) of a 28 day cycle

Protocol documents:
Prot_000.pdf: 
PF-04449913
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Final Protocol Amendment 7, 14 June 2018
PFIZER CONFIDENTIAL
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AN OPEN-LABEL PHASE 1B STUDY OF PF-04449913 (GLASDEGIB) IN 
COMBINATION WITH AZACITIDINE IN PATIENTS WITH PREVIOUSLY 
UNTREATED HIGHER-RISK MYELODYSPLASTIC SYNDROME, ACUTE 
MYELOID LEUKEMIA, OR CHRONIC MYELOMONOCYTIC LEUKEMIA
Compound:
PF-04449913
Compound Name:
Glasdegib
United States (US) Investigational New 
Drug (IND) Number:
105,453
European Clinical Trials Database 
(EudraCT) Number:
2014-001345-24
Protocol Number:
B1371012
Phase:
1b
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by accepting or reviewing this document, 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 
Original protocol
15-July-2014
N/A
Amendment 1
21 October 2014
Figures 1 and 3: Study Schematic updated to 
include the 2 additional safety analyses during 
the Randomized Phase 2 component.
Added in all appropriate sections that patients 
with >30% BM blasts OR a rapidly 
progressive increase in the proportion of BM 
blasts at any point during the trial, must 
discontinue the study drug combination and 
enter follow-up.
Added in all appropriate sections that two 
safety analyses will be performed following 
commencement of the randomized 
Phase 2 component of the study in order to 
carry out an early assessment of the safety 
profile of the study treatment combination in 
addition to the one performed at the end of the 
lead-in phase.  One analysis will be carried out 
after 12 patients have completed 2 cycles of 
treatment, and one after 24 patients have 
completed 2 cycles of treatment.  The EDMC 
will review the results of both analyses.
Deleted all references to allowing the 
continuation of single agent 
PF-04449913/placebo in the event that 
azacitidine is permanently discontinued for 
reasons other than objective disease 
progression, patient refusal, or consent 
withdrawal.
Updated in all appropriate sections that the 
Patient Dosing Diary for PF-04449913/placebo 
will now be required for all treatment cycles.  
Previously the Patient Dosing Diary was 
optional after Cycle 6.
End of Treatment Visit added to Table 4.


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Document
Version Date
Summary of Changes 
The following Exclusion Criteria was added: 
“Patients with AML who are candidates for 
standard induction chemotherapy”.
The following clarification of the definition of 
a missed dose was added to 
Section 5.5.1 General Guidelines in reference 
to PF-04449913: “If a patient 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 patient should continue on their normal 
dosing schedule.” 
For clarification the following sentence was 
added to Section 5.5.2.3.2: PF-04449913 or 
Placebo: “PF-04449913/placebo treatment 
should be interrupted for ANC <100/mm3 and 
/or platelets < 10,000/mm3 regardless of when 
it occurs.” 
In Section 5.5.2.3.2. PF-04449913 or Placebo: 
Investigator judgment allowing 
re-commencement of PF-04449913/placebo 
treatment for non-hematological toxicities if 
returned to baseline or ≤ Grade 2 (if not 
considered a safety risk) was removed.  
Re-commencement can only occur when the 
non-hematological toxicity has returned to 
baseline or ≤ Grade 1.
In Section 5.5.2.4. Dose Reduction for 
Azacitidine and PF-04449913 or Placebo the 
following sentence was deleted: “No specific 
dose adjustments are recommended for Grade 
1/2 treatment-related toxicity.  Investigators 
should, however, manage their patients 
according to their medical judgment based on 
the clinical circumstances.”


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Document
Version Date
Summary of Changes 
Table 7 was updated to include additional and 
new PF-04449913/placebo dose modification 
instructions. 
Table 7 Footnote was updated to include both 
definitions of recovery as well as clarification 
on PF-04449913/placebo interruption criteria.
Table 8: Section referring to 
PF-04449913/placebo related Other 
Non-Hematologic Toxicities was updated to 
also exclude muscle spasms and myalgia.
Table 9. Recommended Dose Modifications 
for PF-04449913/placebo related QTcF 
prolongation was updated.
Table 10. Recommended Dose Modifications 
for PF-04449913/placebo in case of drug class 
related AEs was added.
Section 7.6. Triplicate (12 Lead) ECGs was 
updated to agree with the updated Table 9.
Minor administrative corrections adding 
clarifications and correction of typos.
Amendment 2
15 December 2014
In Section 3.3.2 Breaking the Blind and 
Section 5.2 Breaking the Blind the following 
sentence was removed: “Whenever possible, 
the Investigator or sub investigator consults 
with the Sponsor prior to breaking the blind.”
In Sections 3.3.2 Breaking the Blind and 
5.2 Breaking the Blind the following sentence 
was added: “Immediate unblinding for patient 
safety can occur via the IRT system.”
In the Protocol Summary; Study Treatments, 
Section 3.3.1 Study Treatments, 
Section 5.5.1.3 Treatment Duration and 
Section 6.4 Follow-Up the following sentence 
was added: “In cases of unacceptable toxicity 
or pregnancy, the patient must be withdrawn 
from study drug combination and entered into 
the follow-up phase of the study.”


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Document
Version Date
Summary of Changes 
Throughout the document when referring to 
study endpoints and objectives the terms 
Objective Response Rate (ORR) and Objective 
Response (OR) were changed to Response 
Rate (RR) and Response respectively.
Under Protocol Summary and under 
Section 2.2: Endpoints for the Phase 1b (Safety 
Lead-In Cohort [LIC]) Secondary Endpoints: 
Clarified the definition of Response Rate by 
adding the following in bold: “Response Rate 
(percentage of patients achieving Complete 
Remission (CR) + Partial Remission (PR)) as 
defined by modified International Working 
Group (IWG) criteria (2006) Appendix 2:”
Under Protocol Summary and under 
Section 2.4: Endpoints for the Randomized 
Phase 2 Primary Endpoint: Clarified the 
definition of Response Rate by adding the 
following in bold: “Response Rate 
(percentage of patients achieving CR + PR) 
as defined by modified IWG criteria (2006) 
Appendix 2.”
Section 4.2 Exclusion Criteria 1 (updated in 
bold) to:” Patients with AML who are 
candidates for standard induction 
chemotherapy as first line treatment.”
Minor administrative corrections adding 
clarifications and correction of typos.
Amendment 3
17 February 2015
Section 5.5.2.4 Table 9 and Section 7.6: Will 
be updated with the following sentence:
“If Grade 3 QTcF prolongation (>500 msec) 
occurs, continuous ECG monitoring and 
cardiology specialist evaluation and guidance 
are recommended.”
Minor administrative corrections adding 
clarifications and correction of typos.


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Document
Version Date
Summary of Changes 
Updates to safety and communication of 
results by Pfizer text to incorporate latest 
template changes.
Amendment 4
04 January 2016
Study Title updated to include the drug 
International Nonproprietary Name (INN), 
Glasdegib.
Abbreviations list updated.
Table 1- Schedule of Activities for the Phase 
1b Safety LIC:
Footnotes 14 and 25 updated to clarify 
that study treatment refers to 
PF-04449913 + Azacitidine
Footnote 25, corrected to remove 
mention of PRO assessment collection 
in the Long-Term Follow Up period of 
the Phase 1b Safety LIC. 
Table 2 “Pharmacokinetics and ECG Schedule 
for the Safety LIC” updated to expand ECG 
collection to Day 1 of every cycle and clarify 
that PK collection ends after Cycle 6.
Table 4 “Pharmacokinetics & ECG Schedule 
for the Randomized Phase 2” updated to 
expand ECG collection to Day 1 of every 
cycle.
Section 1.2.12 Summary of Benefit-Risk 
Assessment updated with information 
concerning QTc interval prolongation.
Section 4.0 Patient Selection.  The following 
statement was added to clarify that eligibility 
criteria must be met both at Screening and on 
Cycle 1 Day 1:  “These criteria must also be 
met prior to dosing on Cycle 1 Day 1.”   
Section 4.2 Exclusion Criterion 19 revised to 
include exclusion of all bundle branch blocks.


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Document
Version Date
Summary of Changes 
Section 5.5.2 Dose Modifications updated:
1. The section heading and titles for 
Table 7- Dose Modifications for 
Hematologic Toxicities and Table 
8-Dose Modifications for 
Non-Hematologic Toxicities amended 
to remove the term “Recommended”.  
The term “Recommended” was also 
removed from all dose modification 
references throughout the protocol.
2. The following statement was added “If 
there is a need to deviate from any of 
the dose modifications this first must be 
discussed with the Sponsor Medical 
Monitor.”
3. Table 9- Recommended Dose 
Modifications for 
PF-04449913/placebo related QTcF 
prolongation replaced with a new table 
entitled PF-04449913/placebo Dose 
Modifications for mean QTcF 
(mQTcF) Prolongation.
4. Table 10-Recommended Dose 
Modifications for 
PF-04449913/placebo in Case of Drug 
Class Related AEs updated to remove 
the term “Recommended” from the title 
and replaced with a new table.
5. Sub-Section 5.5.2.3.2 PF-04449913 or 
Placebo, added sub heading entitled 
“QTcF Interval Monitoring and 
Management” language concerning the 
monitoring of potential cardiovascular 
symptoms and guidance on the use of 
moderate/strong CYP3A4/5 inhibitors 
or drugs with a known risk of Torsade 
de pointes are added as concomitant 
therapy with PF-04449913/placebo.


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Document
Version Date
Summary of Changes 
Section 5.8.1 Restricted or Prohibited 
Concomitant Medications:  Added reference to 
new safety monitoring guidance provided in 
Section 7.6 and Table 9.
Section 7.6 Triplicate (12-Lead) ECGs:  New 
safety monitoring guidance provided when 
moderate/strong CYP3A4/5 inhibitors or drugs 
with a known risk of Torsade de pointes are 
added as concomitant therapy with 
PF-04449913/placebo.
Section 8.12 Withdrawal due to Adverse 
Events updated to include the following 
statement: “Please also refer to 
section 6.5 Patient Withdrawal.”  
Section 8.6.1 Protocol-Specified Serious 
Adverse Events updated to include the 
following sentence “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.”
Appendix 4-Strong CYP3A4/5 Inducers source 
reference updated.
Appendix 5- List of Drugs with Known Risk 
of Torsades de Pointes, Appendix 6-Strong 
CYP3A4/5 Inhibitors, and 
Appendix 7 -Moderate CYP3A4/5 Inhibitors 
replaced with new tables and updated source 
references.
Amendment 5
22 August 2017
Study Title updated to remove the Phase 2 part 
and reflect the hematologic malignancies 
enrolled in the entire Phase 1 study.
Abbreviations list updated.
Protocol Summary updated to reflect new 
study design: Phase 2 part removed and Phase 
1 Expansion Component added. 


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Document
Version Date
Summary of Changes 
Table 2 title updated to remove number of LIC
patients.
Table 3 New “Schedule of Activities for the 
Expansion” added.
Table 4 New “Pharmacokinetics & ECG 
Schedule for Expansion” added.
References to “placebo” removed from the 
body of the document.
Table of Content updated.
Section 1.1. Indication for Expansion 
Component added. 
Section 1.2.1. Disease Overview updated to 
reflect new MDS and AML classification.
Section 1.2.3. Rationale for 
PF-04449913/Azacitidine Combination 
Therapy in Patients with AML updated.
Section 1.2.5. PF-04449913 Preclinical 
Toxicity Data updated.
Section 1.2.10. Heading updated to “Clinical 
Relevance of Organ Toxicities Observed in 
Nonclinical studies” from “Impact of 
Preclinical Safety Findings on Patient 
Management”, and data within section 
updated.
Section 1.2.6. Bone Effects in Preclinical 
Studies updated.
Section 1.2.13. Clinical Experience in Patients 
with Selected Myeloid Malignancies updated.
Section 1.2.16.1.Azacitidine Dosing Schedule 
for Expansion Component updated.
Section 1.2.18. Rationale for the Starting Dose 
of PF-04449913 updated.










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Document
Version Date
Summary of Changes 

Removed requirement that disease 
assessments be done >3 weeks from dosing 
of G-CSF or GM-CSF (also sections 5.7.4, 
7.7.3, and 9.3.6).
Section 1.2.20: Summary of glasdegib TQT 
study added.
Sections 1.2.3 and 4.1.2: Added eligibility of 
CMML patients and MDS/MPN, unclassifiable 
patients, for the MDS cohort.
Section 1.2.16: Updated toxicities reported for 
azacitidine.
Sections 1.2.16.2, 5.4.5 and 5.7.4: Replaced all 
azacitidine dose modification criteria with 
reference to local label, Investigational Product 
Manual, or SPC.
Throughout sections applicable to expansion 
cohorts: Clarified azacitidine dosing is to be 
done per local label, Investigational Product 
Manual, or SPC.
Section 4.1.2: Revised definition of adequate 
organ function (inclusion criterion #4).
Section 4.2.2.: Removed exclusion criterion 
for patients with HBV, HCV, HIV or AIDS 
related illness.
Section 4.2.2: Revised cardiac exclusion 
criteria.
Section 5.2: Restricted requirement for 
azacitidine dosage Preparation Record to cases 
where Pfizer is providing azacitidine.
Section 5.4.5: Revised glasdegib dose 
modification.
Sections 5.7.1 and 7.6: Removed requirement 
for additional ECGs when moderate/strrong 
CYP3A4/5 inhibitor or drug with TdP risk is 
initiated.


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Document
Version Date
Summary of Changes 
Section 5.7: Revised allowed and restricted 
concomitant medications.
Section 8.6.2: Added definition of confirmed 
Hy’s law case.
Section 13: Defined end of trial as last patient 
last visit for all countries.
Appendices 3, 10, 16: Corrected literature 
references.
Appendix 4: Added list of moderate 
CYP3A4/5 inducers.
Appendix 8: Edited description of urinalysis.
Appendix 11: Added descriptions of additional 
AML response categories.
Appendix 18: Added France-specific appendix.
Replaced PF-04449913 with glasdegib
throughout.
Abbreviation list updated.
Table of Contents updated.
General spelling, grammar, and consistency 
issues corrected throughout the protocol.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc. 


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Abbreviations
Abbreviation
Term
7 + 3
Induction Chemotherapy with Cytarabine (7 days) plus Daunorubicin (3 days) 
AE
Adverse Event
AHD
Antecedent hematologic disease
AIDS
Acquired Immunodeficiency Syndrome
ALL
Acute lymphocytic leukemia
ALT
Alanine Aminotransferase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
APL
Acute promyelocytic leukemia
ARA-C
Cytarabine 
AST
Aspartate Aminotransferase
AUC
Area Under the Plasma Concentration Curve
AZA
Azacitidine
BM
Bone marrow
BSC
Best Supportive Care
BST
Best Supportive Therapy
C1D1
Cycle 1 Day 1
CBC
Complete blood count
CCR
Conventional Care Regimens
CHF
Congestive heart failure
CI
Confidence Interval
CID
clinically important difference
CL/F
Apparent oral clearance
Cmax
Maximum Plasma Concentration
CMH
Cochran-Mantel-Haenszel
CML
Chronic Myeloid Leukemia
CMML
Chronic Myelomonocytic Leukemia
CNS
Central Nervous System
CR
Complete Remission
CR MRD-
Complete Remission without Minimal Residual Disease
CRh
Complete remission with partial hematologic recovery
CRi
Complete Remission with Incomplete Blood Count Recovery
CRF
Case Report Form
CSA
Clinical Study Agreement
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Lowest concentration before next dose administration
CV
Coefficient of variance
DAI
Dosage and Administration Instructions
DDI
Drug/Drug Interaction
Dhh
Dessert hedgehog
DLT
Dose Limiting Toxicity 
DoR
Duration of Response
DNA
Deoxyribonucleic Acid
DU
Dispensable unit
EC
Ethics Committee
ECG or EKG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group Performance Status
EDMC
External Data Monitoring Committee 
CCI
CCI


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Abbreviation
Term
EDP
Exposure During Pregnancy
EDTA
Ethylenediaminetetraacetic Acid
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer 
EOT
End of Treatment
ELN
European LeukemiaNet
EMD
Extramedullary Disease
EQ-5D-5L
EuroQol-Health Utilities Index
EU
European Union
EudraCT
European Clinical Trials Database
FAB
French American British
FAS
Final analysis set
FDA
Food and Drug Administration (United States)
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony-Stimulating Factor
GI
Gastrointestinal
GliA
Gli activator
GliR
Gli repressor
GLP
Good Laboratory Practices
GM-CSF
Granulocyte Macrophage Colony-Stimulating Factor
HBV
Hepatitis B
HCG
Human Chorionic Gonadotropin
HDPE
High-density polyethylene
HCV
Hepatitis C
hERG
Human ether-à-go-go-related gene
Hh
Hedgehog
HHIP
Human hedgehog-interacting protein
HI
Hematologic Improvement
HIV
Human Immunodeficiency Virus
HMA
Hypomethylating Agent
HR
Hazard Ratio
HRQOL
Health-Related Quality of Life
HSCT
Hematopoietic Stem Cell Transplant
IB
Investigator’s Brochure
IC50
Half maximal inhibitory concentration
ICH
International Conference on Harmonization
ID
Identification
Ihh
Indian hedgehog
IIR
Investigator Initiated Research
IND
Investigational New Drug Application
INN
International Nonproprietary Name
INR
International Normalized Ratio
IPSS
International Prognostic Scoring System 
IPSS-R
International Prognostic Scoring System Revised Classification
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine hormone releasing system
IV
Intravenous
IWG
International Working Group
IWR
Interactive Web Response


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Abbreviation
Term
IVR
Interactive Voice Response
LDAC
Low Dose Cytarabine 
LIC
Lead-in Cohort
LFT
Liver Function Test
LSC
Leukemia Stem Cell
LPLV
Last Patient Last Visit 
mCR
Marrow CR
MDASI
MD Anderson Symptom Inventory
MDS
Myelodysplastic Syndrome
MDR-1
Multi-Drug Resistance 1
MF
Myelofibrosis
MFC
Multiparameter Flow Cytometry
MLFS
Morphologic leukemia-free state
mOS
Median overall survival
MPN
Myeloproliferative Neoplasms 
mQTcF
Mean Corrected QT interval using Fridericia Formula 
MR
Minor response
MRD
Minimal Residual Disease
mRNA
Messenger ribonucleic acid
mOS
Median overall survival
MTD
Maximum Tolerated Dose 
N/A
Not Applicable
NASH
Non-Alcoholic Steatohepatitis 
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
NNRTI
Non-nucleoside Reverse Transcriptase Inhibitors
NOAEL
No Observed Adverse Effect Level 
NRS
Numeric rating scale
OS
Overall Survival 
PB
Peripheral blood
PCD
Primary Completion Date
PCR
Polymerase Chain Reaction
PD
Pharmacodynamics
PE
Physical examination
PFS
Progression-free survival
P-gP
P-glycoprotein
PK
Pharmacokinetics
PML-RARA
Promyelocytic leukemia/retinoic acid receptor alpha
PO
Orally (per os)
PR
Partial Remission
PRI
Partial Remission with Incomplete Blood Count Recovery
PT
Prothrombin Time
PTCH
Patched
QD
Once a Day
Qday
Once Daily
QTc
QT interval corrected for rate
QTcF
Corrected QT interval using Fridericia Formula 
RNA
Ribonucleic Acid
RP2D
Recommended Phase 2 Dose
CCI
CCI
CCI
CCI
CCI
CCI


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Abbreviation
Term
RR
Response Rate
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Stable Disease
SEER
Surveillance, Epidemiology, and End Results
Shh
Sonic hedgehog
SMO
Smoothened (G protein-coupled receptor)
SMOi
Smoothened Inhibitor
SOA
Schedule of Activities
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
SRSD
Single Reference Safety Document
TdP
Torsade de pointes
TEAE 
Treatment-emergent adverse event
TKI
Tyrosine kinase inhibitor
Tmax
Time to First Occurrence of Maximum Plasma Concentration
TQT
Thorough QT
TTR
Time to response
U/A
Urinalysis
ULN
Upper Limit of Normal
US
United States
USA
United States of America
USPI
United States Package Insert
UVA
Ultraviolet A
UVB
Ultraviolet B
Vs
Versus
Vz/F
Volume of distribution
WHO
World Health Organization


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PROTOCOL SUMMARY
INTRODUCTION
Glasdegib (PF-04449913) is a novel small molecule inhibitor of the Sonic Hedgehog (Hh) 
pathway which is currently under development for the treatment of hematologic 
malignancies. 
This multi-center open-label Phase 1b study is designed to evaluate the safety, efficacy, 
pharmacokinetics (PK), and pharmacodynamics (PD) of glasdegib when combined with 
azacitidine in patients with previously untreated Higher-Risk Myelodysplastic Syndrome 
(MDS), Acute Myeloid Leukemia (AML), and Chronic Myelomonocytic Leukemia 
(CMML).  This clinical study includes two components: (a) a safety lead-in cohort (LIC) and 
(b) an expansion phase with two cohorts.
Indication
Safety Lead-In Cohort (LIC)
Previously untreated adult patients with Intermediate-2 or High-Risk MDS according to the 
International Prognostic Scoring System (IPSS), AML with 20%-30% blasts and 
multi-lineage dysplasia according to World Health Organization (WHO) 2008 classification, 
and CMML.
Expansion
(a) Previously untreated adult patients with Intermediate, High, or Very High risk MDS 
according to the International Prognostic Scoring System-Revised (IPSS-R) and (b) AML 
patients who are not candidates for intensive chemotherapy (according to WHO 
2016 classification).
Background and Rationale
Disease Overview
MDS is a heterogeneous group of myeloid disorders defined by a common set of features, of 
which the most prominent is morphologic bone marrow and peripheral blood dysplasia 
associated with inefficient hematopoiesis, the development of peripheral cytopenias and an 
increased risk of transformation to AML.  The incidence of MDS is around 4–5 per 
100,000 individuals annually worldwide, with the prevalence increasing with age.
The French-American-British (FAB) classification system established in 1982 was the first 
approach allowing for a reliable diagnosis of a disease group that had previously been termed 
pre-leukemia.  In 2001 the WHO classification of hematopoietic neoplasms was introduced, 
subsequently updated in 2008, and most recently in 2016.  The principal modifications with 
respect to the FAB classification were to consider patients with 20% or more bone marrow or 
peripheral blood blasts as having AML, and to remove the CMML subtype and place it in a 
newly created category termed Myelodysplastic/ Myeloproliferative Neoplasms 
(MDS/MPN). 


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The standard of care treatment of higher risk (Intermediate-2 and High-Risk) MDS and AML 
with 20-30% bone marrow (BM) blasts and multi-lineage dysplasia, has previously been 
focused on intensive chemotherapy using anthracycline and cytarabine (Ara-C) combinations 
but this approach has led to lower complete response rates and a shorter response duration as 
compared to treatment outcomes in patients with de-novo AML ≥30% BM blasts.  In 
response to this unmet medical need, several multi-center randomized studies comparing
hypomethylating agent (HMA) treatment to supportive care have been conducted and 
demonstrated delayed progression to AML, with prolongation of median progression-free 
survival (PFS) of between 3 to 8 months as compared with best supportive therapy. 
Azacitidine was approved in the US by the Food and Drug Administration (FDA) in 2004 for 
the treatment of all MDS subtypes according to the FAB classification.  This approval was 
based on the overall response rate defined as Complete Response (CR) + Partial Response 
(PR) observed in the randomized CALGB-9221 study.  The overall response rate (CR + PR) 
was 15.7% in the azacitidine treatment group, and there were no responders in the control 
group.
In 2009, results from the international AZA-001 trial, phase 3 randomized trial comparing 
azacitidine to conventional care regimens (CCR) in patients with Intermediate-2 or High Risk 
MDS, showed that the median overall survival (OS) was significantly prolonged in the 
azacitidine arm as compared with the CCR arm (24.5 months for azacitidine vs. 15.0 months 
for CCR; hazard ratio [HR] 0.58; 95% confidence interval [CI] 0.43–0.77) despite a low CR 
rate (17% in the azacitidine arm vs 8% in the CCR arm).  Based on this observed survival 
benefit, azacitidine was approved in the European Union (EU) for the treatment of adults 
who are not eligible for hematopoietic stem cell transplantation and have Intermediate-2 or 
High-Risk MDS, CMML with 10-29% marrow blasts and lacking a myeloproliferative 
component, and AML with 20-30% blasts and multi-lineage dysplasia according to WHO 
2008.
AML is a genetically heterogeneous hematologic malignancy characterized by multiple 
mutations and epigenetic dysregulation at the time of diagnosis that evolves with treatment, 
resulting in treatment resistance, disease relapse, and reduced survival.  It is estimated that 
there will be 21,380 new cases and 10,500 deaths from AML in the United States in 2017.
Existing standards of care such as cytarabine + anthracycline (7+3), or hypomethylating 
agents like decitabine and azacitidine, can induce CR in 5-70% of patients; however, 
remissions are not durable and disease relapse occurs in up to 60% of patients.  For AML 
patients unable to receive intensive chemotherapy, existing standard treatments like Low 
Dose Cytarabine (LDAC) are associated with response rates <20% and median OS times of 
5-6.5 months.  Hypomethylating agents, azacitidine and decitabine, although not approved in 
the US specifically for AML, have shown improved OS vs LDAC in AML patients who were 
not candidates for intensive chemotherapy.  Reducing the incidence of disease progression to 
prolong survival remains the highest unmet medical need in the treatment of AML patients.  
In 2015, results from the international randomized phase 3 AZA-AML trial comparing 
azacitidine to CCRs in patients aged ≥65 years with newly diagnosed or secondary AML 
with >30% bone marrow blasts demonstrated a clinically meaningful improvement in median 


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overall survival (mOS) in the azacitidine arm of 10.4 months (95% CI, 8.0-12.7) versus (vs) 
6.5 months (95% CI, 5.0-8.6) in the CCR arm (HR=0.85; 95% CI, 0.69-1.03; stratified 
log-rank p=0.1009), although the primary endpoint was not met. The CR rate in the 
azacitidine arm was lower than the CCR arm (19.5% vs 21.9%). The 1-year survival rate 
with azacitidine was 46.5% compared with 34.2% with conventional therapy (95% CI, 
3.5%-21.0%). Based on the observed survival benefit, the EU expanded the approval of 
azacitidine in AML to adult patients aged 65 years or older who are not eligible for 
hematopoietic stem cell transplantation (HSCT) with >30% myeloblasts according to the 
WHO classification; previously, the indication covered AML patients with <30% blasts. 
Despite the modest increase in mOS and low CR rate, azacitidine is currently the standard of 
care for AML patients who are not candidates for intensive chemotherapy. New treatments 
are needed to improve outcomes in this older AML population. 
Rationale for Glasdegib/Azacitidine Combination Therapy
Glasdegib was initially evaluated as a single-agent therapy in patients with select myeloid 
malignancies, and had a manageable safety profile at the recommended phase 2 dose (RP2D) 
of 100 mg once a day (QD) per os with early signs of efficacy observed in AML, MDS, 
chronic myeloid leukemia (CML), and Myelofibrosis (MF).
In the safety LIC of the current study, 12 patients with previously untreated high risk MDS 
(n=7), AML with 20-30% blasts and multi-lineage dysplasia (n=3), erythroleukemia (n=1), 
and CMML (n=1) were treated at the glasdegib, 100 mg QD per os, in combination with 
azacitidine 75 mg/m2 daily for 7 days subcutaneously (SC) every 28 days. An internal safety 
review team reviewed the data from this component of the study and determined that the 
safety profile of the combination treatment appeared to be consistent with what was expected 
for glasdegib or azacitidine alone, with no unexpected toxicities identified, and deemed 
acceptable to proceed to the next phase of development. Preliminary efficacy data from the 
LIC showed 5 patients responded: 3 patients with CR, 2 patients with marrow complete 
remission (mCR): of note, after the data cutoff date, the complete blood count of 1 of the 
patients with mCR had normalized, consistent with CR. Of the 5 patients who responded, 
4 responses occurred on or before Day 100. Of the 4 patients with CR (including the mCR 
patient who achieved a CR after the data cutoff date), 3 patients had AML (75% CR rate vs 
the historical control for azacitidine alone, 19.5%) and 1 patient had MDS (14% CR rate vs 
the historical control for azacitidine alone, 17%). A further 4 patients had stable disease 
(SD). No evidence of drug-drug interaction (DDI) was noted. As of September 2016, mOS 
had not been reached. 
In the Phase 1b part of Study B1371003, 52 patients with AML or higher risk MDS were 
treated with glasdegib 100 mg or 200 mg by mouth daily (PO Qday) in combination with low 
dose cytarabine (LDAC) (n=23), decitabine (n=7), or 7 + 3 (n=22). Median OS in the 
combined AML and MDS patients were 4.4 months (80% CI: 2.5, 6.6), 11.5 months (80% 
CI:4.5, 17.4) (vs historical mOS of 7.7 months with decitabine alone), and 34.7 months (80% 
CI: 14.5, not reached), respectively, in the 3 treatment arms.  Of the AML patients treated in 
combination with decitabine, 2/5 (40%) responded (1 CR and 1 complete response with 
incomplete blood count recovery (CRi)). Of the high-risk MDS patients treated in 
combination with decitabine, 2/2 responded (2 mCR). The safety profile of glasdegib in 


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combination with chemotherapy was consistent with what was seen in an earlier 
monotherapy study in patients with selected myeloid malignancies.  A similar population of 
newly diagnosed elderly AML patients was enrolled into a Phase 3 study of decitabine vs 
supportive care vs low dose cytarabine where the CR+ CRi rate was 25.6% in the decitabine 
only arm. 
In the Phase 2 portion of Study B1371003, a prospective, randomized (2:1), open-label 
clinical trial in 132 previously untreated AML patients who were not candidates for intensive 
chemotherapy based on age or other risk factors and higher risk MDS, the addition of 
glasdegib 100 mg orally PO Qday to LDAC vs LDAC alone resulted in a significant 
improvement in OS (mOS 8.8 months (80% CI:6.9, 9.9) vs 4.9 months (80% CI: 3.5, 6.0); 
hazard ratio [HR] 0.513 [80 % CI: 0.394-0.666]; 1-sided p-value=0.0004). The CR/CRi rate 
for AML patients in the glasdegib + LDAC arm was 25% (80% CI: 19.1, 30.9) vs 4.5% (80% 
CI: 0.5, 8.6) in the LDAC alone arm. The safety/tolerability profile was consistent with that 
in elderly AML patients receiving chemotherapy. 
Glasdegib, which targets the Hh pathway component Smoothened (SMO), is an oral inhibitor 
of the Hh pathway currently in clinical development for patients with myeloid malignancies. 
The Hedgehog (Hh) signaling pathway regulates cell differentiation and self-renewal in the 
developing embryo, and is typically silenced in adult tissues. Aberrant Hh signaling in the 
post-embryonic stage may result from mutations in key pathway genes, non-mutational 
mechanisms related to the secretion of Hh ligands, or signals from cells in the tumor 
microenvironment. Aberrant Hh signaling has been identified in a variety of human myeloid 
malignancies, and specifically in leukemia stem cells (LSCs).
In a preclinical MDS model, blocking the Hh pathway with SMO inhibitors in combination 
with the hypomethylating agent (HMA) azacitidine generated synergy in vitro with growth 
inhibition in primary malignant myeloid cells ex vivo. Upregulation of Hh pathway 
components has been observed in chemoresistant 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.  In nonclinical models SMO, 
acting via its effector 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. Recrudescence of LSCs is prevented in 
preclinical hosts pre-treated with Hh pathway inhibitors, including glasdegib. 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. 
The clinical safety database of glasdegib contains over 300 patients with hematologic 
malignancies who received the recommended dose of at least 100 mg daily. The safety 
profile observed so far appears consistent with what has been reported for other marketed 
smoothened (SMO) inhibitors and the underlying chemotherapy backbones when 
administered in combination. Glasdegib has shown clinical activity in patients with higher 
risk MDS and AML patients who were not candidates for intensive chemotherapy when 
combined with other treatments, such as azacitidine and decitabine and demonstrated a 
statistically significant and clinically meaningful improvement in OS when combined with 
LDAC vs LDAC alone.










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Expansion
An open-label expansion consisting of approximately 60 patients with previously untreated 
Intermediate, High, or Very High risk MDS per IPSS-R (n=30) and AML patients who are 
not candidates for intensive chemotherapy (n=30). Patients will receive glasdegib at a 
starting dose of 100 mg QD given orally in combination with azacitidine per local label or 
per the Investigational Product Manual (or Summary of Product Characteristics [SPC]).  
Azacitidine may be administered by SC injection or intravenous (IV) infusion at the starting 
dose of 75 mg/m2/day for 7 days every 28 days.  Alternate dosing schedules to administer the 
7 azacitidine doses to accommodate subject and treatment center availability are allowed.  
The primary objective of the expansion component of the study is to demonstrate that the CR 
rate of the combination treatment in each patient population is reasonably better than the 
historical CR rate for azacitidine alone using a Bayesian decision criterion allowing early 
stopping for futility.  Analysis of specific safety criteria will also be performed to evaluate 
stopping enrollment for a specifc cohort when the rate of pre-defined safety events of interest 
surpasses a pre-defined threshold. 
Figure 1.
Schematic of Study Design
*MDS patients enrolled in the safety lead-in component must have Intermediate-2 or High-Risk disease according to IPSS.  
MDS patients enrolled in the expansion component must have Intermediate, High, or Very High risk disease according to 
IPSS-R.


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Study Assessments
Patients will be followed for efficacy throughout the study by means of bone marrow 
aspirates.  Following study entry, bone marrow biopsies will only be required if adequate 
bone marrow aspirates are not obtained.  A CR or PR needs to be confirmed at least 4 weeks 
after the bone marrow (BM) evaluation by assessing the stability of improved counts on 
peripheral blood (PB) according to the 2006 IWG criteria; an additional marrow 
confirmatory specimen is not required (applies to all patients in the safety LIC and only MDS 
patients in the expansion component).
Blood counts will be monitored for signs of hematologic improvement (HI) (applies to all 
patients in the safety LIC and only MDS patients in the expansion component).
Transfusional support (packed red blood cells and platelets) will also be recorded.  Timely 
and complete disease assessments (BM evaluation and peripheral blood (PB) counts) at 
screening and during the study, whenever clinically indicated, are essential.  Failure to 
perform any of the required disease assessments will result in the inability to determine 
disease status for that time point and may weaken the study conclusions.
Safety assessments (laboratory, instrumental and clinical) and PK assessments will be 
performed regularly during the active treatment period in both components of the study.
DDI assessments were performed in the safety LIC component of the study.
PROs of Health-Related Quality of Life (HRQOL) will be assessed in the expansion 
component of the study.
Please refer to the Schedule of Activities for the Safety Lead-in and the Schedule of
Activities for the Expansion: MDS and AML Patients for a complete list of assessments to be 
performed on patients in the study.
STUDY TREATMENTS
Treatment will be administered in 28-day cycles.  Glasdegib will be administered at the 
starting dose of 100 mg QD given orally and continuously in combination with azacitidine.
Safety Lead-in Cohort
The safety lead-in cohort has been completed.

All patients will be administered glasdegib 100 mg QD orally and continuously.

Azacitidine will be administered SC at the starting dose of 75 mg/m2/day on a 
continuous schedule from Day 1 to Day 7 of each cycle.


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Expansion 

All patients will be administered glasdegib, 100 mg QD orally and continuously.

Azacitidine will be administered per local label or per the Investigational Product 
Manual (or SPC). Azacitidine may be administered by SC injection or IV infusion at 
the starting dose of 75 mg/m2/day for 7 days every 28 days. Alternate dosing 
schedules to administer the 7 doses to accommodate patient and treatment center 
availability are allowed.
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.  If documentation of 
disease progression occurs within the first 6 cycles of study treatment, the patient SHOULD 
NOT be withdrawn from study treatment if, in the Investigator’s judgment, the patient is still 
likely to receive clinical benefit.
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. Treatment should also be continued beyond 6 cycles if patients 
demonstrate reasonable evidence of clinical benefit, defined as HI or better in patients 
enrolled into the safety LIC.  During the expansion component, clinical benefit will be 
defined as SD + HI or better in MDS patients, and not meeting the criteria for disease 
progression for AML patients.
If glasdegib 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 and 
following discussion between the Investigator and Sponsor.
In cases of unacceptable toxicity or pregnancy, the patient must be withdrawn from study 
drug combination and entered into the follow-up phase of the study.
When study treatment with both drugs (azacitidine and glasdegib) is permanently 
discontinued, all patients will enter into the follow-up phase. 
STATISTICAL METHODS
Approximately 10 patients will be included in the LIC.  This sample size provides at least 
80% probability to observe at least one adverse event (AE) if the true incidence of the AE in 
the population is at least 15%.
In the expansion phase of the study, two cohorts of patients (MDS and AML respectively) 
approximately 30 patients each will be enrolled.  Based on Bayesian decision rule, we will 
need 10 to 30 patients for each cohort. For the MDS cohort, with 30 patients the maximum 
width of the exact 2-sided 95% confidence interval for CR will be ≤0.374. For the AML 
cohort, with a maximum of 30 patients the maximum width of the exact 2-sided 95% CI for 
CR will be ≤0.374.  An External Data Monitoring Committee (EDMC) will be established.  








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Footnote for Schedule of Activities
1.
Informed Consent: Must be obtained prior to undergoing any study procedure and may occur within 60 days prior to study entry.
2.
Medical History: Includes cancer history, and prior and concomitant illnesses.
3.
ECOG: See Appendix 9.
4.
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.
5.
Hematology: Platelet count, absolute neutrophil count, hemoglobin, and blast count should be obtained twice during the 28-day screening period at least 1 week apart.  No 
need to repeat on C1D1 if one of the 2 screening assessments is performed within 3 days prior to that date.  The list of required laboratory tests is provided in Appendix 8.  
Patients permanently discontinuing treatment with both study drugs with bone marrow blasts 30%, should have CBCs repeated every 3 months until blasts are >30% or 
until initiation of another anti-cancer therapy.
6.
Blood Chemistry: No need to repeat on C1D1 if screening assessment performed within 3 days prior to that date.  The list of required laboratory tests is provided in 
Appendix 8.
7.
Urinalysis: No need to repeat on C1D1 if screening assessment performed within 3 days prior to that date.  The list of required laboratory tests is provided in Appendix 8.
8.
Coagulation: No need to repeat on C1D1 if screening assessment performed within 3 days prior to that date.  The list of required laboratory tests is provided in Appendix 8.
9.
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 (defined in Section on Lifestyle Guidelines) 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.   
10. ECG: See Table 2 for detailed ECG Schedule. 
11. Glasdegib: Treatment will be administered in 28-day cycles (cycle duration may be extended to allow for toxicity resolution).  Glasdegib will be administered once daily 
continuously, in the morning at approximately the same time each day.  For Cycle 1 only glasdegib dosing will start on Day 2 to accommodate PK samples collection 
for DDI assessment.  In all subsequent cycles glasdegib administration will start on Day 1.
12. Azacitidine Dosing: Azacitidine will be administered subcutaneously on Days 1-7 of each 28-day cycle in the Safety LIC.  The next cycle start can be delayed to allow for 
toxicity resolution.
13. Drug Compliance: All glasdegib bottles including any unused tablets and patient dosing diaries will be returned to the clinic for compliance assessment and drug 
accountability.  






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NOTE: Tables 1 and 2 are applicable ONLY to patients in the lead-in cohort which has been completed.
Table 2.
Pharmacokinetics and ECG Schedule for the Safety Lead-in Cohort (LIC)
Dose Day
Screening
Cycle 1, Day 1
Cycle 1 Day 2
Cycle 1, Day 7&15 (azacitidine samples taken 
only on C1D7)
Cycles ≥2    
Day 1
EOT
HOUR(s) 
post-dose
01
0.25
0.5
1
2
4
6
1
4
01
0.25
0.5
1
2
4
6
24
01
1
4
0
Glasdegib PK 
Samples
X
X
X
X
X
X
X
X
X
X
X
Azacitidine PK 
Samples
X
X
X
X
X
X
X
X
X
X
X
Triplicate 
12-lead ECG2
X
X
X
X
X
X
X
X
X
X
1.
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.  The PK time points for each compound (Azacitidine and Glasdegib) 
are in reference to their respective dosing times. PK samples should only be collected up until Cycle 6.
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.  ECGs 
will be collected: prior to blood sample collection, such that the blood sample is collected at the appropriate time.  All ECG timepoints are in reference to dosing of glasdegib.








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12. Patient Registration: Patient registration and assignment of treatment will be obtained from the centralized Interactive Response Technology (IRT).
13. Glasdegib Dosing: Treatment will be administered in 28-day cycles (cycle duration may be extended to allow for toxicity resolution).  Glasdegib will be administered once 
daily, continuously, in the morning at approximately the same time each day. 
14. Azacitidine Dosing: Azacitidine will be administered per local label or per the Investigational Product Manual (or SPC).  Treatment can be administered as a SC injection 
or IV infusion on Days 1-7 (3 days).  Visit time window added to accommodate varying azacitidine dosing schedules to accommodate patient and treatment center 
availability.  The start of subsequent cycles can be delayed to allow for toxicity resolution.
15. Drug Compliance: All glasdegib 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 every disease evaluation, and will be used for both local clinical 
staging and centralized biomarker assessments.  Bone marrow biopsies are optional unless required for clinical staging (eg, dry tap).  Samples taken prior to consent 
but within the 28-day window may be used for disease evaluation and need not be repeated.  Bone marrow samples required for other study assessments (eg, MRD 
assessment) must be collected after consent is signed.  We recommend, but do not require, patients sign an informed consent prior to a diagnostic bone marrow 
aspiration to avoid an additional procedure to collect bone marrow aspirate for the biomarker assessments required during screening

Timepoints for Bone Marrow Sampling: Bone marrow assessment must be completed at screening (within 28 days prior to first dose), C7D1 (-3/+14 days)
(unless done earlier due to suspected CR), C13D1 and every 12 cycles thereafter (C25D1, C37D1, C49D1, etc), and at any time as per investigators discretion if CR 
is suspected. No bone marrow assessment is necessary if non-response or progressive disease can be diagnosed from peripheral blood evaluation or 
radiological/clinical assessment.
17. Bone Marrow Genetics: Genetics analysis (local), including karyotyping, will be conducted on all patients using any scheduled or unscheduled bone marrow samples 
collected during study participation.  Genetics to be analyzed are specified in Appendix 3 for MDS patients and Appendix 16 for AML patients.  Baseline genetics 
classification must be completed on a sample collected within 28 days prior to first dose. 
18. Adverse Event (AE)/Serious Adverse Event (SAE) Monitoring: Adverse events should be documented and recorded at each visit using the NCI CTCAE version 4.03.  
Recording of AEs/SAEs on the CRF commences with informed consent.  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; 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, even if another anticancer therapy has been started.  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.
19. Concomitant Medications and Treatments: All concomitant medications and treatments should be recorded in the CRF.
20. Red Blood Cells and Platelets Transfusion Recording: Transfusion history up to 8 weeks prior to screening 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.




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Table 4.
Pharmacokinetics & ECG Schedule for the Expansion: MDS and AML Patients
Assessment
Screening
Cycle 1, Day 1
Cycle 1, Day 15
Cycle 2-3, Day 13
Cycles 4, 
Day 1
End of treatment
HOUR post-dose1
01
1
4
01
1
4
01
1
4
1
Gladegib 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
1.
Glasdegib 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.  All post-dose samples are to be collected within 10% of the nominal time (eg, within 6 minutes of a 60 minute sample).  Patients should be reminded not to 
take their study drug prior to arriving at the clinic on protocol scheduled visits.  All PK timepoints are in reference to dosing of glasdegib.
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.  
ECGs will be collected: prior to blood sample collection, such that the blood sample is collected at the appropriate time.  All ECG timepoints are in reference to dosing of 
glasdegib).  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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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................50
LIST OF FIGURES .................................................................................................................50
APPENDICES .........................................................................................................................50
1. INTRODUCTION ...............................................................................................................52
1.1. Indication.................................................................................................................52
1.2. Background and Rationale ......................................................................................52
1.2.1. Disease Overview .......................................................................................52
1.2.2. Hedgehog (Hh) Pathway Signaling in MDS ..............................................54
1.2.3. Rationale for Glasdegib/Azacitidine Combination Therapy in 
Patients with Higher-Risk MDS, AML, and CMML ......................................56
1.2.4. Summary of Glasdegib Product Profile......................................................60
1.2.5. Glasdegib Preclinical Toxicity Data...........................................................60
1.2.5.1. Kidney Effects in Preclinical Studies........................................61
1.2.6. Bone Effects in Preclinical Studies.............................................................61
1.2.7. Cardiovascular Effects in Preclinical Studies.............................................61
1.2.8. Embryo-fetal Effects in Nonclinical Studies ..............................................61
1.2.9. Other Findings in Preclinical Studies .........................................................62
1.2.10. Clinical Relevance of Organ Toxicities Observed in Nonclinical 
studies ..............................................................................................................62
1.2.11. Clinical Pharmacokinetic Summary .........................................................62
1.2.12. Clinical Pharmacodynamic Summary ......................................................63
1.2.13. Clinical Experience in Patients with Selected Myeloid Malignancies .....63
1.2.13.1. Study B1371001: Patients with Select Myeloid 
Malignancies......................................................................................64
1.2.13.2. Study B1371012: Safety Lead-In Cohort................................66
1.2.13.3. Study B1371003: Phase 1b/2 Study in Patients with 
AML or High-Risk MDS...................................................................69
1.2.13.4. Study B1371005: Safety and Efficacy in an Asian 
Population..........................................................................................71
1.2.14. Post Allogeneic HSCT Investigator Initiated Research Study .................72
1.2.15. Summary of Azacitidine Product Profile..................................................72
1.2.16. Azacitidine Toxicities...............................................................................72


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1.2.16.1. Azacitidine Dosing Schedule ..................................................73
1.2.16.2. Azacitidine Dose Modifications..............................................73
1.2.17. Rationale for Testing Glasdegib in Combination with Azacitidine in 
Patients with Previously Untreated Higher-Risk MDS, AML, and 
CMML .............................................................................................................73
1.2.18. Rationale for the Starting Dose of Gladegib.............................................74
1.2.19. Assessment of the Drug-Drug Interaction (DDI) Potential between 
Glasdegib and Azacitidine...............................................................................75
1.2.20. Summary of Benefit-Risk Assessment .....................................................75
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................76
2.1. Objectives for the Safety Lead-In Cohort ...............................................................76
2.2. Endpoints for the Safety Lead-In Cohort ................................................................77
2.3. Objectives for the Expansion ..................................................................................77
2.4. Endpoints for the Expansion ...................................................................................78
3. STUDY DESIGN.................................................................................................................79
3.1. Study Overview.......................................................................................................79
3.2. Safety Lead-In Cohort.............................................................................................79
3.3. Expansion................................................................................................................80
3.3.1. Study Treatments........................................................................................83
3.3.2. Study Assessments Summary.....................................................................84
4. PATIENT SELECTION......................................................................................................84
4.1. Inclusion Criteria.....................................................................................................85
4.1.1. Safety Lead-in Cohort.................................................................................85
4.1.2. Expansion ...................................................................................................86
4.2. Exclusion Criteria....................................................................................................88
4.2.1. Safety Lead-in Cohort.................................................................................88
4.2.2. Expansion Cohorts......................................................................................90
4.3. Lifestyle Guidelines ................................................................................................91
4.4. Sunlight Exposure ...................................................................................................93
4.5. Sponsor’s Qualified Medical Personnel..................................................................93
5. STUDY TREATMENTS.....................................................................................................93
5.1. Allocation to Treatment ..........................................................................................93
5.1.1. Safety Lead-In Cohort and Expansion........................................................93


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5.2. Patient Compliance .................................................................................................94
5.3. Drug Supplies..........................................................................................................94
5.3.1. Formulation and Packaging........................................................................94
5.3.2. Glasdegib....................................................................................................94
5.3.3. Azacitidine..................................................................................................94
5.4. Administration.........................................................................................................95
5.4.1. General Guidelines .....................................................................................95
5.4.2. Safety Lead-In Cohort ................................................................................95
5.4.3. Expansion ...................................................................................................96
5.4.4. Treatment Duration.....................................................................................96
5.4.5. Dose Modifications.....................................................................................97
5.4.5.1. Glasdegib...................................................................................97
5.4.5.2. Azacitidine ..............................................................................102
5.5. Drug Storage .........................................................................................................103
5.6. Drug Accountability..............................................................................................104
5.7. Concomitant Treatment(s).....................................................................................104
5.7.1. Restricted or Prohibited Concomitant Medications..................................104
5.7.2. Permitted Concomitant Medications ........................................................106
5.7.2.1. Best Supportive Therapy.........................................................106
5.7.2.2. Hematopoietic Growth Factors ...............................................106
5.7.2.3. Anti-Emetic and Anti-Diarrheal Therapy ...............................106
5.7.3. Surgery......................................................................................................106
6. STUDY PROCEDURES ...................................................................................................107
6.1. Screening...............................................................................................................107
6.2. Study Period ..........................................................................................................107
6.3. End of Treatment Visit..........................................................................................107
6.4. Follow-up ..............................................................................................................107
7. ASSESSMENTS................................................................................................................109
7.1. Pregnancy Testing.................................................................................................109
7.2. Adverse Events......................................................................................................110
7.3. Laboratory Safety Assessments ............................................................................110
7.4. Transfusions ..........................................................................................................110


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7.5. Vital Signs and Physical Examination ..................................................................110
7.6. Triplicate (12-Lead) ECGs....................................................................................111
7.7. Efficacy Assessments............................................................................................111
7.7.1. Response Criteria......................................................................................111
7.7.4. Pharmacokinetics Assessments ................................................................112
7.7.4.1. Glasdegib (Safety Lead-In Cohort and Expansion) ................112
7.7.4.2. Azacitidine (Safety LIC Only) ................................................112
8. ADVERSE EVENT REPORTING....................................................................................117
8.1. Adverse Events......................................................................................................117
8.2. Reporting Period ...................................................................................................117
8.3. Definition of an Adverse Event.............................................................................118
8.4. Medication Errors..................................................................................................119
8.5. Abnormal Test Findings........................................................................................119
8.6. Serious Adverse Events.........................................................................................120
8.6.1. Protocol-Specified Serious Adverse Events.............................................120
8.6.2. Potential Cases of Drug-Induced Liver Injury..........................................120
8.7. Hospitalization ......................................................................................................122
8.8. Severity Assessment..............................................................................................123
8.9. Causality Assessment............................................................................................123
8.10. Exposure During Pregnancy................................................................................124
8.11. Occupational Exposure .......................................................................................125
8.12. Withdrawal Due to Adverse Events....................................................................125
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8.13. Eliciting Adverse Event Information ..................................................................125
8.14. Reporting Requirements......................................................................................125
8.14.1. Serious Adverse Event Reporting Requirements ...................................126
8.14.2. Non-serious Adverse Event Reporting Requirements............................126
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............126
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................126
9.1. Sample Size Determination...................................................................................127
9.1.1. Safety Lead-In Cohort ..............................................................................127
9.1.2. Expansion .................................................................................................127
9.2. Analysis Populations.............................................................................................127
9.2.1. Full Analysis Set (FAS)............................................................................127
9.2.2. Safety Analysis Set...................................................................................127
9.2.3. PK Analysis Set ........................................................................................127
9.3. Efficacy Analysis ..................................................................................................127
9.3.1. Complete Response ..................................................................................128
9.3.2. Response Rate...........................................................................................128
9.3.3. Overall Survival (Expansion) ...................................................................128
9.3.4. Duration of Response ...............................................................................128
9.3.5. Time to Response .....................................................................................129
9.3.6. Other Efficacy Measures ..........................................................................129
9.4. Safety Analysis......................................................................................................131
9.4.1. Adverse Events.........................................................................................131
9.4.2. Analysis of Primary Endpoint of Safety Lead-in Cohort .........................131
9.4.3. Analysis of Secondary Endpoint of Expansion Component.....................131
9.4.4. Laboratory Test Abnormalities.................................................................132
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9.4.5. Baseline Characteristics............................................................................132
9.4.6. Electrocardiogram Analysis......................................................................132
9.4.7. Summary and Categorical Analysis of Electrocardiogram Findings .......132
9.4.8. Exposure-QTc Analysis............................................................................133
9.6. Pharmacokinetic Analysis.....................................................................................134
9.6.1. PK Parameters ..........................................................................................134
9.6.2. PK Concentrations....................................................................................134
9.6.3. Evaluation of Drug-Drug Interaction Potential (Safety LIC)...................134
9.6.4. Population Pharmacokinetic Analysis or PK/PD Modeling.....................135
9.7. Interim Analyses ...................................................................................................135
9.7.1. Futility Analyses.......................................................................................135
9.7.2. Safety Stopping Analyses.........................................................................135
9.8. Data Monitoring Committee .................................................................................136
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................136
11. DATA HANDLING AND RECORD KEEPING ...........................................................136
11.1. Case Report Forms/Electronic Data Record .......................................................136
11.2. Record Retention.................................................................................................137
12. ETHICS............................................................................................................................137
12.1. Institutional Review Board (IRB)/Ethics Committee (EC).................................137
12.2. Ethical Conduct of the Study ..............................................................................138
12.3. Patient Information and Consent.........................................................................138
12.4. Patient Recruitment.............................................................................................139
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................139
13. DEFINITION OF END OF TRIAL.................................................................................139
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................139
15. PUBLICATION OF STUDY RESULTS........................................................................139
15.1. Communication of Results by Pfizer ..................................................................139
15.2. Publications by Investigators ..............................................................................140
16. REFERENCES ................................................................................................................142
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LIST OF TABLES
Table 1.
Schedule of Activities for the Safety Lead-in Cohort (LIC) ................................32
Table 2.
Pharmacokinetics and ECG Schedule for the Safety Lead-in Cohort (LIC)........37
Table 3.
Schedule of Activities for the Expansion: MDS and AML Patients ....................38
Table 4.
Pharmacokinetics & ECG Schedule for the Expansion: MDS and AML 
Patients..................................................................................................................43
Table 5.
Treatment Emergent Adverse Events with Frequency ≥5% by System 
Organ Class and Preferred Term ..........................................................................66
Table 6.
Baseline Patient Characteristics............................................................................67
Table 7.
Most Frequently Reported TEAEs in the Safety Lead-In Cohort (Any 
Grade, All Causality, in ≥3 Patients)...................................................................68
Table 8.
MDS Efficacy Decision Criteria...........................................................................81
Table 9.
AML Efficacy Decision Criteria ..........................................................................81
Table 10.
Safety Decision Criteria........................................................................................82
Table 11.
Methods of Birth Control......................................................................................92
Table 12.
Available Dose Levels..........................................................................................98
Table 13.
Dose Modifications for Non Hematologic Toxicities (Excluding QTc 
Prolongation, Muscle Spasms, and Myalgia) .......................................................99
Table 14.
Glasdegib Dose Modifications for mean QTcF (mQTcF) Prolongation............100
Table 15.
Dose Modifications for Glasdegib in Case of Drug Class Related AEs.............102
LIST OF FIGURES
Figure 1.
Schematic of Study Design...................................................................................28
Figure 2.
Hh Signaling Pathway ..........................................................................................55
Figure 3.
Schematic of Study Design...................................................................................82
APPENDICES
Appendix 1. 2008 WHO Classification of Myelodysplastic Syndromes (MDS)*................148
Appendix 2. IWG Criteria: Response Criteria and Progression Definitions for 
Myelodysplasia***.............................................................................................149
Appendix 3. Myelodysplastic Syndromes: 2014 Update on Diagnosis, 
Risk-Stratification, and Management* ...............................................................151
Appendix 4. Strong CYP3A4/5 Inducers...............................................................................152
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Appendix 5. List of Drugs with Known Risk of Torsade de Pointes ....................................153
Appendix 6. Strong CYP3A4/5 Inhibitors.............................................................................155
Appendix 7. Moderate CYP3A4/5 Inhibitors ........................................................................156
Appendix 8. Laboratory Assessments....................................................................................157
Appendix 9. Eastern Cooperative Oncology Group Performance Status..............................158
Appendix 10. IPSS-R Classification System for Myelodysplastic Syndromes*...................159
Appendix 11. 2017 ELN Response Criteria for Acute Myeloid Leukemia...........................160
Appendix 12. 2016 WHO Classification of Myelodysplastic Syndromes ............................162
Appendix 16. 2017 ELN AML Risk Stratification by Genetics............................................167
Appendix 17. 2016 WHO Classification of Myeloid Neoplasms and Acute Leukemia .......168
Appendix 18. France Appendix.............................................................................................171
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1. INTRODUCTION
Glasdegib (PF-04449913) is a novel small molecule inhibitor of the Sonic Hedgehog (Hh) 
pathway which is currently under development for the treatment of hematologic 
malignancies.
This multi-center open-label Phase 1b study is designed to evaluate the safety, efficacy, 
pharmacokinetics (PK), and pharmacodynamics (PD) of glasdegib when combined with 
azacitidine in patients with previously untreated Higher-Risk Myelodysplastic Syndrome 
(MDS), Acute Myeloid Leukemia (AML), and Chronic Myelomonocytic Leukemia 
(CMML).  This Phase 1b study includes two components: (a) a safety lead-in cohort (LIC)
and (b) an expansion phase with two cohorts.
1.1. Indication
Safety Lead-In Cohort
Previously untreated adult patients with Intermediate-2 or High-Risk MDS according to the 
International Prognostic Scoring System (IPSS), AML with 20%-30% blasts and 
multi-lineage dysplasia, (according to World Health Organization (WHO) 
2008 classification), and CMML.
Expansion

Previously untreated adult patients with Intermediate, High, or Very High risk MDS 
according to the International Prognostic Scoring System-Revised (IPSS-R), and 

AML patients who are not candidates for intensive chemotherapy (according to WHO 
2016 classification).
1.2. Background and Rationale
1.2.1. Disease Overview
MDS is comprised of a heterogeneous group of myeloid disorders defined by a set of 
common features, of which the most prominent is morphologic bone marrow and peripheral 
blood dysplasia associated with inefficient hematopoiesis, peripheral cytopenias, and 
increased risk of transformation to AML.
The incidence of MDS was previously estimated to be around 4–5 per 100,000 annually 
worldwide, with the prevalence increasing with age.1 An older publication based on the 
Surveillance, Epidemiology, and End Results (SEER)–Medicare database, indicated that in 
the US the incidence of MDS in individuals aged ≥65 years might be as high as 75 per 
100,000.2 A recent analysis published in 2015 estimates the true incidence of MDS to be 
between 5.3 and 13.1 per 100,000 using newer case capture methods. Medicare claims data 
in the US shows the incidence of MDS in patients aged ≥65 years to now be as high as 
162 per 100,000. MDS prevalence is estimated to be 60,000 and –170,000 in the United 
States of America (USA) and projected to increase (Cogle et al, 2015).50


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Genetic and functional studies have demonstrated that MDS results from the acquisition of 
genetic and epigenetic alterations leading to abnormal differentiation and dysregulated 
self-renewal.  Recent data indicate that cytogenetic patterns are not stable in MDS, and that 
as the disease progresses a significant fraction of patients acquire additional cytogenetic 
changes.  This phenomenon is associated with an increased risk of transformation to AML 
and a worse overall survival.3
The French-American-British (FAB) 1982 classification system provided the first approach 
allowing a reliable diagnosis of the MDS group of diseases, previously termed pre-leukemia.4
In 20015 and subsequently in an updated version in 2008,6 a group of clinicians, pathologists 
and cytogeneticists formulated the WHO classification of hematopoietic neoplasms.  The 
principal modifications with respect to the FAB classification were to consider patients with 
20% or more bone marrow or peripheral blood blasts as having AML, and to remove the 
CMML subtype and place it into a newly created category termed Myelodysplastic/ 
Myeloproliferative Neoplasms (MDS/MPN). The WHO 2008 version was used to classify 
patients in the safety LIC component of the current study. The WHO classification was 
recently updated again in 2016, providing more evidence on the impact of genetic markers on 
diagnosis and disease management and will be used to classify the MDS patients in the 
expansion component of the current study (Arber et al, 2016).51
Independent of the classification system applied, MDS prognosis is established by assessing 
key features that include: morphology, percentage blasts, cytopenias and cytogenetic 
characteristics.  According to the 4 category International Prognostic Scoring System (IPSS), 
the higher-risk MDS group (Intermediate-2 and High-Risk) is characterized by a median 
overall survival of less than 12 months and by a high risk of transformation to AML.8 The 
IPSS has been updated to the International Prognostic Scoring System-Revised (IPSS-R) via 
incorporation of additional elements of cytogenetics and further prognostication into 
5 categories (Greenberg et al, 2012).43 Patients enrolled into the safety LIC of the study were 
assessed using IPSS and patients enrolled into the expansion component of the study will be 
assessed using the more contemporary IPSS-R (Appendix 10).  The inclusion of the IPSS-R 
risk of intermediate, high, or very high, has a concordance greater than 80% with the old 
IPSS scoring system.43
AML is a genetically heterogeneous hematologic malignancy characterized by increased 
blast counts, pancytopenias causing infections and bleeding, multiple mutations and 
epigenetic dysregulation at the time of diagnosis that evolves with treatment, resulting in 
treatment resistance, disease relapse, and reduced survival.  Elderly AML patients ineligible 
for intensive chemotherapy present with many more comorbidities, a greater number of 
chromosomal abnormalities, and higher incidence of prior hematologic diseases as compared 
to AML patients able to receive intensive chemotherapy resulting in fewer treatment options, 
lower remission rates and poor survival outcomes. It is estimated that there will be 
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There are two staging systems commonly used for AML. The original FAB 1976 system 
provided the first approach at the morphologic classification of acute leukemias to define 
specific immunotypes, which has since been revised several times. The newer 
WHO 2008 classification system looked at chromosome translocations and evidence of 
dysplasia. In 2016, the WHO classification system was revised, providing more evidence on 
the impact of genetic markers on diagnosis and disease management and will be used to 
classify the AML patients in the expansion component of the current study (Arber et al, 
2016).51
AML is a disease with large differences in prognosis, age and cytogenetic abnormalities 
constituting the strongest prognostic factors for OS (Röllig et al, 2011).52 In 2011, the 
European LeukemiaNet (ELN) proposed a risk reporting system that integrated molecular 
and cytogenetic factors, dividing AML patients into 4 risk categories (favourable, 
intermediate-1, intermediate-2, adverse), demonstrating that these groups varied in terms of 
median survival times. Historical median OS for patients 60 years who did not receive an 
allogeneic stem-cell transplant by risk group are as follows: favorable (63.6 months), 
intermediate-1 (13.6 months), intermediate-2 (18.7 months), and adverse (6.0 months) 
(Röllig et al, 2011).52 Historical mOS for patients >60 years by risk group are as follows: 
favorable (14.6 months), intermediate-1 (9.5 months), intermediate-2 (9.2 months), and 
adverse (4.8 months) (Röllig et al, 2011).52 The ELN system was recently updated in 2017 to 
include new clinical, prognostic, morphologic, immunophenotypic, and genetic data that 
emerged over the last 6 years. In the revised system, the intermediate-1 and 
intermediate-2 risk groups are collapsed into one since they were prognostically 
indistinguishable in elderly patients, resulting in 3 risk categories (favourable, intermediate, 
adverse) (Döhner H et al, 2017).42 In addition, the ELN group proposed new response 
categories (Appendix 11) for AML patients reflective of new data meant to integrate 
definitions across trials. The AML population proposed in the expansion component of the 
current study will be categorized by the 2017 ELN system and assessed by the updated 
response categories.
1.2.2. Hedgehog (Hh) Pathway Signaling in MDS
A milestone in perceiving cancer as a disorder of differentiation and development was the 
identification of cancer stem cells that self-renew, initiate, and re-initiate tumor development 
and give rise to the bulk of the tumor.  The persistence of such tumor-initiating cells may 
contribute to tumor resistance and impact overall survival.  Standard chemotherapy, 
radiotherapy and targeted therapies reduce tumor bulk, but are less effective at targeting 
tumor-initiating cells.  The key challenge has been to identify the molecular mechanisms 
maintaining and sustaining tumor-initiating cell activity, self-renewal and survival. 
Hh signaling is critical in animal patterning and terminal cell differentiation during 
embryogenesis, and may play a key role in human malignancies when aberrantly activated.  
Following birth, the Hh pathway is repressed in most cells, but activated during tissue repair 
and in self-renewing populations.  Hh signaling is initiated when the Hh ligands: Indian Hh 
(Ihh), Sonic Hh (Shh), and/or Desert Hh (Dhh) bind to the Patched (PTCH) transmembrane 
protein and inactivate its function, which in the absence of Hh is to tonically inhibit SMO 
signal transduction.  Following deactivation of PTCH in response to the binding of Hh 


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ligands, the seven-transmembrane protein Smoothened (SMO), which is normally held in an 
inactive state by PTCH, is released and activates a signaling cascade that regulates the Gli 
family of transcription factors (Figure 2).  The Gli family of genes encode proteins that 
function either as transcriptional repressors (in the absence of Hh), or as transcriptional 
activators (in the presence of Hh) of genes controlled by the Hh pathway.  Several proteins 
modulate the ratio of Gli activator (GliA) to Gli repressor (GliR) activity and in so doing 
determine the level of active cellular Hh ligand (Figure 2).9
Since its initial description, the Hh pathway has received increasing attention as a pleiotropic 
oncogenic pathway, and its aberrant activity has been implicated in both hematopoietic and 
solid tumor malignancies through a range of different mechanisms, including a direct cell 
cycle and anti-angiogenic effect.10,11 Given that these cell types and mechanisms are 
unrelated in developmental origin, site, and function, a common dependence of 
tumor-initiating cells on Hh-Gli signaling for survival and self-renewal, paralleling its roles 
in normal development and homeostasis, may underlie its involvement in human cancers.12
An important caveat, is that the Hh signaling pathway is dispensable for adult hematopoietic 
stem cell function.13
Figure 2.
Hh Signaling Pathway
The expression of Hh-related genes has been assessed in primary human CD34+ cells, CD34+
blastic cells (from MDS and AML patients) and BM stromal cells.  Both Ihh and its signal 
transducer SMO, were expressed in CD34+ AML and MDS-derived cells.  Moreover the 
expression of the intrinsic Hh-signaling inhibitor, human Hh-interacting protein (HHIP) was 
markedly lower in AML/MDS-derived stromal cells as compared with healthy donor-derived 
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via demethylation of HHIP gene and reduced the leukemic cell-supporting activity of 
AML/MDS-derived stromal cells.14 These data demonstrate the relevance of Hh signaling in 
primary CD34+ blasts derived from AML and MDS and confirm its involvement in shaping 
the BM microenvironment during the development of myeloid malignancies. 
Furthermore, over-expression of the Hh signaling target gene BMI1 was detected in MDS 
patients, and inversely correlated with the apoptosis of CD34+ cells.  In addition, 
over-expression of BMI1 was correlated with an elevated IPSS score and a shorter overall 
survival in MDS patients, facilitated proliferation, and inhibited apoptosis of MDS cells in 
vitro.  This suggests that over-expression of BMI1, a target of the Hh signaling pathway, 
induces resistance to apoptosis and confers an adverse prognosis in MDS.15
Finally, the role of the Hh signaling pathway was investigated in total BM and in CD34+
cells from MDS patients and healthy donors.  PTCH and SMO showed decreased expression 
in MDS CD34+ cells, whereas GLI1 overexpression was observed, indicating pathway 
activation in MDS progenitors.16
In nonclinical AML models, SMO, acting via its effector 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 
(Sadarangani, 2015; Tauchi, 2015; Fukushima, 2016).54,55,53 Recrudescence of LSCs is 
prevented in preclinical hosts pre-treated with Hh pathway inhibitors, including glasdegib
(Fukushima et al, 2016). 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 (Fukushima, 2016).53
In a preclinical MDS model, blocking the Hh pathway with SMO inhibitors in combination 
with the hypomethylating agent (HMA) azacitidine (Aza) generated synergy in vitro with 
growth inhibition in primary malignant myeloid cells ex vivo (Tibes, 2015).56 Hh inhibition 
in combination with HMAs represents a mechanistically attractive approach for the 
elimination of the LSC population, while at the same time targets the deregulated gene 
expression in patients with higher-risk MDS.  Taken together these results suggest that the 
Hh signaling pathway is frequently aberrantly activated in MDS patients and its inhibition 
represents an attractive therapeutic approach to improve disease control.
1.2.3. Rationale for Glasdegib/Azacitidine Combination Therapy in Patients with 
Higher-Risk MDS, AML, and CMML
Treatment of higher risk (Intermediate-2 and High-Risk) MDS and AML with 20-30% blasts 
and multi-lineage dysplasia, has typically been based on intensive chemotherapy using 
anthracycline and cytarabine (Ara-C) combinations.  This has resulted in lower CR rates and 
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In response to this unmet medical need, several multicenter randomized studies have 
compared treatment with a HMA treatment to supportive care in MDS patients, including the 
D-0007 (decitabine), AZA-001 (azacitidine), CALGB-9221 (azacitidine), and 
EORTC-06011 (decitabine) trials.  These trials have demonstrated delayed progression to 
AML following HMA therapy, with an improvement in median PFS over supportive care 
ranging from 3 to 8 months.18-21
Indeed, MDS is characterized by frequent epigenetic abnormalities, including the 
hypermethylation of genes that control proliferation, adhesion, and other characteristic 
features of this pre- leukemic status.  Aberrant deoxyribonucleic acid (DNA) 
hypermethylation is associated with a poor prognosis in MDS that can be accounted for by a 
more rapid progression to AML.39
Azacitidine was approved in the US by the Food and Drug Administration (FDA) in 2004 for 
the treatment of all MDS subtypes according to the FAB classification.  Effectiveness was 
demonstrated in a randomized trial comparing azacitidine with best supportive care (BSC) 
and in two single-arm studies.  The overall response rate (complete response + partial 
response) observed in the randomized study CALGB-9221 was 15.7% in the azacitidine 
treatment arm and there were no responders in the control arm (P <0.0001). The median 
duration of overall survival did not significantly differ between patients receiving azacitidine 
and those receiving supportive care, although the results were confounded by 49 best 
supportive care patients (53%) that crossed over to azacitidine during the course of the trial.  
In a landmark analysis designed to eliminate this confounding effect, the median duration of 
overall survival was significantly longer in patients initially randomized to azacitidine as 
compared with those initially randomized to supportive care who did not cross over to 
azacitidine or who crossed over after 6 months had elapsed (18 versus 11 months; 
p = 0.03).21
Results published in 2009 from the international AZA-001 phase 3 randomized trial 
comparing azacitidine to conventional care regimens (CCR), including BSC, low dose 
cytarabine (LDAC) and intensive chemotherapy, in 358 intermediate-2 and high-risk MDS 
patients presented additional data to suggest an overall survival benefit.  Despite a low CR 
rate (17%), azacitidine treatment significantly prolonged OS with respect to CCR.  Median 
OS was 24.5 months (9.9–not reached) for the azacitidine arm versus 15.0 months (5.6–24.1) 
for the CCR arm (hazard ratio 0.58; 95% CI 0.43–0.77).  A significantly lower risk of
progression to AML (HR=0.50, 95% CI 0.35–0.70; p<0.0001) was also observed with 
azacitidine as compared with CCR, and transfusion independence was achieved more 
frequently in the azacitidine arm.18 Based on the results of this trial, azacitidine was 
approved in European Union for the treatment of adults who are not eligible for HSCT and 
have Intermediate-2 or High-Risk MDS, CMML with 10-29% marrow blasts without 
myeloproliferative component, and AML with 20-30% blasts and multi-lineage dysplasia, 
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An important observation from the AZA-001 study was that the achievement of CR is not a 
prerequisite for increased OS.  Indeed, the results of this trial demonstrated that patients who 
achieved hematologic improvement (HI) (based on the International Working Group (IWG) 
2000 criteria for MDS) but never attained complete or partial response still obtained a 
survival benefit.18
Azacitidine has become the standard of care in front line higher risk MDS and AML patients 
with 20-30% blasts and multi-lineage dysplasia, although it is not curative.  Continued 
treatment with azacitidine is necessary in order to maintain clinical responses and following 
failure of the azacitidine treatment, life expectancy among MDS patients is short with a 
median survival of less than 6 months.22 As a result of these limitations, combination 
treatments of investigational agents with an HMA as a backbone are currently under 
investigation.23
AML is a genetically heterogeneous hematologic malignancy characterized by multiple 
mutations and epigenetic dysregulation at the time of diagnosis that evolves with treatment, 
resulting in treatment resistance, disease relapse, and reduced survival. 
In 2015, results from the international randomized phase 3 AZA-AML trial comparing 
azacitidine to CCRs in patients aged ≥ 65 years with newly diagnosed or secondary AML 
with >30% bone marrow blasts demonstrated a clinically meaningful improvement in mOS 
in the azacitidine arm of 10.4 months (95% CI, 8.0-12.7) vs 6.5 months (95% CI, 5.0-8.6) in 
the CCR arm (HR=0.85; 95% CI, 0.69-1.03; stratified log-rank p=0.1009), although the 
primary endpoint was not met. The CR rate in the azacitidine arm was lower than the CCR 
arm (19.5% vs 21.9%). The 1-year survival rate with azacitidine was 46.5% compared with 
34.2% with conventional therapy (95% CI, 3.5%-21.0%; Dombret et al, 2015).57 Based on 
the observed survival benefit, the EU expanded the approval of azacitidine in AML to adult 
patients aged 65 years or older who are not eligible for HSCT with >30% myeloblasts 
according to the WHO classification; previously, the indication covered AML patients with 
<30% blasts. Despite the modest increase in mOS and low CR rate, azacitidine is the 
currently the standard of care for AML patients not suitable for intensive chemotherapy. 
New treatments are needed to improve outcomes in this older AML population. 
Preliminary efficacy data from the safety LIC of the current study which enrolled patients 
with high risk MDS per IPSS, AML with 20-30% blasts and multi-lineage dysplasia, and 
CMML, treated with glasdegib 100 mg PO Qday in combination with azacitidine, showed 
5 patients responded: 3 patients with CR, 2 patients with marrow mCR.  Of note, after the 
data cutoff date, the complete blood count of 1 of the patients with mCR had normalized, 
consistent with CR. Of the 5 patients who responded, 4 responses occurred on or before Day 
100. Of the 4 patients with CR (including the mCR patient who achieved a CR after the data 
cutoff date), 3 patients had AML (75% CR rate vs the historical control for azacitidine alone, 
19.5%) and 1 patient had MDS (14% CR rate vs the historical control for azacitidine alone, 
17%). A further 4 patients had SD. No evidence of drug-drug interaction (DDI) was noted.  
As of September 2016, mOS had not been reached.  In the Phase 1b part of Study B1371003, 
52 patients with previously untreated AML or higher risk MDS were treated with glasdegib
100 mg or 200 mg PO Qday in combination with low dose cytarabine (LDAC) (n=23), 


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decitabine (n=7), or 7 + 3 (n=22). Of the AML patients treated in combination with 
decitabine, 2/5 (40%) responded (1 CR and 1 complete response with incomplete blood count 
recovery [CRi]). Of the high-risk MDS patients treated in combination with decitabine, 
2/2 responded (2 mCR). Median OS in the combined AML and MDS patients were 
4.4 months, 11.5 months (vs historical mOS of 7.7 months with decitabine alone), and 
34.7 months respectively in the 3 treatment arms.  A similar population of newly diagnosed 
elderly AML patients was enrolled into a Phase 3 study of decitabine vs supportive care vs 
LDAC where the CR+ CRi rate was 25.6% in the decitabine only arm.
In the Phase 2 portion of Study B1371003, a prospective, randomized (2:1), open-label 
clinical trial in 132 previously untreated AML patients not suitable for intensive 
chemotherapy based on age or other risk factors and higher risk MDS, the addition of 
glasdegib 100 mg orally PO Qday to LDAC vs LDAC alone resulted in a significant 
improvement in OS (mOS 8.8 months (80% CI:6.9, 9.9) vs 4.9 months (80% CI: 3.5, 6.0); 
hazard ratio [HR] 0.513 [80 % CI: 0.394-0.666]; 1-sided p-value=0.0004). In addition, the 
CR/CRi rate for AML patients in the glasdegib + LDAC arm was higher than the LDAC 
alone arm (25% [80% CI: 19.1, 30.9] vs 4.5% [80% CI: 0.5, 8.6]). When glasdegib was 
combined with treatments commonly used in patients with higher risk MDS and AML not 
suitable for intensive chemotherapy (azacitidine, decitabine, and LDAC), improvements in 
response rates and OS in the context of historical controls were observed.
The target population in the safety LIC for this study was aligned with the AZA 001 trial, 
which addressed changes in the FAB and WHO 2008 MDS classifications systems.  The 
population included Intermediate-2 and High-Risk MDS according to IPSS, AML 
20-30% BM blasts and with multi-lineage dysplasia, (WHO 2008) considered smoldering 
leukemias that may remain stable for weeks or months, somewhat MDS-like, and therefore 
not necessarily benefiting from the intensive treatments used for classic AML patients, and 
lastly CMML patients without a myeloproliferative component (MDS type), defined as white 
blood cells (WBC) 13 x 109/L according to the FAB classification.  All three 
hematological malignancies described above have been shown to benefit from azacitidine 
treatment.
In the expansion component of this study, patients with Intermediate, High, or Very High 
risk MDS according to IPSS-R and AML patients who are not candidates for intensive 
chemotherapy (WHO 2016) will be enrolled. CMML patients and patients with 
unclassifiable MDS/MPN are eligible for enrollment into the MDS cohort.  Based on the 
results of the AZA-AML trial, the azacitidine label was expanded in 2009, making 
azacitidine a standard of care treatment in elderly AML patients unable to tolerate intensive 
therapies. This historical data, coupled with the preliminary efficacy data from the safety 
LIC of the current study warrants further investigation of azacitidine’s benefit in a larger 
AML population. Since several prognostic and classification systems were recently updated, 
the following will be implemented in the expansion component of the study to make it more 
contemporary: IPSS-R and the WHO 2016 classification system will be applied to the MDS 
patients and the updated 2017 ELN risk stratification and updated response categories and 
the revised WHO 2016 classification system will be applied to the AML patients. 


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Given the central role that Hh signaling plays in cellular differentiation through modulating 
both the leukemia stem cells (LSC) population and the surrounding stromal environment, Hh 
inhibition in combination with HMAs represents a mechanistically attractive approach for the 
elimination of the LSC population while targeting the gene expression deregulation involved 
in the pathway development in patients with Higher-Risk MDS, AML, and CMML. 
1.2.4. Summary of Glasdegib Product Profile
Glasdegib is a potent and selective inhibitor of the Hh signaling pathway through binding to 
its target SMO.  It is currently being developed for the treatment of hematologic 
malignancies.  Complete information for glasdegib may be found in the single reference 
study document (SRSD), which for this study is the Investigator Brochure (IB).26
Glasdegib inhibited the binding of a known comparator inhibitor of SMO (PF-03451358)
with an half maximal inhibitory concentration (IC50) of 4 nM.  In addition, in a Shh-induced 
Gli-Luciferase reporter assay, glasdegib inhibited the Hh pathway activity with an IC50 of
3 nM.  Using human aortic adventitial fibroblasts, Shh stimulation for 48 hours induced a 
300% increase in endogenous Gli1 levels, assessed using quantitative polymerase chain 
reaction (PCR); glasdegib at 100 nM inhibited 75% of the ligand-induced Gli1 levels.  
Glasdegib was also evaluated in mouse 3T3-L1 preadipocytes, a cell line that forms 
triglycerides through a mechanism activated by insulin and antagonized by Shh.  In this 
model, glasdegib (50 nM) reproducibly antagonized Shh, restoring 60% of lipid production 
relative to control cultures induced with insulin alone.26
In the PTCH/P53 medulloblastoma mouse model of Hh pathway-driven tumors, 
glasdegib inhibited pathway activation (Gli1 expression) and produced rapid and complete 
tumor regression.  Preclinical PK/PD modeling using this model suggests a target human 
dose of 15 mg/day is projected to yield at least 50% of tumor Gli1 messenger ribonucleic 
acid (mRNA) inhibition from baseline levels and approximately 20% of skin Gli1 mRNA 
suppression.26
A series of preclinical studies show that glasdegib has significant activity in imatinib 
resistant chronic myeloid leukemia (CML) blast crisis disease (Abrahamsson-Schairer A. et 
al).38 Patient derived CD34+ imatinib resistant blast crisis CML cells xenotransplanted into 
immunocompromised mice treated with glasdegib alone or in combination with dasatinib 
reduced primary leukemic tumor burden.  In addition, glasdegib treatment reduced leukemic 
tumor formation in secondary recipients, suggesting that glasdegib is able to inhibit the LSC 
population necessary for tumor propagation.  Importantly, this was verified in CML T315I 
mutants, which have escaped tyrosine kinase inhibitor (TKI) inhibition.
1.2.5. Glasdegib Preclinical Toxicity Data
Glasdegib has been extensively characterized in nonclinical safety studies in rats, dogs and 
rabbits.  Glasdegib was evaluated in safety pharmacology studies (cardiovascular, 
neurofunctional, respiratory), definitive toxicology assessments of up to 6- and 9-months 
duration, in vitro and in vivo genetic toxicity studies, local irritation study and embryo-fetal 
developmental toxicity studies.  The primary target organs in rat included kidney, bone, and 


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tooth.  Additional findings were observed in rat testis and peripheral nerve, and clinical 
observations included alopecia and muscle tremor/twitching.  The no observed adverse effect 
level (NOAEL) determined from the 6 month Good Laboratory Practices (GLP) rat study 
was 10 mg/kg/day, corresponding to free plasma concentrations of 116 ng/mL (Cmax) and 
36 ng/mL (Cavgss).  The primary target organs in the dog included kidney and liver.  
Additional observations of alopecia and skin irritation/inflammation, and QTc prolongation 
were identified in the dog.  A NOAEL from the 9-month GLP dog study was not established.  
At the lowest dose tested in this study, 1 mg/kg/day, the free plasma concentrations were 
16 ng/mL (Cmax) and 2 ng/mL (Cavgss).  Glasdegib was teratogenic at all doses tested in rats 
and rabbits.
1.2.5.1. Kidney Effects in Preclinical Studies
The kidney was identified as a target organ in both rat and dog toxicity studies.  Adverse 
kidney damage (tubular degeneration/necrosis, cytomegaly, inflammation, regeneration) was 
observed in rats at ≥50 mg/kg/day and dogs at ≥1 mg/kg/day and was ascribed as the primary 
cause of unscheduled euthanasia in both species.  Kidney damage partially reversed in rats 
and fully reversed in dogs during the recovery phase in both the GLP 6-month rat and 
9-month dog studies.
1.2.6. Bone Effects in Preclinical Studies 
Bone (epiphysis) and tooth (incisor) effects were observed in rat GLP studies with glasdegib.  
Bone changes in the femur and sternum were characterized by decreased/disorganized 
chondrocytes and partial to complete closure of epiphysis.  The odontopathy were 
characterized by incisor tooth necrosis and/or complete loss of the tooth and in some animals 
was coincident with oral mucosal ulceration and inflammation.  The effects on bone and 
teeth persisted during recovery phases and did not reverse.  The changes in the epiphyseal 
growth plate are consistent with inhibiting the hedgehog (Hh) pathway in growing bone 
(Kimura et al, 2008)24 and chondrogenesis (Amano et al, 2008)25 and the generation of 
ameloblast progenitors from stem cells in the continuously growing rodent incisor (Seidel et 
al, 2010; Dassule et al, 2000)61,62 is dependent on Hh pathway activity.
1.2.7. Cardiovascular Effects in Preclinical Studies 
The potential for QT prolongation was identified from the in vitro human 
ether-à-go-go-related gene (hERG) assay and in vivo cardiovascular dog study.  Glasdegib
produced dose related changes in the QTc interval.  At 5 mg/kg, a small (5 msec) but 
statistically significant increase in QTc interval occurred at free plasma exposures of 
420 ng/mL (Cmax).  At 30 mg/kg, a statistically significant increase in QTc interval (24 msec) 
occurred at free plasma exposures of 1848 ng/mL (Cmax).  The QTc prolongation observed in 
the dog is consistent with the hERG IC50 for glasdegib (3.1 uM).
1.2.8. Embryo-fetal Effects in Nonclinical Studies
Teratogenicity was identified in rat and rabbit embryo fetal developmental toxicity studies.  
Glasdegib treatment was associated with increased spontaneous abortions, lower 
embryo-fetal survival, higher incidence of skeletal anomalies, lower fetal body weights, and 
higher incidences of external, visceral and skeletal malformations and variations.  A 


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developmental NOAEL could not be established in rat or rabbit due to adverse teratogenic 
effects at all doses.  Inhibition of Hh signaling has been shown to induce teratogenicity in 
animals as SMO is involved in embryonic development.  Accordingly, inhibition of Hh 
signaling by small molecules can lead to teratogenic effects (Chen et al, 2002, Cooper et al, 
1998).63,64
1.2.9. Other Findings in Preclinical Studies 
Additional glasdegib-related findings in rats were observed in testis and peripheral nerve, and 
clinical observations included alopecia and muscle tremor/twitching.  Microscopic changes 
in the nerve and clinical observations of alopecia and muscle tremors fully recovered.  
Testicular degeneration did not recover; however this finding was only seen in young 
growing rats and not in adult dogs and is consistent with inhibition of Hh signaling which 
plays a role in postnatal testis spermatogenesis (Mäkelä et al, 2011).65 In dog toxicity studies 
with glasdegib, mild liver inflammation with increased liver enzymes was observed in some 
dogs.  However, this finding was only evidenced in dogs with adverse renal damage and is 
likely secondary to kidney findings.  The liver findings partially recovered.
Glasdegib was not genotoxic in any in vitro or in vivo assessment, did not cause local 
irritation when administered intravenously or perivascularly to rabbits and did not cause 
photo-irritancy in the eye or skin.
1.2.10. Clinical Relevance of Organ Toxicities Observed in Nonclinical studies
In general, many findings in the rat and dog predict drug reactions reported in the clinic with 
glasdegib; these include muscle spasms, alopecia and QTc prolongation.  However; not all of 
the organ toxicities observed in animals have been observed in humans when treated with 
glasdegib. Although mild axonal degeneration was observed in rat mesenteric peripheral 
nerve, there have been no reported clinical effects related to worsening or new onset of 
peripheral nerve deficits.  The kidney is a target organ in rat and dog. In the clinical 
program, at glasdegib, 100 mg dose, acute kidney injury has been reported, primarily Grade 
1-2. These events were often associated with prerenal confounders or consequent to or 
exacerbated by other glasdegib effects (eg, diarrhea, vomiting, and/or decreased oral intake). 
An imbalance in creatinine elevations was not seen in the AML unfit LDAC + glasdegib arm 
versus the LDAC arm alone.
There have not been any liver events or significant increases in liver transaminases reported 
in the clinic.  Findings in bone, teeth and testis are considered only a potential concern for 
pediatric patients as Hh signaling is important in growth and development of these tissues as 
cited above, thus, these effects have not manifest in adult patients and are not a risk for adults 
being treated with glasdegib.
1.2.11. Clinical Pharmacokinetic Summary
Data following single and multiple doses of glasdegib from Study B1371001 in patients with 
selected hematologic malignancies are summarized for all cohorts tested (5, 10, 20, 40, 80, 
120, 180, 270, 400, and 600 mg QD).


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The exposure [Cmax, AUCinf (single dose) and AUCtau (multiple dose)] increased in a 
generally dose-proportional manner over the dose range of 5 to 600 mg following 
glasdegib administration on the lead-in day and Cycle 1 Day 21.
Following repeated daily dosing, steady-state was achieved by Day 8 based on comparison of 
Ctrough values across PK days in Cycle 1.  Median Tmax of glasdegib ranged from 1-2 hours 
following a single dose and 1-4 hours following multiple dosing.  The mean 
glasdegib volume of distribution (Vz/F) ranged from 185-455 L.  The geometric 
% coefficient of variance (CV) for AUCinf across all dose levels ranged from 19% to 
109% following a single dose (safety LIC) and from 10% to 61% for AUCtau after multiple 
dosing (Day 21).  Similarly, the geometric % CV for Cmax ranged from 3.0% to 79% after a 
single dose and 7.0% to 83% following multiple dosing.
The geometric mean t½ for glasdegib ranged from 17.4 to 34.3 hours across the various dose 
levels; however, at most dose levels, the half-life was ~24 hours.  The geometric mean 
apparent oral clearance (CL/F) ranged from 5.63 to 12.7 L/hour following a single dose and 
5.33 to 13.3 L/hour following multiple dosing.  Glasdegib accumulated following repeated 
dosing with a median Rac ranging from 1.2 to 2.5.  This was consistent with the observed t½, 
as the predicted Rac is in agreement with the estimated Rac.  The median linearity ratio (Rss) 
ranged from 0.76 to 2.1, with the ratio being close to unity for most of the tested dose levels.
The geometric mean for the percentage of administered dose excreted unchanged in the urine 
over the dosing interval of 24 hours ranged from 5.89% to 16.8%.  The geometric mean for 
renal clearance ranged from 0.385 L/hr to 1.36 L/hr.
1.2.12. Clinical Pharmacodynamic Summary
Analysis of Hh pathway gene expression changes in surrogate tissue (skin) in samples 
collected from both the B1371001 (n=3) and B1371002 (n=15)  studies indicated 
>75% down regulation of the expression of the Hh pathway gene GLI1 at doses of 80 mg or 
higher in all patients with evaluable samples.  Evaluation of circulating cytokine modulation 
demonstrated a post-treatment decrease in IL-8 and IL-10 in one MF patient who responded 
to treatment in B1371001, although limited conclusions can be drawn due to the small 
number of samples available for analysis.
1.2.13. Clinical Experience in Patients with Selected Myeloid Malignancies
Currently there are five clinical studies with glasdegib in patients with hematological 
malignancies (B1371001, B1371003, B1371005, B1371013, and Investigator Initiated 
Research (IIR) Studies (WS2233096 and WI171861).  Study B1371001 was a multi-center, 
open-label, non-randomized, escalating dose Phase 1 study in patients with select advanced 
hematologic malignancies.  Study B1371003 (ongoing) is a Phase 1b/2, open-label, 
multicenter safety and efficacy study of glasdegib in combination with low-dose cytarabine 
(Ara-C), decitabine, or intensive chemotherapy, in patients with AML or high risk MDS. 
Study B1371005 (ongoing) is a Phase 1 dose-finding study of single-agent glasdegib in 
Japanese patients with select advanced hematologic malignancies, or glasdegib in 
combination with intensive chemotherapy (cytarabine and daunorubicin) or LDAC in 


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patients with previously untreated AML or high-risk MDS. Study B1371013 (ongoing) is a 
Phase 2 study of single-agent glasdegib versus placebo in patients with primary or secondary 
myelofibrosis who have been previously treated with a Janus kinase inhibitor.  An ongoing 
Phase 2 IIR study at the University of Colorado (WS2233096) is evaluating the effects of 
glasdegib monotherapy on relapse free survival, remission and OS in patients with AML, 
MDS, or acute lymphocytic leukemia (ALL) at high risk for relapse post-allogeneic HSCT. 
Additionally, an ongoing Phase 2 IIR study at the Lee Moffitt Cancer Center (WI171861) is 
evaluating the glasdegib in patients with MDS. Refer to the glasdegib IB for further 
details.26
1.2.13.1. Study B1371001: Patients with Select Myeloid Malignancies
A total of 47 patients were screened and assigned to treatment in this Phase 1 dose escalation 
study aimed to identify the Maximum Tolerated Dose (MTD) and RP2D of glasdegib in 
patients with select myeloid malignancies.  The dose levels tested in this study were: 5, 10, 
20, 40, 80, 120, 180, 270, 400 and 600 mg QD on a continuous regimen.  The majority 
(28/47 patients, 59.6%) of patients were male.  The median age was 69 years (range 
25-89 years).  The diagnoses of enrolled patients included: AML (28 patients, 59.6%), CML 
(5 patients, 10.6%), CMML (1 patient, 2.1%), MDS (6 patients, 12.8%), and MF (7 patients, 
14.9%).  The median duration of treatment with glasdegib was 64.5 days (range: 5-261 days) 
in AML patients, 36.0 days (range: 1-280 days) in CML patients, 54.0 days (range: 
54-54 days) in CMML patients, 153.0 days (range: 36-537 days) in MDS patients, and 
182.0 days (range: 44-371 days) in MF patients.
Out of the 41 dose limiting toxicity (DLT) evaluable patients, 2 patients experienced DLTs 
during Cycle 1.  One patient in the 80 mg QD cohort experienced non hematologic DLTs of 
Grade 3 hypoxia and pleural effusion for which glasdegib dosing was interrupted 
temporarily, and the dose reduced.  Additionally one patient in the 600 mg QD cohort 
experienced a non-hematologic DLT of Grade 3 peripheral edema for which glasdegib was 
stopped temporarily. 
The majority of treatment related AEs reported were Grades 1 to 3 in severity.  The most 
frequently reported treatment related AEs were dysgeusia (27.7%), decreased appetite 
(19.1%) and alopecia (14.9%).  A summary of treatment related AEs occurring in >5% of all 
patients is provided in Table 5 below.
Grade 3 laboratory test results independent of causality included: lymphocytes decreased 
(n=16), platelets decreased (n=8), WBC decreased (n=8), hemoglobin decreased (n=10), 
neutrophils decreased (n=3), alanine aminotransferase (ALT) increased (n=1), alkaline 
phosphatase increased (n=2), total bilirubin increased, hypokalemia, hyponatremia 
(n=4 each), hyperglycemia (n=3), hypoalbuminemia, hypocalcemia and hypophosphatemia 
(n=1 each).  Grade 4 laboratory test results independent of causality included: platelets 
decreased (n=33), neutrophils decreased (n=26), WBC decreased (n=15), lymphocytes 
decreased (n=6), hemoglobin decreased (n=4), bicarbonate increased (n=1). 


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Based on electrocardiogram (ECG) results, 3 patients (1 patient in the 400 mg QD group and 
2 patients in the 600 mg QD group) had a post baseline maximum Corrected QT interval 
using Fridericia Formula (QTcF) of 500 msec, and 6 patients (1 from the 5 mg group and 
5 from the 600 mg group) had a maximum QTcF increase from baseline of 60 msec.  
Higher frequencies and grades of QTcF prolongation were observed at the highest dose 
levels (400 mg QD and 600 mg QD).  All these events were asymptomatic and transient and 
did not result in significant clinical sequelae.
The MTD was defined as 400 mg after considering the one DLT at 600 mg (Grade 
3 peripheral edema) and the high frequency of QTc prolongation observed at the 600 mg QD 
dose level.  The Recommended Phase 2 Dose (RP2D) for glasdegib was determined to be 
200 mg, based on the following factors:

Doses of glasdegib up to 200 mg were safe and well tolerated following prolonged 
administration (most patients tolerated study drug for a minimum of 3 cycles in the 
dose range of 5-180 mg); 

At doses >200 mg, 3 patients (1 patient in the 400 mg group and 2 patients in the 
600 mg group) had a post baseline maximum QTcF interval of 500 msec;

An overall lower frequency of treatment related Grade 3/4 AEs was observed at doses 
of 200 mg or less.  Over this dose range, the most commonly reported treatment 
related AEs were of Grade 1 or 2 severity suggesting that glasdegib is generally well 
tolerated in this dose range. 
Although evaluation of efficacy was not the primary objective of this study, patients were 
evaluated for disease specific efficacy endpoints.  A total of 4 MDS/CMML patients 
(4/7 patients: 3/6 MDS patients and 1/1 CMML patient, 57.1%) achieved stable disease or 
better, among whom 2 patients (2/7 patients, 28.6%) showed hematologic improvement.  For 
the 7 MF patients, 2 patients achieved clinical improvement.  For patients with AML 
(28 patients), 1 patient (3.6%) had morphologic complete remission with incomplete blood 
count recovery (CRi), 4 patients (14.3%) had partial remission with incomplete blood count 
recovery (PRI), and 4 patients (14.3%) had minor response (MR).  Treatment failures 
occurred in 7 AML patients (25%) due to resistant disease.  Clinical benefit (CR + CRI + PR 
+ PRI + SD + MR) was shown in 16 AML patients (57.1%), including 7 patients (25%) with 
SD.
Out of the 46 patients evaluated for efficacy, 2/7 MDS/CMML patients (28.6%), 2/7 MF 
patients (28.6%), and 9/28 AML patients (32.1%) had an objective response. 
In summary, glasdegib appears to be well tolerated with early signs of efficacy observed in 
all the hematologic diseases studied.  Several patients with aggressive malignancies remained 
on trial for prolonged durations.  On target AEs (eg, dysgeusia and alopecia) were observed 
at multiple dose levels.  Taken together, this data support testing glasdegib as a combination 
therapy in patients with AML and MDS for whom there are few effective therapeutic options 
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Table 5.
Treatment Emergent Adverse Events with Frequency 5% by System 
Organ Class and Preferred Term
Source: B1371001 Full Clinical Study Report (Table 28).
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, N/n = number of patients, 
QT = in electrocardiography, the time corresponding to the beginning of depolarization to repolarization of the 
ventricles, SOC = system organ class.
a.
MedDRA (version 16.0) coding dictionary applied.
1.2.13.2. Study B1371012: Safety Lead-In Cohort
As of 23 September 2015, twelve patients were enrolled into the safety LIC of the current 
study with higher risk MDS (n=7), AML (n=4), and CMML (n=1) and treated with glasdegib
100mg QD orally in combination with azacitidine 75 mg/m2 SC daily for 7 days.  As of a 
data cutoff date of 19 September 2015, a safety review was conducted in 11/12 patients who 
received at least 1 cycle of treatment. Baseline characteristics are summarized in Table 6. 
One additional patient was enrolled and treated after the data cut-off period (MDS IPSS-risk 
Intermediate-2).
The median glasdegib treatment duration was 51 days, range 23-128 days.  The median 
relative glasdegib dose intensity was 92.0% across all cycles.  The median relative 
azacitidine dose intensity was 98.0% across all cycles.


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Table 6.
Baseline Patient Characteristics
Characteristic
Glasdegib 100 mg/
Aza 75 mg/m2 (N = 11)
N (%)
Male/Female
7:4
Mean (range) age, in 
years
71.7 (59-89)
   ≥65, n (%)
8 (72.7)
Race
   White
10 (90.9)
   Non-White
1 (9.1)
Disease, n (%)
   MDS IPSS high
2 (18.2)
   MDS IPSS 
intermediate-2
4 (36.4)
   AML
3 (27.3)
NP-CMML
1 (9.1)
Other* 
1 (9.1)
*Erythroleukemia. IPSS, International Prognostic Scoring System; 
MDS, myelodysplastic syndrome; NP-CMML, non-proliferative 
chronic myelomonocytic leukemia; oAML, oligoblastic acute 
myeloid leukemia
All patients who received at least one dose of study treatment (n=11) experienced Treatment 
Emergent Adverse Events (TEAEs). The most frequently reported TEAEs of any grade and 
regardless of causality, occurring in 3 or more patients, are summarized in Table 7. 
Electrocardiogram (EKG) QT prolonged (1 patient Grade 3; 3 patients Grade 1/2). Nine 
patients (81.8%) experienced ≥ Grade 3 TEAEs. The most frequently reported
Grade ≥3 TEAEs regardless of causality, occurring in 3 or more patients were anemia 
(72.7%) and neutropenia (45.5%).


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Table 7.
Most Frequently Reported TEAEs in the Safety Lead-In Cohort (Any 
Grade, All Causality, in 3 Patients)
MedDRA PTa
N (%)
Anemia
8 (72.7%)
Constipation
8 (72.7%)
Fatigue
7 (63.6%)
Dysgeusia
6 (54.5%)
Nausea
6 (54.5%)
Neutropenia
5 (45.5%)
Dyspnea
4 (36.4%)
Electrocardiogram QT prolonged
4 (36.4%)
Pyrexia
4 (36.4%)
Vomiting
4 (36.4%)
Weight decreased
4 (36.4%)
Cough
3 (27.3%)
Diarrhea
3 (27.3%)
Injection site erythema
3 (27.3%)
Source: PHASE 1B SAFETY LEAD-IN DATA FOR STUDY B1371012 (Table 14.3.1.2.11.1) 
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, N/n = number of patients, 
QT = in electrocardiography, the time corresponding to the beginning of depolarization to repolarization of the ventricles, 
TEAE = Treatment Emergent Aderse Events.
a.
MedDRA (version 18.1) coding dictionary applied.
Overall 7 patients (63.6%) experienced SAEs. Of these, the most frequently reported SAEs 
(reported in 2 patients each, 18.2%) were cellulitis, febrile neutropenia, and pyrexia. As of 
the data cut-off, 3 patients (27.3%) discontinued study treatment due to the following AEs 
(n=1 each): grade 4 cellulitis, sepsis, and septic shock not related to either study drug; grade 
3 malignant lung neoplasm not related to either study drug; grade 3 QTc prolongation related 
to glasdegib. One patient died within 28 days of last dose of study medication due to a grade 
5 acute myocardial infarction as a result of underlying coronary artery disease and 
cardiovascular risk factors of obesity and hypertension, deemed unrelated to either study 
drug by the Investigator.
The reported AEs were consistent with the individual toxicity profiles of glasdegib, 
azacitidine, and complications from the underlying disease itself. The addition of glasdegib
to standard of care azacitidine did not appear to adversely impact azacitidine dosing nor did it 
result in a significant number of discontinuations due to toxicity in the subject population.  
An internal Pfizer review team declared the combination of glasdegib and azacitidine in the 
patient population as having an acceptable safety and tolerability profile, consistent with 
what is expected for glasdegib or azacitidine alone, and deemed acceptable to proceed to the 
next phase of development.
As of 23 March 2016, preliminary data showed a total of 5 patients responded: 3 patients 
with CR and 2 patients with mCR (of note, after the data cutoff date, the complete blood 
count of one of the patients with mCR had normalized, consistent with CR).  Of the 
4 patients with CR (including the mCR patient who became CR after the data cutoff date), 


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3 patients had oligoblastic AML.  Of the 5 patients who responded, 4 responses occurred on 
or before Day 100.  Of the 4 patients with CR (including the mCR patient who achieved a 
CR after the data cutoff date), 3 patients had AML (75% CR rate vs the historical control for 
azacitidine alone, 19.5%) and 1 patient had MDS (14% CR rate vs the historical control for 
azacitidine alone, 17%).18,57 A further 4 patients had stable disease.  At the time of the 
cutoff, median survival had not been reached. An evaluation of the DDI potential between 
glasdegib and azacitidine was conducted in this component of the study and no evidence of 
DDI potential was observed. (Borate et al, 2016).45
As of 10 March 2017, the safety LIC is complete with no patients on active treatment, 
1 patient in follow-up, 4 patients withdrew from follow up, and 7 patients have died due to 
the following reasons deemed unrelated to study treatment by the study Investigators: Sepsis 
leading to Multi-organ failure, Acute myocardial infarction, Unknown (n=1 each), and 
Disease progression (n=4). No deaths were reported as the reason for discontinuation of 
study treatment, 2 deaths occurred within 28 days after last treatment dose and, 5 deaths 
occurred after 28 days from last dose.
Based on the acceptable safety and tolerability profile of glasdegib in combination with 
azacitidine and the early clinical activity seen, further investigation of this combination is 
warranted.
1.2.13.3. Study B1371003: Phase 1b/2 Study in Patients with AML or High-Risk MDS
This is an open-label, multicenter safety and efficacy study of glasdegib in combination with 
LDAC, decitabine, or intensive chemotherapy in patients with AML or high-risk MDS. This 
study includes two portions:

Phase 1b: To evaluate the safety and RP2D determination of three first-line 
combination regimens of glasdegib plus: LDAC, decitabine, or ‘7+3’ induction 
chemotherapy (cytarabine/daunorubicin).

Phase 2: To assess the efficacy of two combination regimens:

A Phase 2 randomized (2:1) open-label component in unfit patients (P2 Unfit) 
enrolled to receive either LDAC in combination with glasdegib or LDAC alone;

A Phase 2 single arm component in fit patients (P2 Fit) to receive glasdegib in 
combination with 7+3 induction chemotherapy. Please refer to the glasdegib IB 
for further details on this part of the study.
Phase 1b Part
In the Phase 1b part of Study B1371003, 52 patients with AML or higher risk MDS were
treated with glasdegib 100 mg or 200 mg PO Qday in combination with LDAC (n=23),
decitabine (n=7), or 7 + 3 (n=22).


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In Arm A (LDAC + glasdegib), 23 unfit patients were enrolled (15 males/8 females).  
Seventeen (17) patients received a starting glasdegib dose of 100 mg and 6 patients of 
200 mg QD.  No DLTs were observed. The most frequently reported treatment-related AEs 
in patients were nausea (n = 6, 35.3%), diarrhoea and neutropenia (n = 5, 29.4% each), and 
muscle spasms and dysgeusia (n = 4, 23.5% each). 
In Arm B (Decitabine + glasdegib) 7 unfit patients were enrolled (5 male/2 female).  Four (4) 
patients received glasdegib 100 mg and 3 patients received glasdegib 200 mg.  No DLTs
were reported.  The most frequently reported treatment-related AEs of any grade were nausea 
(n=3, 75%), diarrhoea, thrombocytopenia, and neutropenia (n=2, 50% each). Of the AML 
patients treated in combination with decitabine, 2/5 (40%) responded (1 CR and 1 complete 
response with incomplete blood count recovery (CRi)), a similar population of newly 
diagnosed elderly AML patients was enrolled into a Phase 3 study of decitabine vs 
supportive care vs low dose cytarabine where the CR+ CRi rate was 25.6% in the decitabine 
only arm (Kantarjian et al, 2012).58 Of the high-risk MDS patients treated in combination 
with decitabine, 2/2 achieved a response of mCR. Median OS in the combined AML and 
MDS patients was 4.4 months, 11.5 months (historical mOS of 7.7 months; Kantarjian et al, 
2012),58 and 34.7 months respectively in the 3 treatment arms. This arm was not evaluated in 
the Phase 2 component of Study B1371003. 
In Arm C (Cytarabine/Daunorubicin + glasdegib), 22 fit patients were enrolled 
(12 males/10 females).  Sixteen patients received a starting glasdegib dose of 100 mg QD and 
6 patients of 200 mg QD.  The most frequently reported treatment-related AEs in patients 
who received glasdegib 100 mg + cytarabine + daunorubicin of any grade were nausea 
(n =13, 81.3%), diarrhea, febrile neutropenia and muscle spasms (n = 7, 43.8% each), 
dysgeusia (n = 6, 37.5%), stomatitis, headache, fatigue and pyrexia (n = 5, 31.3% each), 
constipation, dyspepsia, vomiting, anaemia, neutropenia, white blood cell count decreased, 
hypocalcaemia, hypokalaemia and alopecia (n = 4, 25% each). A DLT of Grade 
4 polyneuropathy, later attributed to concomitant medication, was reported at the 
100 mg dose level and treatment was permanently discontinued in that patient. 
Of the 45 AML patients treated in the entire Phase 1b cohort of Study B1371003, 
1/20 treated patients in combination with LDAC responded (1 CR), 2/5 treated in 
combination with decitabine responded (1 CR, 1 complete response with incomplete blood 
count recovery (CRi), and 11/20 treated patients in combination with 7 + 3 responded 
(10 CR, 1 CRi).
Median OS (in AML and MDS patients combined) were 4.4 months (80% CI: 2.5, 6.6), 
11.5 months (80% CI:4.5, 17.4), and 34.7 months (80% CI: 14.5, Not Reached), 
respectively.
Of the 7 high-risk MDS patients treated in the entire Phase 1b cohort of Study B1371003, 
2/3 treated in combination with LDAC responded (1 CR, 1 mCR), 2/2 treated in combination 
with decitabine responded (2 mCR), and 2/2 treated in combination with 7 + 3 induction 
chemotherapy responded (1 CR, 1 mCR).


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Phase 2 Randomized Combination Part (Phase 2 Unfit)
In the Phase 2 portion of Study B1371003, a prospective, randomized (2:1), open-label 
clinical trial in 132 AML patients not suitable for intensive chemotherapy based on age or 
other risk factors, the addition of glasdegib 100 mg PO Qday to LDAC vs LDAC alone 
resulted in a significant improvement in OS (median 8.8 months (80% CI:6.9, 9.9) vs 
4.9 months (80% CI: 3.5, 6.0); HR 0.513 [80% CI: 0.394-0.666]; 1-sided 
p-value=0.0004 based on stratified log-rank test.  This benefit in OS was also consistent 
within prespecified subgroups and supported by higher rates of complete remission in the 
LDAC + glasdegib arm (17% [80% CI: 11.9, 22.2] vs 2.3% [80% CI: 0.0, 5.2]).  The 
addition of glasdegib to LDAC was well-tolerated, with 14 (16.7%) discontinuations due to 
adverse events. Thirteen of 84 (15%) patients were treated for at least 1 year (vs none in the 
LDAC alone arm). The median treatment duration was 83 days (range 3, 972 days) in the 
LDAC + glasdegib arm versus 47days (range 6, 239 days) in the LDAC alone arm. 
The safety profile was consistent with that in elderly AML patients receiving chemotherapy, 
namely cytopenias and gastrointestinal (GI) side effects, and had the safety/tolerability 
profile of other marketed SMO inhibitors.  In the LDAC + glasdegib arm, serious adverse 
events (SAEs) of febrile neutropenia, occurred more frequently (28.6%) than in the LDAC 
alone arm (19.5%); however, frequencies of pneumonias were similar between treatment 
arms (21.4% in the LDAC + glasdegib arm and 17.1% in the LDAC alone arm), and sepsis 
rates were lower in the LDAC + glasdegib arm (3.6% in the LDAC + glasdegib arm and 
12.2% in the LDAC alone arm). The most common AEs in the LDAC + glasdegib arm were 
cytopenias and GI events, consistent with that in elderly AML patients receiving 
chemotherapy. Cytopenias were not accompanied with higher rates of infections or bleeding 
as compared to the LDAC alone arm. QTcF prolongation >500 msec (Grade 3) was less 
frequent in the LDAC + glasdegib arm (6%) than in the LDAC alone arm (11.8%). SMO 
inhibitor-associated AEs in the LDAC + glasdegib arm included dysgeusia (25%), muscle 
spasms (21.4%) and alopecia (10.7%). In the LDAC + glasdegib arm 28 (33%) patients were 
permanently discontinued due to AEs vs 20 (49%) patients in the LDAC alone arm, mostly 
for disease progression or infection. The most common cause of death was disease 
progression in both treatment arms. 
The safety profile and magnitude of improvement in OS appeared to be consistent with that 
in other ongoing single-arm studies of glasdegib as monotherapy or in combination with 
other chemotherapies in other MDS and AML populations.
1.2.13.4. Study B1371005: Safety and Efficacy in an Asian Population
In the ongoing Phase 1 Study B1371005, 25 Japanese patients with selected hematologic 
malignancies were enrolled into three cohorts: 1) Thirteen (13) patients with AML, MDS, 
CMML, or MF enrolled into the open label, dose escalation monotherapy cohort and 
received glasdegib as a single agent at doses ranging from 25-100 mg PO Qday, 2) Six (6) 
patients with untreated AML or high risk MDS patients unsuitable to receive intensive 
induction chemotherapy received glasdegib 100 mg PO QD in combination with LDAC , and 
3) Six (6) untreated AML or high risk MDS patients eligible for intensive chemotherapy 
enrolled in combination cohort #2 and received glasdegib 100 mg PO QD in combination 
with cytarabine (7days)/daunorubicin (3 days) chemotherapy. 


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No DLTs were observed at any dose level. The most frequently reported treatment related 
AEs occurring in ≥3 patients were: dysgeusia (69.2%), muscle spasms (38.5%), alopecia 
(30.8%), and decreased appetite (30.8%), blood creatinine phosphokinase increased (23.1%), 
constipation (23.1%), and diarrhea (23.1%).  The safety and PK profiles in Japanese patients 
were consistent with what was observed in Western patients and in Study B1371001.
Preliminary efficacy data showed that 1 out of 7 AML patients achieved morphologic 
complete remission and 1 out of 4 MDS patients achieved marrow complete remission at the 
100 mg dose level and 4 achieved SD across all dose levels (Yoshimoto et al, 2016).46
1.2.14. Post Allogeneic HSCT Investigator Initiated Research Study
In an ongoing IIR, single-arm study in patients with MDS, AML, or acute lymphocytic 
leukemia (ALL) with evidence of minimal residual disease (MRD) or other high-risk 
characteristics associated with a high rate of disease relapse at the time of allo HSCT, the 
addition of glasdegib 100 mg PO Qday post absolute neutrophil count (ANC) engraftment 
for up to a year resulted in 10/13 patients free of disease relapse: 12/13 patients remained
alive (Gutman et al, 2015).47 Historically, patients with measureable MRD at the time of 
HSCT have disease relapse rates >60%, and mOS of ~1 year. (Walter et al, 2015)48 Araki et 
al, 2016)49
1.2.15. Summary of Azacitidine Product Profile 
Azacitidine (VIDAZA®) is a chemical analogue of the cytosine nucleoside whose mechanism 
of action involves inhibition of DNA methyltransferase at low doses, causing 
hypomethylation of DNA, and direct cytotoxicity in abnormal hematopoietic cells in the 
bone marrow through its incorporation into DNA and ribonucleic acid (RNA) at high doses, 
resulting in cell death.  Azacitidine was approved by the FDA in 2004 for the treatment of all 
subtypes of MDS according to the FAB classification.  Azacitidine was approved in the EU 
in 2009 for the treatment of adult patients who are not eligible for hematopoietic stem cell 
transplantation with intermediate-2 and High-Risk MDS (per IPSS), CMML with 
10-29% bone marrow blasts without myeloproliferative disorder and AML with 
20-30% blasts and multi-lineage dysplasia. In 2015, the EU expanded the approval of 
azacitidine in AML to include adult patients aged 65 years or older who are not eligible for 
HSCT with >30% myeloblasts according to the WHO classification.
1.2.16. Azacitidine Toxicities
Per the VIDAZA® EU Summary of Product Characteristics (SPC), the following (very 
common 1/10) adverse reactions associated with azacitidine treatment were obtained from 
clinical studies and post marketing surveillance: pneumonia, nasopharyngitis, febrile 
neutropenia, neutropenia, leukopenia, thrombocytopenia, anemia, anorexia, decreased 
appetite, hypokalemia, insomnia, dizziness, headache, dyspnea, epistaxis, diarrhea, vomiting, 
constipation, nausea, abdominal pain, petechiae, pruritus, rash, ecchymosis, arthralgia, 
musculoskeletal pain, fatigue, pyrexia, asthenia, chest pain, injection site erythema, injection 
site pain, injection site reaction (unspecified), and weight decreased.


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1.2.16.1. Azacitidine Dosing Schedule
The dosing schedule in the safety LIC is 75 mg/m2/day SC for 7 consecutive days every 
28 days.  In the expansion component, azacitidine will be administered per local label or per 
the Investigational Product Manual (or SPC).  Azacitidine may be administered by SC 
injection or IV infusion at the starting dose of 75 mg/m2/day for 7 days every 28 days.  
Alternate dosing schedules to administer the 7 doses to accommodate patient and treatment 
center availability are allowed.
A trial which compared 3 different azacitidine schedules36 showed 44% HI (22/50) for the 
5-2-2 dosing schedule (95% CI, 31 to 60), another trial (AZA 001), showed 49% HI in the 
azacitidine arm (87/177) (p <0.0001).  There are no data showing that varying 
7 day schedules are not equivalent, therefore, the Investigators can choose the appropriate 
schedule based on the standard of care at their institution. 
1.2.16.2. Azacitidine Dose Modifications
For azacitidine dose modification, refer to the local label or the Investigational Product 
Manual (or SPC).
Complete information for azacitidine may be found in the SRSD, which for this study is the 
EU SPC for Vidaza®.27
1.2.17. Rationale for Testing Glasdegib in Combination with Azacitidine in Patients 
with Previously Untreated Higher-Risk MDS, AML, and CMML
The combination of glasdegib with azacitidine is proposed for testing in this therapeutic 
setting based on:

Clinical and pre-clinical data suggesting a role for aberrant Hh pathway activation in 
MDS, AML and CMML (See Section 1.2.2 and 1.2.3);

Non-clinical data demonstrating that glasdegib limits LSC proliferation and evidence 
of glasdegib synergy with chemotherapy (See Section 1.2.2);

The acceptable safety, tolerability and pharmacokinetic profile observed for 
glasdegib in clinical studies in patients with hematological malignancies both as a 
single agent and in combination with decitabine and azacitidine (see Section 1.2.6);

The clinical activity observed following single-agent and combination treatment with 
glasdegib in patients with select hematological malignancies (see Section 1.2.6);

The glasdegib pharmacodynamic data for Hh pathway inhibition obtained in 
surrogate tissues from a limited number of patients (n=18) with select hematological 
malignancies and advanced solid tumors (see Section 1.2.13.2).


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The above data along with the high unmet medical need for more effective therapies (higher 
response rates and hematologic improvement that translate into survival benefit) for patients 
with higher-risk MDS, AML, and CMML, support the evaluation of glasdegib in 
combination with azacitidine in this population.
1.2.18. Rationale for the Starting Dose of Gladegib
As reported in Section 1.2.13.1, the B1371001 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. 
Subsequent evaluation of potential dose levels for further studies in patients with 
hematologic malignancies suggested the 100 mg QD dose level (MTD -4) as the optimal 
starting dose of single agent glasdegib.  This was supported by the following data:

Clinical benefit observed in 16 patients in the B1371001 study (including some with a 
diagnosis MDS and CMML) with doses of glasdegib as low as 10 mg QD, with the 
highest frequency of responses being observed at 80 mg QD; 

GLI1 (a biomarker of Hh pathway signaling activation) expression is down regulated 
by 80% at doses of 50 mg QD and higher in surrogate (skin) tissue, suggesting there 
will be adequate target modulation at the 100 mg QD dose;

Potential for increase in glasdegib plasma exposures in the presence of a strong 
CYP3A4 inhibitor(s) (~140% increase in AUCinf and a 40% increase in the Cmax) 
such as azoles which are medically necessary for management of infections in AML 
patients.

Taking into consideration 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, a dose of 100 mg QD was chosen as 
the appropriate glasdegib starting dose for further clinical studies both as a single 
agent and in combination. In the randomized Phase 2 portion of Study 
B1371003 (Section 1.2.13.3), clincal benefit was demonstrated with LDAC ± 
glasdegib (100 mg Qday continuously in 132 first line AML patients. The mOS was 
8.8 months (80% CI:6.9, 9.9) vs. 4.9 months (80% CI: 3.5, 6.0) for LDAC alone, 
with a hazard ratio of 0.513 [80% CI: 0.394-0.666]. The safety profile of glasdegib +
LDAC was generally tolerable and manageable.

In the single arm Phase 2 portion of Study B1371003 (Section 1.2.13.3), for older 
AML pts receiving intensive chemotherapy, the mOS stratified by subgroup was 
improved by adding glasdegib. The combination of glasdegib with ‘7+3’ was 
well-tolerated, with a safety profile consistent with that typically seen in AML 
patients receiving standard intensive chemotherapy.
These data provides additional rationale for the 100 mg QD dose of glasdegib being a safe 
and potentially clinically effective dose in combination with azacitadine.


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1.2.19. Assessment of the Drug-Drug Interaction (DDI) Potential between 
Glasdegib and Azacitidine
Glasdegib has been shown to be extensively metabolized by CYP3A4 (99.8%) using human 
liver microsomes and hepatocytes.  For azacitidine, the exact route of elimination and 
metabolic fate is not known in humans.  One of the pathways of elimination for azacitidine 
appears to be deamination by cytidine deaminase principally located in the liver but also in 
granulocytes, the intestinal epithelium, and whole blood (Vidaza® US package insert).  The 
potential for a DDI was considered to be low for the glasdegib and azacitidine, as enzyme 
systems other than CYP3A may be involved in the metabolism of azacitidine.  However, 
since this was a combination setting for dosing of glasdegib and azacitadine, a DDI 
assessment was conducted in twelve subjects as part of the safety LIC.  Based on preliminary 
PK results, there was no evidence of changes in the PKs of either glasdegib or azacitadine 
when dosed in combination as compared to single agent dosing.
1.2.20. Summary of Benefit-Risk Assessment
An evaluation of the anticipated risks and benefits of treatment with glasdegib in the defined 
patient population as required in Article 3(2)(a) of Directive 2001/20/EC (cf. Article 6(3)(b) 
of Directive 2001/20/EC) has been conducted.
Based on the available clinical data, the safety profile of glasdegib as a single agent and in 
combination administered orally on a once daily continuous dosing regimen is characterized 
by manageable and potentially reversible toxicities that are generally mild to moderate in 
severity.  The key observed toxicities are: muscle spasms, dysgeusia, decreased appetite, and 
alopecia. 
Small but significant increases in the QTc interval have been reported in non-clinical studies 
with glasdegib. Across the clinical program at glasdegib doses of 100 mg QD, cases of 
QTcF prolongation >500 msec or change in QTcF >60 msec from baseline have been 
reported, generally in settings of multiple confounders; causal relationship could not be 
determined. Specific dosing modification and additional monitoring may apply in case of 
prolonged QTcF (refer to Section 5.4.5.1 and Table 14). Concomitant administration of 
glasdegib with moderate/strong CYP3A4/5 inhibitors (Appendix 6 and Appendix 7) and 
drugs with known risk of Torsade de Pointes (TdP) (Appendix 5) is not recommended due to 
the potential for DDI to prolong the QTc interval.
In a thorough QT (TQT) study (Study B1371023), a large effect (>20 msec, the threshold of 
clinical concern for cancer drugs) of glasdegib on the QTc interval was not demonstrated at 
therapeutic (exposure equivalent to 100 mg QD) and supratherapeutic (exposure equivalent 
to 200 mg QD) doses.  The largest mean QTc interval change at any time point following the 
therapeutic dose was 8.03 msec.  The upper bound of the 2-sided 90% CIs for all 
time-matched least squares (LS) mean differences between glasdegib and placebo was below 
20 msec (the maximum 90% CI upper bound was 15.6 msec at the supratherapeutic dose).  
Based on PK-PD analysis in cancer patients, there was no observed relationship between 
glasdegib concentration and heart rate.  The predicted mean change in QT interval corrected 
for heart rate using Fridericia’s formula (QTcF) from baseline was 5.30 msec (95% CI: 4.40, 
6.24) at the mean Cmax at the therapeutic dose of 100 mg QD, and 12.1 msec (95% CI: 10.0, 










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3.3. Expansion
Patients with previously untreated Intermediate, High, or Very High risk MDS per IPSS-R 
(n=30) or patients with AML who are not candidates for intensive chemotherapy (n=30) will 
receive glasdegib 100 mg orally once/day in combination with azacitidine per local label or 
per the Investigational Product Manual (or SPC). Azacitidine may be administered by SC 
injection or IV infusion at the starting dose of 75 mg/m2/day for 7 days every 28 days.  
Alternate dosing schedules to administer the 7 doses to accommodate subject and treatment 
center availability are allowed. 
The attribution of ‘not being candidates’ for intensive chemotherapy will be determined by 
the Investigator based on the patient’s baseline eligibility, comorbidities and other factors 
according to 2017 ELN recommendations. The primary objective of the expansion 
component is to demonstrate that the CR rate of the combination treatment in each patient 
population is reasonably better than the historical CR rate for azacitidine alone in that 
population using a Bayesian decision criteria allowing early stopping for futility. 
Patients in the expansion MDS and AML cohorts will be enrolled continuously. The CR rate 
among the MDS and AML patients will be continuously monitored throughout the expansion 
component. After a certain number of patients have been enrolled in each cohort 
(Table 8 and Table 9, respectively) and observed for at least 28 weeks for the expansion 
MDS cohort and 24 weeks for the expansion AML cohort, the Sponsor will conduct a review 
of the CR rate within each expansion cohort to determine if the minimum number of 
responses are achieved to continue enrollment into that cohort.  If the minimum number of 
CRs in any group is not achieved, then study enrollment will stop for futility. If the study is 
stopped for futility, patients on active treatment that are deriving clinical benefit will 
continue on study treatment until they meet the criteria for discontinuation (Section 3.3.1).  
The Bayesian prior parameter assumptions for each cohort are based on glasdegib
combination study data in the respective populations, while prior assumption for control 
groups are based on historical control data.56
Analysis of specific safety criteria will be performed to evaluate stopping enrollment for a 
specifc cohort when there is at least 70% probability that the toxicity rate of any of the below
pre-defined safety events of interest in that cohort is above 25% (Section 9.7.2):

Treatment-related deaths that occur during study treatment through 28 days following 
the last dose of any study treatment, or the beginning of another anti-cancer therapy, 
whichever occurs first.

Drug-induced liver injury (Hy’s Law cases), confirmed as detailed in Section 8.6.2, 
that occurs during study treatment through 28 days following the last dose of any 
study treatment, or the beginning of another anti-cancer therapy, whichever occurs 
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
Grade 3 non-hematologic treatment-related AEs in the first cycle of treatment that 
have failed to recover to baseline or ≤ Grade 1 within 21 days from when the second 
cycle is due to start (corresponding to recovery before or/on Day 49 of the first cycle) 
and required permanent discontinuation of study treatment.

Grade 4 treatment-related neutropenia (ANC <500/mm3) lasting 42 days from the 
start of cycle 1 in the presence of bone marrow hypoplasia without evidence of active 
AML or MDS.
A safety event of interest is defined as any of the above deemed related to glasdegib and /or 
azacitidine as assessed by the investigator.  All AEs will be classified according to CTCAE 
version 4.03.
The safety stopping criteria will be applied within a cohort (AML or MDS) starting when at 
least 10 patients have completed the required follow-up period (28/24 weeks for MDS/AML 
respectively) and applied continuously afterwards.  Enrollment will continue unless the 
stopping boundary is crossed (Table 10).  The same stopping criteria will be used for the 
AML and MDS cohorts; however, the two cohorts will be analyzed independently.
Table 8.
MDS Efficacy Decision Criteria
# Patients with mature 
response data (inclusive)
Stop expansion MDS 
enrollment if there are 
this many responses total:
1-9
No stop
10-13
≤2
14-16
≤3
17-20
≤4
21-24
≤5
25-27
≤6
28-29
≤7
30
Full enrollment
Table 9.
AML Efficacy Decision Criteria
# Patients with mature 
response data (inclusive)
Stop expansion AML 
enrollment if there are 
this many responses total:
1-10
No stop
11-13
0
14-17
≤1
18-20
≤2
21-23
≤3
24-27
≤4
28-29
≤5
30
Full enrollment


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Table 10.
Safety Decision Criteria
# Patients* 
Stop cohort enrollment if there 
are this many patients with 
any pre-defined safety events 
of interest**
1-9
No stopping
10-12
≥4
13-16
≥5
17-20
≥6
21-23
≥7
24-27
≥8
28-30
≥9
*Patients who have completed the required follow-up period (ie, 28/24 weeks for MDS/AML respectively) or 
patients who have experienced any pre-defined safety events of interest within the required follow-up period 
will be counted. 
**A weak prior of Beta (0.5,0.5) was used in the calculation.
Figure 3.
Schematic of Study Design
*MDS patients enrolled in the Safety Lead-In component must have Intermediate-2 or High-Risk disease according to IPSS.  
MDS patients enrolled in the Expansion component must have Intermediate, High, or Very High risk disease acoording to 
IPSS-R.


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3.3.1. Study Treatments
Treatment will be administered in 28-day cycles.  Glasdegib will be administered at the 
starting dose of 100 mg orally once/day and continuously in combination with azacitidine.
Safety Lead-In Cohort
The safety lead-in cohort has been completed.

All patients will be administered glasdegib, 100 mg orally once/day and continuously;

Azacitidine will be administered SC at the starting dose of 75 mg/m2/day on a 
continuous schedule from Day 1 to Day 7 of each cycle (Schedule 1).  Patients with 
>30% BM blasts OR a rapidly progressive increase in the proportion of BM blasts at 
any point during the course of treatment must discontinue the study drug combination 
and enter follow up.
Expansion

All patients will be administered glasdegib 100 mg orally once daily and 
continuously;

Azacitidine will be administered per local label or per the Investigational Product 
Manual (or SPC).  Azacitidine may be administered by SC injection or IV infusion at 
the starting dose of 75 mg/m2/day for 7 days every 28 days. Alternate dosing 
schedules to administer the 7 doses to accommodate patient and treatment center 
availability are allowed.
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 death, 
unacceptable toxicity, or patient refusal whichever occurs first.  If documentation of disease 
progression occurs within the first 6 cycles of study treatment the patient SHOULD NOT be 
withdrawn from study treatment if, in the Investigator’s judgment, the patient is still likely to 
receive clinical benefit.  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. Treatment should also be continued 
beyond 6 cycles if patients demonstrate reasonable evidence of clinical benefit, defined as HI 
or better in patients enrolled into the safety LIC, SD + HI or better in MDS patients enrolled 
to the expansion, and not meeting the criteria for disease progression for AML patients 
enrolled into the expansion.
If glasdegib 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 and 
following discussion between the Investigator and Sponsor.


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In cases of unacceptable toxicity or pregnancy, the patient must be withdrawn from study 
drug combination and entered into the follow-up phase.
When study treatment with both drugs (glasdegib and azacitidine) is permanently 
discontinued, patients will enter into the follow-up phase. Patients receiving at least one dose 
of study treatment will be followed up for survival for up to 2 years from the first visit of the 
last patient enrolled in the expansion component of the study, or until death, lost to 
follow-up, or consent withdrawal.
3.3.2. Study Assessments Summary
Patients will be followed for efficacy throughout the study by means of bone marrow 
aspirates.  Following study entry, bone marrow biopsies will only be required if adequate 
bone marrow aspirates are not obtained.  A CR or PR response needs to be confirmed at least 
4 weeks following the BM evaluation by assessing the stability of improved counts on PB, an 
additional bone marrow confirmatory specimen is not required (applies to all patients in the 
safety LIC and only MDS patients in the expansion component).
  Transfusional support (red blood cells and 
platelets) will also be recorded.  Timely and complete (bone marrow AND peripheral blood 
counts) disease assessments at screening and during the study, whenever clinically indicated,
are essential.  Failure to perform any of the required disease assessments will result in the 
inability to determine disease status for that time point and may weaken the conclusions of 
the study.
Safety assessments (laboratory, instrumental and clinical) and PK assessments will be 
performed regularly during the active treatment period in both components of the study.
DDI assessments were performed in the safety LIC only.
Please refer to the Schedule of Activities for the Safety Lead-in Cohort and the Schedule of 
Activities for the Expansion: MDS and AML Patients for a complete list of assessments to be 
performed on patients in the study.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient.  These 
criteria must also be met prior to dosing on Cycle 1 Day 1.  No exceptions will be granted.
CCI
CCI


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4.1. Inclusion Criteria
Patient eligibility must be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.
Patients must meet all the following inclusion criteria to be eligible for enrollment into the 
study:
4.1.1. Safety Lead-in Cohort
The safety lead-in cohort has been completed.
1. Morphologically confirmed diagnosis of one of the following:
a.
MDS according to the WHO 2008 classification (Appendix 1), and bone marrow 
blasts 5%;
b. AML with 20-30 % BM blasts and multi-lineage dysplasia, according to WHO 
2008 classification(Appendix 1), WBC <20x109/L;CMML according to the WHO 
2008 classification (Appendix 1) and BM blasts between 10% - 19% and WBC 
<13x109/L.
2. MDS patients must have Intermediate-2 (1.5 to 2.0 points) or High-Risk (≥2.5 points) 
disease according to the International Prognostic Scoring System 1997 (IPSS).
3. MDS patients must have normal levels of vitamin B12 within the institutional range 
of normal as determined within 28 days of study entry. 
4. AML patients with 20-30% BM blasts and multi-lineage dysplasia, must have stable 
blast counts per Investigator’s judgment.
5. Clinical indication for treatment with azacitidine for MDS, AML or CMML.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2.  See 
Appendix 9.
7. ≥18 years of age.
8. Adequate Renal Function:

Serum creatinine ≤1.5 x upper limit of normal (ULN); 
OR

Estimated creatinine clearance ≥60 ml/min (calculated using the standard method 
for the institution). 
9. Adequate Liver Function:


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
Total serum bilirubin ≤1.5 x ULN (unless the bilirubin is principally unconjugated 
and there is strong suspicion of sub-clinical hemolysis or the patient has 
documented Gilbert's disease);

Aspartate transaminase (AST) and Alanine transaminase ( ALT) ≤2.5 x ULN;

Alkaline phosphatase ≤2.5 x ULN.
10. Serum amylase or lipase <1.5 x ULN.
11. Serum or urine pregnancy test (for female patients of childbearing potential) with a 
minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin 
(HCG) negative at screening.
12. Male and female patients of childbearing potential and at risk for pregnancy must 
agree to use two highly effective method(s) of contraception throughout the study and 
for 90 days after the last dose of azacitidine and the last dose of glasdegib or placebo, 
whichever occurs later.
13. Female patients who are not of childbearing potential (ie, 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 
14. 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 within the laboratory’s reference range for postmenopausal women.
15. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study.
16. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests and other procedures (including BM assessments). 
4.1.2. Expansion
Patients must meet all the following inclusion criteria to be eligible for enrollment into the 
expansion cohorts:
1. Patients must have previously untreated MDS or AML according to the WHO 
2016 classification. (Appendix 17).
a.
The following AML patients will be included:


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
AML arising from MDS or another antecedent hematologic disease (AHD).

AML after previous cytotoxic therapy or radiation (secondary AML).
b. MDS patients must have Intermediate (>3 to 4.5 points), High-Risk (>4.5 – 6) or 
Very High-Risk (>6 points) disease according to the Revised International 
Prognostic Scoring System 2012 (IPSS-R). (Appendix 10).

CMML patients according to the WHO 2016 classification (Appendix 17) are
included in the MDS cohort.

MDS/MPN, unclassifiable patients according to the WHO 2016 classification 
(Appendix 17) are included in the MDS cohort.
2. Clinical indication for treatment with azacitidine for MDS or AML.
3. ≥18 years of age.
4.
Adequate organ function as defined by the following:

Total serum bilirubin ≤2 x ULN (unless the bilirubin is principally unconjugated 
and there is strong suspicion of sub-clinical hemolysis or the patient has 
documented Gilbert's disease);

Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤3 x ULN, 
excluding patients with liver function abnormalities due to underlying 
malignancy;

Estimated creatinine clearance 30 mL/min as calculated using the standard 
method for the institution.
5. Serum or urine pregnancy test (for female patients of childbearing potential) with a 
minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin 
(HCG) negative at screening.
6. Male and female patients of childbearing potential and at risk for pregnancy must 
agree to use at least (1) highly effective method(s) of contraception throughout the 
study and for 180 days after the last dose of azacitidine and the last dose of glasdegib, 
whichever occurs later.
7. Female patients who are not of 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 


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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 within the laboratory’s reference range for 
postmenopausal women.
All other female patients (including female patients with tubal ligations) are 
considered to be of childbearing potential.
8. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study.
9. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests and other procedures (including BM assessments). 
4.2. Exclusion Criteria 
4.2.1. Safety Lead-in Cohort
The safety lead-in cohort has been completed.
Patients with any of the following may not be included in the study:
1. Patients with AML who are candidates for standard induction chemotherapy as first 
line treatment.
2. Therapy-related (secondary to radiation or chemotherapy) MDS or AML. 
3. Prior hypomethylating agents or cytotoxic chemotherapy for MDS, AML or CMML 
(prior immunosuppressive therapy and hydroxyurea are permitted provided that 
treatment is stopped within 8 and 2 weeks from study entry, respectively).
4. Previous hematopoietic stem cell transplant. 
5. Prior treatment with a licensed or experimental smoothened inhibitor (SMOi) and/or 
hypomethylating agent (HMA).
6. Participation in a clinical study involving an investigational drug(s) (Phases 1-4) 
within 4 weeks prior to study entry.
7. Major surgery or radiation within 12 weeks prior to study entry.
8. Patients known to be refractory to platelet or packed red cell transfusions as per 
institutional guidelines, or who are known to refuse or who are likely to refuse blood 
product support.


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9. Treatment with hematopoietic growth factors including: erythropoietin, granulocyte 
colony stimulating factor (G-CSF), and granulocyte macrophage colony stimulating 
factor (GM-CSF), or thrombopoietin receptor agonists within 3 weeks prior to study 
entry.
10. Any ongoing medical condition requiring chronic use of moderate to high dose 
steroids (defined as ≥10 mg/day of prednisone or equipotent dose of another 
corticosteroid).
11. Any anti-cancer treatment within 2 weeks prior to study entry.
12. Current use or anticipated requirement for drugs that are known strong 
CYP3A4/5 inducers (Appendix 4).
13. Diagnosis of any malignant disease other than MDS, AML or CMML within the prior 
12 months, with the exception of adequately treated: (i) in-situ carcinomas, (ii) basal 
or squamous cell carcinoma, or (iii) non-melanoma skin cancer.
14. Known malabsorption syndrome or other condition that may impair the absorption of 
the study drug (eg, gastrectomy, lap band, Crohn's disease) and inability or 
unwillingness to swallow tables or capsules.
15. Patients with active, uncontrolled bacterial, fungal or viral infection, including 
hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV), 
or acquired immunodeficiency syndrome (AIDS) related illness.
16. Known uncontrolled central nervous system (CNS) involvement.
17. Known moderate to severe chronic obstructive pulmonary disease, interstitial lung 
disease, or pulmonary fibrosis.
18. Prior history of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune 
hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemachromatosis, hepatic 
tumors, non-alcoholic steatohepatitis [NASH]).
19. Any one of the following ongoing or in the previous 6 months: myocardial infarction, 
congenital long QT syndrome, Torsades de pointes, arrhythmias (including sustained 
ventricular tachyarrhythmia), right or left bundle branch block and 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 bpms.
20. Active cardiac dysrhythmias of NCI CTCAE Grade ≥2 (eg, atrial fibrillation) or 
QTcF interval >470 msec.
21. Pregnant or breastfeeding female patients.


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22. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study.
23. Documented or suspected hypersensitivity to azacitidine or mannitol.
24. Other severe acute or chronic medical or psychiatric conditions, including recent 
(within the past year) or active/ongoing suicidal ideation or behavior, or laboratory 
abnormalities that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and that in the judgment of the investigator, would make the patient 
inappropriate for entry into the study.
4.2.2. Expansion Cohorts
Patients with any of the following may not be included in the study:
1. Acute Promyelocytic Leukemia (APL) patients (French-American-British [FAB] 
M3 classification) with t(15;17) or APL with promyelocytic leukemia/retinoic acid 
receptor alpha (PML-RARA) (WHO 2016 classification).
2. Patients with a t(9:22) cytogenetic translocation (AML with BCR-ABL1) as a sole 
abnormality.
3. Patients with AML who are candidates for standard induction chemotherapy as first 
line treatment.
4. Patients with known active CNS leukemia.
5. Prior treatment with a smoothened inhibitor (SMOi) and/or hypomethylating agent.
6. Participation in a clinical study involving an investigational drug(s) (Phases 1-4) 
within 4 weeks prior to study entry.
7. Major surgery or radiation within 12 weeks prior to study entry for safety LIC, 
4 weeks in the expansion component.
8. Patients known to be refractory to platelet or packed red cell transfusions as per 
institutional guidelines, or who are known to refuse or who are likely to refuse blood 
product support.
9. Current use or anticipated requirement for drugs that are known strong 
CYP3A4/5 inducers.


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10. Diagnosis of any active malignancy on treatment with the exception of adequately 
treated: (i) in-situ carcinomas, (ii) basal or squamous cell carcinoma, or (iii) 
non-melanoma skin cancer.  Other prior or concurrent malignancies will be 
considered on a case-by-case basis.
11. Known malabsorption syndrome or other condition that may impair the absorption of 
the study drug (eg, gastrectomy, lap band, Crohn's disease) and inability or 
unwillingness to swallow tablets or capsules.
12. Patients with an active, life threatening or clinically significant uncontrolled systemic 
infection.
13. Current drug or alcohol abuse.
14. 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 bpms.
15. QTc interval >470 msec using the Fredericia correction (QTcF). 
16. Pregnant or breastfeeding female patients.
17. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study.
18. Documented or suspected hypersensitivity to azacitidine or mannitol.
19. Other severe acute or chronic medical or psychiatric conditions, including recent 
(within the past year) or active/ongoing suicidal ideation or behavior, or laboratory 
abnormalities that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and that in the judgment of the investigator, would make the patient 
inappropriate for entry into the study.
4.3. Lifestyle Guidelines
In this study, male subjects who are able to father children and female subjects who are of 
childbearing potential will receive azacitidine, a compound that has been shown to cause 
congenital malformations in animals and glasdegib, a compound which has been associated 
with teratogenic risk.  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 


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form of contraception throughout the study and for at least 180 days after the last dose of 
investigational product.  Male subjects must, additionally, use a condom to prevent potential 
transmission of investigational product in seminal fluid.  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
Table 3 Schedule of Activities for the Expansion: MDS and AML Patients, 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 11.
Table 11.
Methods of Birth Control
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

Progestogen only contraceptive implant;

Intrauterine hormone releasing system 
(IUS);

Intrauterine device (IUD);

Bilateral tubal occlusion.
Combined hormonal contraception (estrogen 
and progestogen)

Oral;

Intravaginal;

Transdermal;

Injectable.
Vasectomized partner:
A vasectomized partner is a highly effective 
form of contraception provided they are the sole 
male partner of the women of child bearing 
potential and the absence of sperm has been 
confirmed. If not an additional highly effective 
method of contraception should be used.
Progestogen only hormonal contraception

Oral;

Injectable.


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4.4. 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 
patients’ exposure to light including high intensity ultraviolet b (UVb) sources such as 
tanning beds, tanning booths and sunlamps.  Patients should be advised to apply 
sunscreen/sunblock daily.
4.5. 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 Study Reference Manual.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers,
contact information for the investigational site, and contact details for a help desk in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The help desk number can also be used by investigational 
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 investigational 
site and the study team are not available.  It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational 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 patient directly, and if a patient calls that number, he or 
she will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
5.1.1. Safety Lead-In Cohort and Expansion
During both components of the study, allocation of patients 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 
patient.  The site personnel will then be provided with a treatment assignment and 
dispensable unit (DU) or container number when drug is being supplied via the IRT.  The 
IRT system will provide a confirmation report containing the patient number and DU or 
container number assigned. The confirmation report must be stored in the site’s files.
There is a 24 hour a day, 365 days a year IRT helpdesk available for any questions or issues.  
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT.  Note: The IRT is the source of the patient number.  The IRT 
system will provide the patient number at the end of the first IRT patient transaction.
In the Safety LIC and expansion, allocation to treatment will occur in an open label fashion. 


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5.2. Patient Compliance
For glasdegib, all patients will maintain patient dosing diaries throughout the study which 
will record the date of administration and all regular, missed, changed, or delayed doses. 
Patients are required to return all bottles, unused study drug and the patient dosing diary, at 
each cycle and at End of Treatment visit for compliance assessment and drug accountability.  
The number of tablets returned by the patient at the end of the cycle will be counted, 
documented and recorded.
For azacitidine provided by the Sponsor, the site should complete the required dosage 
Preparation Record located in the Study Reference 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 patient body surface area.  This may be used in place 
of the Preparation Record after approval from the Sponsor.
5.3. Drug Supplies
5.3.1. Formulation and Packaging
5.3.2. Glasdegib
Glasdegib will be supplied by Pfizer Worldwide Research and Development as 25 mg and 
100 mg tablets for oral administration.  Supplies will be labeled according to local regulatory 
requirements.
Glasdegib 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.  Patients 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 patients 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.
5.3.3. Azacitidine
Azacitidine 25 mg/mL powder for suspension for injection will be used in this study.  Please 
refer to the local package insert (or SPC) or the investigational product manual for detailed 
formulation, preparation and IV and SC administration instructions.
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents.


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5.4. Administration
5.4.1. General Guidelines
Both study drugs are administered in 28-day cycles.  Cycle duration maybe extended beyond 
28 days to allow resolution of toxicities related to study treatments.  It is suggested that sites 
contact the patients via phone during the first week of Cycle 1 and anytime there is a dose 
reduction just to confirm that the patient adequately understands the dosing instructions.
Glasdegib will be self-administered by the patient at home, unless otherwise specified.  
Glasdegib will be administered orally with approximately 8 ounces (240 mL) of water and 
should be taken in the morning, at the same time each day.  Tablets must not be crushed or 
cut; they must be swallowed whole, not manipulated or not chewed prior to swallowing.  
Patients should be instructed to self-administer their medication in the morning at 
approximately the same time each day and to not take more than the prescribed dose at any 
time.  If a patient 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 patient should continue on their normal dosing schedule.  If a patient 
misses a day’s dose entirely, they must be instructed not to “make it up” the next day.  If a 
patient 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 patient inadvertently takes 
1 extra dose during a day, the patient should not take the next dose of glasdegib.  The patient 
will be reminded NOT to take their dose at home on clinic days but to bring their bottle(s) 
and patient dosing diary into clinic so that glasdegib may be administered there.
Patients requiring glasdegib dose reduction(s) will be administered multiples of 25 mg tablets 
and should continue taking the glasdegib at the same time each morning at the dose 
prescribed by the Investigator (ie, 75 mg QD and 50 mg QD in the form of three or two 
25 mg tablets respectively).  In situations where clinical benefit is observed, glasdegib can be 
reduced below 50 mg QD upon Sponsor approval. 
Dose modifications are discussed in Section 5.4.5.
5.4.2. Safety Lead-In Cohort
The safety lead-in cohort has been completed.

Azacitidine will be administered SC daily at a dose of 75 mg/m2/day on Days 
1-7 (every 28 days).  No other dosing schedule is permitted.

Glasdegib will be orally administered daily and continuously.  In Cycle 1 only, 
administration of glasdegib will commence on Day 2 of the cycle (C1D2) to permit 
DDI evaluation.  The starting dose will be 100 mg. 

Dose modifications are discussed in Section 5.4.5.


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5.4.3. Expansion

Azacitidine will be administered per local label or per the Investigational Product 
Manual (or SPC).  Azacitidine may be administered by SC injection or IV infusion at 
the starting dose of 75 mg/m2/day for 7 days every 28 days. Alternate dosing 
schedules to administer the 7 doses to accommodate patient and treatment center 
availability are allowed.

Glasdegib will be orally administered daily and continuously.  The starting dose will 
be 100 mg daily. 
Dose modifications are discussed in Section 5.4.5.
5.4.4. Treatment Duration
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 death, 
unacceptable toxicity, or patient refusal whichever occurs first. If documentation of disease 
progression occurs within the first 6 cycles of study treatment the patient SHOULD NOT be 
withdrawn from study treatment if, in the Investigator’s judgment, the patient is still likely to 
receive clinical benefit.  In the safety LIC, patients with >30% BM blasts OR a rapidly 
progressive increase in the proportion of BM blasts at any point during the trial, must 
discontinue the study drug combination and enter follow-up.
Treatment with the study drug combination should be continued beyond 6 cycles of treatment 
until objective disease progression or relapse, death, unacceptable toxicity, or patient refusal 
whichever occurs first. Treatment should also be continued beyond 6 cycles if patients 
demonstrate reasonable evidence of clinical benefit, defined as HI or better in patients 
enrolled into the safety LIC, SD + HI or better in MDS patients enrolled to the expansion, 
and not meeting the criteria for disease progression for AML patients enrolled into the 
expansion.
If glasdegib 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 and 
following discussion between the Investigator and Sponsor.
In cases of unacceptable toxicity or pregnancy, the patient must be withdrawn from study 
drug combination and entered into the follow-up phase of the study.
When study treatment with both drugs (glasdegib and azacitidine) is permanently 
discontinued, patients will enter into the follow-up phase.


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5.4.5. Dose Modifications
Every effort should be made to administer the study drug treatment according to the planned 
dose and schedule.
In the event of significant toxicity, dosing must be interrupted, delayed and/or reduced as 
outlined below.  In the event of multiple toxicities, dose modification should be based on the 
worst toxicity observed.  Patients must be instructed to notify investigators at the first 
occurrence of any adverse symptom/s.
Dose modifications may occur in three ways:

Within a cycle: Dosing interruption until adequate recovery followed by dose 
reduction (if required) of glasdegib during a given treatment cycle. 

Between cycles: The next treatment cycle may be delayed if toxicity from the 
preceding cycle persists.

In the next cycle: Dose reduction may be required based on toxicities experienced in 
the previous cycle.
A cycle is determined by the azacitidine administration schedule.  A cycle is 28 days, but will 
be extended if there are dose delays or modifications for azacitidine.  Azacitidine
administration should not be interrupted if glasdegib dosing is interrupted for toxicity.
If start of glasdegib administration in the next cycle is delayed due to toxicities potentially 
attributable to glasdegib, azacitidine administration should not be delayed, and the day when 
azacitidine administration occurs will be counted as Day 1 of the next cycle for both study 
drugs.
5.4.5.1. Glasdegib
Glasdegib does not need to be delayed or dose reduced for hematologic toxicity deemed 
unrelated/unlikely related to glasdegib by the Investigator.
Patients experiencing Grade 3 or 4 non-hematological toxicities potentially attributable to 
glasdegib should have their glasdegib 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 13. If these parameters have not been met following >28 consecutive days of dose 
interruption, glasdegib should be permanently discontinued.  If glasdegib treatment is 
permanently discontinued, patients may continue single agent treatment with azacitidine, if 
according to the investigator’s judgment a clinical benefit has been observed, and following 
discussion between the investigator and the sponsor.
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 within the cycle.  If the AE leading to 


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treatment interruption recovers within the same cycle, re-commencement of dosing in that 
cycle is allowed.  The need for a dose reduction at the time of treatment resumption should 
be based on the criteria outlined in Table 13, unless specifically agreed otherwise following 
discussion between the Investigator and the Sponsor.  If a dose reduction for glasdegib is 
applied in the same cycle, the patient must return to the clinic to receive a new supply of 
drug.  Glasdegib 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 doses 
during that cycle). 
Glasdegib may be interrupted or permanently discontinued for any reason as per good 
clinical practice.  In the event of glasdegib 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.
Dose reduction of glasdegib by 1 or, if necessary, 2 dose levels (Table 12) will be allowed 
depending on the type and severity of toxicity encountered.  NOTE: In the specific situations 
where clinical benefit is observed, glasdegib can be reduced below 50 mg QD upon Sponsor 
approval.  All dose modifications/adjustments must be clearly documented in the patient's 
notes and case report form (CRF).
Once the glasdegib dose has been reduced, all subsequent cycles should be administered at 
that dose level, unless further dose reduction is required.  Dose re-escalation is not allowed.  
Deviations from any of the dose modifications must be discussed and agreed with the 
Sponsor Medical Monitor.
Table 12.
Available Dose Levels
Glasdegib (mg QD)
100
75
50
   25 *
* NOTE: If clinical benefit is observed, glasdegib may be reduced below 
50 mg QD following Sponsor approval.
Dose modifications for treatment-related non-hematologic toxicities (excluding QTc 
prolongation, muscle spasms, and myalgia) are outlined in Table 13.










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5.5. Drug Storage
The investigator, or an approved representative, eg, pharmacist will ensure that all 
investigational products, including any comparative agents and/or marketed products are 
stored in a secured area with controlled access under recommended storage conditions and in 
accordance with applicable site and regulatory requirements.
Storage conditions stated in the SRSD (IB for glasdegib and EU SPC for Vidaza®27) will be 
superseded by the storage conditions stated in the labeling.
Glasdegib should be stored as described on the drug label.  Note that the storage conditions 
in any study documentation will be superseded by the storage conditions stated on the 
product label.  Patients should be instructed to keep their medication in its original container.  
Returned medication should be stored at the clinical site separately from medication that 
needs to be dispensed.
Azacitidine will be stored according to the labeled storage conditions.
Investigators and site staff are reminded to check temperatures daily (ie, manually or by 
using alarm systems to alert of any excursions) and ensure that thermometers are working 
correctly as required for proper storage of investigational products.  These include 
thermometers for both the room storage and refrigerator storage.  Any temperature 
excursions should be reported to the sponsor.
The investigational product(s) must be stored as indicated.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to the sponsor.  
Once a deviation is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.
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 study.  Even for 
continuous monitoring systems, a log or site procedure which ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order.
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to labeled storage 
conditions, as soon as possible.  Deviations from the storage requirements, including any 
actions taken, must be documented and reported to the sponsor.
Once a temperature excursion is identified, the investigational product must be quarantined 
and not used until the sponsor provides documentation of permission to use the 
investigational product.  Specific details regarding information the site should report for each 
excursion will be provided to the site.
Site staff will instruct patients on the storage requirements for take home medications 
including how to report temperature excursions.


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5.6. Drug Accountability 
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the drug supplies.  At each dispensing visit (Cycle 2 Day 1, 
Cycle 3 Day 1, etc. or when there is a dose reduction), all unused or partially used bottles 
must be returned by patients to the Investigator.  The number of tablets returned by the 
patient at the end of the cycle will be counted, documented and recorded.
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 study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
sponsor or designee and all destruction must be adequately documented.
5.7. Concomitant Treatment(s)
All concomitant medications and treatments must be recorded in the CRF.  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.
In addition, any transfusion (red blood cells or platelets) within 8 weeks prior to screening 
should be recorded in the CRF.
All prior immunosuppressive therapy (eg, cyclosporine) used to treat MDS, or all prior 
cyto-reduction therapy (eg, hydroxyurea) used to treat AML or CMML, will be recorded 
regardless of when they were received by the patient.  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 patients 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.
All concomitant medications the patient is currently receiving must be reviewed by the 
Sponsor prior to enrollment in the safety LIC.  Study entry criteria are defined in Section 4.
5.7.1. Restricted or Prohibited Concomitant Medications
The following medications are not allowed during the active study treatment period:

Agents used to treat AML or MDS; 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;

Investigational agents;


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
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 4.  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 vitro studies with human liver microsomes and recombinant
CYP enzymes indicated that glasdegib metabolism is primarily mediated by the 
drug-metabolizing enzyme CYP3A4/5.  Clinically, there is likelihood that 
glasdegib plasma concentrations may be increased in the presence of co-administered 
inhibitors of the CYP3A4/5 enzymes.  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 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, the guidance provided in Section 7.6 and dose 
modifications for QT prolongation per Table 14 must be followed. 

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 and at doses 
>200 mg (see Section 1.2.20 for summary of TQT study).  While the glasdegib dose 
being 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 5.  Use of these 
drugs is not recommended unless there are no alternatives.  If a TdP drug is to be 
initiated in addition to glasdegib, the guidance provided in Section 7.6 and dose 
modifications for QT prolongation per Table 14 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 
and must be discussed with the Sponsor Medical Monitor. 


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5.7.2. Permitted Concomitant Medications
5.7.2.1. Best Supportive Therapy
Best Supportive Therapy (BST) administration is permitted according to Institutional 
guidelines for all patients on study.  BST will be provided by the site and may vary 
depending on the patient’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 and treat bacterial, fungal or viral infections.  BST may include:

Blood transfusions;

Platelet transfusions;

Antibiotics;

Anti-fungal agents;

Anti-viral agents.
5.7.2.2. Hematopoietic Growth Factors
Hematopoietic growth factors (eg, G-CSF, GM-CSF) may be used according to local practice 
and guidelines.
5.7.2.3. Anti-Emetic and Anti-Diarrheal Therapy
Patients should be pre-medicated with anti-emetics for nausea and vomiting before each dose 
of azacitidine in all cycles 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 assuming the drug is not contraindicated as 
described in Section 5.7.1.
5.7.3. Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and glasdegib required to minimize the risk of 
impaired 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.


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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 patient 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 the Safety Lead-in and the Schedule of Activities for the
Expansion: MDS and AML Patients for a complete list of assessments and procedures to be 
collected during the screening visit.
6.2. Study Period
See the Schedule of Activities for the Safety Lead-in and the Schedule of Activities for the 
Expansion: MDS and AML Patients for a detailed list of the assessments and procedures to 
be collected.  Study entry is defined as when the patient is enrolled into the IRT system.  
Patients must be enrolled into the IRT system prior to receiving first dose of study drug. 
All assessments on Cycle 1 Day 1 should be collected pre-dose, unless documented 
otherwise.
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 for the Safety Lead-in and the Schedule 
of Activities for the Expansion: MDS and AML Patients.
6.4. Follow-up 
The first follow up contact should occur at least 28 days, and no more than 35 days after the 
last dose of study drug to capture any potential adverse events (refer to Section 8.2) and to 
confirm appropriate contraception usage (refer to Section 4.3).  Contact with the patient may 
be done via phone.  For a detailed list of assessments and procedures to be completed please 
refer to the Schedule of Activities for the Safety Lead-in and the Schedule of Activities for 
the Expansion: MDS and AML Patients.
In cases of unacceptable toxicity or pregnancy, the patient must be withdrawn from study 
drug combination and entered into the follow-up phase of the study.
Patients who permanently discontinue both study drugs (azacitidine and glasdegib) for any 
reason (except death, or withdrawal of patient consent) will enter into the follow-up phase.
Patients continuing to experience toxicity following discontinuation of treatment will 
continue to be followed minimally every 4 weeks until resolution or determination, in the 
clinical judgment of the Investigator, that no further improvement is expected. 




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
Study terminated by Sponsor;

Death.
Reasons for withdrawal from study may include:

Study terminated by Sponsor;

Lost to follow-up;

Withdrawal of patient consent for any further contact;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The Investigator should inquire 
about the reason for withdrawal, request that the patient return all unused investigational 
product(s), request that the patient return for a final visit, if applicable, and follow up with 
the patient regarding any unresolved AEs.
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further study specific 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. 
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, which 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 patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
they have taken to ensure that normal processes are adhered to as soon as possible.  The 
study team must be informed of these incidents in a timely manner.
7.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed on two occasions prior to starting study 
therapy - once at the start of screening and once at the baseline visit, immediately before 
investigational product administration.  Following a negative pregnancy result at screening, 
appropriate contraception (defined in Section 4.3) 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.  Pregnancy tests will also be routinely repeated at every cycle during 
the active treatment period, at the end of study treatment, and additionally whenever one 


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menstrual cycle is missed or when potential pregnancy is otherwise suspected.  In the case of 
a positive confirmed pregnancy, the patient will be withdrawn from administration of study 
drug combination and enter into the Follow-up phase.  Additional pregnancy tests may also 
be undertaken if requested by Institutional Review Boards (IRBs)/Ethic Committees (ECs) or 
if required by local regulations.
7.2. 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.
7.3. Laboratory Safety Assessments
Hematology, blood chemistry, coagulation and urinalysis assessments will be drawn at the 
time points described in the Schedule of Activities for the Safety Lead-in and the Schedule of 
Activities for the Expansion: MDS and AML Patients and will be analyzed by the 
site/Investigator at local laboratories.  Laboratory certifications and normal ranges with units 
must be provided to the Sponsor. 
If hematology [Complete blood count (CBC) with differentials] is obtained within 3 days of 
scheduled blood draw, the collection need not be repeated.  For those patients achieving a CR 
or PR, a CBC should be done at least 4 weeks after the BM assessment in order to confirm 
response (applies to all patients in the safety LIC and only MDS patients in the expansion 
component).  Hematology tests may be repeated also as clinically indicated.
If blood chemistry or coagulations are obtained within 3 days of scheduled blood draw, the 
collection need not be repeated. 
If a urinalysis was obtained within 3 days of the scheduled collection, it should not be 
repeated.  For urinalysis, dipstick is acceptable.  Microscopic analyses should be done if 
abnormal results (ie, the presence of protein or blood).
See Appendix 8 for list of required tests. 
7.4. 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 patient is on 
treatment.  Transfusion histories for the 8 weeks prior to screening must also be recorded in 
the CRF.  Note that the number of units (not the number of bags) must be recorded.
7.5. Vital Signs and Physical Examination
Vital signs will include blood pressure and heart rate (to be recorded in sitting position).  
Patients will have a physical exam (PE) including an examination of major body systems
(includes general appearance, head, neck, lungs, heart, abdomen, musculoskeletal, 
extremities, skin, lymph nodes, neurological), measurement by palpation of spleen and liver, 
weight, height and assessment of ECOG status.  If PE obtained within 48 hours of previous 
















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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.
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.
Death must be reported if it occurs during the SAE reporting period after the last dose of 
investigational product, irrespective of any intervening treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient 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 symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse;

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure;


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
Worsening of signs and symptoms of the malignancy under study should be reported 
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.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error case report form (CRF) which is a specific version of the adverse event (AE) page, and 
on the SAE form when appropriate.  In the event of medication dosing error, the sponsor 
should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient 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 patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the adverse 
event (AE) page and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

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 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 
reporting as an AE.


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8.6. Serious Adverse Events
An SAE 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.
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 safety reporting 
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 
safety reporting period, then the event leading to death must be recorded as an AE and as an 
SAE with CTCAE Grade 5 (see Section 8.8 on Severity Assessment).
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 patient 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.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  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 by 
the investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events. 


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The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin value 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 X ULN or not available.

For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above:

For patients with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).
Concurrent with

For patients with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 X ULN or
if the value reaches ≥3 X ULN (whichever is smaller).
The patient should return to the investigational 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, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/ international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected. 
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at 
the time, should be considered potential Hy’s law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s law cases should be reported as SAEs.
A potential Hy’s law case becomes a confirmed case only after all results of reasonable 
investigations have excluded an alternative etiology.


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8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.


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Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. 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 patient's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. 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 in the CRF, as appropriate, 
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 (see the section on Reporting Requirements).  If the 
investigator's causality assessment is “unknown but not related to investigational product,” 
this should be clearly documented on study records. 


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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, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. 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).
2. 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 study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on a Serious Adverse Event (SAE) Report Form 
and Exposure During Pregnancy (EDP) supplemental form, regardless of whether an SAE 
has occurred.  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a patient reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) 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 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 preprocedure 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.


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Additional information about pregnancy outcomes that are reported 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 exposure during pregnancy may be requested by the 
investigator.  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 study patient with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The investigator must document in the source 
documents that the patient was given the Pregnant Partner Release of Information Form to 
provide to his partner.
8.11. 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 adverse event.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE Report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a Case Report Form (CRF), however a copy of the 
completed SAE Report form is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.  When a patient withdraws because of an SAE, the SAE must be reported in 
accordance with the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient/legally acceptable representative.  In addition, each study patient/legally 
acceptable representative will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.


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8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer Safety is to be notified within 24 hours of investigator awareness of 
the event. 
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding and occupational exposure cases.
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. 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.
9. DATA ANALYSIS/STATISTICAL METHODS
A detailed methodology for summary and statistical analysis of the data collected in this 
study will be documented in a Statistical Analysis Plan will be maintained by the Sponsor.  
The document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.




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9.3.1. Complete Response
The proportion of patients achieving CR is the primary endpoint for the expansion cohorts.  
The endpoint of CR will be analyzed when the endpoint is mature in the specific expansion 
cohort.
A confirmation of response (peripheral blood only) is required 4 weeks after the first 
assessment per IWG 2006 for MDS patients.  The final analyses for MDS cohorts will be 
performed after all patients in the expansion MDS cohort have been followed for at least
28 weeks (to allow for confirmation of response per IWG 2006). No confirmation is needed 
for the expansion AML cohort. The final anslyses for the AML cohort will be performed 
after all patients in this cohort have been followed for at least 24 weeks.
The proportion and two-sided 95% CI of patients achieving CR will be provided separately 
for the two expansion cohorts.
9.3.2. Response Rate
The proportion of patients achieving response (CR+PR) is a secondary endpoint for the 
safety LIC.  A confirmation of response (Peripheral Blood only) is required 4 weeks after the 
first assessment per IWG 2006.  The final analyses will be conducted after all patients in the 
safety LIC have been followed for 28 weeks (to allow for confirmation of response per IWG 
2006).  The proportion and two-sided 95% CI (using exact method) of patients achieving 
response (CR+PR) will be provided for the safety LIC.
9.3.3. Overall Survival (Expansion)
Overall survival (OS) is defined as the time from date of first study treatment to date of death 
due to any cause.  Patients last known to be alive will be censored at the date of last contact.
OS will be analyzed and displayed graphically for each expansion cohort separately using the 
Kaplan-Meier method.  The median event time for each expansion cohort and corresponding 
two-sided 95% CI will be provided.  The Kaplan-Meier estimate of survival probabilities at 
12, 18, and 24 months and their two-sided 95% CI (using log-log transformation and 
back-transformation) will be provided for each arm separately.
First, OS will be analyzed when the primary endpoint of CR is analyzed in the respective 
expansion cohort.  A follow-up analysis of updated OS will be conducted when the study 
concludes. OS is defined as the date of the first dose of any of the study medications to the 
date of death from any cause.
9.3.4. Duration of Response
Duration of Response (DoR) is only defined in MDS patients or AML patients achieving a 
CR in the expansion component. DoR is defined as the duration from date of first achieving 
CR to the date of disease progression (relapse) after CR, or death due to any cause.  Patients 
last known to be alive who are free from disease progression or relapse after CR are censored 
at the date of the last assessment that verifies their disease status.  The minimum DoR is 
4 weeks for MDS patients by definition (CR must last at least 4 weeks to qualify as such per 
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In all summaries, emphasis will be placed on treatment emergent adverse events (TEAEs), 
namely, those with initial onset or that worsen in severity after the first dose of study drug.  
Adverse events will be summarized by the frequency of patients 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.
9.4.4. Laboratory Test Abnormalities
The number and percentage of patients 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 (Cycle 1 and Cycles beyond 1).  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. 
9.4.5. Baseline Characteristics
Patient 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 for definitions of study populations).
9.4.6. 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 patients.  The most appropriate correction method that eliminates any QT vs.  
RR relationship may be chosen after review of the data.
9.4.7. Summary and Categorical Analysis of Electrocardiogram Findings
The analysis of ECG results will be based on patients 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 






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9.6.4. Population Pharmacokinetic Analysis or PK/PD Modeling
PK and PD 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 
glasdegib exposure and 
 significant safety endpoints.  The results of these 
analyses, if performed, may be reported separately.
9.7. Interim Analyses
9.7.1. Futility Analyses
A Bayesian decision rule (Section 3.3) will be used to continuously monitor CR rate without 
holding enrollment in the expansion component to allow early stopping of the study for 
futility. The decision rule is to stop enrollment for a specific expansion cohort if the 
posterior probability of the CR rate in study treatment is no more than 0.2 higher than 
historical azacitidine is greater than 95% in an expansion cohort, ie, Pr (glasdegib+Aza 
response < historical Aza reponse + 0.2) >0.95. The prior distribution assumptions for the 
Bayesian model are as follow: for MDS cohort, we assume a prior distribution of Beta(1,6) 
for the study treatment (based on data from MDS patients accumulated in the safety LIC
[1 out of 7 MDS patients achieved CR]), and a prior distribution of Beta(15,75) by 
discounting historical CR rate by half (AZA 001 trial); for the AML cohort, a prior 
distribution of Beta(4,4) for the study treatment (based on pooled data on AML patients from 
the B1371003 study [1 out of 4 AML patients achieved CR] and the LIC [3 out of 4 AML 
patients achieved CR]), and a prior distribution of Beta(23.5,97) by discounting historical CR 
rate by half.57 The Multc Lean software (Version 2.1.0) developed by MD Anderson Cancer 
Center is used 
(https://biostatistics.mdanderson.org/softwaredownload/SingleSoftware.aspx?Software_Id=1
2), which properly models variability in historical control that is more often than not ignored. 
Stopping for toxicity is not modeled.
The Bayesian decision rule applies once the minimum number of patients (ie, 10) in each 
expansion cohort has achieved the required follow-up duration (ie, 28 weeks for the 
expansion MDS cohort and 24 weeks for the expansion AML cohort). The enrollment to the 
respective expansion cohort will be stopped if the minimum number of responders in that 
expansion cohort is not achieved (Table 8 for expansion MDS cohort, and Table 9 for 
expansion AML cohort in Section 3.3). For instance, if there are no more than 4 responders 
in the first 17 patients who have achieved 28 weeks follow-up, the enrollment into the 
expansion MDS cohort should be stopped for futility.
9.7.2. Safety Stopping Analyses
Analysis of specific safety criteria will be performed to evaluate stopping enrollment for a 
specifc cohort when there is at least 70% probability that the toxicity rate of any of the 
pre-defined safety events of interest (Section 3.3) in that cohort is above 25%.
The safety stopping criteria will be applied within each cohort (AML or MDS) starting when 
at least 10 patients have completed the required follow-up period (28/24 weeks for 
MDS/AML respectively) and applied continuously afterwards.  Enrollment will continue 
CCI


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unless the stopping boundary is crossed (Table 10 in Section 3.3). Patients who have 
completed the required follow-up period or patients who have experienced any pre-defined 
safety events of interest within the required follow-up period will be included in the safety 
decision making.  The same stopping criteria will be used for the AML and MDS cohorts; 
however, the two cohorts will be analyzed independently.
9.8. Data Monitoring Committee
This study will use an external data monitoring committee (EDMC).  The EDMC will be 
responsible for ongoing monitoring of the safety of subjects in the study according to the 
charter.  The recommendations made by the EDMC 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 EDMC will be convened to monitor safety in 
the study at least once per year. 
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits 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.
The study site may be subject to review by the institutional review board (IRB)/ethics 
committee (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.
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 
process.
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 patient.  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 


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CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is 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's or the physician's patient chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent/assentdocuments, 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 International Conference on Harmonization 
(ICH), 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 
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.
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/assent 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 
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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 patients.  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 legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Patients (Council for International Organizations of Medical 
Sciences 2002), Guidelines for Good Clinical Practive (GCP) (ICH 1996), and the 
Declaration of Helsinki (World Medical Association 1996 & 2008).
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications or other disclosures, except where 
required by laws. 
When study data is compiled for transfer to Pfizer and other authorized parties, patient 
names, address, birth date and other identifiable data will be replaced by a numerical code 
consisting of a numbering system provided by Pfizer in order to de-identify the study patient.  
The study site will maintain a confidential list of patients who participated in the study 
linking their numerical code to the patient’s actual identity.  In case of data transfer, Pfizer 
will maintain high standards of confidentiality and protection of patient personal data 
consistent with applicable privacy laws.
The informed consent/assent document must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements including applicable privacy laws.
The informed consent/assent document(s) used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study patient, or his or her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation.
Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited he/she cannot reasonably be consulted, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, then 
the patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his/her own consent, the source documents 
must record why the patient did not provide consent (eg, minor, decisionally impaired adult), 


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how the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 
spouse) and that the patient’s assent was obtained, or waived.  If assent is obtained verbally it 
must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legally acceptable representative before any 
study-specific activity is performed unless a waiver of informed consent has been granted by 
an IRB/EC.  The investigator will retain the original of each patient's signed consent/assent 
document.
12.4. Patient Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures. 
12.5. 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 
competent 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 patients 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
End of Study in all participating countries is defined as Last Patient 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, drug 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 or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients 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.
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. 


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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 patients 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 for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final patient 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 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 primary completion date for studies in adult populations or within 6 months of the 
primary completion date 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 patients 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 has no objection to publication by an investigator of any information collected or 
generated by the investigator, whether or not the results are favorable to the investigational 
drug.  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 before it is submitted or otherwise disclosed.
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are 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 (other than the study results themselves) before disclosure.


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If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all centers.  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.


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16. REFERENCES

Jadersten M, Hellström-Lindberg E. Myelodysplastic syndromes: biology and 
treatment. J Intern Med 2009 Mar;265(3):307-28.

Cogle CR, Craig BM, Rollison DE. List AF. Incidence of the myelodysplastic 
syndromes using a novel claims-based algorithm: high number of uncaptured cases by 
cancer registries. Blood 2011;117:7121–25.

Jabbour E, Takahashi K, Wang X, et al. Acquisition of cytogenetic abnormalities in 
patients with IPSS defined lower-risk myelodysplastic syndrome is associated with poor 
prognosis and transformation to acute myelogenous leukemia. Am J Hematol 2013 
Oct;88(10):831-7.

Bennett, JM, Catovsky D, Daniel MT. Proposals for the classification of the 
myelodysplastic syndromes. Br J Haematol 1982;5:189–99.

Jaffee ES, Harris NL, Stein H, (Eds). World Health Organization classification of 
tumours, pathology and genetics of haematopoietic and lymphoid tissues. IARC Press, 
Lyon (2001).

Swerdlow S, Campo E, Harris NL, et al. WHO classification of tumours of 
haematopoietic and lymphoid tissues. IARC, London (2008).

Giagounidis A, Haased D. Morphology, cytogenetics and classification of MDS. Best 
Pract Res Clin Haematol 2013 Dec;26(4):337-53.

Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating 
prognosis in myelodysplastic syndromes. Blood1997;89:2079–88.

Amakye D, Jagani Z, Dorsch M. Unraveling the therapeutic potential of the hedgehog 
pathway in cancer. Nat Medicine Nov 2013; (11):1410-22.

Thomas BJ. Cell cycle control during development; taking it up a notch. Dev Cell Apr 
2005;8(4):451-2.

Straface G, Aprahamian T, Flex A, et al. Sonic hedgehog regulates angiogenesis and 
myogenesis during post-natal skeletal muscle regeneration. J Cell Mol Med 2008 Jul 
26.J Cell Mol Med. 2009 Aug;13(8B):2424-35.

Altaba AR. Therapeutic inhibition of hedgehog-GLI signaling in cancer: epithelial, 
stromal, or stem cell targets. Cancer Cell 7 Oct 2008; 14: 281-82.

Gao J, Graves S, Koch U. Hedgehog signaling is dispensable for adult hematopoietic 
stem cell function. Cell Stem Cell 2009 Jun 5;4(6):548-58.


PF-04449913
B1371012
Final Protocol Amendment 7, 14 June 2018
PFIZER CONFIDENTIAL
Page 143

Kobune M, Iyama S, Kikuchi S, et al. Stromal cells expressing hedgehog-interacting 
protein regulate the proliferation of myeloid neoplasms. Blood Cancer J 2012 Sep 
7;2:e87. doi: 10.1038/bcj.2012.36.

Xu F, Yang R, Wu L, et al. Overexpression of BMI1 confers clonal cells resistance to 
apoptosis and contributes to adverse prognosis in myelodysplastic syndrome. Cancer 
Lett 2012;317:33-40.

Xavier.J, Duarte A, Pericole F,et al. Hedgehog pathway is deregulated in 
myelodysplastic syndrome progenitor bone marrow cells. (ASH 2013 Annual Meeting 
Abstract 1533).

Cutler CS, Lee SJ, Greenberg P et al. A decision analysis of allogeneic bone marrow 
transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk 
myelodysplasia is associated with improved outcome. Blood 2004;104: 579–58.

Fenaux P, Mufti GF, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with 
that of conventional care regimens in the treatment of higher-risk myelodysplastic 
syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009 
Mar;10(3):223-32.

Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in 
myelodysplastic syndromes: results of a phase III randomized study. Cancer 
2006;106:1794–803.

Lubbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in 
elderly patients with intermediate- or High-Risk myelodysplastic syndrome (MDS) 
ineligible for intensive chemotherapy: final results of the randomized phase III study of 
the European Organisation for Research and Treatment of Cancer Leukemia Group and 
the German MDS Study Group. J Clin Oncol 2011;29:1987–96.

Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of 
azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and 
Leukemia group B. J Clin Oncol 2002;20:2429–40.

Gore SD, Fenaux P, Santini V, et al. A multivariate analysis of the relationship between 
response and survival among patients with higher-risk myelodysplastic syndromes 
treated within azacitidine or conventional care regimens in the randomized AZA-001 
trial. Haematologica 2013 Jul;98(7):1067-72.

Prebet T, Gore SD, Esterni B, et al. Outcome of High-Risk myelodysplastic syndrome 
after azacitidine treatment failure. J Clin Oncol 2011;29:3322–7.

Kimura H, Ng JM, Curran T. Transient inhibition of the hedgehog pathway in young
mice causes permanent defects in bone structure. Cancer Cell 2008 Mar;13(3):249-60.


PF-04449913
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Final Protocol Amendment 7, 14 June 2018
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Page 144

Amano K, Ichida F, Sugita A, et al. MSX2 stimulates chondrocyte maturation by 
controlling Ihh expression. J Biol Chem 2008; 283:29513-21.

Glasdegib Investigator’s Brochure, February 2016.

EU Summary of Product Characteristics (SPC) for Vidaza®, Celgene Europe Ltd; 2017.

2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An 
Evidence-Based Clinical Practice Guideline. JCO Jul 1, 2006:3187-3205.

Aaronson, NK, Ahmedzai S, Bergman B, et al. The European Organization for 
Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst 1993:85(5):365-76.

Aaronson, NK, Kaasa S, Sprangers MAG. The European Organization for Research and 
Treatment of cancer (EORTC) modular approach to quality of life assessment in 
oncology: an update in Quality of Life and Pharmocoeconomics in Clinical Trials. 2nd 
ed. 1996, Raven Press: New York. 179-89.

Rabin R, de Charro F, EQ-5D: A measure of health status from the EuroQol Group. 
Ann Med 2001;33(5):337-43.

Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for 
modification of the international working group (IWG) response criteria in 
myelodysplasia. Blood 2006; 108(2) 419-25.

Garcia-Manero G. Myelodysplastic syndromes: 2014 update on diagnosis, 
risk-stratification, and management. American Journal of Hematology 2014; 89:97-108.

Oken MM, Creech RH, Tormey DC. et al. Toxicity and response criteria of the eastern 
cooperative oncology group. Am J Clin Oncol 1982; 5:649-55.

Vardiman JW, Thiele J, Arber D. et al. The 2008 revision of the World Health 
Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale 
and important changes. Blood 2009; 114(5):937-51.

Lyons RM, Cosgriff TM, Modi SS. et al. Hematologic response to three alternative 
dosing schedules of azacitidine in patients with myelodysplastic syndromes. JCO April 
10, 2009:1850-1856.

Cortes JE, O’Connell A, Shaik MN. Et al. Phase IB Study of PF-04449913, a Hedgehog 
(Hh) Inhibitor, in Combination with Low-Dose Cytarabine or Intensive Chemotherapy, 
in Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome 
(MDS).Poster Presented at the 19th Congress of the European Hematology Association, 
June 12-15, 2014, Milan, Italy.


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
Abrahamsson-Schairer AE, Shih A, Ifat G. Et al. Smoothening the way for human 
leukemia stem cell inhibition in chronic myeloid leukemia. Abstract Presented at the 
101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 
17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 
Suppl):Abstract nr LB-258.  

Issa JP, Epigenetic Changes in Myelodysplastic Syndrome. Hematol Oncol Clin North 
Am. 2010 April ; 24(2): 317–330.

Cheson, BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the 
International Working group for diagnosis, standardization of response criteria, 
treatment on outcomes and reporting standards for therapeutic trials in acute myeloid 
leukemia. J Clin Oncol 2003; 21(24)4642-4649.

Kantarjian H, O'brien S, Cortes J, et al. Results of intensive chemotherapy in 998 
patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic 
syndrome: predictive prognostic models for outcome. Cancer 2006; 106:1090.

Döhner 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.

Greenberg PL, Tuechler H, Schanz J et al. Revised International prognostic scoring 
system for myelodysplastic syndromes. Blood 2012;120(12):2454-65.

American Cancer Society: Cancer Facts and Figures 2017. Atlanta: American Cancer 
Society, 2017.

Borate U, Smith D, Gore S et al. Phase IB Study of Glasdegib (PF-04449913) in 
combination with azacitidine in patients with Higher-Risk Myelodysplastic Syndrome, 
Oligoblastic Acute Myeloid Leukemia, or Chronic Myelomonocytic Leukemia. Poster 
presented at; 21st Annual Meeting of the European Hematology Association; 2016 Jun 
6-9; Copenhagen, Denmark.

Yoshimoto G, Minami Y, Minami H, et al. Phase I study of glasdegib (PF-04449913) in 
Japanese patients with select hematologic malignancies. Jpn J Clin Hematol 
2016;57(9):403 (Abstr OS-3·58). 

Gutman J, Denoncourt E, Schatz D, et al. A phase 2 study of the Hedgehog pathway 
smoothened inhibitor PF-04449913 to reduce relapse in high risk acute leukemia and 
MDS patients following allogeneic stem cell transplantation. Biol Blood Marrow 
Transplant 2015;21(2 Suppl):S286. 


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
Walter RB, Gyurkocza B, Storer B, et al. Comparison of minimal residual disease as 
outcome predictor for AML patients in first complete remission undergoing 
myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation. 
Leukemia 2015;29(1):137-44.

Araki D, Wood BL, Othus M, et al. Allogeneic hematopoietic cell transplantation for 
acute myeloid leukemia: Time to move toward a minimal residual disease–based 
definition of complete remission? J Clin Oncol 2016;34(4):329-36.

Cogle CR. Incidence and burden of the myelodysplastic syndromes. Curr Hematol 
Malig Rep 2015; 10:272–281. 

Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health 
Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;  
127(20):2391-405.

Röllig C, Bornhäuser M, Thiede C, et al. Long-term prognosis of acute myeloid 
leukemia according to the new genetic risk classification of the European Leukemia Net 
recommendations: evaluation of the proposed reporting system. J Clin Oncol. 2011;10; 
29(20):2758-65.

Fukushima N, Minami Y, Kakiuchi S, Kuwatsuka Y, Hayakawa F, Jamieson C, Kiyoi 
H, Naoe T. Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation 
potential of acute myeloid leukemia cells. Cancer Sci. 2016 Jul 27. doi: 
10.1111/cas.13019. [Epub ahead of print].

Sadarangani A, Pineda G, Lennon KM, et al. GLI2 inhibition abrogates human 
leukemia stem cell dormancy. J Transl Med. 2015 Mar 21;13:98. 

Tauchi T, Okabe S, Katagiri S, et al. Targeting the Hedgehog Signaling Pathway By 
PF-04449913 Limits the Self-Renewal of MDS-Derived Induced Potent Stem Cells 
(iPSC): Molecular Mechanisms. Blood 2015 126:791.

Tibes R, Al-Kali A, Oliver G, et al.The Hedgehog pathway as targetable vulnerability 
with 5-azacytidine in myelodysplastic syndrome and acute myeloid leukemia. J 
Hematol Oncol, 2015 8:114.

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): 291-299.

Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, 
open-label, phase III trial of decitabine versus patient choice, with physician advice, of 
either supportive care or low-dose cytarabine for the treatment of older patients with 
newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30 (21):2670-7.


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
Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA et al. 
Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders 
in the United States, 2001-2004, using data from the NAACCR and SEER programs. 
Blood 2008; 112: 45–52. |

Dinmohamed AG, van Norden Y, Visser O, Posthuma EF, Huijgens PC, Sonneveld P et 
al. The use of medical claims to assess incidence, diagnostic procedures and initial 
treatment of myelodysplastic syndromes and chronic myelomonocytic leukemia in the 
Netherlands. Leukemia research 2014; 39: 177–182.

Seidel K, Ahn CP, Lyons D, Nee A, Ting K, Brownwell I, Cao T, Carano RA, Curran 
T, Schober M, Fuchs E, Joyner A, Martin GR, de Sauvage FJ, and Klein OD. Hedgehog 
signaling regulates the generation of ameloblast progenitors in the continuously 
growing mouse incisor. Development 2010; 137:3753-61.

Dassule HR, Lewis P, Bei M, et al. Sonic Hedgehog regulates growth and 
morphogenesis of the tooth. Development 2000; 127:4775-4785.

Chen JK, Taipale J, Cooper MK, et al. Inhibition of Hedgehog signaling by direct 
binding of cyclopamine to Smoothened. Genes Dev 2002; 16:2743-8.

Cooper MK, Porter JA, Young KE, et al. Teratogen-mediated inhibition of target tissue 
response to Shh signaling. Science 1998; 280:1603-7.

Mäkelä JA, Saario V, Bourguidba-Hachemi S, et al. Hedgehog signalling promotes 
germ cell survival in the rat testis. Reproduction 2011 Nov; 142(5):711–721.

Schanz J, Tüchler H, et al. New comprehensive cytogenetic scoring system for primary 
myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS 
dertive from an international database merge. J Clin Onc 2012; 30:820-29.


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Appendix 1. 2008 WHO Classification of Myelodysplastic Syndromes (MDS)*
Appendix 1 applies ONLY to patients in the lead-in cohort which has been completed.
Vardiman, JW, Thiele, J, Arber, D, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms 
and acute leukemia: rationale and important changes.  Blood 2009; 114(5):937-51. * Only applies to MDS patients enrolled into the safety 
lead-in component of the study. 


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Appendix 2. IWG Criteria: Response Criteria and Progression Definitions for Myelodysplasia***
Response Criteria (responses 
CR, PR, mCR must last at 
least 4 weeks)
Peripheral Blood
Bone Marrow Blasts 
(BMB) (%)
Other
Hgb(g/dL)
Neutrophils (L)
Platelets (L)
Blasts (%)
Complete Remission 
(CR)**
11
1 x 109
100 x 109
0
5
Normal maturation of all cell lines, note if has 
persistent dysplasia
Partial Remission (PR)**
Decreased by 50% 
but still >5%
All CR criteria if abnormal before treatment except 
BMB
Marrow CR (mCR)
If hematologic improvement (HI) response, note in addition to 
Marrow CR
5% & decreased by
50%
Stable Disease*
Failure to achieve PR & no evidence of progression* 
Failure
Death, or disease progression:  worsening cytopenia, 
increase in % BM blasts, progression to a more 
advanced MDS FAB subtype
Relapse after (m)CR or PR
ICH
At least one of the following:
Return to pre-treatment BMB %
Decrement of 50% from maximum 
remission/response levels in granulocytes or platelets
Reduction in Hgb 1.5g/dL or transfusion 
dependence
Cheson BD, Greenberg PL, Bennett JM et al.  Clinical application and proposal for modification of the international working group (IWG) response criteria in 
myelodysplasia.  Blood 2006; 108(2) 419-25. 
*SD must last >8 weeks but response is documented regardless of duration. 
**Stability of the improved counts is sufficient to define CR or PR without the need to repeat a second BM.
***This criteria will be applied to MDS patients enrolled in the Safety Lead-In and Expansion components of the study and patients with AML with 20-30% 
blasts and multi-lineage dysplasia and CMML without proliferative disorder enrolled into the Safey Lead-In component of the study.


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Additional Response Criteria for Myelodysplasia***
Cytogenetic Response
Complete
Partial
Disappearance of chromosomal abnormality with no appearance of new ones
50% reduction of chromosomal abnormality
Disease Progression
For patients with % blasts at screening:
<5% bone marrow blasts
5-10% bone marrow blasts
11-20% bone marrow blasts
21-30% bone marrow blasts
For all categories, any of:
50% increase to >5% bone marrow blasts
50% increase to >10% bone marrow blasts
50% increase to >20% bone marrow blasts
50% increase to >30% bone marrow blasts
At least 50% decrease from maximum remission/response in granulocytes or platelets
Reduction in Hgb by 2 g/dL
Transfusion dependence
Proposed modified IWG Myelodysplasia Response Criteria for Hematologic Improvement (HI)**
Erythroid response (pre-treatment <11g/dL)*
Hgb increase by 1.5 g/dL
Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 weeks as 
compared to the pretreatment transfusion number in the previous 8 weeks (only RBC transfusions given for Hb 
9 g/dL pretreatment will count in the RBC transfusion evaluation).
Platelet Response (pretreatment <100 x109/L)*
Absolute increase of 30 x109/L if starting with >20 x 109/L platelets
Increase from <20 x 109/L to >20 x109/L and by at least 100%
Neutrophil Response (pretreatment <1 x 109/L)*
At least a 100% increase and an absolute increase >0.5 x109/L
Progression or relapse after HI in the absence of another 
explanation
At least one of the following:

At least 50% decrease from maximum response levels in granulocytes or platelets;

Reduction in Hgb by 1.5g/dL;

Transfusion dependence.
*Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) 1 week apart.
** Hematologic Improvement must last > 8 weeks and is derived based on lab data entered in the database.
***This criteria will be applied to MDS patients enrolled in the Safety Lead-In and Expansion components of the study and patients with oligoblastic AML and CMML without 
proliferative disorder enrolled into the Safey Lead-In component of the study.


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Appendix 3. Myelodysplastic Syndromes: 2014 Update on Diagnosis, Risk-Stratification, and Management*
* Applies to MDS patients enrolled in the Safety Lead-In and Expansion components of the study and patients with AML with 
20-30% blasts and multi-lineage dysplasia and CMML without proliferative disorder enrolled into the Safey Lead-In component of the 
study.
Source:  Schanz J, Tüchler H, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and 
oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Onc 2012; 30:820-29.
Figure from Garcia-Manero G. Myelodysplastic syndromes: 2014 update on diagnosis, risk stratification, and management.  American Journal of 
Hematology 2014; 89(1):97-108.


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Appendix 4. Strong CYP3A4/5 Inducers
Strong CYP3A4/5 Inducers
Inducer
Therapeutic Class
Rifampin
Antibiotics
Rifabutin
Antibiotics
Avasimibe
Antilipedimics
Phenytoin
Anticonvulsants
Carbamazepine
Anticonvulsants
Phenobarbital
Anticonvulsants
Enzalutamide
Antiandrogens
St. John’s Wort
Herbal Medications
Mitotane
Antineoplastic
Moderate CYP3A4/5 Inducers
Inducer
Therapeutic Class
Semagacestat
Alzheimers 
Efavirenz
Non-nucleoside Reverse 
Transcriptase Inhibitors
(NNRTI)
Bosentan
Endothelin Receptor Antagonist
Genistein
Food Product
Thioridazine
Antipsychotics
Naficillin 
Antibiotics
Talviraline
NNRTI
Lopinavir
Protease Inhibitor
Modafinil
Psychostimulant
Etravirine
NNRTI
Lersivirine
NNRTI
Source: University of Washington Drug Interaction Database.  “Copyright University of 
Washington 1999-2015, UW Metabolism and Transport Drug Interaction Database, 
accessed: May 2017”.


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Appendix 5. 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
Amiodarone
Anti-arrhythmic
Abnormal heart rhythm
oral,injection
Anagrelide
Phosphodiesterase 
3 inhibitor
Thrombocythemia
oral
Arsenic trioxide
Anti-cancer
Leukemia
injection
Astemizole 
(Off US mkt)
Antihistamine
Allergic rhinitis
oral
Azithromycin
Antibiotic
Bacterial infection
oral,injection
Bepridil 
(Off US mkt)
Anti-anginal
Heart pain
oral
Chloroquine
Anti-malarial
Malaria infection
oral
Chlorpromazine
Anti-psychotic / 
Anti-emetic
Schizophrenia/ nausea
oral, injection,
suppository
Cilostazol
Phosphodiesterase 
3 inhibitor
Intermittent claudication
oral
Ciprofloxacin
Antibiotic
Bacterial Infection
oral, injection
Cisapride 
(Off US mkt)
GI stimulant
Heartburn
oral
Citalopram
Anti-depressant, SSRI
Depression
oral
Clarithromycin
Antibiotic
Bacterial infection
oral
Disopyramide
Anti-arrhythmic
Abnormal heart rhythm
oral
Dofetilide
Anti-arrhythmic
Abnormal heart rhythm
oral
Domperidone (Not 
on US mkt)
Anti-nausea
Nausea
oral,injection,
suppository
Donepezil
Cholinesterase 
inhibitor
Dementia
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
Escitalopram
Anti-depressant, SSRI
Major depression/ Anxiety 
disorders
oral
Flecainide
Anti-arrhythmic
Abnormal heart rhythm
oral
Fluconazole
Anti-fungal 
Fungal infection
oral, injection
Gatifloxacin (Off 
US mkt)
Antibiotic
Bacterial infection
oral, injection


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Generic Name
Drug Class
Therapeutic Use
Route
Grepafloxacin (Off 
market worldwide)
Antibiotic
Bacterial infection
oral
Halofantrine
Anti-malarial
Malaria infection
oral
Haloperidol
Anti-psychotic
Schizophrenia, agitation
oral, injection
Ibutilide
Anti-arrhythmic
Abnormal heart rhythm
injection
Levofloxacin
Antibiotic
Bacterial infection
oral, injection
Levomethadyl 
(Off US mkt)
Opiate
Pain control, narcotic 
dependence
oral
Mesoridazine 
(Off US mkt)
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
Pentamidine
Antibiotic
Pneumocystis pneumonia
injection, 
inhaled
Pimozide
Anti-psychotic
Tourette's tics
oral
Probucol 
(Off US mkt)
Antilipemic
Hypercholesterolemia
oral
Procainamide 
(Oral off US mkt)
Anti-arrhythmic
Abnormal heart rhythm
injection
Propofol
Anesthetic
Anesthesia
injection
Quinidine
Anti-arrhythmic
Abnormal heart rhythm
oral, injection
Sevoflurane
Anesthetic, general
Anesthesia
inhaled
Sotalol
Anti-arrhythmic
Abnormal heart rhythm
oral
Sparfloxacin 
(Off US mkt)
Antibiotic
Bacterial infection
oral
Sulpiride 
(Not on US mkt.)
Anti-psychotic, 
atypical
Schizophrenia
oral
Terfenadine 
(Off US mkt)
Antihistamine
Allergic rhinitis
oral
Thioridazine
Anti-psychotic
Schizophrenia
oral
Vandetanib
Anti-cancer
Thyroid cancer
oral
US mkt = United States Market.
Source: Credible Meds.org (http://crediblemeds.org/healthcare-providers/drug-list/?rf=All).  
TdP risk category filtered on Drugs with known TdP risk.  Assessed 11 October 2015.


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Appendix 6. Strong CYP3A4/5 Inhibitors
Strong CYP3A4/5 Inhibitors
Inhibitor
Therapeutic Class
Ketoconazole
Antifungal
Itraconazole
Antifungal
Voriconazole
Antifungal
Posaconazole
Antifungal
Troleandomycin
Antibiotics
Clarithromycin
Antibiotics
Telithromycin
Antibiotics
Mibefradil
Calcium Channel Blocker
Conivaptan
Diuretics
Nefazodone
Antidepressants
Cobicistat
--
Indinavir/Ritonavir
Protease Inhibitors
Tipranavir/Ritonavir
Protease Inhibitors
Ritonavir
Protease Inhibitors
Indinavir
Protease Inhibitors
Nelfinavir
Protease Inhibitors
Saquinavir
Protease Inhibitors
Saquinavir/Ritonavir
Protease Inhibitors
Lopinavir/Ritonavir
Protease Inhibitors
Telaprevir
Antivirals
Boceprevir
Antivirals
Danoprevir/Ritonavir
Antivirals
Elvitegravir/Ritonavir
Antivirals
LCL161
Cancer treatment
Idelalisib
Kinase Inhibitors
Grapefruit Juice DS
Food Products
Source: University of Washington Drug Interaction Database.  “Copyright University of 
Washington 1999-2015.  UW Metabolism and Transport Drug Interaction Database, 
accessed: 11 October 2015.”


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Appendix 7. Moderate CYP3A4/5 Inhibitors
Moderate CYP3A4/5 Inhibitors
Inhibitor
Therapeutic Class
Fluconazole
Antifungals
Erythromycin
Antibiotics
Ciprofloxacin
Antibiotics
Diltiazem
Calcium Channel Blockers
Verapamil
Calcium Channel Blockers
Dronedarone
Antiarrhythmics
Aprepitant
Antiemetics
Casopitant
Antiemetics
Netupitant
Antiemetics
Tofisopam
Benzodiazepines
Cyclosporine
Immunosuppressant
Schisandra sphenanthera
Herbal Medication
ACT-178882
Renin Inhibitor
Cimetidine
H2 Receptor Antagonist
FK1706
Central Nervous System Agent
Faldaprevir
Antivirals
Crizotinib
Kinase Inhibitor
Nilotinib
Kinase Inhibitor
Atazanivir/Ritonavir
Protease Inhibitor
Darunavir
Protease Inhibitor
Darunavir/Ritonavir
Protease Inhibitor
Atazanavir
Protease Inhibitor
Amprenavir
Protease Inhibitor
Imatinib
Antineoplastic agent
Grapefruit Juice
Food Products
Source: University of Washington Drug Interaction Database.  “Copyright University of 
Washington 1999-2015.  UW Metabolism and Transport Drug Interaction Database, 
accessed: 11 October 2015.”


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Appendix 8. Laboratory Assessments
Hematology
Blood Chemistry
Urinalysis 
(microscopic analysis)
Coagulation 
Tests
Hemoglobin
ALT
If urine dipstick is positive for
protein, perform urinalysis (U/A)
with microscopic.
If U/A with microscopic shows 
>2+ protein, collect 24-hour urine 
for protein.
aPTT
Platelets
AST
Urine dipstick for urine blood: 
If positive, collect a U/A with 
microscopic (unless hematuria can 
be explained by local bleeding 
such as menses).
INR
WBC
Alk Phos
Specific Gravity
Neutrophils
Sodium
PH
Lymphocytes
Potassium
Protein
Monocytes
Magnesium
Glucose
Eosinophils
Chloride
RBC
Basophils
Calcium
WBC
Bands
Total Bilirubin
Ketones
Blast Count
BUN or Urea
Leukocyte Esterase
Creatinine
Casts
Uric Acid
Crystals
Glucose (non-fasting)
Nitrate
Albumin
Total Protein
Phosphorus
LDH
CPK
Bicarbonate
B12*
* Applies to Safety Lead-In patients only: Needed only at Screening Visit only for eligibility 
requirement.


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Appendix 9. 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 10. IPSS-R Classification System for Myelodysplastic Syndromes*
Prognostic 
variable
0
0.5
1
1.5
2
3
4
Cytogenetics
Very Good
Good
Intermediate
Poor
Very 
Poor
Bone Marrow 
Blast %
≤2
>2 to <5
5-10
>10
Hemoglobin
≥10
8 to <10
<8
Platelets
≥100
50-<100
<50
ANC
≥0.8
<0.8
Risk Category
Risk Score
Very Low
≤1.5
Low
>1.5-3
Intermediate
>3-4.5
High
>4.5-6
Very High
>6
Adapted from Greenberg PL et al.  Revised International Prognostic Scoring System for Myelodysplastic Syndromes.  
Blood 2012; 120(12) 2454-2465. 
*Only applies to MDS patients enrolled in the Expansion component of the study.


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Appendix 11. 2017 ELN Response Criteria for Acute Myeloid Leukemia
Response Criteria
Neutrophils 
(L)
Platelets 
(L)
Bone Marrow Blasts
(%)
Other
Complete 
Remission 
without Minimal 
Residual Disease 
(CRMRD-)
If studied pretreatment, CR 
with negativity for a genetic 
marker by RT qPCR, or CR 
with negativity by 
multiparameter flow 
cytometry
Morphologic 
Complete
Response (CR)
1,000
100,000
<5; 
no peripheral blasts;
no blasts with Auer rods
No EMD;
Transfusion independent
Complete 
Remission with 
partial 
hematologic 
recovery 
(CRh)1
>500
>50,000
<5; 
no peripheral blasts;
no blasts with Auer rods
No EMD;
Not qualifying for CR
Morphologic CR 
with incomplete 
blood count
recovery (CRi)
<1,000
-or-
<100,000
<5; 
no peripheral blasts;
no blasts with Auer rods
No EMD;
Either neutrophils or
platelets not recovered;
Not qualifying for CRh
Morphologic 
leukemia-free
state (MLFS)
<1,000
-and-
<100,000
<5;
no blasts with Auer rods
No EMD;
Neutrophils and platelets 
not recovered;
BM not merely “aplastic”;
BM cellularity must be 10%, 
or 200 cells enumerated;
Not qualifying for CRi
Partial remission
(PR)
1,000
100,000
blasts decrease to 5-25 and 
50% decrease from
pretreatment
Blasts 5% if Auer rod positive
Stable Disease
(SD)
Absence of CR MRD-, CR, 
CRh, CRi, PR, MLFS and 
criteria for PD not met. 
Should last at least 
3 months.




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Appendix 12. 2016 WHO Classification of Myelodysplastic Syndromes
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of 
myeloid neoplasms and acute leukemia. Blood 2016;127(20):2391-405.










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Appendix 16. 2017 ELN AML Risk Stratification by Genetics
From:  Döhner 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): 424-47.42


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Appendix 17. 2016 WHO Classification of Myeloid Neoplasms 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 18. 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.

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Protocol B1371012 Statistical Analysis Plan 
 
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 PFIZER CONFIDENTIAL 
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9. REFERENCES ....................................................................................................................28 
10. APPENDICES ...................................................................................................................29 
 
LIST OF FIGURES 
Figure 1. 
Schematic of Study Design .....................................................................................6 
 
APPENDICES 
Appendix 1. Categorical Classes for ECG and Vital Signs .....................................................29 
Appendix 2. IWG Criteria: Response Criteria and Progression Definitions for 
Myelodysplasia*** ...............................................................................................30 
Appendix 3. IPSS-R Classification System for Myelodysplastic Syndromes* .......................32 
Appendix 4. 2017 ELN Response Criteria for Acute Myeloid Leukemia ...............................33 
 
 


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PF-04449913 is a novel small molecule inhibitor of the Sonic Hedgehog (Hh) Pathway 
which is currently under development for the treatment of hematologic malignancies and 
solid tumors.  
This multi-center open-label Phase 1b study is designed to evaluate the safety, efficacy, 
pharmacokinetics (PK), and pharmacodynamics (PD) of PF-04449913 when combined with 
azacitidine in patients with previously untreated Higher-Risk Myelodysplastic Syndrome 
(MDS), Acute Myeloid Leukemia (AML), and Chronic Myelomonocytic Leukemia (CMML).  
This Phase 1b study includes two components: (a) a safety lead-in cohort (LIC) and (b) an 
expansion phase with two cohorts. 
6WXG\'HVLJQ
This multi-center, open-label Phase 1b study is designed to evaluate the safety, efficacy, PK, 
and PD of PF-04449913 when combined with azacitidine in patients with previously 
untreated Higher-Risk MDS, AML, and CMML. The Phase 1b study includes two 
components: (a) a safety LIC, and (b) an expansion phase with two cohorts. 
Safety Lead-In Cohort (LIC) 
As of 23 September 2015, a safety LIC of 12 patients with previously untreated 
Intermediate-2 or High-Risk MDS per IPSS (n=7), AML with 20-30% blasts and 
multi-lineage dysplasia (n=3), erythroleukemia (n=1), and CMML (n=1) were enrolled and 
received open-label treatment with PF-04449913 at a starting dose of 100 mg given orally 
once/day in combination with azacitidine at the starting dose of 75 mg/m2/day given SC for 
7 consecutive days every 28 days. An evaluation of the DDI potential between 
PF-04449913 and azacitidine was performed.  An internal safety review team reviewed the 
LIC data after each patient had received at least 4 weeks of treatment and determined that 
the safety profile of PF-04449913 in combination with azacitidine in the defined population 
was consistent with what is expected for PF-04449913 or azacitidine alone with no 
unexpected toxicities identified, therefore the combination was deemed acceptable to proceed 
to the next phase of development. 
CCI


Protocol B1371012 Statistical Analysis Plan 
 
DMB02-GSOP-RF02 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE 31-Jan-2013 
 PFIZER CONFIDENTIAL 
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2.1.2. Expansion 
Patients with previously untreated Intermediate, High, or Very High risk MDS per IPSS-R 
(n=30) or patients with AML who are not candidates for intensive chemotherapy (n=30) will 
receive PF-04449913 100 mg orally once/day in combination with azacitidine 75 mg/m2/day 
given by SC or IV for 7 days (±3 days) every 28 days.  
Figure 1. Schematic of Study Design 
 
*MDS patients enrolled in the Safety Lead-In component must have Intermediate-2 or High-Risk disease according to IPSS. 
**MDS patients enrolled in the Expansion component must have Intermediate, High, or Very High risk disease according to 
IPSS-R. 
2.2. Study Objectives 
2.2.1. Objectives for the Safety LIC 
Primary Objective 
 To assess the safety and tolerability of PF-04449913 when administered in 
combination with azacitidine in patients with previously untreated Intermediate-2 or 
High-Risk MDS, AML with 20-30% blasts and multi-lineage dysplasia, and CMML. 
Secondary Objectives 
 To assess the Response Rate (RR); 
 To assess other clinical efficacy measures;  
 To characterize the PK of PF-04449913 and azacitidine alone and in combination; 




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Protocol B1371012 Statistical Analysis Plan 
 
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 PFIZER CONFIDENTIAL 
Page 9 
for MDS/AML respectively) and applied continuously afterwards. Enrollment will continue 
unless the stopping boundary is crossed (Table 10 in Section 3.3 of the Protocol). Patients 
who have completed the required follow-up period or patients who have experienced any 
pre-defined safety events of interest within the required follow-up period will be included in 
the safety decision making. The same stopping criteria will be used for the AML and MDS 
cohorts; however, the two cohorts will be analyzed independently. 
 
Final Analysis 
The timing of the final analysis is determined by the expansion component of the study. The 
final analyses for MDS cohorts will be performed after all patients in the expansion MDS 
cohort have been followed for at least 28 weeks (to allow for confirmation of response per 
IWG 2006). The final analyses for the AML cohort will be performed after all patients in this 
cohort have been followed for at least 24 weeks. 
Unblinding 
The safety LIC and expansion component of the study are open-label and unblinding does 
not apply.  
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
There are no formal statistical hypotheses for the Phase 1b safety LIC and expansion 
component of the study. 
4.2. Statistical Decision Rules 
The decision rule at the interim analysis is described in Section 3.   
5. ANALYSIS SETS 
5.1. Full Analysis Set (FAS) 
The full analysis set will include all enrolled patients in the respective cohort (LIC, 
expansion MDS, and expansion AML cohort separately), who received at least one dose of 
any study treatment (PF-04449913 or azacitidine). This will be the primary analysis 
population for evaluating efficacy endpoints and patient characteristics. 
5.2. Safety Analysis Set 
The safety analysis set will include all patients in the respective cohort (LIC, expansion 
MDS, and expansion AML cohort separately) who receive at least one dose of any study 
treatment (PF-04449913, or azacitidine).  It will be the primary analysis population for 
evaluating treatment administration/compliance and safety endpoints.  
5.3. PK Analysis Set 
The PK concentration analysis set is defined as all patients who are treated and who have at 
least 1 value of analyte concentration of PF-04449913 or azacitidine available.  The PK 














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7.2. Efficacy Analysis 
For primary and secondary efficacy analyses, no values will be imputed for missing data. 
Censoring for time-to-event endpoints are defined in Section 6.1.  In the assessment of 
response (at interim or final analysis), patients who are not known to have achieved response 
will be counted as non-responders.  
7.3. Pharmacokinetics 
Concentrations below the limit of quantification 
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification). 
Deviations, missing concentrations and anomalous values 
In summary tables and plots of median profiles, statistics will be calculated with 
concentrations set to missing if one of the following cases is true: 
1. A concentration has been reported as ND (i.e., not done) or NS (i.e., no sample), 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist. 
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing. 
Pharmacokinetic parameters 
Actual PK sampling times will be used in the derivation of PK parameters. 
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (i.e., not calculated).  (Note that NC values will not be generated beyond the 
day that a subject discontinues). 
For evaluation of changes in pharmacokinetics of a compound when administered alone vs. 
in combination, only subjects with matching pair of pharmacokinetic assessments under both 
conditions will be included in the pharmacokinetic summary (i.e., alone and in combination). 
In summary tables, statistics will not be presented for a particular treatment group if more 
than 50% of the data are NC.  For statistical analyses (i.e., analysis of variance), PK 
parameters coded as NC will also be set to missing. 
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all drug is absorbed in the body), this will be 
footnoted in summary tables and will not be included in the calculation of summary statistics 
or statistical analyses. 




Protocol B1371012 Statistical Analysis Plan 
 
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Page 18 
Median event times and two-sided 95% confidence intervals for each time-to-event endpoint 
will be provided. Point estimate of selected survival probabilities and two-sided 95% 
confidence intervals will also be provided, where the log-log transformation and back-
transformation will be used in the calculation. 
8.1.3. Analyses for Continuous Data  
Descriptive statistics, such as the mean, standard deviation, coefficient of variation, median, 
minimum, and maximum values, will be provided for continuous endpoints. Biomarker and 
PK summaries will also include coefficient of variation percent (%CV). 
8.2. Statistical Analyses  
8.2.1. Analysis of Primary Endpoints 
Analysis of Primary Endpoint of Safety LIC 
The primary endpoint of safety LIC of the study is safety and is detailed in Section 8.2.3.1. 
Analysis of Primary Endpoint of the Expansion Component 
The proportion of patients achieving CR is the primary endpoint for the expansion cohorts. 
A confirmation of response (peripheral blood only) is required 4 weeks after the first 
assessment per IWG 2006 for MDS patients. The final analyses for MDS cohorts will be 
performed after all patients in the expansion MDS cohort have been followed for at least 
28 weeks (to allow for confirmation of response per IWG 2006). No confirmation is needed 
for the expansion AML cohort.  The final analyses for the AML cohort will be performed 
after all patients in this cohort have been followed for at least 24 weeks. 
The proportion and two-sided 95% CI (using exact method) of patients achieving CR will be 
provided at the time of the final analysis based on the FAS for MDS cohort and AML cohort 
separately.  
 
8.2.2. Analysis of Secondary Endpoints 
8.2.2.1. Analysis of Secondary Endpoints of Safety LIC 
8.2.2.1.1. Response Rate (RR) 
Response rate (CR+PR) is a secondary endpoint for the safety LIC. A confirmation of 
response (Peripheral Blood only) is required 4 weeks after the first assessment per IWG 
2006. The final analyses will be conducted after all patients in the safety LIC have been 
followed for 28 weeks (to allow for confirmation of response per IWG 2006). 
The proportion and two-sided 95% CI (using exact method) of patients achieving response 
will be provided for the safety LIC. 


Protocol B1371012 Statistical Analysis Plan 
 
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Page 19 
8.2.2.1.2. Other Efficacy Measures  
The proportion of patients ever achieving HI (MDS only), mCR, Cytogenetic Response 
(complete and partial), and SD will be estimated with two-sided 95% CI (using exact 
method) respectively for the safety LIC.  
8.2.2.2. Analysis of Secondary Endpoints of Expansion Component 
8.2.2.2.1. Overall Survival (OS) 
OS will be analyzed and displayed graphically using the Kaplan-Meier method for each 
expansion cohort separately.  The median event time and corresponding two-sided 95% CI 
will be provided for expansion MDS and AML cohorts separately.   
The Kaplan-Meier estimate of survival probabilities at 12, 18, and 24 months and their 
two-sided 95% CI (using log-log transformation and back-transformation) will be provided 
for each cohort separately.   
The FAS will be used.  
8.2.2.2.2. Other Efficacy Measures  
Specifically, for AML cohort, the following binary efficacy endpoints (with 95% exact CI) 
will be summarized in frequency tables, proportion of patients achieving CR, CRh, CRi,  
CR/CRi, MLFS, PR, SD, CRc, , CRm, and CR+PR.   
For MDS cohort, the following binary efficacy endpoints (with 95% exact CI) will be 
summarized in frequency tables, proportion of patients achieving CR, marrow CR, PR, SD, 
CR+PR, and Partial or Complete Cytogenetic Response, as well as the proportion of patients 
ever achieving HI.   
The FAS will be used.  
8.2.2.2.3. DoCR 
DoCR will be analyzed and displayed graphically for each expansion cohort separately using 
the Kaplan-Meier method. The median DoCR for each cohort and corresponding two-sided 
95% CI will be provided.   
The subset of patients in the FAS who have ever achieved CR on study will be used.  
8.2.2.2.4. Time to Response (CR)   
For patients in the expansion cohorts with an objective CR, TTR will be analyzed and 
displayed graphically for each cohort separately using the Kaplan-Meier method. The median 
TTR for each cohort and corresponding two-sided 95% CI will be provided.  
The subset of patients in the FAS who have ever achieved CR on study will be used.  
8.2.3. Analysis of Safety Data 
Summaries and analyses of safety parameters will include all patients in the Safety Analysis 
Set for safety LIC and expansion cohorts.   


Protocol B1371012 Statistical Analysis Plan 
 
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Unless otherwise specified, the same definition applies to the endpoints in the safety LIC and 
the expansion component.  
Adverse Events: 
The focus of AE summaries will be on Treatment Emergent Adverse Events, those with 
initial onset or increasing in severity after the first dose of study medication.  The number 
and percentage of patients who experienced any AE, serious AE (SAE), treatment related 
AE, and treatment related SAE will be summarized according to worst toxicity grades.  The 
summaries will present AEs both on the entire study period and by cycle (Cycle 1 and Cycles 
beyond 1).  
Laboratory Test Abnormalities: 
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each lab assay.  The analyses will 
summarize laboratory tests both on the entire study period and by cycle (Cycle 1 and all 
Cycles beyond 1).  A shift summary of baseline grade by maximum post-baseline CTCAE 
grade will be presented.   
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal or not done.  
8.2.3.1. Analysis of Primary Endpoint of Safety LIC 
All patients who receive any study treatment will be included in the summaries and listings 
of safety data.  Overall safety profile and tolerability 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 MedDRA classification system.  The severity of 
the toxicities will be graded according to the NCI CTCAE version 4.03.  
Safety analysis set for safety LIC will be used. 
8.2.3.2. Analysis of Secondary Endpoint of Expansion Component 
All patients who receive any study drug will be included in the summaries and listings of 
safety data. Overall safety profile and tolerability of PF-04449913 + azacitidine 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 MedDRA classification system. The severity of 
the toxicities will be graded according to the NCI CTCAE version 4.03.  
The safety analysis set will be used for expansion MDS cohort and AML cohort, separately. 
The pooled analysis of safety data will utilize the combined LIC and expansion cohorts. 




Protocol B1371012 Statistical Analysis Plan 
 
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PF-04449913+ azacitidine vs. PF-04449913 alone.  A similar assessment may be conducted 
for azacitidine + PF-04449913 vs. azacitidine. 
 
PF-04449913 AUC and Cmax when administered alone (Cycle 1/Day 15) will be compared to 
Cycle 1/Day 7 AUC and Cmax, when administered in combination with azacitidine.  A similar 
assessment will be performed to determine the effect of PF-04449913 on azacitidine.  The 
AUC and Cmax on Cycle 1 Day 1 when azacitidine is administered alone will be compared to 
Cycle 1/Day 7 AUC and Cmax when azacitidine is administered in combination with 
PF-04449913. 
 
PK data from the lead-in portion of the PK analysis set will be used. 
8.2.4.2. Population Pharmacokinetic Analysis or PK/PD Modeling 
PK and PD 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 
PF-04449913 exposure and biomarkers or significant safety endpoints.  The results of these 
analyses, if performed, may be reported separately. 
8.2.5. Electrocardiogram Analysis 
The QT measurements corrected by heart rate (QTc) will be used for the data analysis and 
interpretation.  QTcF (per Fridericia’s correction) is planned to be the primary analysis 
method for the QTc endpoint.  In addition a study-specific correction method (QTcS) and 
QTcB (per Bazett’s correction) may also be evaluated for the QTc evaluable patients.  The 
most appropriate correction method that eliminates any QT vs. RR relationship may be 
chosen after review of the data.  Study conclusions will be based on the most appropriate 
correction method for the analysis.   
8.2.5.1. Summary and Categorical Analysis of Electrocardiogram Findings 
The analysis of ECG results will be based on patients 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 (typically the pre-dose ECG prior to first dose of 
PF-04449913) 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 by 
treatment phase (safety LIC or expansion cohorts). 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. 












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9. REFERENCES  
1. 
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for 
modification of the international working group (IWG) response criteria in 
myelodysplasia. Blood 2006; 108(2) 419-25. 
2. 
Döhner 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. 
3. 
Greenberg PL, Tuechler H, Schanz J et al. Revised International prognostic scoring 
system for myelodysplastic syndromes. Blood 2012;120(12):2454-65. 
 


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10. APPENDICES  
Appendix 1. Categorical Classes for ECG and Vital Signs 
Categories for QTcB and QTcF 
QTcB/QTcF 
(ms) 
max. < 450 
450≤ max. <480
480≤ max.<500
max. ≥500 
QTcB/QTcF 
(ms) increase 
from baseline 
max. < 30 
30≤ max. <60
max. ≥60
 
 
Categories for PR and QRS 
PR (ms) 
max ≥300 
 
PR (ms) increase 
from baseline 
Baseline 
>200 and max. 
≥25% increase 
Baseline ≤200 and 
max. ≥50% 
increase 
QRS (ms) 
max ≥200 
  
QRS (ms) 
increase from 
baseline 
Baseline 
>100 and max. 
≥25% increase 
Baseline ≤100 and 
max. ≥50% 
increase 
 
Categories for Vital Signs 
Systolic BP (mm Hg) 
min. <90
 
Systolic BP (mm Hg) 
change from baseline 
max. decrease ≥30
max. increase ≥30
Diastolic BP (mm Hg) 
min. <50
 
Diastolic BP (mm Hg) 
change from baseline 
max. decrease ≥20
max. increase ≥20
Supine pulse rate (bpm) 
min. <40
max. >120
 Measurements that fulfill these criteria are to be listed in Appendix A of the study report. 
 


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Appendix 2. IWG Criteria: Response Criteria and Progression Definitions for Myelodysplasia*** 
Response Criteria (responses 
CR, PR, mCR must last at 
least 4 weeks) 
Peripheral Blood 
Bone Marrow Blasts 
(BMB) (%) 
Other 
Hgb(g/dL) 
Neutrophils (L) 
Platelets (L) 
Blasts (%) 
 
 
Complete Remission 
(CR)** 
11 
1 x 109 
100 x 109 
0 
5 
Normal maturation of all cell lines, note if has 
persistent dysplasia 
Partial Remission (PR)** 
 
 
 
 
Decreased by 50% 
but still >5% 
All CR criteria if abnormal before treatment except 
BMB 
Marrow CR (mCR) 
If hematologic improvement (HI) response, note in addition to 
Marrow CR 
5% & decreased by 
50% 
 
Stable Disease* 
 
 
 
 
 
Failure to achieve PR & no evidence of progression*  
Failure 
 
 
 
 
 
Death, or disease progression:  worsening cytopenia, 
increase in % BM blasts, progression to a more 
advanced MDS FAB subtype 
Relapse after (m)CR or PR 
 
 
 
 
ICH 
At least one of the following: 
Return to pre-treatment BMB % 
Decrement of 50% from maximum 
remission/response levels in granulocytes or platelets 
Reduction in Hgb 1.5g/dL or transfusion 
dependence 
 


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Additional Response Criteria for Myelodysplasia 
Cytogenetic Response 
 
Complete 
 
Partial 
 
Disappearance of chromosomal abnormality with no appearance of new ones 
 
50% reduction of chromosomal abnormality 
Disease Progression 
For patients with % blasts at screening: 
<5% bone marrow blasts 
5-10% bone marrow blasts 
11-20% bone marrow blasts 
21-30% bone marrow blasts 
 
For all categories, any of: 
 
50% increase to >5% bone marrow blasts 
50% increase to >10% bone marrow blasts 
50% increase to >20% bone marrow blasts 
50% increase to >30% bone marrow blasts 
 
At least 50% decrease from maximum remission/response in granulocytes or platelets 
Reduction in Hgb by 2 g/dL 
Transfusion dependence 
Proposed modified IWG Myelodysplasia Response Criteria for Hematologic Improvement (HI)** 
Erythroid response (pre-treatment <11g/dL)* 
 
 
Hgb increase by 1.5 g/dL 
Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 weeks as 
compared to the pretreatment transfusion number in the previous 8 weeks (only RBC transfusions given for Hb 
9 g/dL pretreatment will count in the RBC transfusion evaluation). 
Platelet Response (pretreatment <100 x109/L)* 
Absolute increase of 30 x109/L if starting with >20 x 109/L platelets 
Increase from <20 x 109/L to >20 x109/L and by at least 100% 
Neutrophil Response (pretreatment <1 x 109/L)* 
At least a 100% increase and an absolute increase >0.5 x109/L 
Progression or relapse after HI in the absence of another 
explanation 
At least one of the following: 
 
At least 50% decrease from maximum response levels in granulocytes or platelets; 
 
Reduction in Hgb by 1.5g/dL; 
 
Transfusion dependence. 
*Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) 1 week apart. 
** Hematologic Improvement must last > 8 weeks and is derived based on lab data entered in the database. 
***This criteria will be applied also to patients with oligoblastic AML and CMML without proliferative disorder. 


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Appendix 3. IPSS-R Classification System for Myelodysplastic Syndromes* 
Prognostic variable 
0 
0.5 
1 
1.5 
2 
3 
4 
Cytogenetics 
Very Good 
 
Good 
 
Intermediate 
Poor 
Very Poor 
Bone Marrow Blast % 
≤2 
 
>2 to <5 
 
5-10 
>10 
 
Hemoglobin 
≥10 
 
8 to <10 
<8 
 
 
 
Platelets 
≥100 
50-<100 
<50 
 
 
 
 
ANC 
≥0.8 
<0.8 
 
 
 
 
 
Risk Category 
Risk Score 
Very Low 
≤1.5 
Low 
>1.5-3 
Intermediate 
>3-4.5 
High 
>4.5-6 
Very High 
>6 
Adapted from Greenberg PL, Bennett JM et al.  Clinical application and proposal for modification of the international working group (IWG) response criteria in myelodysplasia.  
Blood 2006; 108(2) 419-25.  
*Only applies to MDS patients enrolled in the Expansion component of the study. 


Pr ot oc ol B 1 3 7 1 0 1 2 Statistical A nal ysis Pla n 
 
D M B 0 2- G S O P- R F 0 2 2. 0 S T A TI S TI C A L A N A L Y SI S P L A N T E M P L A T E 3 1-Ja n- 2 0 1 3 
 P FI Z E R C O N FI D E N TI A L 
P a ge 3 3 
 
A p pe n di x 4.  2 0 1 7 E L N Res p o nse Criteri a f or  Ac ute M yel oi d Le u ke mi a 
R esp o nse Criteri a  
Ne utr o p hils 
(L)  
Pl atelets 
(L)  
B o ne M arr o w Bl asts 
( %) 
Ot her  
C o m plete 
Re missi o n 
wit h o ut Mi ni m al 
Resi d u al Dise ase 
( C RM R D- ) 
 
 
Assess e d i n C R a n d C Ri 
patie nts o nl y b y ce ntral 
m ulti para meter fl o w 
c yt o metr y 
M or p h ol o gic 
C o m plete 
Res p o nse ( C R)  
> 1, 0 0 0 
1 0 0, 0 0 0 
< 5 wit h s pic ules; n o 
p eri p h eral blasts, n o blasts 
wit h A uer r o ds 
Tra nsf usi o n i n de pe n de nt, 
n o E M D 
C o m plete 
Re missi o n wit h 
p arti al 
he m at ol o gic 
rec o ver y 
( C R h)1 
> 5 0 0 
> 5 0, 0 0 0  
< 5; 
n o peri p h eral blasts;  
n o blasts wit h A uer r o ds 
N o E M D; 
N ot q ualif yi n g f or C R 
M or p h ol o gic C R 
wit h i nc o m plete 
bl o o d c o u nt 
rec o ver y ( C Ri)  
< 1, 0 0 0 
- or- 
< 1 0 0, 0 0 0  
< 5 
Eit her ne utr o p hils or 
platelets  n ot rec o vere d, n o 
E M D 
M or p h ol o gic 
le u ke mi a-free 
st ate ( M L F S) 
< 1, 0 0 0 
- a n d- 
< 1 0 0, 0 0 0  
< 5 wit h s pic ules a n d n o 
blasts wit h A uer r o ds 
Ne utr o p hils a n d platelets 
n ot  rec o vere d, Fl o w 
c yt o metr y  ne gati ve, n o 
E M D 
P arti al re missi o n 
( P R) 
1, 0 0 0 
1 0 0, 0 0 0 
d ecrease t o 5- 2 5 blasts a n d 
5 0 % d ecrease fr o m 
pretreat me nt 
Blasts 5 % if A u er r o d p ositi ve 
St a ble Dise ase 
( S D) 
 
 
 
A bse n ce of C R M R D -, C R, 
C Ri, P R, M L F S a n d criteria 
f or P D n ot met.  S h o ul d last 
at least 3 m o nt hs. 


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Progressive 
Disease (PD) 
 
 
>50% increase in blasts from 
pretreatment (if baseline is 
<30% blasts, must have at 
least 15% increase; or >70% 
blasts for ≥3 months; no 
improvement in ANC (>0.5 
x 109/L [500 L], and/or 
platelet count to >50 x 109/L 
[50 000 L nontransfused]; 
or > 50% increase in 
peripheral blasts (WBC 
count x % blasts) to >25 x 
109/L (25000 L); or new 
EMD 
 
ANC=Absolute neutrophil count; WBC=white blood cell; EMD=extramedullary disease. 
There is no minimum requirement for bone marrow cellularity or hemoglobin concentration for response criteria. 
Composite from Cheson, BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working group for diagnosis, standardization of 
response criteria, treatment on outcomes and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003; 21(24)4642-4649 and Döhner 
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 
1CRh is not part of the 2017 ELN recommendations, but is a required assessment for this study.