Conditions: Acute Myeloid Leukemia Myelodysplastic Syndrome Chronic Myelomonocytic Leukemia
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
An open-label study available to all eligible participants from Study B1371019 and participants originating from Study B1371012 continuing on study intervention with azacitidine with or without glasdegib.

Detailed description:

Arms:
arm 1: Azacitidine will be administered 75 mg/m2/day for 7 days every 28 days on Days 1-7 (±3 days) per local label or per the IP Manual (or SPC). Azacitidine may be administered by SC injection or IV infusion. Alternate dosing schedules to administer the 7 doses to accommodate participant and treatment center availability are allowed.

The starting dose regimen will be the same as the most recent regimen received on the B1371019 or B1371012 study.

Glasdegib 50, 75 or 100 mg will be orally administered daily and continuously. The starting dose regimen will be the same as the most recent regimen received on the B1371012 or B1371019 study.

Interventions: intervention 1: Glasdegib intervention 2: Azacitidine
Intervention descriptions: intervention 1: 25 mg or 100 mg tablet intervention 2: 100 mg/vial powder for 25 mg/mL suspension for injection

Protocol document:
Prot_000.pdf: 
Glasdegib PF-04449913 
Protocol B1371019 
Final Protocol Amendment 6, 02 February 2021 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
 
 
 
Title Page 
 
A MULTI-CENTER CONTINUATION STUDY EVALUATING AZACITIDINE 
WITH OR WITHOUT GLASDEGIB (PF-04449913) IN PATIENTS WITH 
PREVIOUSLY UNTREATED ACUTE MYELOID LEUKEMIA, 
MYELODYSPLASTIC SYNDROME OR CHRONIC MYELOMONOCYTIC 
LEUKEMIA 
 
Study Intervention Number: 
PF-04449913 
Study Intervention Name: 
Glasdegib 
US IND Number: 
EudraCT Number: 
CCI  
CCI 
 
Protocol Number: 
B1371019 
Phase: 
Phase 3 
Short Title: Continuation Study Evaluating Azacitidine With Or Without Glasdegib 
(PF-04449913) In Patients With Previously Untreated AML, MDS or CMML. 
 
 
 
 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified. 


Glasdegib PF-04449913 
Protocol B1371019 
Final Protocol Amendment 6, 02 February 2021 
PFIZER CONFIDENTIAL 
Page 2 
 
 
Protocol Amendment Summary of Changes Table 
 
Amendment 6 (02 February 2021) 
Overall Rationale for the Amendment: Amendment 6 was necessary to enable (1) any 
participant in the NINT cohort who (in the investigator’s clinical judgement) continues to 
derive clinical benefit may access study medication(s), and (2) participants previously 
enrolled in B1371012 who (in the investigator’s clinical judgement) continue to derive 
clinical benefit can enroll in this study purely for continued access to study medication(s). 
 
The protocol amendment summary of changes table for past amendment(s) is provided in 
Appendix 13. 
 
Document History 
Document 
Version Date 
Summary and Rationale for Changes 
Amendment 6 
02 February 2021 
This amendment has extensive changes 
throughout. An overview of the changes is as 
follows: 
(1) The title of the protocol has been updated to 
indicate only participants in the NINT cohort are 
continuing in the study starting with this 
amendment and moving forward that the study is 
unblinded and not placebo controlled, and 
participants with MDS or CMML may be 
included. 
(2) Efficacy assessments are no longer applicable 
in this Amendment (Section 3 and Section 8.1). 
(3) Statistical hypothesis and analysis applicable in 
previous amendments are no longer applicable in 
this Amendment. The only reporting is safety 
analyses (Section 3, Section 8.2, and Section 9). 
(4) The SOA found in Section 1.3 is replacing the 
previous SOA and has been revised to decrease the 
frequency of study procedures while maintaining 
appropriate assessment of patient safety. 
(5) INT cohort Population: Given the EDMC 
futility conclusion, standard of care therapy will be 
maintained until the end of the Consolidation 
phase. Experimental therapy will end in the post 
consolidation phase. 
(6) Restricted concomitant medications have been 
updated to further align with the information in the 
Investigator’s Brochure. 


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Protocol B1371019 
Final Protocol Amendment 6, 02 February 2021 
PFIZER CONFIDENTIAL 
Page 3 
 
 
 
Document History 
Document 
Version Date 
Summary and Rationale for Changes 
In addition, the following Letters to Investigators 
that were issued since the release of Amendment 5 
are addressed as follows: 
Letter dated 12 Jun 2019: 
• The content of this letter was to clarify 
discrepancies between all versions of the 
protocol up to and including Amendment 5, 
and the Japanese translated version of the 
protocol. The Japanese-translated protocols 
had additional supportive instructions 
which did not appear in the English 
version. 
• The content of the letter is no longer 
applicable to this Amendment so is not 
incorporated in this amendment. The letter 
is attached to Appendix 13. 
Letter dated 1 Aug 2019: 
• The contraception language for male 
participants (which includes condom use) 
is included in Section 10.4.1. 
• The definition of postmenopausal women 
in Section 5.3.2 has been revised to not 
include “age 60 or older”. 
• The change in one of the items in footnote 
for the SOA is no longer applicable in this 
protocol. 
Letter dated 09 Apr 2020: 
• New data capturing scenarios was 
communicated as a result of COVID-19. 
The data capture communicated in the 
letter was in effect in the trial conduct as of 
the date of the letter until the last 
participant completed amendment 5 of the 
protocol. The letter is incorporated in 
Appendix 13. 
• For this Amendment (Amendment 6) 
COVID-related measures are described in 
Appendix 7. 


Glasdegib PF-04449913 
Protocol B1371019 
Final Protocol Amendment 6, 02 February 2021 
PFIZER CONFIDENTIAL 
Page 4 
 
 
 
Document History 
Document 
Version Date 
Summary and Rationale for Changes 
Letter dated 21 Oct 2020: 
• The letter was issued to communicate that 
EDMC concluded that the intensive cohort 
would not meet the primary objectives of 
the study. The content of the letter is 
summarized in Section 2.2.1 of this 
amendment. 
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs. 


Glasdegib PF-04449913 
Protocol B1371019 
Final Protocol Amendment 6, 02 February 2021 
PFIZER CONFIDENTIAL 
Page 5 
 
 
TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 9 
1. PROTOCOL SUMMARY ................................................................................................... 10 
1.1. Synopsis ................................................................................................................... 10 
1.1.1. INT Cohort Population (Investigator Instructions Communicated for 
Both Cohorts Following Amendment 5 Study Design) ................................... 10 
1.2. Schema .................................................................................................................... 12 
1.3. Schedule of Activities .............................................................................................. 13 
2. INTRODUCTION ................................................................................................................ 15 
2.1. Study Rationale ........................................................................................................ 15 
2.2. Background .............................................................................................................. 16 
2.2.1. INT Cohort Population (Investigator Instructions Communicated for 
Both Cohorts Following Amendment 5 Study Design) ................................... 16 
2.3. Benefit/Risk Assessment ......................................................................................... 17 
2.3.1. Risk Assessment ......................................................................................... 17 
3. OBJECTIVES AND ENDPOINTS ..................................................................................... 17 
4. STUDY DESIGN ................................................................................................................. 17 
4.1. Overall Design ......................................................................................................... 17 
4.2. Scientific Rationale for Study Design ..................................................................... 18 
4.3. Justification for Dose ............................................................................................... 18 
4.4. End of Study Definition ........................................................................................... 18 
5. STUDY POPULATION ...................................................................................................... 18 
5.1. Inclusion Criteria ..................................................................................................... 19 
5.2. Exclusion Criteria .................................................................................................... 19 
5.3. Lifestyle Considerations .......................................................................................... 19 
5.3.1. Contraception .............................................................................................. 19 
5.3.2. Postmenopausal Defined ............................................................................. 20 
5.3.3. Sunlight Exposure ....................................................................................... 20 
5.4. Screen Failures ........................................................................................................ 20 
6. STUDY INTERVENTION .................................................................................................. 20 
6.1. Study Intervention(s) Administered ......................................................................... 21 
6.1.1. Administration ............................................................................................. 21 
6.1.2. Dosing Regimen .......................................................................................... 22 


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Protocol B1371019 
Final Protocol Amendment 6, 02 February 2021 
PFIZER CONFIDENTIAL 
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6.1.3. Treatment Duration .....................................................................................22 
6.2. Preparation/Handling/Storage/Accountability ..........................................................22 
6.2.1. Preparation and Dispensing .........................................................................24 
6.2.1.1. Glasdegib ...................................................................................24 
6.2.1.2. Azacitidine .................................................................................24 
6.3. Measures to Minimize Bias: Randomization and Blinding .....................................24 
6.4. Study Intervention Compliance ...............................................................................25 
6.5. Concomitant Therapy ..............................................................................................25 
6.5.1. Restricted or Prohibited Concomitant Medications ....................................25 
6.5.2. Permitted Concomitant Medications ...........................................................26 
6.5.2.1. Best Supportive Therapy ...........................................................26 
6.5.2.2. Hematopoietic Growth Factors ..................................................27 
6.5.2.3. Antiemetic and Antidiarrheal Therapy ......................................27 
6.5.3. Surgery ........................................................................................................27 
6.5.4. HSCT ..........................................................................................................27 
6.6. Dose Modification ...................................................................................................27 
6.6.1. Glasdegib ....................................................................................................28 
6.6.2. Azacitidine ..................................................................................................32 
6.7. Intervention After the End of the Study ..................................................................32 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................32 
7.1. Discontinuation of Study Intervention .....................................................................32 
7.2. Participant Discontinuation/Withdrawal From the Study .......................................33 
7.2.1. Withdrawal of Consent ...............................................................................34 
7.3. Lost to Follow-up ....................................................................................................34 
8. STUDY ASSESSMENTS AND PROCEDURES ...............................................................34 
8.1. Efficacy Assessments ..............................................................................................35 
8.2. Safety Assessments ..................................................................................................35 
8.2.1. Physical Examinations/Vital Signs/ECG ....................................................35 
8.2.2. Clinical Safety Laboratory Assessments .....................................................35 
8.2.3. Pregnancy Testing .......................................................................................36 
8.2.4. Disease Assessment ....................................................................................36 


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Protocol B1371019 
Final Protocol Amendment 6, 02 February 2021 
PFIZER CONFIDENTIAL 
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8.2.5. One Month Safety Follow-up ...................................................................... 36 
8.3. Adverse Events and Serious Adverse Events .......................................................... 37 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information ....... 37 
8.3.1.1. Reporting SAEs to Pfizer Safety ............................................... 38 
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF ................... 38 
8.3.2. Method of Detecting AEs and SAEs ........................................................... 38 
8.3.3. Follow-up of AEs and SAEs ....................................................................... 38 
8.3.4. Regulatory Reporting Requirements for SAEs ........................................... 39 
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ........................................................................................................... 39 
8.3.5.1. Exposure During Pregnancy ...................................................... 39 
8.3.5.2. Exposure During Breastfeeding ................................................. 41 
8.3.5.3. Occupational Exposure .............................................................. 41 
8.3.6. Cardiovascular and Death Events ............................................................... 41 
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 41 
8.3.8. Adverse Events of Special Interest ............................................................. 42 
8.3.8.1. Lack of Efficacy ........................................................................ 42 
8.3.9. Medical Device Deficiencies ...................................................................... 42 
8.3.10. Medication Errors ..................................................................................... 42 
8.3.11. Protocol-Specified Serious Adverse Events ............................................. 43 
8.4. Treatment of Overdose ............................................................................................ 43 
8.5. Pharmacokinetics ..................................................................................................... 43 
8.6. Pharmacodynamics .................................................................................................. 43 
8.7. Genetics ................................................................................................................... 43 
8.8. Biomarkers ............................................................................................................... 44 
8.9. Immunogenicity Assessments ................................................................................. 44 
8.10. Health Economics .................................................................................................. 44 
9. STATISTICAL CONSIDERATIONS ................................................................................. 44 
9.1. Statistical Hypotheses .............................................................................................. 44 
9.2. Sample Size Determination ..................................................................................... 44 
9.3. Analysis Sets ............................................................................................................ 44 
9.3.1. Safety Analysis Set ..................................................................................... 44 


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Protocol B1371019 
Final Protocol Amendment 6, 02 February 2021 
PFIZER CONFIDENTIAL 
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9.4. Statistical Analyses ..................................................................................................44 
9.4.1. Safety Endpoint(s) .......................................................................................44 
9.5. Interim Analyses ......................................................................................................45 
9.6. Data Monitoring Committee or Other Independent Oversight Committee .............45 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...........................................................................................................46 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................46 
10.1.1. Regulatory and Ethical Considerations .....................................................46 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP .........................................................................46 
10.1.2. Financial Disclosure ..................................................................................47 
10.1.3. Informed Consent Process ........................................................................47 
10.1.4. Data Protection ..........................................................................................48 
10.1.5. Dissemination of Clinical Study Data .......................................................48 
10.1.6. Data Quality Assurance.............................................................................49 
10.1.7. Source Documents ....................................................................................50 
10.1.8. Study and Site Start and Closure ...............................................................51 
10.1.9. Publication Policy .....................................................................................51 
10.1.10. Sponsor’s Qualified Medical Personnel ..................................................52 
10.2. Appendix 2: Clinical Laboratory Tests .................................................................53 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .......................................................................54 
10.3.1. Definition of AE ........................................................................................54 
10.3.2. Definition of SAE .....................................................................................55 
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs .......................57 
10.3.4. Reporting of SAEs ....................................................................................60 
10.4. Appendix 4: Contraceptive Guidance ....................................................................61 
10.4.1. Male Participant Reproductive Inclusion Criteria ....................................61 
10.4.2. Female Participant Reproductive Inclusion Criteria .................................61 
10.4.3. Woman of Childbearing Potential .............................................................62 
10.4.4. Contraception Methods .............................................................................63 
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments .........65 
10.6. Appendix 6: ECG Findings of Potential Clinical Concern ....................................67 


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Protocol B1371019 
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PFIZER CONFIDENTIAL 
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10.7. Appendix 7: Alternative Measures During Public Emergencies ........................... 69 
10.7.1. Telehealth Visits ....................................................................................... 69 
10.7.2. Alternative Facilities for Safety Assessments ........................................... 69 
10.7.2.1. Laboratory Testing ................................................................... 69 
10.7.3. Study Intervention ..................................................................................... 70 
10.7.4. Adverse Events and Serious Adverse Events ........................................... 70 
10.8. Appendix 8: France Contrat Unique ...................................................................... 72 
10.9. Appendix 9: Strong and Moderate CYP3A4/5 Inducers ....................................... 73 
10.10. Appendix 10: Strong CYP3A4/5 Inhibitors ......................................................... 74 
10.11. Appendix 11: Moderate CYP3A4/5 Inhibitors .................................................... 75 
10.12. Appendix 12: List of Drugs with Known Risk of Torsade de Pointes ................ 76 
10.13. Appendix 13: Protocol Amendment History ....................................................... 80 
10.14. Appendix 14: Letters Sent to Investigators After Amendment 5 ........................ 93 
10.15. Appendix 15: Abbreviations ................................................................................ 94 
11. REFERENCES (NOT APPLICABLE) .............................................................................. 98 
 
LIST OF TABLES 
Table 1. 
Available Dose Levels ..............................................................................29 
Table 2. 
Dose Modifications for Non Hematologic Toxicities (Excluding 
QTc Prolongation, Muscle Spasms, and Myalgia) ...................................29 
Table 3. 
Glasdegib Dose Modifications for mQTcF Prolongation ..........................30 
Table 4. 
Dose Modifications for Glasdegib in Case of Drug Class Related 
AEs ............................................................................................................31 


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Protocol B1371019 
Final Protocol Amendment 6, 02 February 2021 
PFIZER CONFIDENTIAL 
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: Continuation Study Evaluating Azacitidine With or Without Glasdegib 
(PF-04449913) In Patients With Previously Untreated AML, MDS, or CMML. 
 
Rationale 
The B1371012 Parent Study (Amendment 7, 14 June 2018) is closing; however, participants 
in the MDS expansion cohort continue to demonstrate clinical benefit per their treating 
investigator, therefore are allowed to continue study intervention under Study B1371019 
Protocol Amendment 6. 
 
The B1371019 Protocol (Amendment 5, 12 April 2019) contained 2 cohorts: INT and NINT. 
The EDMC concluded that glasdegib offered no survival benefit in either the INT or NINT 
cohorts. There were no unexpected safety findings. 
 
As Per Protocol B1371019 Amendment 5, Section 9, methodology for summary and 
statistical analyses are detailed in the SAP. Per the SAP, the goals of the interim analyses are 
to allow early stopping of the study for futility or efficacy. The EDMC reviewed data before 
the study was unblinded to investigators. Following the EDMC conclusion of futility for both 
cohorts, investigators and participants on the B1371019 study were unblinded to study 
treatment prior to starting Amendment 6 and no further study therapy would be given in the 
INT cohort once consolidation therapy completes. No further follow-up is required past the 
mandatory 28 days safety follow-up period. . 
 
The purpose of Amendment 6 is to provide continued access to study intervention 
(azacitidine with or without glasdegib), and collection of safety data for eligible participants 
who continue to derive a clinical benefit from study treatment in studies B1371019 and 
B1371012. 
 
1.1.1. INT Cohort Population (Investigator Instructions Communicated for Both 
Cohorts Following Amendment 5 Study Design) 
Study participants - consolidation phase: 
• Study participants must be contacted to review treatment therapy. 
• May continue to receive consolidation treatment on study (with or without glasdegib) 
if in the investigator’s clinical judgement the participant is deriving clinical benefit. 
• Participants receiving consolidation treatment on the study (with or without 
glasdegib), must be re-consented by signing the IRB/EC approved consent addendum. 
• Participants who continue study intervention must follow the protocol and have all 
procedures and assessments done. Once treatment ends, study participants will be 
followed for 28 days after last dose or until the date consent is withdrawn, then no 
further follow-up will be required. 


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Protocol B1371019 
Final Protocol Amendment 6, 02 February 2021 
PFIZER CONFIDENTIAL 
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• Once consolidation therapy ends, no further treatment will be given. Following that 
time, no further follow-up is required outside the 28 day safety reporting period (if 
consent is not withdrawn). 
 
• Study participants – post consolidation phase: 
• Participants must end study treatment as soon as possible. 
• Participants must sign the IRB/EC approved consent addendum noting that post 
consolidation treatment will end. 
• Once post-consolidation therapy ends, no further treatment will be given. Participants 
will be followed for 28 days after last dose or until the date consent is withdrawn. 
Following that time, no further follow-up is required. 
 
• Study participants -in follow-up (past 28 day safety reporting period): 
• Participants in either cohort (INT or NINT) must end follow-up procedures in the 
study as soon as possible. 
 
Objectives and Endpoints 
 
Objective 
Endpoint 
• 
To monitor the safety and tolerability of the 
investigational drugs in participants continuing 
study intervention from this study and 
participants originating from Study B1371012. 
• 
All AEs and SAEs 
 
Overall Design 
Study design is as described in the B1371019 Protocol (Amendment 5, 12 April 2019) and 
Study B1371012 Protocol (Amendment 7, 14 June 2018). This is an open-label, continuation 
protocol for eligible NINT cohort participants enrolled in Study B1371019 or Study 
B1371012 eligible participants. 
 
Number of Participants 
A maximum of 34 participants from Study B1371019 and 3 participants originating from 
Study B1371012 who continue to derive clinical benefit per the treating investigators will be 
allowed continued access to the study intervention per Amendment 6. 
 
Note: "Enrolled" means a participant's, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility for 
the study, but do not participate in the study, are not considered enrolled, unless otherwise 
specified by the protocol. 


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Protocol B1371019 
Final Protocol Amendment 6, 02 February 2021 
PFIZER CONFIDENTIAL 
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Intervention Groups and Duration 
• Azacitidine will be administered 75 mg/m2/day for 7 days every 28 days as per local label 
or per the IP Manual (or SPC). Azacitidine may be administered by SC injection or IV 
infusion. Alternate dosing schedules to administer the 7 doses to accommodate 
participant and treatment center availability are allowed. The starting dose regimen will 
be the same as the most recent regimen received on the B1371019 or B1371012 study. 
 
• Glasdegib will be orally administered daily (50, 75 or 100 mg) and continuously. The 
starting dose regimen will be the same as the most recent regimen received on the 
B1371019 or B1371012 study. 
 
• Study intervention should be continued until objective disease progression or relapse, 
death, unacceptable toxicity, or participant refusal, whichever occurs first. 
 
Data Monitoring Committee or Other Independent Oversight Committee: None as the 
EDMC has been retired after study futility conclusions prior to Amendment 6. 
 
Statistical Methods 
Detailed methodology for summary and statistical analyses of the safety data collected in this 
continuation study is outlined in Section 9. 
 
The safety analyses of participants from Study B1371019 and participants originating from 
Parent Study B1371012 will be conducted separately and independently of each other. 
 
1.2. Schema 
Not applicable. 


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Protocol B1371019 
Final Protocol Amendment 6, 02 February 2021 
PFIZER CONFIDENTIAL 
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1.3. Schedule of Activities 
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
 
Visit Identifier 
Abbreviations used in this 
table may be found in 
Appendix 15. 
Screening 
Day 1 
(28 day cycles) 
End of 
Treatment/Withdrawal 
1-Month 
Safety 
Follow-upa 
Notes 
Visit Window (days) 
-3/+14 
Obtain assessments if not 
completed in the last week. 
28 days after 
last dose 
Data Collection Required on CRF 
• 
ICD date of consent to Amendment 6, dosing information, 
AEs, and SAEs will be collected on the CRF. 
• 
Additional CRFs applicable as described in CRF Completion 
Guide. 
Informed re-consent 
X 
X 
Study intervention 
Glasdegib 
X 
• 
Administered once daily, continuously, at approximately the 
same time each day 
• 
Treatment will be administered in 28-day cycles. Cycle 
duration may be extended to allow for toxicity resolution. 
Azacitidine 
X 
• 
Azacitidine will be administered per local label or per IP 
manual (or SPC). 
• 
The starting dose regimen will be the same as the most recent 
regimen received on the B1371019 or B1371012 study 
• 
Treatment can be administered as a SC injection or IV infusion 
on Days 1-7 (±3 days) per local label. 
• 
Alternate dosing schedules to administer the 7 doses to 
accommodate participant and treatment center availability are 
allowed. 
Serious and nonserious 
adverse event monitoring 
X 
X 
X 
X 
• 
NCI CTCAE version 4.03 will be used. 


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PFIZER CONFIDENTIAL 
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Visit Identifier 
Abbreviations used in this 
table may be found in 
Appendix 15. 
Screening 
Day 1 
(28 day cycles) 
End of 
Treatment/Withdrawal 
1-Month 
Safety 
Follow-upa 
Notes 
Visit Window (days) 
-3/+14 
Obtain assessments if not 
completed in the last week. 
28 days after 
last dose 
Data Collection for the following will be in the Medical Records only (not required on 
CRF) 
Physical 
examination/Vitals/ECG 
As per Standard of Care at the Study Site 
Clinical Laboratory 
Assessment 
As per Standard of Care at the Study Site 
Pregnancy 
test/Contraception check 
X 
X 
X 
• 
Male participants with female partner of childbearing potential 
and female participants who are of childbearing potential will 
need to affirm that they meet the criteria for correct use of the 
selected methods of contraception. In addition, the investigator 
or his or her designee will instruct the participant to call 
immediately if the selected contraception method is 
discontinued, or if pregnancy is known or suspected in the 
participant or the participant’s partner. Refer to Appendix 4 for 
contraceptive guidance. Appropriate contraception usage for at 
least 180 days after the last dose of study intervention is to be 
confirmed 
Disease Assessment 
As per Standard of Care at the Study Site 
Concomitant treatment(s) 
X 
X 
X 
a. 
Study participants will be followed (can be by telephone) for 28 calendar days after the last administration of study treatment to capture any AE/SAEs. 
There will be no further follow-up required after the 28-day safety reporting period. 


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2. INTRODUCTION 
Protocol Amendment 6 is applicable to all eligible participants from Study B1371019 and 
participants originating from Study B1371012 continuing on study intervention with 
azacitidine with or without glasdegib. 
Please refer to Protocol Amendment 5, 12 April 2019, for the full protocol design. Glasdegib 
(PF-04449913) is a novel small molecule inhibitor of the Sonic Hh pathway approved in the 
US by the FDA in 2018 to be used in combination with LDAC for the treatment of newly- 
diagnosed AML in adults who are 75 years of age or older or who have comorbidities that 
may preclude the use of intensive chemotherapy. Glasdegib is being developed for the 
treatment of hematologic malignancies. 
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 RNA at high doses, resulting in cell 
death. Use of azacitidine has been approved by the FDA and EMA. 
 
2.1. Study Rationale 
The B1371012 Parent Study (Amendment 7, 14 June 2018) is closing; however, participants 
in the MDS expansion cohort continue to demonstrate clinical benefit per their treating 
investigator, therefore are allowed to continue study intervention under Study B1371019 
Protocol Amendment 6. 
 
The B1371019 Protocol (Amendment 5, 12 April 2019) contained 2 cohorts: INT and NINT. 
The EDMC concluded that glasdegib offered no survival benefit in either the INT or NINT 
cohort. There were no unexpected safety findings. 
 
Per Section 9 in Protocol B1371019 Amendment 5, detailed methodology for summary and 
statistical analyses are detailed in the SAP. Per the SAP, the goal of the interim analyses was 
to allow early stopping of the study for futility or efficacy. The EDMC reviewed data before 
the study was unblinded to investigators. Following the EDMC conclusion of futility for both 
cohorts, all investigators and participants on the B1371019 study were unblinded to study 
treatment prior to consenting for Amendment 6. No further study therapy would be given in 
the INT cohort once the standard of care consolidation chemotherapy is completed. No 
further follow-up is required past the mandatory 28 days safety follow-up period. 
 
The purpose of Amendment 6 is to provide continued access to study intervention 
(azacitidine with or without glasdegib), and collection of safety data for eligible participants 
who continue to derive a clinical benefit from study intervention in studies B1371019 and 
B1371012. 


Glasdegib PF-04449913 
Protocol B1371019 
Final Protocol Amendment 6, 02 February 2021 
PFIZER CONFIDENTIAL 
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2.2. Background 
Study B1371019 was a randomized (1:1), double-blind, multicenter, placebo controlled study 
evaluating intensive chemotherapy with or without glasdegib (PF-04449913) or azacitidine 
with or without glasdegib in participants with previously untreated AML. 
 
The goals of the interim analyses were to allow early stopping of the study for futility or 
efficacy. Following a planned interim analysis on 30 September 2020 for the Intensive 
cohort, Pfizer accepted the Committee’s (EDMC) conclusion that in this trial the randomized 
arm (7+3 intensive chemotherapy [cytarabine + daunorubicin] + glasdegib) would not meet 
the primary objective of improving overall survival with respect to intensive chemotherapy 
alone. No unexpected safety issues were identified. Following EDMC review of the data and 
conclusion, investigators were unblinded to study treatment following the EDMC conclusion. 
The Parent Study B1371012 was a multicenter open label Phase 1b study designed to 
evaluate the safety, efficacy, PK, and PD of glasdegib when combined with azacitidine in 
participants with previously untreated Higher Risk MDS, AML, and CMML. This Phase 1b 
study included 2 components: a safety lead-in cohort and an expansion phase with 2 cohorts. 
Since the B1371012 study is closing, participants who wish to continue treatment may do so 
on Study B1371019 Amendment 6. 
This amendment describes the procedures for NINT cohort participants from B1371019 and 
B1371012 who elect to continue to receive study treatment. The Investigator is to follow the 
guidance below for the conduct of this study. 
 
2.2.1. INT Cohort Population (Investigator Instructions Communicated for Both 
Cohorts Following Amendment 5 Study Design) 
Study participants - consolidation phase: 
• Study participants must be contacted to review treatment therapy. 
• May continue to receive consolidation treatment on study (with or without glasdegib) 
if in the investigator’s clinical judgement the participant is deriving clinical benefit. 
• Participants receiving consolidation treatment on the study (with or without 
glasdegib), must be re-consented by signing the IRB/EC approved consent addendum. 
• Participants who continue study intervention must follow the protocol and have all 
procedures and assessments done. Once treatment ends, study participants will be 
followed for 28 days after last dose or until the date consent is withdrawn, then no 
further follow-up will be required. 
• Once consolidation therapy ends, no further treatment will be given. Following that 
time, no further follow-up is required outside the 28 day safety reporting period (if 
consent is not withdrawn). 


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Study participants – post consolidation phase: 
• Participants must end study treatment as soon as possible. 
• Participants must sign the IRB/EC approved consent addendum noting that post 
consolidation treatment will end. 
• Once post-consolidation therapy ends, no further treatment will be given. Participants 
will be followed for 28 days after last dose or until the date consent is withdrawn. 
Following that time, no further follow-up is required. 
Study participants -in follow-up (past 28 day safety reporting period): 
• Participants in either cohort (INT or NINT) must end follow-up procedures in the 
study as soon as possible. 
 
2.3. Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of glasdegib may be found in the investigator’s brochure, which is the SRSD 
for this study. The SRSD for azacitidine is the package insert. 
 
2.3.1. Risk Assessment 
Risk assessment will be based on continued monitoring and clinical management as per GCP 
guidelines. 
 
3. OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• 
To monitor the safety and tolerability of the 
investigational drugs in participants continuing 
study intervention from this study and 
participants originating from Study B1371012 
• 
All AEs and SAEs 
 
4. STUDY DESIGN 
4.1. Overall Design 
Study design is as described in the B1371019 Protocol (Amendment 5, 12 April 2019) and 
Study B1371012 Protocol (Amendment 7, 14 June 2018). This is an open-label, continuation 
protocol for eligible NINT cohort participants enrolled in Study B1371019 or Study 
B1371012 eligible participants. 
 
Following a planned interim analysis on 30 September 2020 for the INT cohort, Pfizer 
accepted the Committee’s EDMC conclusion that glasdegib offered no survival benefit. 


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A maximum of 34 unblinded participants from Study B1371019 and 3 participants 
originating from Study B1371012 who continue to derive clinical benefit per the treating 
investigators will be allowed access to the study intervention per Amendment 6. 
 
Amendment 6 is a continuation protocol for NINT cohort participants from Study B1371019 
or Study B1371012. A maximum of 34 participants from Study B1371019 and 3 participants 
from Study B1371012 will continue to receive access to study intervention. 
 
4.2. Scientific Rationale for Study Design 
The scientific rationale is as described in the B1371019 Protocol (Amendment 5, 12 April 
2019) and Study B1371012 Protocol (Amendment 7, 14 June 2018). 
 
4.3. Justification for Dose 
The doses administered to participants have already been established in the B1371019 
Protocol (Amendment 5, 12 April 2019) and Study B1371012 Protocol (Amendment 7, 
14 June 2018). 
 
4.4. End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the 28-day safety follow-up period. 
 
The end of this Study is defined as when all participants have discontinued from study 
treatment and have completed the Safety Follow-up Period. The safety follow-up period is 
defined as 28 days after last dose of last study drug. The study may also be terminated at any 
time at the discretion of the Sponsor. 
 
5. STUDY POPULATION 
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol. 
 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 


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5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Any participant who continues to demonstrate clinical benefit (as determined by the 
Principal Investigator) from study treatment with azacitidine with or without 
glasdegib in this Study or from Study B1371012. 
2. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol. 
 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study. 
 
2. Female participants who are pregnant or breastfeeding (if continuing to receive study 
intervention); 
 
3. Participant has been withdrawn from Study B1371019 and Study B1371012 for any 
reason (including INT cohort participants required to end study treatment). 
 
5.3. Lifestyle Considerations 
5.3.1. Contraception 
Glasdegib has been associated with teratogenic risk and azacitidine has been shown to cause 
congenital malformations in animals. The investigator or his or her designee, in consultation 
with the participant, will confirm that the participant has selected an appropriate method of 
contraception for the individual participant and his or her partner(s) from the permitted list of 
contraception methods (see Appendix 4 Section 10.4.4) and will confirm that the participant 
has been instructed in its consistent and correct use. At time points indicated in the SoA, the 
investigator or designee will inform the participant of the need to use highly effective 
contraception consistently and correctly and document the conversation and the participant’s 
affirmation in the participant’s chart (participants need to affirm their consistent and correct 
use of at least 1 of the selected methods of contraception). In addition, the investigator or 
designee will instruct the participant to call immediately if the selected contraception method 
is discontinued or if pregnancy is known or suspected in the participant or partner. 


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5.3.2. Postmenopausal Defined 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
• A high FSH level in the postmenopausal range (as per the reference range used by the 
laboratory) may be used to confirm a postmenopausal state in women under 60 years 
old and not using hormonal contraception or HRT. 
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods described in 
Section 10.4.3 if they wish to continue their HRT during the trial. Otherwise, they 
must discontinue HRT to allow confirmation of postmenopausal status before trial 
enrollment. 
 
5.3.3. Sunlight Exposure 
Participants 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 
participants’ exposure to light including high intensity UVB sources such as tanning beds, 
tanning booths and sunlamps. Participants should be encouraged to apply 
sunscreen/sunblock daily. 
 
5.4. Screen Failures 
Participants who do not meet the inclusion/exclusion criteria will not be permitted to 
participate in Amendment 6. See Section 8 regarding screening evaluations. 
 
6. STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol. 
 
For the purposes of this study, and per ICH guidelines, investigational product is defined as a 
pharmaceutical form of an active ingredient or placebo being tested or used as a reference in 
a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use 
(ICH E6 1.33). For the purpose of this study, the study interventions are glasdegib and 
azacitidine. 


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6.1. Study Intervention(s) Administered 
 
Intervention Name 
Glasdegib 
Azacitidine 
ARM Name 
(group of participants receiving a 
specific treatment (or no 
treatment) 
NA 
NA 
Type 
Drug 
Drug 
Dose Formulation 
Tablet 
Powder for injection 
Unit Dose Strength(s) 
25 mg or 100 mg tablet 
100 mg/vial powder for 25 
mg/mL suspension for injection 
Dosage Level(s) 
50, 75 or 100 mg daily 
75 mg/m2/day for 7 days every 
28 days, or per the local label, IP 
Manual (or SPC) or if dose 
modified 
Route of Administration 
Oral 
IV or SC 
Use 
Experimental 
Other 
IMP or NIMP 
IMP 
NIMP 
Sourcing 
Provided centrally by the sponsor 
In US and Germany drug is 
sourced by the sites. 
All other countries, the drug is 
sourced by the Sponsor. 
Packaging and Labeling 
Study intervention will be provided 
in HDPE bottles. Each bottle will be 
labelled as required per country 
requirement. 
Study intervention will be 
provided in sealed single-use 
colorless type 1 glass vials. Each 
vial will be labelled as required 
per country requirement. 
Current/Former Name(s) or 
Alias(es) 
PF-04449913 
NA 
 
6.1.1. Administration 
Both glasdegib and azacitidine 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 participant via phone anytime there is a dose reduction to 
confirm that the participant adequately understands the dosing instructions. 
 
Glasdegib will be self-administered by the participant at home, unless otherwise specified. 
Glasdegib will be administered orally with approximately 8 ounces (240 mL) of water, 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. If a participant forgets to take their dose at 
the regularly scheduled time, and if fewer 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 participant should 
continue their normal dosing schedule. If a participant misses a day’s dose entirely, they must 
be instructed not to “make it up” the next day. If a participant 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 participant inadvertently takes 1 extra dose during a day, the 


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participant should not take the next dose of glasdegib. The participant will be reminded to 
bring their bottle(s) and participant dosing diary into clinic to evaluate dosing compliance. 
 
Participants requiring glasdegib dose reduction(s) will be administered multiples of 25 mg 
tablets and should continue taking the glasdegib at the same time each day 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 6.6. 
 
Study intervention administration details will be recorded on the CRF. 
 
6.1.2. Dosing Regimen 
• Azacitidine will be administered 75 mg/m2/day for 7 days every 28 days on Days 1-7 
(±3 days) per local label or per the IP Manual (or SPC). Azacitidine may be 
administered by SC injection or IV infusion. Alternate dosing schedules to administer 
the 7 doses to accommodate participant and treatment center availability are allowed. 
The starting dose regimen will be the same as the most recent regimen received on 
the B1371019 or B1371012 study. 
 
• Glasdegib 50, 75 or 100 mg will be orally administered daily and continuously. The 
starting dose regimen will be the same as the most recent regimen received on the 
B1371012 or B1371019 study. 
 
Dose modifications are discussed in Section 6.6. 
 
6.1.3. Treatment Duration 
Treatment with the study treatment should be continued until objective disease progression or 
relapse, death, unacceptable toxicity, or participant refusal, whichever occurs first. 
 
If glasdegib is permanently discontinued for reasons other than objective disease progression, 
participant 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 participant must be withdrawn from study 
treatment. 
 
6.2. Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 


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interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business. 
 
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual. 
 
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. 
 
5. Study interventions should be stored in their original containers. 
 
6.  Site staff will instruct participants on the proper storage requirements for take home 
study intervention. 
 
7.  See the package insert, or SPC for storage conditions of the azacitidine once 
reconstituted and/or diluted. 
 
8. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record. All glasdegib that is taken 
home by the participant, both used and unused bottles/tablets, must be returned to the 
investigator by the participant. Returned study intervention must not be redispensed 
to the participants. 
 
9. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer. 
 
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP Manual. 


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6.2.1. Preparation and Dispensing 
6.2.1.1. Glasdegib 
Glasdegib will be supplied by Pfizer Worldwide Research and Development as 25 mg and 
100 mg tablets for oral administration. Supplies will be labelled according to local regulatory 
requirements. 
 
Glasdegib will be packaged in 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. Participants 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 participants clearly 
understand the directions for self-medication. 
 
Study intervention should be dispensed using the IRT system (IWR) that provides a 
confirmation report containing the participant identification number and DU(s) or container 
number(s) assigned 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. The confirmation report must be stored in the site’s files. 
 
The study specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 
 
6.2.1.2. 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 IP 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. 
 
If azacitidine is provided by sponsor, it should be dispensed using the IRT system that 
provides a confirmation report containing the participant identification number and DU(s) or 
container number(s) assigned 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. The confirmation report must be stored in the site’s 
files. 
 
6.3. Measures to Minimize Bias: Randomization and Blinding 
Randomization and blinding are not applicable to this protocol amendment. Participants on 
Study B1371019 will be unblinded prior to dosing on Amendment 6. 


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6.4. Study Intervention Compliance 
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 participants to the Investigator. The number of tablets returned by the 
participant 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. 
 
For azacitidine, the site should complete the required dosage Preparation Record located in 
the Investigational Product Manual. The use of the Preparation Record is preferred but it 
does not preclude the use of an existing appropriate clinical site documentation system. The 
existing clinical site's documentation system should capture all pertinent/required 
information on the preparation and administration of the dose including the methodology 
used to calculate the participant body surface area. This may be used in place of the 
Preparation Record after approval from the Sponsor. 
 
6.5. Concomitant Therapy 
Concomitant medications will be assessed at screening and all clinic visits. 
 
Concomitant treatment considered necessary for the participant’s well-being may be given at 
discretion of the treating physician. If a participant is offered, in accordance with the 
prevailing local guidelines, a COVID-19 vaccine, it should be permitted. This would be 
recorded as a concomitant medication in the medical records and standard AE collection and 
reporting processes would be followed. 
 
6.5.1. Restricted or Prohibited Concomitant Medications 
The following medications are not allowed during the active study treatment period: 
• Agents used to treat AML or MDS; 
• Investigational agents; This exclusion does not apply to any COVID-19 vaccine. 
• CYP3A4/5 Strong Inducers: A drug-drug interaction study in healthy participants 
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, coadministration of glasdegib and 
strong CYP3A4/5 inducers is not permitted. A comprehensive list of strong 
CYP3A4/5 inducers is provided in Appendix 9. The Sponsor study team should be 
contacted if there is uncertainty whether a concomitant medication is contraindicated. 
• CYP3A4/5 Moderate Inducers (Appendix 9): Avoid concomitant use of glasdegib 
with moderate CYP3A4 inducers. If use cannot be avoided, double the glasdegib 


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dose, as tolerated. After the moderate CYP3A4 inducer has been discontinued for 
7 days, resume glasdegib dose taken prior to initiating the moderate CYP3A4 inducer. 
The following medications have use restrictions during the active study treatment period: 
• CYP3A4/5 Inhibitors: In a healthy volunteer study, ketoconazole, a potent 
CYP3A4/5 inhibitor, produced a 2.4 fold increase in plasma exposure and a 1.4 fold 
increase in peak plasma concentration of glasdegib. Therefore, a potential exists for 
drug-drug interactions with CYP3A4/5 inhibitors, and coadministration of 
glasdegib in combination with strong/ moderate CYP3A4/5 inhibitors is not 
recommended. Selection of concomitant medication with no or minimal 
CYP3A4/5 inhibition potential is recommended. Strong/moderate 
CYP3A4/5 inhibitors (Appendix 10 or Appendix 11) 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 Appendix 6. 
• Drugs with a known risk of TdP: Glasdegib has been shown to have the potential to 
prolong the QTc interval in preclinical studies. In the first in participant study as 
single agent, Grade 3 QTcF prolongation was observed at the highest doses tested 
(400 mg and 600 mg). While the glasdegib dose evaluated in this study is 100 mg, the 
concomitant administration of glasdegib and drugs with a known risk of Tdp should 
be avoided whenever possible. A list of such drugs is provided in Appendix 12. 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 6.6.1 dose 
modifications for QT prolongation per Table 3 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. 
 
6.5.2. Permitted Concomitant Medications 
6.5.2.1. Best Supportive Therapy 
BST administration is permitted according to institutional guidelines for all participants on 
study. BST will be provided by the site and may vary depending on the participant’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; 
• Antifungal agents; 
• Antiviral agents. 


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6.5.2.2. Hematopoietic Growth Factors 
Hematopoietic growth factors (eg, G-CSF, GM-CSF) may be used according to local practice 
and guidelines. 
6.5.2.3. Antiemetic and Antidiarrheal Therapy 
Participants 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 6.5.1. 
 
6.5.3. 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. 
 
6.5.4. HSCT 
Participants who are eligible for HSCT will undergo HSCT per local standard of care. 
 
For post disease remission HSCT, glasdegib will be interrupted at least 28 days before HSCT 
(date of stem cell infusion). 
 
Glasdegib may be resumed 30-60 days post HSCT once there is ANC engraftment, no 
≥ Grade 2 ongoing GVHD, and no ongoing SAEs in the judgement of the investigator. 
6.6. Dose Modification 
Every effort should be made to administer the study drug treatment according to the planned 
dose and schedule. 
 
In the event of Grade 3 or Grade 4 non-hematologic, study-treatment-related toxicity, dosing 
may be delayed and/or dose reduced. The glasdegib dose should be reduced 1 dose level at a 
time, in increments of 25 mg (75 mg QD, 50 mg QD, in the form of 3 or 2 x 25 mg tablets 
respectively). Glasdegib does not need to be delayed or dose reduced for hematologic, study- 
treatment-related toxicity. 
 
Glasdegib may be interrupted or permanently discontinued for any reason as per GCP. 
Glasdegib should be permanently discontinued if: 
interruptions are for more than 28 consecutive days when not required by the protocol (ie, 
HSCT period). 


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Dose escalations will not be allowed following glasdegib/placebo dose reductions. Dose 
modifications may occur in 3 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. 
 
When chemotherapy is given, a Cycle is determined by chemotherapy administration 
schedule. A Cycle is 28 days, but will be extended if there are dose delays or modifications 
in the chemotherapy backbone. 
6.6.1. Glasdegib 
Glasdegib does not need to be delayed or dose reduced for hematologic toxicity deemed 
unrelated/unlikely related to glasdegib by the investigator. 
Participants experiencing Grade 3 or 4 nonhematological 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 2. 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, participants 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 
participant missing all subsequent planned doses of glasdegib within the cycle. If the AE 
leading to treatment interruption recovers within the same cycle, recommencement 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 2, 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 participant may need 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 to make up for any missed glasdegib doses during 
that cycle). 
Glasdegib may be interrupted or permanently discontinued for any reason as per GCP. 
Glasdegib should be permanently discontinued if interruptions are for more than 28 
consecutive days. In the event of glasdegib treatment interruption for reasons other than 


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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 1) 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 
discussion with the sponsor. All dose modifications/adjustments must be clearly documented 
in the participant's notes and eCRF. 
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 1. 
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 2. 
 
Table 2. 
Dose Modifications for Non Hematologic Toxicities (Excluding QTc 
Prolongation, Muscle Spasms, and Myalgia) 
 
Toxicity 
(NCI CTCAE version 4.03) 
Glasdegib 
≥ Grade 3 toxicity (nausea, vomiting, and/or 
diarrhea must persist at ≥ Grade 3 (despite 
maximal appropriate medical therapy) to require 
dose modification). 
Hold glasdegib until toxicity has recovered to baseline or 
≤ Grade 1. 
First episode: Decrease by 1 dose level 
Second episode: Decrease by 1 dose level 
Third episode: Permanently discontinue 
Potential drug induced liver injury/Hy’s Law (as 
defined in Appendix 5). 
Interrupt glasdegib dosing. If an alternative cause is 
found, restarting of glasdegib at the same dose may be 
considered. 
Confirmed drug induced liver injury/Hy’s Law 
(as defined in Appendix 5). 
Glasdegib should be permanently discontinued. 


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Participants will be closely monitored for potential cardiovascular symptoms per standard of 
care. Appropriate monitoring should include clinical examinations, vital signs, routine ECGs, 
and AE monitoring. In case of QTcF prolongation, concomitant conditions such as 
electrolyte imbalances, hypoxia, or use of medications affecting the QT interval should be 
ruled out and/or corrected. In case of clinically significant toxicities, glasdegib administration 
should be interrupted and the dose reduced as indicated in Table 3. 
 
Concomitant administration of glasdegib with strong/moderate CYP3A4/5 inhibitors 
(Appendix 10 or Appendix 11) and drugs with known risk of TdP (Appendix 12) is not 
recommended due to the potential for drug-drug interaction to prolong the QTc interval. 
However, if it is medically necessary for participants to use these medications please refer to 
Appendix 6 for monitoring procedures. Investigators must be aware of the QTcF prolonging 
potential of all medications that participants on study are taking, and should take appropriate 
action when clinically indicated. Given the potential for QTcF prolongation, the 
measurement and immediate correction of electrolyte abnormalities such as potassium and 
magnesium, and of other reversible causes of QTcF prolongation such as hypoxia, are 
especially important. In the event that the QTcF interval is prolonged beyond 480 msec 
(CTCAE v. 4.03 ≥Grade 2), Table 3 must be referenced and actioned. Additional ECG and 
cardiac consultation should be obtained if clinically indicated. 
 
Table 3. 
Glasdegib Dose Modifications for mQTcF Prolongation 
 
CTCAE v 4.03 
ECG QTc interval 
prolonged* 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
450-480 msec 
481-500 msec 
≥501 msec on at 
least 2 separate 
ECGs 
QTc >501 msec or 
>60 msec change 
from baseline and 
TdP or polymorphic 
ventricular 
tachycardia or 
signs/symptoms of 
serious arrhythmia 
*The severity of QTc prolongation assessment is to be determined by calculating a mean QT of 
3 consecutive ECGs performed approximately 2 minutes (but no longer than 5 minutes) apart using the 
Frederica correction method (mQTcF). 
**Please see Section 8.3.9 for protocol specified SAE reporting requirement of Grade 3 or 4 mQTcF 
prolongation. 
Category 
Action 
1 
Grade 
2 
3 
4 
General 
management 
Assess electrolyte levels and supplement as 
clinically indicated 
X 
X 
X 
Review and adjust concomitant medications with 
known QTc interval-prolonging effects 
X 
X 
X 
ECG monitoring 
Monitor ECGs at least weekly for 2 weeks 
following resolution of mQTcF prolongation to 
≤480 msec 
X 
X 
X 
Initial glasdegib 
action 
Discontinue and do not rechallenge 
X 
Interrupt treatment 
X 
Continue treatment at same dose 
X 
X 


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Table 3. 
Glasdegib Dose Modifications for mQTcF Prolongation 
 
Resume 
glasdegib dosing 
If no prior glasdegib dose interruption related to 
QTcF prolongation has occurred, resume at a 
reduced dose of 75 mg once daily when mQTcF 
interval returns to within 30 msec of baseline or 
≤480 msec 
X 
If 1 prior glasdegib dose interruption related to 
QTcF prolongation has occurred, resume at a 
reduced dose of 50 mg once daily when mQTcF 
interval returns to within 30 msec of baseline or 
≤480 msec 
X 
Discontinue 
glasdegib 
permanently 
If 2 prior glasdegib dose interruptions related to 
QTcF prolongation have occurred 
X 
 
Dose modifications for glasdegib in case of drug class related AEs are outlined in Table 4. 
 
Table 4. 
Dose Modifications for Glasdegib in Case of Drug Class Related AEs 
Muscle Spasms 
or Myalgia 
Grade 1 
Grade 2 
Grade 3 
Continue at same dose 
level. 
Continue at same dose 
level. 
Hold dose. 
Administer oral re-hydration 
salts containing electrolytes.a 
Consider other appropriate 
interventions (eg, 
anti-spasmodics) as per 
institutional guidelines. 
Evaluate levels of: CK, Vit 
B6, Vit D, ferritin, 
transferrin and electrolytes 
(Na, K, Mg, Ca and P).b 
If CK is elevated, evaluate 
urine and serum myoglobin, 
CK isoenzymes, and serum 
creatinine. 
Upon resolution to Grade ≤ 
1, restart study treatment at 
next lower dose level. 
If the event does not resolve 
within 3 weeks to Grade ≤1, 
at the discretion of the 
Investigator the dose may be 
restarted at the next lower 
Glasdegib 
Administer oral 
rehydration solutions 
containing electrolytes.a 
Administer oral 
re-hydration salts 
containing electrolytes.a 
Consider other appropriate 
interventions (eg, 
anti-spasmodics) as per 
institutional guidelines. 
Consider other appropriate 
interventions (eg, 
anti-spasmodics) as per 
institutional guidelines. 
Evaluate levels of: CK, Vit 
B6, Vit D, ferritin, 
transferrin and electrolytes 
(Na, K, Mg, Ca and P).b 
Evaluate levels of: CK, Vit 
B6, Vit D, ferritin, 
transferrin and electrolytes 
(Na, K, Mg, Ca and P).b 
If CK is elevated, evaluate 
urine and serum 
myoglobin, CK 
isoenzymes, and serum 
creatinine. 
If CK is elevated, evaluate 
urine and serum 
myoglobin, CK 
isoenzymes, and serum 
creatinine. 
If event persists, hold dose 
until resolution to 
Grade ≤1. 


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Table 4. 
Dose Modifications for Glasdegib in Case of Drug Class Related AEs 
Muscle Spasms 
or Myalgia 
Grade 1 
Grade 2 
Grade 3 
Upon resolution, restart at 
prior dose, or for 
prolonged muscle spasms, 
consider reducing dose by 
one dose level. 
dose level or the participant 
may be permanently 
discontinued from study 
treatment. 
a. 
Electrolyte replacement drinks should include Na, K, Mg, Ca and P. Consideration should be given to 
ensuring adequate hydration prior to bedtime, and whenever fluid intake is decreased for a prolonged 
duration. 
b. Labs may be drawn between protocol visits. 
In the event of alopecia or dysgeusia, investigator discretion should be applied with respect to dose 
interruption and/or dose reduction of glasdegib as preliminary analysis of available clinical data suggests that 
these events are not dose dependent. 
 
6.6.2. Azacitidine 
For azacitidine dose modification, refer to the local package insert (or SPC) or IP Manual. 
 
6.7. Intervention After the End of the Study 
No intervention will be provided to study participants at the end of the study. 
 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention may include the following: 
 
• Objective disease progression or relapse 
• Participant refusal 
• Consent withdrawal 
• Unacceptable toxicity 
• Pregnancy 
• Initiation of another anti-cancer treatment 
If study intervention is definitively discontinued, the participant will not remain in the study 
for further evaluation. See the SoA for data to be collected at the time of discontinuation of 
study intervention. 


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Note that discontinuation of study intervention does not represent withdrawal from the study. 
If study intervention is definitively discontinued, the participant will remain in the study to 
be evaluated for 28 calendar days after the last dose of study treatment administration. See 
the SoA for data to be collected at the time of discontinuation of study intervention and 
follow-up for any further evaluations that need to be completed. 
 
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information. 
 
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study may include the following: 
• Refused further follow-up; 
• Lost to follow-up; 
• Death; 
• Study terminated by sponsor; 
• Progressive Disease; 
• Pregnancy; 
• Global deterioration of health status; 
• Unacceptable toxicity 
• Withdrawal of consent; 
• Significant noncompliance. 
The participant will be permanently discontinued both from the study intervention and from 
the study at that time. 
 
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly. 
 
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 
 
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved. 


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7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of study intervention or also from study procedures and/or 
posttreatment study follow-up, and entered on the appropriate CRF page. In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law. 
 
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
 
The following actions must be taken if a participant fails to return to the clinic for/attend a 
required study visit: 
 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study; 
 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record; 
 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 
8. STUDY ASSESSMENTS AND PROCEDURES 
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures. 
 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. Refer to Appendix 7 for alternative measures during the 
COVID-19 pandemic. 
 
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention. 


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Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
 
Every effort should be made to ensure that -protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a -protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner. 
 
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study. 
 
8.1. Efficacy Assessments 
Not applicable. 
 
8.2. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues. 
 
8.2.1. Physical Examinations/Vital Signs/ECG 
Physical examinations and vital signs will be performed as per standard of care at the Study 
Center but will not be recorded in the CRF. A finding representing an AE will be recorded in 
the AE CRF as described in Section 8.3.1. 
 
ECG values of potential clinical concern are listed in Appendix 6: ECG. 
 
8.2.2. Clinical Safety Laboratory Assessments 
Timing and frequency of clinical safety laboratory tests are to be performed per standard of 
care and at any time during the study to assess any perceived safety issues. Appendix 2 
includes laboratory tests recommended to determine dosing eligibility. 
 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 


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the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition. 
 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. 
 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 
 
See Appendix 5 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury. 
 
8.2.3. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA. 
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced, and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the study intervention/study treatment. Pregnancy tests will 
also be done whenever 1 menstrual cycle is missed during the active treatment period (or 
when potential pregnancy is otherwise suspected) and at the end of the study treatment. 
Pregnancy tests may also be repeated if requested by IRBs/ECs or if required by local 
regulations. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded if the serum 
pregnancy result is positive. 
 
8.2.4. Disease Assessment 
Imaging and tumor assessments will be conducted per the site’s standard of care and will not 
be recorded in the CRF. A finding representing an AE will be recorded in the AE CRF as 
described in Section 8.3.1. 
 
8.2.5. One Month Safety Follow-up 
For follow-up procedures see SoA and Section 8. 
 
Study participants will be followed for 28 calendar days after the last administration of study 
treatment to capture any potential AEs leading to permanent study treatment 
discontinuation/SAEs. 
 
In the event a participant is unable to return to the clinic for the follow-up visit, telephone 
contact with the participant to assess AEs and treatment is expected. If laboratory 
assessments are needed to follow up unresolved AEs, retrieval of assessments performed at 
an institution local to the participant is acceptable. No further follow-up is required after the 
28 day safety reporting period. 


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8.3. Adverse Events and Serious Adverse Events 
The definitions of an AE and an SAE can be found in Appendix 3. 
 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative). 
 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
 
Each participant/parent/legal guardian/legally authorized representative will be questioned 
about the occurrence of AEs in a nonleading manner. 
 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days after the last administration of the study intervention. 
 
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment. 
 
For participants who are screen failures, the active collection period ends when screen failure 
status is determined. 
 
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn. 
 
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form. 
 
Investigators are not obligated to actively seek AEs or SAEs after the participant has 
concluded study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and he/she considers the event 
to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the CT SAE Report Form. 


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8.3.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
 
If a participant begins a new anticancer therapy, SAEs occurring during the above -indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment. Note that a switch to a commercially available version of the study intervention is 
considered as a new anticancer therapy for the purposes of SAE reporting. 
 
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF 
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF. 
 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant. 
 
If a participant begins a new anticancer therapy, the recording period for nonserious 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. Note that a switch to a 
commercially available version of the study intervention is considered as a new anticancer 
therapy for the purposes of SAE reporting. 
 
8.3.2. Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
 
8.3.3. Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). 
 
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 


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Further information on follow-up procedures is given in Appendix 3. 
 
8.3.4. Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators. 
 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
 
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements. 
 
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure 
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness. 
 
8.3.5.1. Exposure During Pregnancy 
An EDP occurs if: 
• A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 
• A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception. 
• A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental exposure during pregnancy: 
• A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion or skin contact. 
 
• A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion or skin contact then exposes his female partner prior to 
or around the time of conception. 
 
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 


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should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
• If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 5 terminal 
half-lives after the last dose. 
• If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file. 
 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedural test findings are conclusive for a congenital anomaly and the findings are 
reported). 
 
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 
 
• Spontaneous abortion including 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 study intervention. 
 
Additional information regarding the EDP may be requested by the sponsor. Further follow- 
up of birth outcomes will be handled on a case by case basis (eg, follow-up on preterm 
infants to identify developmental delays). In the case of paternal exposure, the investigator 
will provide the participant with the Pregnant Partner Release of Information Form to deliver 
to his partner. The investigator must document in the source documents that the participant 
was given the Pregnant Partner Release of Information Form to provide to his partner. 


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8.3.5.2. Exposure During Breastfeeding 
An exposure during breastfeeding occurs if: 
• A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention. 
• A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact. 
 
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file. 
 
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding. 
 
8.3.5.3. Occupational Exposure 
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE. Such persons may 
include healthcare providers, family members, and other roles that are involved in the trial 
participant’s care. 
 
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE. The information 
must be reported using the CT SAE Report Form. Since the information does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed CT SAE Report Form is maintained in the investigator site file. 
 
8.3.6. Cardiovascular and Death Events 
Not applicable. 
 
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable. 


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8.3.8. Adverse Events of Special Interest 
Not applicable. 
 
8.3.8.1. Lack of Efficacy 
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE. Refer to 
Appendix 3, Section 10.3.1 for additional information. 
 
8.3.9. Medical Device Deficiencies 
Not applicable. 
 
8.3.10. Medication Errors 
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength. 
 
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors. 
 
Safety Event 
Recorded on the CRF 
Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 
Hours of Awareness 
Medication errors 
All (regardless of whether 
associated with an AE) 
Only if associated with an SAE 
 
Medication errors include: 
• Medication errors involving participant exposure to the study intervention; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant. 
• If the dose administered is >120% of the scheduled dose, <80% of the scheduled 
dose, or dosed outside a 28 day window. If the drug is administered as incorrect 
formulation (ie, pills cut in half instead of administering a lower dosage tablet, pills 
crushed and administered via feeding tube without direction from Sponsor). 
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF. 
 
Medication errors will NOT include: 
• Cases where commercial backbone drug was used instead of supplied stock; 
• Cases where the wrong lot number of drug was dispensed; 
• Dose modifications outlined in Section 6.6. 
In the event of a medication dosing error, the sponsor should be notified within 24 hours. 


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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF. 
 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 
 
8.3.11. Protocol-Specified Serious Adverse Events 
All cases of Grade 3 or 4 mQTcF prolongation regardless of causality and treatment arm 
must be reported as an SAE for up to 28 calendar days after the last dose of study drug 
administered. All SAEs will be reported to Pfizer Safety by the investigator as described in 
previous sections, and will be handled as SAEs in the safety database. 
 
8.4. Treatment of Overdose 
For this study, an overdose is considered >120% of the scheduled dose of study treatment. 
 
There is no specific treatment for an overdose. Management of glasdegib overdose should 
include symptomatic treatment and ECG monitoring. 
 
In the event of an overdose, the investigator should: 
 
1. Contact the medical monitor within 24 hours. 
 
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of study intervention 
(whichever is longer). Closely monitor the participant for any AEs/SAEs. 
 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 
 
4. Overdose is reportable to Safety only when associated with an SAE. 
 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
 
8.5. Pharmacokinetics 
No pharmacokinetic assessments will be conducted. 
 
8.6. Pharmacodynamics 
No pharmacodynamic assessments will be conducted. 
 
8.7. Genetics 
No genetic assessments will be conducted. 


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8.8. Biomarkers 
No biomarker assessments will be conducted. 
 
8.9. Immunogenicity Assessments 
No immunogenicity assessments will be conducted. 
 
8.10. Health Economics 
No health economic assessments will be conducted 
 
9. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined below. 
 
9.1. Statistical Hypotheses 
Not applicable. 
 
9.2. Sample Size Determination 
Not applicable. 
 
9.3. Analysis Sets 
9.3.1. Safety Analysis Set 
The safety analyses of participants from Study B1371019 and participants originating from 
Parent Study B1371012 will be conducted separately and independently of each other. 
 
The safety analysis set will include all participants who receive at least one dose of study 
treatment after consenting to this Protocol Amendment 6. 
 
9.4. Statistical Analyses 
This section is a summary of the planned statistical analyses of the safety endpoints. 
 
9.4.1. Safety Endpoint(s) 
All participants who receive any study treatment (safety analysis set) will be included in the 
summaries and listings of safety data. Overall safety profile and tolerability of azacitidine or 
glasdegib + azacitidine will be characterized by type, frequency, severity, seriousness, 
timing, and relationship to study therapy of AEs. 
 
AEs will be classified using the MedDRA classification system. The severity of the toxicities 
will be graded according to the NCI CTCAE version 4.03. 
 
In all summaries, emphasis will be placed on TEAEs (events occurring from Amendment 6 
consent up to last dose + 28 days). AEs will be summarized by the frequency of participants 
experiencing TEAEs corresponding to body systems and MedDRA preferred term and by 
worst NCI CTCAE (version 4.03) grade. 


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AEs leading to permanent discontinuation of any study treatment, and SAEs will be 
considered with special attention. AE reporting, including SUSARs, will be carried out in 
accordance with applicable local regulations. Reasons for discontinuation from study 
treatment will be summarized by the frequency of participants with each reason described. 
 
Descriptive statistics ie, number of non-missing values and number of missing values (ie, n 
[missing]), mean, median, SD, minimum, maximum and first and third quartile (Q1 and Q3) 
for treatment duration ([last dose date - first dose date after Amendment 6 consent +1]/7) will 
be provided. 
 
9.5. Interim Analyses 
The interim analyses were performed prior to Amendment 6. 
 
9.6. Data Monitoring Committee or Other Independent Oversight Committee 
The EDMC was retired after study futility conclusions prior to Amendment 6. 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines; 
• Applicable ICH GCP guidelines; 
• Applicable laws and regulations, including applicable privacy laws. 
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor and submitted to an IRB/EC 
by the investigator and reviewed and approved by the IRB/EC before the study is initiated. 
 
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
 
The investigator will be responsible for the following: 
 
• Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC; 
 
• Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures; 
 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations. 
 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, 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 participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of. 


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10.1.2. Financial Disclosure 
Investigators and sub investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
 
10.1.3. Informed Consent Process 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study. The participant or his/her legally authorized representative should be given sufficient 
time and opportunity to ask questions and to decide whether or not to participate in the trial. 
 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, where applicable, and the IRB/EC or study center. 
 
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities. 
 
The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and correct his or 
her personal data and to withdraw consent for the processing of his or her personal data. 
 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICD. 
 
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study. 
 
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative. 


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10.1.4. Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
 
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law. 
 
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws. 
 
10.1.5. Dissemination of Clinical Study Data 
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs. 
 
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 results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law. 
 
EudraCT 
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements. 


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www.pfizer.com 
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are 
posted to www.clinicaltrials.gov. 
Documents within marketing authorization packages/submissions 
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015. 
 
Data Sharing 
 
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted. 
 
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes. 
 
10.1.6. Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
 
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties. 
 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) and 


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their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process. 
 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan. 
 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
 
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained. 
 
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems. 
 
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings. 
 
10.1.7. Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site. 
 
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 


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investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
 
Definition of what constitutes source data can be found in the clinical monitoring plan. 
Description of the use of computerized system is documented in the Data Management Plan. 
10.1.8. Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
 
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date. 
 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
 
The investigator may initiate study-site closure at any time upon notification to the sponsor if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants. 
 
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines; 
• Discontinuation of further study intervention development. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
 
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights. 
 
10.1.9. Publication Policy 
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 


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provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results. 
 
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors. 
 
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
 
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply. 
 
10.1.10. 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 supporting study documentation. 
 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent. The contact card contains, at a minimum, protocol and study intervention identifiers, 
participant numbers, contact information for the investigator site, and contact details for a 
contact center in the event that the investigator site staff cannot be reached to provide advice 
on a medical question or problem originating from another healthcare professional not 
involved in the participant’s participation in the study. The contact number can also be used 
by investigator staff if they are seeking advice on medical questions or problems; however, it 
should be used only in the event that the established communication pathways between the 
investigator site and the study team are not available. It is therefore intended to augment, but 
not replace, the established communication pathways between the investigator site and the 
study team for advice on medical questions or problems that may arise during the study. The 
contact number is not intended for use by the participant directly, and if a participant calls 
that number, he or she will be directed back to the investigator site. 


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10.2. Appendix 2: Clinical Laboratory Tests 
 
Clinical laboratory tests will be conducted as per standard of care at the individual Study site. 
They will not be collected in the CRF. The laboratory tests described in the table below are 
recommended to determine participant dosing eligibility. Unscheduled clinical laboratory 
measurements may be obtained at any time during the study to assess any perceived safety 
issues. As per the investigator's evaluation, if any laboratory test is determined as an AE or 
SAE, this should be reported to the Sponsor as described in Appendix 3. 
 
Hematology 
Blood Chemistry 
Urinalysis 
(microscopic analysisa) 
Coagulation 
Tests 
Hemoglobin 
ALT 
If urine dipstick is positive for 
protein, perform U/A with 
microscopy. 
If U/A with microscopy shows 
>2+ protein, collect 24-hour urine 
for protein. 
aPTT 
Platelets 
AST 
Urine dipstick positive for urine 
blood: 
Collect a U/A with microscopy 
(unless dipstick 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 
Blast Count 
Total Bilirubin 
Ketones 
BUN or Urea 
Leukocyte Esterase 
Creatinine 
Nitrite 
Uric Acid 
Glucose (non-fasting) 
Albumin 
Total Protein 
Phosphorus 
LDH 
CPK 
Bicarbonate 
a. Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase. if the dipstick is 
positive for blood, protein, nitrites and leukocytes, suggestive of UTI, then send sample for laboratory 
microscopy and culture. 
 
Investigators must document their review of each laboratory safety report. 


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1. Definition of AE 
 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE: 
• Is associated with accompanying symptoms. 
• Requires additional diagnostic testing or medical/surgical intervention. 
• Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy. 
• Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as an AE or SAE if they fulfill the definition of an AE or SAE and meet 
the requirements as per Section 8.3.8.1. Also, “lack of efficacy” or “failure of 
expected pharmacological action” does not constitute an AE or SAE. 


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Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
• Worsening of signs and symptoms of the malignancy under study should be 
recorded as AEs in the appropriate section of the CRF. Disease progression 
assessed by measurement of malignant lesions on radiographs or other methods 
should not be reported as AEs. 
 
 
10.3.2. Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 


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An SAE is defined as any untoward medical occurrence that, at any dose: 
a.  Results in death 
b. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
c.  Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e.  Is a congenital anomaly/birth defect 
f. Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, 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. 


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• Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within 
the active collection period. Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE. If the malignancy has a fatal 
outcome during the study or within the active collection period, then the event 
leading to death must be recorded as an AE on the CRF, and as an SAE with 
CTCAE Grade 5 (see the Assessment of Intensity section). 
• If the HIV-related disease has a fatal outcome during the study or within the active 
collection period, then the event leading to death must be recorded as an AE on the 
CRF and as an SAE. 
• 
Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious. The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product. The terms “suspected transmission” and “transmission” are 
considered synonymous. These cases are considered unexpected and handled as 
serious expedited cases by pharmacovigilance personnel. Such cases are also 
considered for reporting as product defects, if appropriate. 
 
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs 
 
AE and SAE Recording/Reporting 
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety. These requirements are 
delineated for 3 types of events: (1) SAEs; (2) nonserious AEs and (3) exposure to the 
study intervention under study during pregnancy or breastfeeding, and occupational 
exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must be 
completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information. 
Safety Event 
Recorded on the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness 
SAE 
All 
All 
Nonserious AE 
All 
None 


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Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure 
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding 
Occupational exposure is 
not recorded. 
All (and EDP supplemental 
form for EDP) 
Note: Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event. 
• The investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study based on NCI CTCAE Version 4.03: 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
GRADE Clinical Description of Severity 
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 


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Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
• The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
• If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements. 


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Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers. 
• If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information. 
10.3.4. Reporting of SAEs 
 
SAE Reporting to Pfizer Safety via CT SAE Report Form 
• Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety. 
• In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames. 


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10.4. Appendix 4: Contraceptive Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria 
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 180 days after the last dose of study intervention, 
which corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s) plus an additional 90 days (a spermatogenesis cycle): 
• Refrain from donating sperm. 
PLUS either: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent. 
 
OR 
 
• Must agree to use contraception/barrier as detailed below. 
• Agree to use a male condom when engaging in any activity that allows for passage of 
ejaculate to another person. 
• Use of an additional highly effective contraceptive method with a failure rate of <1% per 
year as described below in Section 10.4.4 for a female partner of childbearing potential. 
 
10.4.2. Female Participant Reproductive Inclusion Criteria 
• A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least 1 of the following conditions applies: 
 
• Is not a WOCBP (see definitions below in Section 10.4.3). 
• OR 
• Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as described 
below during the intervention period and for at least 180 days after the last dose 
of study intervention, which corresponds to the time needed to eliminate any 
reproductive safety risk of the study intervention(s). The investigator should 
evaluate the effectiveness of the contraceptive method in relationship to the first 
dose of study intervention. 
 
• Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), with high user dependency, as described below 
during the intervention period and for at least 180 days after the last dose of study 
intervention, which corresponds to the time needed to eliminate any reproductive 
safety risk of the study intervention(s). In addition, a second effective method of 
contraception, as described below, must be used. The investigator should evaluate 


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the effectiveness of the contraceptive method in relationship to the first dose of 
study intervention. 
 
A WOCBP agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during 
this period. The investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention. 
 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
 
10.4.3. Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered. 
 
Women in the following categories are not considered WOCBP: 
1. Premenarchal. 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy; 
• Documented bilateral salpingectomy; 
• Documented bilateral oophorectomy. 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
 
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study. 
 
3. Postmenopausal female: 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In addition, 
 
• high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT. 


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• Female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
 
10.4.4. Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
 
Highly Effective Methods That Have Low User Dependency 
 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation. 
2. Intrauterine device. 
3. Intrauterine hormone-releasing system. 
4. Bilateral tubal occlusion. 
5. Vasectomized partner. 
• Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days. 
 
Highly Effective Methods That Are User Dependent 
 
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
• Oral; 
• Intravaginal; 
• Transdermal; 
• Injectable. 
2. Progestogen-only hormone contraception associated with inhibition of ovulation: 
• Oral; 
• Injectable. 
3. Sexual abstinence: 
• Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be 


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evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
 
One of the following effective barrier methods must be used in addition to the highly 
effective methods listed above that are user dependent: 
• Male or female condom with or without spermicide; 
• Cervical cap, diaphragm, or sponge with spermicide; 
• A combination of male condom with either cervical cap, diaphragm, or sponge 
with spermicide (double-barrier methods). 


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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments 
Potential Cases of Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are an “adaptor” or are “susceptible.” 
 
LFTs are not required as a routine safety monitoring procedure in this study. However, 
should an investigator deem it necessary to assess LFTs because a participant presents with 
clinical signs/symptoms, such LFT results should be managed and followed as described 
below. 
 
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated within 
the same laboratory sample). In rare instances, by the time TBili elevations are detected, 
AST/ALT values might have decreased. This occurrence is still regarded as a potential DILI. 
Therefore, abnormal elevations in either AST OR ALT in addition to TBili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases 
and should always be considered important medical events, even before all other possible 
causes of liver injury have been excluded. 
 
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values: 
 
• Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available. 
• For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline: 
• Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller). 
• Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller). 


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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
 
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also 
be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology. A detailed history, including relevant information, 
such as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum samples for acetaminophen/paracetamol drug and/or protein adduct levels may be 
warranted. 
 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities. 
 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 


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10.6. Appendix 6: ECG Findings of Potential Clinical Concern 
 
ECG Findings That May Qualify as AEs 
• Marked sinus bradycardia (rate <40 bpm) lasting minutes. 
• New PR interval prolongation >280 msec. 
• New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from baseline. 
• New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm. 
• New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration. 
• Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes. 
ECG Findings That May Qualify as SAEs 
• New ST-T changes suggestive of myocardial ischemia. 
• New-onset left bundle branch block (QRS >120 msec). 
• New-onset right bundle branch block (QRS >120 msec). 
• Symptomatic bradycardia. 
• Asystole: 
• In awake, symptom-free patients in sinus rhythm, with documented periods of 
asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 
• In awake, symptom-free patients with atrial fibrillation and bradycardia with 1 
or more pauses of at least 5 seconds or longer; 
• Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm. 
• Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute). 
• Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (heart 
rate <40 bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm (such as 
torsades de pointes)). 
• Type II second-degree (Mobitz II) AV block. 
• Complete (third-degree) heart block. 


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ECG Findings That Qualify as SAEs 
• QTcF prolongation >500 msec. 
• Change in pattern suggestive of new myocardial infarction. 
• Sustained ventricular tachyarrhythmias (>30 seconds’ duration). 
• Second- or third-degree AV block requiring pacemaker placement. 
• Asystolic pauses requiring pacemaker placement. 
• Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion. 
• Ventricular fibrillation/flutter. 
• At the discretion of the investigator, any arrhythmia classified as an adverse 
experience. 


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10.7. Appendix 7: Alternative Measures During Public Emergencies 
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer. 
 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
 
Details for entering the data in the CRF are described in the CRF Completion Guidelines. 
 
10.7.1. Telehealth Visits 
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study participants at scheduled visits per the Schedule of 
Activities or unscheduled visits. Telehealth visits may be used to continue to assess 
participant safety and collect data points. Telehealth includes the exchange of healthcare 
information and services via telecommunication technologies (eg, audio, video, video- 
conferencing software) remotely, allowing the participant and the investigator to 
communicate on aspects of clinical care, including medical advice, reminders, education, and 
safety monitoring. The following assessments must be performed during a telehealth visit: 
• Review and record study intervention(s), including compliance and missed doses. 
• Review and record any AEs and SAEs since the last contact. Refer Section 8.3 and 
Appendix 3. 
• Review and record any new concomitant medications or changes in concomitant 
medications since the last contact. 
• Review and record contraceptive method and results of pregnancy testing. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. Refer to Appendix 4 and Section 10.7.2.1 of this appendix regarding 
pregnancy tests. 
Study participants must be reminded to promptly notify site staff about any change in their 
health status. 
 
10.7.2. Alternative Facilities for Safety Assessments 
10.7.2.1. Laboratory Testing 
If a study participant is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local regulations. 
The local laboratory may be a standalone institution or within a hospital. The following 
safety laboratory evaluations may be performed at a local laboratory: 
• Hematology 
• Chemistry 


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• Coagulation: PT/INR, PTT/aPTT 
• Urinalysis 
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/ 
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible. The local laboratory reports should be filed in the participant’s source 
documents/medical records. 
 
If a participant requiring pregnancy testing cannot visit a local laboratory for pregnancy 
testing, a home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL may be 
used by the participant to perform the test at home, if compliant with local regulatory 
requirements. The pregnancy test outcome should be documented in the participant’s source 
documents/medical records. Confirm that the participant is adhering to the contraception 
method(s) required in the protocol. 
 
10.7.3. Study Intervention 
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered. 
 
Study intervention may be shipped by courier to study participants if permitted by local 
regulations and in accordance with storage and transportation requirements for the study 
intervention. Pfizer does not permit the shipment of study intervention by mail. The tracking 
record of shipments and the chain of custody of study intervention must be kept in the 
participant’s source documents/medical records. 
 
The following is recommended for the administration of study intervention for participants 
who have active [confirmed (positive by regulatory authority-approved test) or presumed 
(test pending/clinical suspicion)] SARS-CoV2 infection: 
 
• For symptomatic participants with active SARS-CoV2 infection, study intervention 
should be delayed for at least 14 days from the start of symptoms. This delay is intended 
to allow the resolution of symptoms of SARS-CoV2 infection. 
• Prior to restarting treatment, the participant should be afebrile for 72 hours, and SARS- 
CoV2-related symptoms should have recovered to ≤ Grade 1 for a minimum of 72 hours. 
Notify the study team when treatment is restarted. 
• Continue to consider potential drug-drug interactions as described in Section 6.5 for any 
concomitant medication administered for treatment of SARS-CoV2 infection. 
 
10.7.4. Adverse Events and Serious Adverse Events 
If a participant has COVID-19 during the study, this should be reported as an AE or SAE and 
appropriate medical intervention provided. Study treatment should continue unless the 


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investigator/treating physician is concerned about the safety of the participant, in which case 
temporary or permanent discontinuation may be required. 
 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 


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10.8. Appendix 8: France Contrat Unique 
1. GCP Training 
Before enrolling any participants, 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 do the same before performing study related duties. For studies of 
applicable duration, the investigator and sub investigators will complete Pfizer GCP 
Training or equivalent every 3 years during the term of the study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials. 
 
2. Study Intervention 
No participants or third-party payers will be charged for study intervention. 
 
3. Urgent Safety Measures 
In addition, the investigator will inform Pfizer immediately of any urgent safety 
measures taken by the investigator to protect the study participants against any 
immediate hazard, and of any serious breaches of this protocol or of ICH GCP that 
the investigator becomes aware of. 
 
4. Termination Rights 
Pfizer retains the right to discontinue development of PF-04449913 at any time. 
 
The investigator agrees to abide by the ethical principles set forth in the World Health 
Organization’s Guiding Principles for Human Cell, Tissue and Organ Transplantation 
(WHA63.22) (http://www.who.int/transplantation/en/) with regard to the study. 


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10.9. Appendix 9: Strong and Moderate CYP3A4/5 Inducers 
 
Strong CYP3A4/5 Inducers 
Inducer 
Therapeutic Class 
Rifampin 
Antibiotics 
Ivosidenib 
Antineoplastics 
Rifapentine 
Antibiotics 
Avasimibe 
Antilipedimics 
Phenytoin 
Anticonvulsants 
Carbamazepine 
Anticonvulsants 
Phenobarbital 
Anticonvulsants 
Enzalutamide 
Antiandrogens 
Apalutamide 
Antiandrogens 
St. John’s Wort 
Herbal Medications 
Mitotane 
Antineoplastics 
Lumacaftor 
Cystic Fibrosis Treatments 
Moderate CYP3A4/5 Inducers 
Inducer 
Therapeutic Class 
Semagacestat 
Alzheimer’s Treatments 
Bosentan 
Endothelin Receptor Antagonist 
Genistein 
Food Product 
Thioridazine 
Antipsychotics 
Nafcillin 
Antibiotics 
Daclatasvir and asunaprevir and beclabuvir Antivirals 
Lopinavir 
Protease Inhibitor 
Tipranavir and ritonavir 
Protease Inhibitors 
Modafinil 
Psychostimulant 
Efavirenz 
NNRTI 
Etravirine 
NNRTI 
Lersivirine 
NNRTI 
Talviraline 
NNRTI 
PF-06282999 
Myeloperoxidase Inactivators 
Telotristat ethyl 
Antidiarrheals 
Lesinurad 
Antigout and Uricosuric Agents 
Dabrafenib 
Kinase Inhibitors 
Cenobamate 
Anticonvulsant 
Rifabutin 
Antibiotic 
Lorlatinib 
Kinase Inhibitor 
Elagolix 
GnRH Antagonist 
Source: University of Washington Drug Interaction Database. “Copyright University of Washington 2005- 
2018, UW Metabolism and Transport Drug Interaction Database, Oct2020”. 


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10.10. Appendix 10: 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 
VIEKIRA PAK 
Antivirals 
Elvitegravir/Ritonavir 
Treatment of AIDS 
LCL161 
Cancer treatment 
Idelalisib 
Kinase Inhibitors 
Ribociclib 
Kinase Inhibitors 
Grapefruit Juice DS 
Food Products 
Mifepristone 
Antiprogestins 
Ceritinib 
Kinase Inhibitor 
Tucatinib 
Kinase Inhibitor 
Source: University of Washington Drug Interaction Database. “Copyright University of Washington 2005 
2018. UW Metabolism and Transport Drug Interaction Database, October 2020.” 


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10.11. Appendix 11: Moderate CYP3A4/5 Inhibitors 
 
Moderate CYP3A4/5 Inhibitors 
Inhibitor 
Therapeutic Class 
Fluconazole 
Antifungals 
Ravuconazole 
Antifungals 
Isavuconazole 
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 
Letermovir 
Antivirals 
Crizotinib 
Kinase Inhibitor 
Nilotinib 
Kinase Inhibitor 
Atazanivir/Ritonavir 
Protease Inhibitor 
Darunavir 
Protease Inhibitor 
Darunavir/Ritonavir 
Protease Inhibitor 
Atazanavir 
Protease Inhibitor 
Fedratinib 
Kinase Inhibitor 
Imatinib 
Antineoplastic agent 
GSK2647544 
Alzheimer's Disease & Dementia Treatments 
Grapefruit Juice 
Food Products 
Duvelisib 
Kinase Inhibitor 
ACT-539313 
Hypnotic - Sedative 
Lefamulin 
Antibiotic 
Istradefylline 
Other Antiparkinsonians 
Voxelotor 
Hemoglobin S Polymerization Inhibitor 
Source: University of Washington Drug Interaction Database. “Copyright University of Washington 2005- 
2018. UW Metabolism and Transport Drug Interaction Database, October 2020.” 


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10.12. Appendix 12: List of Drugs with Known Risk of Torsade de Pointes 
The following drugs are known to have the risk of Torsade de Pointes due to QTc 
prolongation and their current use in combination with glasdegib is not recommended. If any 
of these drugs are considered to be medically necessary, then they should be used with 
caution in combination with glasdegib. 
 
Generic Name 
Drug Class 
Therapeutic Use 
Route 
Aclarubicin (Only on 
Non US Market) 
Anti-cancer 
Cancer 
injection 
Amiodarone 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral, 
injection 
Anagrelide 
Phosphodiesterase 
3 inhibitor 
Thrombocythemia 
oral 
Arsenic trioxide 
Anti-cancer 
Leukemia 
injection 
Astemizole 
(Removed from 
Market) 
Antihistamine 
Allergic rhinitis 
oral 
Azithromycin 
Antibiotic 
Bacterial infection 
oral, 
injection 
Bepridil 
(Removed from 
Market) 
Anti-anginal 
Heart pain 
oral 
Chloroquine 
Anti-malarial 
Malaria infection 
oral 
Chlorpromazine 
Anti-psychotic/Anti-emeti 
c 
Schizophrenia, 
nausea, many others 
oral, 
injection, 
suppositor 
y 
Cilostazol 
Phosphodiesterase 
3 inhibitor 
Intermittent 
claudication 
oral 
Ciprofloxacin 
Antibiotic 
Bacterial Infection 
oral, 
injection 
Cisapride 
(Removed from 
market) 
GI stimulant 
Increase GI motility 
oral 
Citalopram 
Anti-depressant, SSRI 
Depression 
oral 
Clarithromycin 
Antibiotic 
Bacterial infection 
oral, 
inhaled 
Cocaine 
Local anesthetic 
Anesthesia (topical) 
oral, nasal 
Disopyramide 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral, 
injection 
Dofetilide 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral 


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Generic Name 
Drug Class 
Therapeutic Use 
Route 
Domperidone (Only on 
Non US market) 
Anti-emetic 
Nausea, vomiting 
oral, 
injection, 
suppositor 
y 
Donepezil 
Cholinesterase inhibitor 
Dementia 
(Alzheimer’s 
Disease) 
oral 
Dronedarone 
Anti-arrhythmic 
Atrial Fibrillation 
oral 
Droperidol 
Anti-psychotic/Anti-emeti 
c 
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 (Removed 
from market) 
Antibiotic 
Bacterial infection 
oral, 
injection 
Grepafloxacin 
(Removed from 
market) 
Antibiotic 
Bacterial infection 
oral 
Halofantrine (Only on 
Non US market) 
Anti-malarial 
Malaria infection 
oral 
Haloperidol 
Anti-psychotic 
Schizophrenia, 
agitation 
oral, 
injection 
Hydroquinidine 
Anti-arrhythmic 
Arrhythmia 
oral 
Ibogaine (Only on Non 
US market) 
Psychedelic 
Narcotic addiction, 
unproven 
oral 
Ibutilide 
Anti-arrhythmic 
Abnormal heart 
rhythm 
injection 
Levofloxacin 
Antibiotic 
Bacterial infection 
oral, 
injection 
Levomepromazine 
(methotrimeprazine) 
(Only on Non US 
Market) 
Anti-psychotic 
Schizophrenia 
oral, 
injection 
Levomethadyl acetate 
(Removed from 
market) 
Opiate 
Narcotic dependence 
oral 
Levosulpiride (Only on 
Non US market) 
Anti-psychotic 
Schizophrenia 
oral, 
injection 


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Generic Name 
Drug Class 
Therapeutic Use 
Route 
Mesoridazine 
(Removed from 
market) 
Anti-psychotic 
Schizophrenia 
oral 
Methadone 
Opiate 
Pain control, narcotic 
dependence 
oral, 
injection 
Meglumine Antimonite 
Anti-parasitic 
Leishmaniasis 
injection 
Moxifloxacin 
Antibiotic 
Bacterial infection 
oral, 
injection 
Nifekalant 
Anti-arrhythmic 
Arrhythmia 
oral 
Ondansetron 
Anti-emetic 
Nausea, vomiting 
oral, 
injection 
Oxaliplatin 
Anti-cancer 
Cancer 
injection 
Papaverine HCl (Intra- 
coronary) 
Vasodilator, Coronary 
Diagnostic adjunct 
injection 
Pentamidine 
Anti-fungal 
Pneumocystis 
pneumonia 
injection, 
inhaled 
Pimozide 
Anti-psychotic 
Tourette's tics 
oral 
Probucol 
(Removed from 
market) 
Antilipemic 
Hypercholesterolemi 
a 
oral 
Procainamide 
Anti-arrhythmic 
Abnormal heart 
rhythm 
injection 
Propofol 
Anesthetic, general 
Anesthesia 
injection 
Quinidine 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral, 
injection 
Roxithromycin (Only 
on Non US market) 
Antibiotic 
Bacterial infection 
oral 
Sevoflurane 
Anesthetic, general 
Anesthesia 
inhaled 
Sertinidole 
Anti-psychotic 
Schizophrenia, 
anxiety 
oral 
Sotalol 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral 
Sparfloxacin 
(Removed from 
market) 
Antibiotic 
Bacterial infection 
oral 
Sulpiride 
(Only on Non US 
market) 
Anti-psychotic, atypical 
Schizophrenia 
oral, 
inhaled 
Sultopride (Only on 
Non US market) 
Anti-psychotic, atypical 
Schizophrenia 
oral, 
injection 
Terfenadine 
(Removed from 
market) 
Antihistamine 
Allergic rhinitis 
oral 


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Generic Name 
Drug Class 
Therapeutic Use 
Route 
Terlipressin (Only on 
Non US market) 
Vacoconstrictor 
Septic shock 
injection 
Terodiline (Only on 
Non US market) 
Muscle relaxant 
Bladder spasm 
oral 
Thioridazine 
Anti-psychotic 
Schizophrenia 
oral 
Vandetanib 
Anti-cancer 
Thyroid cancer 
oral 
Source: CredibleMeds.org (http://crediblemeds.org/healthcare providers/drug list/?rf=All). TdP risk 
category filtered on Drugs with known TdP risk. December 2020. 


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10.13. Appendix 13: Protocol Amendment History 
The protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the TOC. The protocol amendment summary of changes tables for past 
amendment(s) can be found below: 
 
Document History 
Document 
Version Date 
Summary and Rationale for Changes 
Amendment 5 
12 April 2019 
Note that 2 tables have been removed from the 
introduction section, resulting in updated table 
numbers. 
Schedule of Activities: 
Tables 1 and 3, Footnote 1: clarify that 
assessments performed as standard of care within 
28 days of randomization do not need to be 
repeated to be used for screening. 
Tables 1 and 3, Footnote 4: clarified that Response 
Assessment includes assessment of EMD (eg, 
disease in CSF). 
Table 1, Footnotes 6 and 7: clarified that weekly 
hematology and chemistry tests must continue 
weekly until the next phase of study/treatment 
begins. 
Table 1, Footnote 14 and Table 3, Footnote 13: 
Morning dosing of therapy is preferred but not 
mandatory, rationale for change added to Section 
5.5.1.1. 
Tables 1 and 3, Deleted individual rows for each 
Patient Reported Outcome survey since they are 
administered together and are outlined in footnote 
and Section 7.4. 
Table 1, Footnote 32 and Table 3, Footnote 36: 
added “if able” to the PRO collection during 
HSCT period. 
Table 3 and Section 5.5.1.3: Participants enrolled 
in the Non Intensive study may undergo HSCT per 
local standard of care and at the Investigator’s 
discretion. 
Table 1, Footnotes 26, 27, 38 and Table 3, 
Footnotes 24, 25, 31: Updated with text related to 
China samples. 


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Document History 
Document 
Version Date 
Summary and Rationale for Changes 
Table 1, Footnote 19, Table 3, Footnote 16 and 
Section 7.2.3: Bone marrow assessments within 3 
weeks of growth factor administration are 
evaluable and do not need to be repeated. Original 
text that these BM assessments would not be 
considered evaluable has been deleted. 
Introduction: Background (Section 1.2) and 
Rationale sections have been separated and 
updated to reflect current data and IB. 
Removed Nonclinical Toxicology text 
(Section 1.2.3). 
Clinical Development (Section 1.2.4): Removed 
Table 5 and Table 6. Safety and Efficacy sections 
removed and new section inserted describing 
Glasdegib Clinical Pharmacology. Updates to 
relevant clinical studies with glasdegib made to 
provide relevant background. Data from thorough 
QTc study included. 
Section 4.2, Inclusion/Exclusion: 
Inclusion #1: Clarified that participants with 
FLT3+ AML not receiving and not intended to 
receive a FLT3 inhibitor during study participation 
are allowed per regulatory agreement. 
Inclusion #5: Removed ATRA since it is meant to 
treat APL and removed anageride. Text added, 
continuation or resumption of hydroxyurea or 
leukapheresis after described time period must be 
approved by the Sponsor. 
Exclusion #1: Clarified that APL is associated 
with t(15;17). 
Exclusion #2: Clarified that the mutation must be 
known. 
Exclusion #4: QTc exclusion does not apply to 
participants with cardiac pacemaker. 
• Exclusion #14: Removed local radiation as 
an excluded treatment modality during the 
screening period. 


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Document History 
Document 
Version Date 
Summary and Rationale for Changes 
Section 4.3: Text added defining Screen Failures 
as participants who consent to participate in the 
clinical study but are not subsequently 
randomized. Added data collection required for 
Screen Failure participants. 
Section 4.4.1: Text updated to require one method 
of birth control, consistent with sponsor 
requirements. Language added to clarify 
Investigator responsibility for reproductive 
capability assessment. 
Table 6: Updated to include abstinence. 
Section 4.4.2: Added to provide postmenopausal 
definition. 
Section 5.2 Breaking the Blind: Text now reflects 
that CRF does not collect Break blind data, but 
that this will be documented within the source. 
Additionally, participants may not continue on 
study treatment once an investigator breaks the 
blind for that participant. 
Section 5.5.1.2: Clarification text added regarding 
the timing and terms of bone marrow assessments. 
Section 5.5.2: Adverse events and concomitant 
medications will not be collected during long-term 
follow-up. 
Table 10 Glasdegib/placebo Dose Modifications 
for mean QTcF Prolongation: updated in 
alignment with the USPI. Also added comment 
that mQTcF dose mods do not apply to 
participants with cardiac pacemakers. 
Figure 2: Updated for clarity and to align terms 
with CRF fields. 
Figure 3: Updated with addition of option for 
HSCT. 
Section 5.8.1: Removed requirement of discussion 
with Medical Monitor for the concomitant use of 
CYP3A4 inhibitors/inhibitors. 
Section 5.8.2.2: Removed text requiring a repeat 
BM assessment if done within 3 weeks from last 


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Document History 
Document 
Version Date 
Summary and Rationale for Changes 
dose of growth factor. Growth factors may be 
given per local standard of care and local label. 
Section 6.4, Table 1, Footnote 31 and Table 3, 
Footnote 29: Text added regarding the use of 
public records for long term survival follow-up as 
allowed by local law. 
Section 7.2.1: Additional text describing the AML 
response assessment added for clarity. 
Section 7.2.2: Text added allowing post baseline 
genetic assessments to be limited to abnormalities 
noted at baseline and molecular assessments to 
follow standard of care. 
CCI 
Add Section 7.3.2: Biomarker Assessments: 
Updated to reflect current biomarker plans. 
Section 7.4: Updates to account for hospitalized 
participant schedules, participants with visual 
problems, and clarification that for patients 
hospitalized or with a timepoint falling on a 
weekend or holiday, PRO questionnaires may be 
performed on the next business day. 
Section 7.1.4: Re-screening is allowed. 
Section 9: 
9.1 : clarified percentage of patients censored for 
OS used in the sample size determination. 
9.2 : clarified all analyses of intensive and 
nonintensive chemotherapy participants will be 
conducted separately and independently of each 
other. 
9.3.1 : added region (rest of world versus China) as 
a stratification factor to the primary and secondary 
analyses for intensive patients due to potentially 
different rates of stem cell transplantation. 
9.3.2 : clarified all secondary PRO and efficacy 
endpoints will be based on the full analysis set 
unless stated otherwise; clarified method for 
calculating confidence intervals for binary efficacy 


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Document History 
Document 
Version Date 
Summary and Rationale for Changes 
endpoints; removed Kaplan-Meier analysis for 
time to response as analysis is for responders only; 
clarified censoring for those without event-free 
survival events; clarified which event-free survival 
methods are for responders only. 
9.4: clarified transfusion conversion rate is 
analyzed in the safety analysis set. 
9.5.1: clarified safety analyses are analyzed in both 
intensive and non-intensive studies. 
9.7: clarified DMC will convene at least once 
yearly per DMC charter. 
Clarified throughout document that restarting 
glasdegib/placebo Post HSCT requires no ongoing 
≥ Grade 2 GVHD. 
Section 14: Added text regarding options for 
Non-Intensive participants to continue treatment at 
study end. 
Appendix 1: Added abbreviation for HGRAC. 
Appendix 4: Updates for clarity and readability. 
Appendices 5, 6, 7, 8 and references updated. 
General spelling, grammar, repetitions and 
formatting corrected. 
Amendment 4 
02 July 2018 
Amendment 4 changes will be applicable to 
participants enrolling in Germany. 
German ethics committee requested collection of 
unrelated SAEs during the HSCT period. This edit 
was made in Section 8.1. 
Section 9.5.1: deleted text impacted by update to 
Section 8.1. 
Amendment 3 
01 March 2018 
All changes were made prior to start of the study 
in response to regulatory requests except where 
indicated. Other minor changes were added for 
clarity. 
Added BRIGHT AML1019 study logo to cover 
page. 


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Document History 
Document 
Version Date 
Summary and Rationale for Changes 
Endpoints: clarified response definition by 
defining CRi or better to include CR (including 
CRMRD-negative) or CRi for intensive chemotherapy 
participants, and CR (including CRMRD-negative), 
CRh, or CRi for non-intensive chemotherapy 
participants. CRh or better is only defined for 
non-intensive chemotherapy participants as CR 
(including CRMRD-negative) or CRh. Also updated 
Section 9.3 (and subsections) and Appendix 4 with 
these definitions. 
Schedule of Activities: 
• Clarified that bone marrow assessments for 
study assessments other than disease 
classification must be done after informed 
consent signed in footnotes, as specified in 
the Protocol Administrative Change Letter, 
dated 20 Dec 2017. 
• Added whole blood collection for 
immunophenotyping and molecular 
profiling on Day 1, prior to dosing study 
drug to provide a baseline sample to 
compare to future samples for MRD 
assessment. 
• Removed whole blood collection for 
pharmacogenomic analysis from intensive 
and non-intensive chemotherapy studies 
because pharmacogenomic analysis of drug 
metabolizing enzymes and transporters was 
no longer a priority for this study as it was 
unlikely to provide valuable information 
that would inform either safety or efficacy. 
Also removed Section in protocol defining 
this analysis. 
• Added additional times when bone marrow 
samples must be collected post 
consolidation for the Intensive Study so 
MRD status may be confirmed in a timely 
manner. 
• Table 3: blood chemistry deleted from 
follow-up visits; added in error. 


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Document History 
Document 
Version Date 
Summary and Rationale for Changes 
Section 1.2.3: Edited text for glasdegib nonclinical 
toxicity to align with updated data. 
Inclusion criterion #5: specified anti-cancer agents 
for clarity in response to regulatory request. 
Exclusion criteria #7: removed right bundle branch 
blocks as this is common and it should not be 
excluded. 
Section 4.3.1: Added a requirement for a backup 
contraception method in response to regulatory 
request. 
Section 5.4.1.3: removed subcutaneous route for 
cytarabine since this will not be an option. 
Removed term allogeneic because either 
autologous or allogeneic HSCT is allowed during 
the Intensive Chemotherapy Study per regulatory 
feedback. 
Section 5.8.1: re-organized CYP3A4/5 inducers so 
bullet appears under proper heading. 
Table 11 now specifies that glasdegib/placebo 
should be permanently discontinued for all cases 
of confirmed DILI/Hy’s Law and potential cases 
require glasdegib/placebo dose interruption and 
potential restarting. Added in response to 
regulatory request. 
Table 14 now includes required bicarbonate testing 
to determine dose reductions per azacitidine label, 
per regulatory request. Also clarified indication for 
U/A with microscopic evaluation and 24-hour 
urine protein. 
Sections 7.1.7: removed additional QTc 
monitoring requirements if a moderate/strong 
CYP3A4/5 inhibitor or TdP drug administered 
during study since additional monitoring was not 
required. 
Section 9.3: Changes in the PRO section were 
made to improve clarity regarding planned 
analyses per regulatory request. Other changes 


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Document History 
Document 
Version Date 
Summary and Rationale for Changes 
clarified method by which response will be 
analyzed. 
Removed section specifying end of trial in a 
member state because LSLV will be considered 
the end of trial in all participating countries. 
Removed due to regulatory request. 
Appendix 16 added per country specific 
requirement in France. 
General spelling, grammar, and consistency issues 
corrected throughout the protocol. 
Amendment 2 
15 November 
2017 
All changes were made prior to start of the study 
in response to FDA request except where 
indicated. Other minor changes were added for 
clarity. 
Secondary endpoints updated: 
• CR/CRh was added to duration of response 
assessment to match statistical analysis section. 
• CR/CRh was added to time to response 
assessment to match statistical analysis section. 
• Schedule of Activities (Intensive study): 
Pregnancy testing added for Day 1 of each 
Consolidation Cycle with single agent cytarabine 
and Day 1 of each cycle where single agent 
glasdegib/placebo administered to ensure 
appropriate safety monitoring. 
• Schedule of Activities (Intensive and 
Nonintensive studies): 
Immunophenotyping was removed because it is 
not required for any study analysis. 
Immunophenotyping was also removed from 
Sections 7.1 and 7.2.2 for consistency. 
X’s added to tables so tables now match footnotes 
indicating specified instances AEs and SAEs may 
be collected during the follow-up period. 
Table 2 and Table 4 now provide time windows 
for assessments allowing sites flexibility in 
obtaining assessments without jeopardizing data. 


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Document History 
Document 
Version Date 
Summary and Rationale for Changes 
Other minor footnote clarifications to ensure 
consistency with tables. 
Inclusion Criterion #4: removed bullet indicating 
that the criterion does not apply to participants 
with bundle branch blocks and is otherwise 
asymptomatic. This conflicted with an exclusion 
criterion and was confusing. 
Exclusion Criterion #4: specified that a participant 
could not participate in other clinical studies 
involving other investigational drugs to clarify that 
this did not apply to glasdegib in this study. 
Section 5.4.1.2: Reduced the text describing the 
azacitidine supply to match information supplied 
for other chemotherapy drugs in this study. Edits 
added for clarity, instructing sites to follow local 
regulations. 
Section 5.5.5 updated per FDA request to provide 
more information regarding glasdegib/placebo 
dose modifications. 
• Corrected typographical error in 
Section 5.5.5.1 indicating that 
glasdegib or placebo does not need to 
be delayed or dose reduced for 
hematologic, study treatment related 
toxicity. 
• Specified dose escalations will not be 
allowed following glasdegib/placebo 
dose reductions. 
• Added Section 5.5.5.2 for dosing 
interruptions for glasdegib/placebo 
non-hematological toxicities. 
• Section 5.8.1: corrected a typographical error, 
removing word permitted. 
Section 7.1.3: Added text specifying that 
assessment of acute GVHD will be graded by 
standard criteria based on the Consensus 
conference on acute GVHD grading and 
assessment of chronic GVHD will be assessed 
based on the NIH criteria with associated 


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Document History 
Document 
Version Date 
Summary and Rationale for Changes 
references. Grading and Staging for acute GVHD 
is summarized in Appendix 15. 
• Section 7.1.4: Clarified that laboratory tests 
only need to be obtained during screening, and 
there is no need to repeat these tests on Day 1 
if performed within 3 days prior to 
randomization. 
• Section 7.1.7: specified type of ECGs (supine) 
for clarity. 
• Section 7.4.3 updated per FDA request: 
• Changed PGIS from a 7 point scale to a 4 point 
scale. The FDA recommended that Pfizer 
revise the PGIS to 4 response options (eg, 
absent (no symptoms), mild, moderate, and 
severe) so patients can easily distinguish 
severity. 
• Section 9.2.5: updated for clarity; now 
specifies Intensive and Nonintensive studies. 
• Section 9.3.2: updated per FDA request, 
specifying type of analysis required for fatigue 
and to correct minor errors. 
This section also includes an update to correct a 
typographical error: Method 1 sensitivity analysis 
for EFS must include CRi and Method 4 must not 
include CRi for the Intensive Study. 
For the Nonintensive study, Method 2 for the EFS 
definition now specifies CR or CRi will be 
evaluated following up to 6 cycles of therapy. 
Now specifies the Brookmeyer and Crowley 
method will be used to evaluate EFS for clarity. 
PK Parameters now specify Ctrough will be reported 
for glasdegib metabolites, if relevant. Though 
there is no activity anticipated for the N-desmethyl 
metabolite (M3) that is <10% in circulation; 
possible metabolite measurement is added, if 
applicable as a conservative approach. 


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Version Date 
Summary and Rationale for Changes 
Appendix 4 updated to match data analysis section 
for consistency: 
• Absence of CRh added to SD 
definition. 
• Treatment failure definitions added for 
Intensive and Non-intensive studies. 
• Appendix 11 updated to address FDA 
comments: 
PGIS now includes question regarding leukemia 
symptoms. 
General spelling, grammar, and consistency issues 
corrected throughout the protocol. 
Amendment 1 
19 September 
2017 
All changes were made prior to start of the study 
and made per FDA comments except where 
indicated. Other minor changes were added for 
clarity. 
Schedule of Activities for the Intensive and 
Non-intensive Studies and applied throughout 
protocol: 
• For bone marrow assessments, bone marrow 
aspirates are required; however, we now added 
preference for bone marrow biopsies in 
addition to aspirates. In the event of an 
inadequate aspirate, a bone marrow biopsy is 
required. 
• Baseline genetics edits made for clarification 
that known genetics at the time of 
randomization will be used to stratify 
participants. 
• Red blood cell and platelet transfusion history 
required 8 and not 24 weeks prior to 
randomization for the nonintensive study only. 
• Added windows for follow-up assessments. 
Schedule of Activities for the Intensive Study 
only: 


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Document History 
Document 
Version Date 
Summary and Rationale for Changes 
• Removed collection of prior transfusions; only 
collect during study. 
• Changed from every 28 day to weekly 
chemistries. 
• Consolidation with cytarabine changed from 
13 g/m2 to 3 g/m2 for adults <60 years and 
1 g/m2 for adults ≥60 years. 
• Following HSCT, participants will not be 
allowed to have ≥Grade 2 GVHD before 
resuming glasdegib/placebo. 
PGIC not collected at baseline for non-intensive 
study, updated as a correction 
Table 2: Made a correction by adding the time, 
1 hour post-dose, for the column labeled 
“Glasdegib following chemotherapy”. 
Cycle ≥1, Day 1 
Secondary Endpoint (Section 2 and throughout 
protocol): added CR with partial hematologic 
recovery (CRh) for the Non-intensive study only. 
CCI 
Inclusion Criterion 5: removed one single dose of 
Ara-C of up to 2 grams for control of blasts 
counts. 
Exclusion Criterion 10: clarified that dose 
equivalent of ≥550 mg/m2 of daunorubicin is a 
criterion for the Intensive Chemotherapy study 
only. 
Dose Modifications (Section 5.5.5): clarified 
glasdegib or placebo does not be delayed or dose 
reduced for Grade 3/Grade 4 nonhematologic, 
study treatment related toxicity and should be 
permanently discontinued if interruptions are for 
more than 28 consecutive days. 
Concurrent administration of herbal preparations 
prohibited (Section 5.8.1), added as a clarification 
since it is already an exclusion criterion. 


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Document History 
Document 
Version Date 
Summary and Rationale for Changes 
Prophylactic Intrathecal Chemotherapy allowed 
per investigator discretion in Permitted 
Concomitant Medications in Section 5.8.2. 
Efficacy Assessments (Section 7.2) now includes 
definition for CR with partial hematologic 
recovery for the Non-intensive study. 
Immunophenotyping and Genetics (Section 7.2.2) 
clarifications added regarding requirement to 
stratify based on known genetic risk classification 
at the time of randomization. 
Section 9.3.2: Added updated definitions for EFS 
and includes CR/CRh as response (in duration of 
response and time to response endpoints) for the 
nonintensive study. Added additional sensitivity 
analyses for EFS. 
Appendix 4: Added response definition for CRh 
and clarified CRi requires either criteria for 
residual neutropenia or thrombocytopenia must be 
met. 
Appendix 14: added ELN Risk Stratification by 
Genetics table. 
General spelling and grammar issues corrected. 
CCI 
Original 
protocol 
27 July 2017 
N/A 


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10.14. Appendix 14: Letters Sent to Investigators After Amendment 5 
The following letters were sent to investigators after Amendment 5, but the content of the 
letters are no longer relevant in this amendment: 
Letter dated 12 Jun 2019 
Letter dated 09 Apr 2020 


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10.15. Appendix 15: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
APL 
acute promyelocytic leukemia 
aPTT 
activated partial thromboplastin time 
Ara-C 
cytarabine 
AST 
aspartate aminotransferase 
ATRA 
all-trans retinoic acid 
AUC 
area under the plasma concentration curve 
AUCinf 
area under the plasma concentration-time profile from time 0 to 
infinity 
AV 
atrioventricular 
BM 
bone marrow 
BST 
Best Supportive Therapy 
BUN 
blood urea nitrogen 
Ca 
calcium 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
Cmax 
maximum plasma concentration 
CMML 
chronic myelomonocytic leukemia 
COVID-19 
Coronavirus Disease 2019 
CPK 
creatine phosphokinase 
CR 
complete remission 
CRF 
case report form 
CRh 
complete remission with partial hematologic recovery 
CRi 
complete remission with incomplete hematologic recovery 
CRMRD-neg 
complete remission with negative minimal residual disease 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
CT 
Clinical Trial 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
plasma trough concentration 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid 
DU 
dispensable units 


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Abbreviation 
Term 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDP 
Exposure During Pregnancy 
EDMC 
External Data Monitoring Committee 
EFS 
event-free survival 
ELN 
European Leukemia Net 
EMA 
European Medicines Agency 
EMD 
Extra Medulary Disease 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration (United States) 
FLT3-ITD 
fms-like tyrosine kinase internal tandem duplication 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GGT 
gamma-glutamyl transferase 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
GnRH 
gonadotropin-releasing hormone 
GVHD 
graft-versus-host disease 
HDPE 
high-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HGRAC 
Human Genetics Resources Administration of China 
Hh 
Hedgehog 
HI 
hematologic improvement 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
HSCT 
hematopoietic stem cell transplant 
IB 
Investigator’s Brochure 
ICD 
informed consent document 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IND 
investigational new drug application 
INR 
international normalized ratio 
INT 
intensive 
IP 
investigational product 
IPAL 
Investigational Product Accountability Log 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IWR 
Interactive Web Response 


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Abbreviation 
Term 
IV 
intravenous 
IVR 
Interactive Voice Response 
K 
potassium 
LDAC 
low dose cytarabine 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LIC 
lead-in cohort 
LS 
least squares 
LSLV 
last subject last visit 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
magnesium 
mQTcF 
mean QTcF 
MRD 
minimal residual disease 
NA 
not applicable 
Na 
sodium 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NIMP 
non-investigational medicinal product 
NINT 
non-intensive 
NNRTI 
non-nucleoside reverse transcriptase inhibitors 
OS 
overall survival 
PD 
pharmacodynamics 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Symptoms 
PK 
Pharmacokinetics 
PRO 
patient reported outcomes 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
PVC 
premature ventricular contraction/complex 
Q 
quartile 
QD 
once a day 
QTc 
corrected QT 
QTcF 
corrected QT (Fridericia method) 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV2 
severe acute respiratory syndrome coronavirus 2 
SC 
Subcutaneous 
SD 
standard deviation 
SoA 
schedule of activities 
SOP 
standard operating procedure 


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Abbreviation 
Term 
SPC 
Summary of Product Characteristics 
SRSD 
single reference safety document 
SSRI 
selective serotonin reuptake inhibitor 
SUSAR 
suspected unexpected serious adverse reactions 
TBili 
total bilirubin 
TdP 
Torsade de Pointes 
TEAE 
treatment emergent adverse event 
TOC 
Table of Contents 
U/A 
urinalysis 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
UTI 
urinary tract infection 
UVB 
ultraviolet B light 
UV 
University of Washington 
Vit 
vitamin 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential 


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11. REFERENCES (Not Applicable) 

SAP_001.pdf: 
Protocol B1371019 glasdegib (PF-04449913) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol B1371019  
A MULTI-CENTER CONTINUATION STUDY EVALUATING AZACITIDINE
WITH OR WITHOUT GLASDEGIB (PF-04449913) IN PATIENTS WITH
PREVIOUSLY UNTREATED ACUTE MYELOID LEUKEMIA,
MYELODYSPLASTIC SYNDROME OR CHRONIC MYELOMONOCYTIC
LEUKEMIA
Statistical Analysis Plan 
(SAP)
Version:
6.0
Date:
19-May-2021


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TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
LIST OF TABLES.....................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................5
2.1. Study Objective.........................................................................................................5
2.2. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................6
3.1. Efficacy Endpoint......................................................................................................6
3.2. Baseline Variables.....................................................................................................6
3.2.1. Stratification .................................................................................................6
3.3. Safety Endpoints .......................................................................................................6
3.3.1. Adverse Events.............................................................................................6
3.3.2. Laboratory Data............................................................................................6
4. ANALYSIS SETS .................................................................................................................7
5. GENERAL METHODOLOGY AND CONVENTIONS......................................................7
5.1. Hypotheses and Decision Rules ................................................................................7
5.2. General Methods .......................................................................................................7
5.2.1. Pooling of Data by Center ............................................................................7
5.2.2. Definition of Study Day................................................................................7
5.2.3. Definition of Cycle and Cycle Day ..............................................................8
5.2.4. Date of Last Contact .....................................................................................8
5.2.5. Disease Assessment Date .............................................................................8
5.2.6. Unscheduled Assessments............................................................................8
5.2.7. Standard Derivations and Reporting Conventions .......................................8
5.2.8. Analyses for Continuous Data......................................................................9
5.2.9. Analyses for Categorical Data......................................................................9
5.2.10. Analyses for Time to Event Data................................................................9
5.3. Methods to Manage Missing Data ............................................................................9
5.3.1. Missing Dates ...............................................................................................9
5.3.2. Missing Toxicity Grade of Adverse Events................................................11
5.3.3. Missing Pharmacokinetic (PK) Data ..........................................................12


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5.3.4. Missing ECG Data......................................................................................12
5.3.5. Missing Biomarker Data.............................................................................12
6. ANALYSES AND SUMMARIES ......................................................................................12
6.1. Efficacy Endpoint....................................................................................................12
6.2. Baseline and Other Summaries and Analyses.........................................................12
6.2.1. Baseline Summaries....................................................................................12
6.2.2. Study Conduct and Patient Disposition......................................................12
6.2.3. Study Treatment Exposure .........................................................................13
6.2.4. Concomitant Medications and Non-Drug Treatments................................14
6.2.5. Prior and Subsequent Anti-Cancer Therapies/Procedures..........................14
6.3. Safety Summaries and Analyses .............................................................................14
6.3.1. Adverse Events...........................................................................................14
6.3.2. Deaths .........................................................................................................16
6.3.3. Laboratory Data..........................................................................................16
6.3.4. Electrocardiogram.......................................................................................16
6.3.5. Physical Examination .................................................................................16
6.3.6. Left Ventricular Ejection Fraction (LVEF) ................................................16
6.3.7. Performance Status.....................................................................................16
6.3.8. Hospitalization............................................................................................16
7. INTERIM ANALYSES.......................................................................................................16
8. REFERENCES ....................................................................................................................17
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments....................................4


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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B1371019 is based on Protocol 
Amendment #6 dated 02 Feb2021. 
Table 1.
Summary of Major Changes in SAP Amendments
SAP 
Version
Change
Rationale
1
Not Applicable
Not Applicable
2
The PRO sections were
revised following 
comments from FDA.
Minor clarifications were 
made in other sections.
Following Protocol Amendment #2
3
The Pharmacogenomics 
Analysis Set was 
removed. 
Clarification regarding 
select endpoints were 
made (CRi or better, and 
CRh or better).
Add analysis method for 
China subset patients.
Following Protocol Amendment #3 and 
satisfying CFDA requirement
4
Region (rest of world 
versus China) added as a 
stratification factor to the 
applicable efficacy 
analyses for the intensive 
study.
Updated the definition of 
“on-treatment” for 
assessments and 
treatment-emergent 
adverse events.
Following Protocol Amendment #5
5
Add OS subgroup 
analysis.
Add sensitivity analyses
for handling potential 
missing or unclean data
due to COVID-19.
Following FDA feedback
6
SAP is updated 
throughout. 
Following Protocol Amendment #6


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The efficacy analysis is
no longer applicable.
The safety analysis will 
be conducted for 
B1371019 and B1371012
separately and 
independently. 
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the 
safety data collected in study B1371019 Protocol Amendment 6. This analysis plan is meant
to supplement the study protocol. Any deviations from this analysis plan will be described in 
the Clinical Study Report.
The purpose of Protocol Amendment 6 is to provide continued access to study intervention
(azacitidine with or without glasdegib), and collection of safety data for eligible participants
who continue to derive a clinical benefit from study treatment in studies B1371019 and
B1371012. The safety analyses of participants from Study B1371019 and participants 
originating from Parent Study B1371012 will be conducted separately and independently.
The safety analysis set will include all participants who receive at least one dose of study
treatment after consenting to Protocol Amendment 6.
2.1. Study Objective
Type
Objectives
Endpoints
Additional 
Definitions
Analyses and 
Summaries
Safety
To monitor the safety and 
tolerability of the investigational 
drugs in participants continuing 
study intervention from this study 
and participants originating from 
Parent Study B1371012.
All AEs 
and SAEs
Section 3.3
Section 6.3.1
2.2. Study Design
Study design is as described in the B1371019 Protocol (Amendment 5, 12 April 2019) and 
Study B1371012 Protocol (Amendment 7, 14 June 2018). This is an open-label, continuation 
protocol for eligible NINT cohort participants enrolled in Study B1371019 or Study 
B1371012 eligible participants.
A maximum of 34 participants from Study B1371019 and 3 participants from Study 
B1371012 may continue to access to study intervention.


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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Efficacy Endpoint
Not Applicable.
3.2. Baseline Variables
The date of first dose (start date) of study treatment is the earliest date of non-zero dosing of 
any study drug. The date of last dose of study treatment is the latest date of non-zero dosing 
of any study drug.
No windowing will be applied when defining baseline. Any deviations from the protocol 
specified window will be documented as protocol deviations. 
3.2.1. Stratification
Not applicable.
3.3. Safety Endpoints
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.
On-treatment is defined as the time from the first non-zero dose of study treatment to the last 
non-zero dose + 28 days. 
3.3.1. Adverse Events
An adverse event is considered treatment emergent (TEAE) relative to a given treatment if
the event occurs during the on-treatment period (regardless if it was seen prior to the start of 
treatment).  An adverse event is considered treatment-related as assigned by the investigator.
Adverse events (AEs) will be coded to preferred term (PT) and system organ class (SOC) 
using the Medical Dictionary for Regulatory Activities (MedDRA) and classified by severity
using the National Cancer Institutes (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE), version 4.03.  Adverse events occurring on the same day as the first dose 
of study treatment will be considered to have occurred during the on-treatment period.  All 
other assessments which occur on the same day as the first dose of study treatment will be 
considered as baseline assessments.
Safety data collected outside the on-treatment period as described above will be listed but not 
summarized.
3.3.2. Laboratory Data
Not applicable.


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4. ANALYSIS SETS
The B1371019 and B1371012 participants will be analyzed separately and independently.
Analysis sets and the applicable analysis using the analysis set is summarized in the table 
below.
Analysis Set
Population
Applicable Analysis (for 
additional information see 
Section 6)
Safety Analysis
(SA) Set
All participants who received at 
least one dose of study after 
consenting to participate in Protocol 
Amendment 6
Safety analysis for B1371019
Safety analysis for B1371012
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
Not applicable.
5.2. General Methods 
For study B1371019, demographic data will be summarized by treatment arm and for both 
treatment arms combined.  Disposition, exposure, and safety data will be summarized by 
treatment arm only. For study B1371012, summary will be provided for all participants 
continuing to Protocol Amendment 6.
The safety analyses of participants from Study B1371019 and participants originating from
Parent Study B1371012 will be conducted separately and independently of each other.
5.2.1. Pooling of Data by Center
Not applicable. 
5.2.2. Definition of Study Day
Start day of study treatment is the day of the first non-zero dose of any study treatment.
The study day for assessments occurring on or after the start day of study treatment 
(eg, adverse event onset, laboratory date) will be calculated as:
Study day = Date of the assessment/event - start date of study treatment + 1. 
The study day for assessments occurring prior to the start day of study treatment (eg, baseline 
characteristics, medical history) will be negative and calculated as:
Study day = Date of the assessment/event –start date of study treatment.
The study day will be displayed in all relevant data listings.


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5.2.3. Definition of Cycle and Cycle Day
Cycle start and end dates are derived per patient and not per study treatment. 

For Cycle X, the actual cycle start date for each subject is the earliest start date of 
dosing (dose>0 at that visit) in Cycle X visit CRF exposure page.

For all but the last cycle. 

Actual cycle end date is calculated as the start date of the next cycle minus one 
day.

Actual cycle duration is calculated from Day 1 of a cycle to the day prior to 
Day 1 of the next cycle, as follows: 
Actual Cycle Duration = cycle end date – cycle start date + 1.

For the last cycle, actual cycle duration is calculated as follows:

Actual Cycle Duration = last date of non-zero study treatment– cycle start 
date + 1.
The cycle day will be calculated as:
Cycle day = Date of the assessment/event – cycle start date + 1. 
5.2.4. Date of Last Contact
Not applicable.
5.2.5. Disease Assessment Date
Not applicable.
5.2.6. Unscheduled Assessments
Not Applicable.
5.2.7. Standard Derivations and Reporting Conventions
The following conversion factors will be used to convert days into weeks, months or years: 
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Percentages will be reported to one decimal place. The rounding will be performed to closest 
integer/first decimal using the common mid-point between the two consecutive values, 
eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 to 5.9 will be rounded to an 
integer of 6.


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5.2.8. Analyses for Continuous Data
Continuous variables will be summarized using descriptive statistics ie, number of 
non-missing values and number of missing values [ie, n (missing)], mean, median, standard 
deviation (SD), minimum, maximum and first and third quartile (Q1 and Q3). 
In case the analysis refers only to certain visits, estimates will be based on the number of 
patients with an assessment at that visit, unless otherwise specified.
5.2.9. Analyses for Categorical Data
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore counts of missing observations will be included in the denominator and presented 
as a separate category.
In case the analysis refers only to certain visits, percentages will be based on the number of 
patients with an assessment at that visit, unless otherwise specified.
5.2.10. Analyses for Time to Event Data
Not applicable.
5.3. Methods to Manage Missing Data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.
Any imputations will occur at the analysis dataset level.  Additionally, in all patient data 
listings imputed values will be presented and flagged as imputed.
Missing statistics, eg, when they cannot be calculated, should be presented as ‘ND’ for not 
done, ‘NR’ for not reached or ‘NA’ for not applicable.  For example, if N=1, the measure of 
variability cannot be computed and should be presented as ‘ND’ or ‘NA’. 
CDISC Safety Rulebook will be followed when handling the missing/partial dates, treatment 
emergent AE algorithm, missing AE grades, etc. 
5.3.1. Missing Dates
For purposes of data listings, dates will reflect only the information provided by the 
investigator on the CRF.
If start dates for adverse events are completely missing a worst case approach will be taken 
whereby the events will be considered treatment emergent.  If only partial information are 
available (eg, only a month and year or only a year) and the partial information provide 
sufficient information to indicate the dates are prior to the start of study treatment 
(eg, month/year less than month/year of first dose) then these will be considered to have 
started prior to treatment; otherwise a similar worst case approach will apply and these will 
be considered to have started after treatment.


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Date of Last Dose of Study Treatment
No imputation will be done for first dose date. Date of last dose of study treatment, if 
unknown or partially unknown, will be imputed as follows:

If the last date of study treatment is completely missing and there is no Disposition 
CRF page for the treatment phase and no death date, the patient should be considered 
to be ongoing and use the data cutoff date for the analysis as the last dosing date; or

If the last date of study treatment is completely or partially missing and there is 
EITHER a Disposition CRF page for the treatment phase OR a death date available 
(on or prior to the data cutoff date), then impute this date as the last dose date:
= 31DECYYYY, if only Year is available and Year < Year of min (Date of 
Completion/Discontinuation from the Disposition CRF page for the treatment phase, 
death date),
= Last day of the month, if both Year and Month are available and Year = Year of 
min (Date of Completion/Discontinuation from the Disposition CRF page for the 
treatment phase, death date) and Month < the month of min (Date of 
Completion/Discontinuation from the Disposition CRF page for the treatment phase, 
death date), or
= min (Date of Completion/Discontinuation from the Disposition CRF page for the 
treatment phase, death date), for all other cases.
Missing or Partial Death Dates
Not Applicable.
Date of Start of New Anti-cancer Therapy
Not applicable.
AE Onset Date:
The following imputation rules apply if the event is unique for a patient or it is the first of a 
series of similar events; otherwise, the AE Onset Date will not be imputed:

If the AE Collection Date is not missing, is less than the Date of First Exposure to 
Treatment, and is less than the AE Stop Date, then AE Onset Date is set to the Date of 
AE Collection.

If the Previous Visit Date is greater than the Date of First Exposure to Treatment and
less than the AE Stop Date, the AE Start Date is set to the previous visit date.


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
If the Date of First Exposure to Treatment is greater than the previous visit date and 
less than the AE Stop Date, the AE Onset Date is set to the Date of First Exposure to 
Treatment.

Otherwise AE Onset Date is set to the AE Stop Date.
AE Stop Date:
Ongoing events will have the AE Stop Date set to one of the following values:

Date of Death, if the patient died and a date of death exists.

Maximum of (Withdraw date, AE Onset Date, AE Collection Date) if the patient 
withdrew from the study and a date of withdraw exists.

Maximum of (AE Onset Date, Subject Summary Collection Date, AE Collection 
Date) if the Disposition CRF page for the long-term follow-up phase exists but a date 
of completion/discontinuation does not exist.

Maximum of (Last Treatment Date, AE Onset Date) if no Disposition CRF page for 
the long-term follow-up phase exists.
Imputation will only occur if event is unique for the patient, or it is the last of a series of 
similar events; otherwise the Stop Date will not be imputed.  Adverse Events are deemed 
similar if they have the same verbatim term.
Resolved events will have the AE Stop Date set to the maximum of the AE collection date 
and the AE Onset date.
Other Missing or Partial Dates
Imputation methods for other partial dates are as follows: 

If the day of the month is missing for a start date used in a calculation, the first day of 
the month will be used to replace the missing date. 

If both the day and month are missing for a start date, the first day of the year is used. 

For stop dates, the last day of the month, or last day of the year is used if the day or 
day and month are missing, respectively. 

If the date is completely missing, no imputation will be performed.
5.3.2. Missing Toxicity Grade of Adverse Events
During Study Treatment: If no toxicity grade is available or the grade is reported as unknown 
for an adverse event during the study treatment, then the event will be considered treatment 
emergent.


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In summaries which present maximum toxicity grade, the maximum of non-missing grades 
will be displayed.  Missing grade will only be displayed for cases where a patient reported 
only one event and the grade is missing. 
5.3.3. Missing Pharmacokinetic (PK) Data
Not applicable.
5.3.4. Missing ECG Data
Not applicable.
5.3.5. Missing Biomarker Data
Not applicable.
6. ANALYSES AND SUMMARIES
Analyses for B1371019 and B1371012 will be conducted separately and independently.
All participants who receive any study treatment (safety analysis set) will be included in the
summaries and listings of safety data. Overall safety profile and tolerability of azacitidine or
glasdegib + azacitidine will be characterized by type, frequency, severity, seriousness,
timing, and relationship to study therapy of AEs.
AEs will be classified using the MedDRA classification system. The severity of the 
toxicities will be graded according to the NCI CTCAE version 4.03.
In all summaries, emphasis will be placed on TEAEs (events occurring from Amendment 6
consent up to last dose + 28 days). AEs will be summarized by the frequency of participants
experiencing TEAEs corresponding to body systems and MedDRA preferred term and by
worst NCI CTCAE (version 4.03) grade.
6.1. Efficacy Endpoint
Not applicable.
6.2. Baseline and Other Summaries and Analyses
6.2.1. Baseline Summaries
Not applicable.
6.2.2. Study Conduct and Patient Disposition
The following analyses will be based on the SA set by treatment arm for study B1371019 and 
by pooling across cohorts for study B1371012.
6.2.2.1. Patient Disposition
A summary of the number of patients enrolled overall will be provided.


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Discontinuation of treatment overall and for each study drug, and discontinuation of study
will be summarized separately and by reason for discontinuation.  Discontinuations from 
study treatment will be summarized using the safety analysis set. Once a patient discontinues 
all study drugs they will be considered discontinued overall from study treatment.  The 
reason and date corresponding to the last drug discontinued should be used for the overall 
summary.  If multiple drugs were discontinued on the same date with different reasons then 
the reason for discontinuing blinded therapy will be used.
Discontinuations from study treatment due to adverse events will be identified as either 
related or not related to study treatment. If causality is missing the event will be considered 
related to treatment.
An additional summary to meet European Union Disclosure requirements will categorize 
discontinuations due to adverse events based on the following categories:

Adverse Event, not serious.

Adverse event, serious non-fatal.

Adverse event, serious fatal.
6.2.2.2. Protocol Deviations
Protocol deviations will be compiled prior to database closure and important protocol 
deviations will be summarized by category (n(%)) for the SA set by treatment arm.  
Categories will be assigned by the study Clinician.
6.2.3. Study Treatment Exposure
The following analyses will be based on the SA set.
6.2.3.1. Exposure to Glasdegib
The summary of treatment exposure for glasdegib will include the following information:

Treatment duration (weeks).
The duration of glasdegib (in weeks) is defined as:
Treatment duration (weeks) = (last dose date – first dose date + 1)/7.
6.2.3.2. Exposure to Cytarabine (Induction, Intensive Study Only)
Not applicable.
6.2.3.3. Exposure to Cytarabine (Consolidation, Intensive Study Only)
Not applicable.
6.2.3.4. Exposure to Daunorubicin (Induction Only, Intensive Study Only)
Not applicable.


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6.2.3.5. Exposure to Azacitidine (Non-intensive Study Only)
The summary of treatment exposure for azacitidine will include the following information:

Treatment duration (weeks).
Azacitidine is administered by subcutaneous injection (SC) or intravenous (IV) infusion 
75 mg/m2 daily for 7 days, in 28 day cycles.
The dose level for azacitidine captured in the CRF is calculated as actual dose 
administered/body surface area (BSA) (mg/m2).  The last available weight of the patient on 
or prior to the day of dosing will be used.
The duration of azacitidine (in weeks) during the study for a patient is defined as:
Treatment duration (weeks) = (last dose date – first dose date + 1)/7.
6.2.3.6. Dose Reductions and Interruptions due to Adverse Events
A dose reduction due to an AE is defined as a non-zero dose where reason for adjustment on 
the dosing CRF is AE.
The number and percentage of patients with at least one dose reduction as well as a
breakdown of dose reductions (1 / 2 / ≥3) and/or the dosage administered will be summarized 
by treatment and by treatment arm.  
An interruption due to an AE is defined as a 0 mg dose administered where reason for 
adjustment on the dosing CRF is AE. The number and percentage of patients with dose 
interruptions will be summarized by treatment and by treatment arm.  Percentages will be 
calculated based on the total number of patients in the safety analysis set.
6.2.4. Concomitant Medications and Non-Drug Treatments
Not applicable.
6.2.5. Prior and Subsequent Anti-Cancer Therapies/Procedures
Not applicable.
6.3. Safety Summaries and Analyses
Unless otherwise specified, summaries of AEs and other safety parameters will be based on 
the safety analysis population by treatment arm.
6.3.1. Adverse Events
All analyses will be based on treatment emergent events unless otherwise specified.  
Treatment emergent is defined in Section 3.3.1.
Seriousness, toxicity grade, study drug action taken (interruption, reduction, and withdraw) 
are as reported by the investigator on the adverse event CRF.


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Summaries by treatment arm, SOC and PT in decreasing frequency based on the frequencies 
observed in the glasdegib arm will be provided for:

Treatment Emergent Events by Maximum Toxicity Grade (All Causality);

Treatment Emergent Events by Maximum Toxicity Grade (Treatment 
Related);Serious Treatment Emergent Events by Maximum Toxicity Grade (All 
Causality);

Serious Treatment Emergent Events by Maximum Toxicity Grade (Treatment 
Related).
An event will be considered treatment related if the investigator considered the event related 
to the study drug or this information is unknown.

Treatment Emergent Adverse Events Leading to Dose Interruptions by Maximum 
Toxicity Grade (All Causality) separately for each study drug, for chemotherapy, and 
for any study treatment;

Treatment Emergent Adverse Events Leading to Dose Reductions by Maximum 
Toxicity Grade (All Causality) separately for each study drug, for chemotherapy, and
for any study treatment;

Treatment Emergent Adverse Events Leading to Permanent Withdrawal by 
Maximum Toxicity Grade (All Causality) separately for each study drug, for 
chemotherapy, and for any study treatment;

Serious Treatment Emergent Events (All Causality).
Each patient will be counted only once within each PT.  
As described in Section 5.3.2, in case a patient has events with missing and non-missing 
toxicity grades, the maximum of the non-missing grade will be displayed.  Missing grade will
only be displayed in the event that only one event has been reported for a patient and the 
grade is missing.
6.3.1.1. Basic Results
For basic results disclosures in the US and EU the following additional summaries will be
provided:

Treatment Emergent Non Serious Adverse Events by SOC and PT in >5% of patients
in either treatment arm;

Treatment Emergent Serious Adverse Events by SOC and PT; and 

Fatal Adverse Events by SOC and PT.


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Each of the above summaries will include a count of the number of patients with all causality 
events and the number of patients with treatment related events.
6.3.1.2. 3-Tiered Adverse Events Analysis
Not Applicable.
6.3.1.3. Adverse Events of Special Interest
Not applicable.
6.3.2. Deaths
Not applicable.
6.3.3. Laboratory Data
Not applicable.
6.3.4. Electrocardiogram
Not applicable. 
6.3.5. Physical Examination
Not applicable.
6.3.6. Left Ventricular Ejection Fraction (LVEF)
Not applicable.
6.3.7. Performance Status
Not applicable.
6.3.8. Hospitalization
Not applicable.
7. INTERIM ANALYSES
The interim analyses were performed prior to Amendment 6.


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8. REFERENCES
None.