Conditions: Acute Myeloid Leukemia
Keywords: Hematologic Malignancies
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 48
Healthy volunteers: no

Brief summary:
This is an open-label, multi-center, Phase 1 study of PF-04449913 in Japanese patients. PF-04449913 will be administered orally as a single agent in patients with select advanced hematologic malignancies, or in combination with LDAC \[Low-Dose Ara-C\] or cytarabine and daunorubicin in previously untreated patients with AML \[Acute Myeloid Leukemia\] or high-risk MDS \[Myelodysplastic Syndrome\], or in combination with azacitidine in previously untreated patients with AML.

Detailed description:

Arms:
arm 1: PF-04449913 Monotherapy arm 2: PF-04449913 in combination with low dose ARA-C (LDAC) arm 3: PF-04449913 in combination with intensive chemotherapy: PF-04449913 administered continuously for 28 days. Daunorubicin given using 60 mg/m2 for 3-days together with cytarabine 100 mg/m2 on days 1 through 7 followed by cytarabine 1g/m2 on days 1, 3, and 5 during 2-4 cycles of consolidation therapy. arm 4: PF-04449913 in combination with azacitidine arm 5: PF-04449913 Monotherapy for one patient rolled-over from another trial in the same project. arm 6: PF-04449913 in combination with LDAC to evaluate efficacy

Interventions: intervention 1: PF-04449913 intervention 2: PF-04449913 intervention 3: Low dose ARA-C (LDAC) intervention 4: PF-04449913 intervention 5: Daunorubicin intervention 6: Cytarabine intervention 7: PF-04449913 intervention 8: Azacitidine intervention 9: PF-04449913 intervention 10: LDAC
Intervention descriptions: intervention 1: PF-04449913 administered orally and continuously in 28 day cycles. intervention 2: PF-04449913 administered orally and continuously in 28 day cycles. intervention 3: Low dose ARA-C (LDAC) administered at 20 mg SQ, BID on Days 1 through 10. intervention 4: PF-04449913 administered orally and continuously in 28 day cycles. intervention 5: Daunorubicin given using 60 mg/m2 for 3-days. intervention 6: Cytarabine 100 mg/m2 on days 1 through 7. intervention 7: PF-04449913 administered orally and continuously in 28 day cycles. intervention 8: Azacitidine Combination Cohort; Azacitidine 75 mg/m2 for 7 days. intervention 9: PF-04449913 administered orally and continuously in 28 day cycles. intervention 10: Low dose ARA-C (LDAC) administered at 20 mg SQ, BID on Days 1 through 10.

Protocol document:
Prot_000.pdf: 
PF-04449913
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A PHASE 1 STUDY TO EVALUATE THE SAFETY, TOLERABILITY, EFFICACY,
PHARMACOKINETICS, AND PHARMACODYNAMICS OF 
PF-04449913 (GLASDEGIB), AN ORAL HEDGEHOG INHIBITOR, 
ADMINISTERED AS A SINGLE AGENT IN JAPANESE PATIENTS WITH 
SELECT HEMATOLOGIC MALIGNANCIES AND IN COMBINATION WITH 
INTENSIVE CHEMOTHERAPY, LOW-DOSE ARA-C, OR AZACITIDINE IN 
PATIENTS WITH ACUTE MYELOID LEUKEMIA OR HIGH-RISK 
MYELODYSPLASTIC SYNDROME
Compound:
PF-04449913 
Compound Name :
Glasdegib 
US IND Number :
 
European Clinical Trial Database 
(EudraCT) Number:
"Not Applicable" 
Protocol Number:
B1371005 
Phase:
Phase 1
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  
In the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
CCI


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Document History
Document
Version Date
Summary of Changes 
Protocol Amendment 8
25 March 2021

Schedule of Activities Table 3:
The tests and assessments in the 
Expansion Cohort of LDAC 
combination for efficacy (unfit 
patients) were simplified.

Section 1.2.8: Updated 
Summary of Safety, Efficacy 
and PK data

Section 7.1: Text was added to 
reflect the simplification of the 
safety assessment.

Section 9: Updated the final 
analysis.
Following Table and Sections were 
update according to the Protocol 
Administrative Change Letter dated 
02 June 2020 regarding COVID-19 
related reasons.

Table 6

Section 4.3

Section 5.3.2

Section 5.3.3

Clarified throughout what is no 
longer required after Protocol 
Amendment 8 or will be 
conducted according to local 
clinical practice.
Protocol Amendment 7
21 January 2019

The Expansion Cohort of LDAC 
combination for efficacy (unfit 
patients) was added and all protocol 
contents related to this Cohort were 
updated. 

Minor administrative changes were 
made to correct typographical 


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Document
Version Date
Summary of Changes 
errors, emphasize subtle points, or 
improve internal consistency with 
the protocol.
Protocol Amendment 6
17 July 2018

Survival follow-up was added in the 
Combination Cohort 1 (unfit 
patients).

Minor administrative changes were 
made to correct typographical 
errors, emphasize subtle points, or 
improve internal consistency with 
the protocol.
Protocol Amendment 5
8 November 2017

The Continuation Cohort 
(Monotherapy Cohort) was added 
and all protocol contents related to 
Continuation Cohort were updated.
Protocol Amendment 4
4 July 2017

The Combination Cohort 3 
(Azacitidine Combination) was 
added and all protocol contents 
related to Combination Cohort 3 
were updated. 

Minor administrative changes were 
made to correct typographical 
errors, emphasize subtle points, or 
improve internal consistency with 
the protocol.
Protocol Amendment 3
2 March 2017

Evaluation of PD data at the 25 mg 
QD dose was added.

Table 7: Sample collection timing 
was clarified.

Eligibility criteria corrected an 
inconsistency for Combination 
cohorts inclusion criteria #2 (Acute 
Promyelocytic Leukemia (APL) 
patients with t(15;17) are excluded).

Table 17: Recommended Dose 
Modifications for PF-04449913 


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Document
Version Date
Summary of Changes 
related QTcF prolongation was
added.

Table 18: Recommended Dose 
Modifications for PF-04449913 in 
case of drug class related AEs was
added.

Sections 5.3.10 and 7.1.5: Revised 
dosing modification guidelines for 
treatment-related QTcF
prolongation.

Minor administrative changes were 
made to correct typographical 
errors, emphasize subtle points, or 
improve internal consistency with
the protocol.

Updated safety data throughout 
section 1.

Updated information in section 5.5. 
Concomitant Medications.
Protocol Amendment 2
11 August 2014

Transplant exclusion criteria has 
been removed.

The schedule of events for 
biomarker sample collection has 
been modified.

The schedule of events added 
creatine kinase at select timepoints.

The bone marrow assessment
schedule has clarified aspirate 
collection requirements, changed 
initial hematologic recovery bone 
marrow collection from 7 days to 14 
days, and for Unfit patients changed 
the timepoints to Cycle 3/Day 1 and 
every third cycle to better align with 
standard of care and removed the 
treatment duration criteria. 


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Document
Version Date
Summary of Changes 

For fit patients Maintenance Day 15 
visit has been removed. 

Continuous PF-04449913 dosing 
during induction and/or 
consolidation cycles > 28 days has 
been clarified.

Concomitant medication restrictions 
have been clarified.

Appendix 11 containing list of 
drugs with known risk of Torsade 
de Pointes has been added.

Appendix 12 containing list of 
strong and moderate CYP3A4/5 
inhibitors has been added.

Appendix 13 containing list of 
strong and moderate CYP3A4/5 
inducers has been added.

Updates to Adverse Event 
Reporting sections and Publication 
of Study Results section were added 
to align with revised protocol 
template.

Minor administrative changes were 
made to correct typographical 
errors, emphasize subtle points, or 
improve internal consistency with 
the protocol.
Protocol Amendment 1
12 December 2013

An additional informed consent
form will be obtained at the end of 
Cycle 1.

Removed previously untreated 
patients from the Inclusion Criteria 
for Monotherapy Cohort.

Administrative corrections and 
clarifications made throughout the 
protocol.


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Document
Version Date
Summary of Changes 
Original protocol
20 November 2013
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and Institutional Review Boards (IRBs)/Ethics 
Committees (ECs).


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PROTOCOL SUMMARY
Indication:
Hematologic malignancies, including acute myeloid leukemia (AML) and high-risk 
myelodysplastic syndrome (MDS).
Objectives:
The study incorporates six cohorts: 1) a monotherapy cohort in which PF-04449913 is 
administered as a single agent in up to 15 Japanese patients with select advanced 
hematologic malignancies, 2) two combination cohorts (combination cohorts 1 and 2) in 
which PF-04449913 is administered with different chemotherapy backbones in up to 12 
Japanese patients (6 in each different combination cohort) with previously untreated AML or 
high-risk MDS, 3) expansion cohort of low-dose ara-c [LDAC] combination for efficacy in 
which PF-04449913 is administered with LDAC in 15 Japanese patients with previously 
untreated AML or high-risk MDS, 4) additional one combination cohort (combination cohort 
3) in which PF-04449913 is administered with azacitidine in 6 Japanese patients with 
previously untreated AML who are eligible for non-intensive chemotherapy, and 5) a 
continuation cohort (monotherapy cohort) in which PF-04449913 is administered as a single 
agent in 1 Japanese myelofibrosis (MF) patient who has been treated in Study B1371013.  
Specific objectives and endpoints for each cohort are outlined below. A total of up to 49
patients will be treated across all six cohorts.
Monotherapy Cohort:
Primary Objective

To determine the safety and tolerability of PF-04449913 administered as 
monotherapy in Japanese patients with select advanced hematologic malignancies.
Secondary Objectives

To evaluate the pharmacokinetics (PK) of PF-04449913 as monotherapy in Japanese 
patients with select advanced hematologic malignancies;

To evaluate the pharmacodynamics (PD) of PF-04449913 as monotherapy in 
Japanese patients with select advanced hematologic malignancies;

To assess preliminary evidence of clinical efficacy of PF-04449913 administered as 
monotherapy in Japanese patients with select advanced hematologic malignancies.
Combination Cohorts 1 and 2 (Unfit and Fit Patients):
Primary Objective

To determine the safety and tolerability of PF-04449913 administered in combination 
with LDAC (Combination Cohort 1, unfit patients), or cytarabine/daunorubicin (7:3) 


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(Combination Cohort 2, fit patients) to Japanese patients with previously untreated 
AML, or high-risk MDS.
Secondary Objectives

To evaluate the PK of PF-04449913 and potential drug-drug interaction (DDI) 
between PF-04449913 and LDAC (Combination Cohort 1, unfit patients) or 
cytarabine/daunorubicin (7:3) (Combination Cohort 2, fit patients) administered to 
Japanese patients with previously untreated AML or high-risk MDS;

To evaluate the PD of PF-04449913 administered in combination with LDAC 
(Combination Cohort 1, unfit patients) or cytarabine/daunorubicin (7:3) (Combination 
Cohort 2, fit patients) to Japanese patients with previously untreated AML or high-
risk MDS;

To assess any preliminary evidence of clinical efficacy (including disease-specific 
measures) of PF-04449913 administered in combination with LDAC (Combination 
Cohort 1, unfit patients) or cytarabine/daunorubicin (7:3) (Combination Cohort 2, fit 
patients) to Japanese patients with previously untreated AML or high-risk MDS.
Expansion Cohort of LDAC combination for efficacy (Unfit Patients):
Primary Objective

To evaluate the efficacy (Disease Modifying Response [DMR]a rate) of PF-04449913 
administered in combination with LDAC to Japanese patients with previously 
untreated AML or high-risk MDS.
Secondary Objectives

To evaluate the safety of PF-04449913 administered in combination with LDAC to 
Japanese patients with previously untreated AML or high-risk MDS;

To evaluate the efficacy (including overall survival [OS]) of PF-04449913 
administered in combination with LDAC to Japanese patients with previously 
untreated AML or high-risk MDS;

To evaluate the PK and PD of PF-04449913 administered in combination with LDAC 
to Japanese patients with previously untreated AML or high-risk MDS.
                                                
a Disease Modifying Response (DMR) rate includes Complete Remission (CR), CR with incomplete 
blood count recovery (CRi), Morphologic Leukemia-Free State (MLFS), marrow CR (mCR) and 
Partial Remission (PR) (Appendix 5 and Appendix 8).


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Combination Cohort 3 (Azacitidine Combination):
Primary Objective

To determine the safety and tolerability of PF-04449913 administered in combination 
with azacitidine in Japanese patients with previously untreated AML who are eligible 
for non-intensive chemotherapy.
Secondary Objectives

To evaluate the PK of PF-04449913 and azacitidine when administered to Japanese 
patients with previously untreated AML who are eligible for non-intensive 
chemotherapy;

To evaluate the PD of PF-04449913 administered in combination with azacitidine to 
Japanese patients with previously untreated AML who are eligible for non-intensive 
chemotherapy;

To assess any preliminary evidence of clinical efficacy including OS of PF-
04449913 administered in combination with azacitidine to Japanese patients with 
previously untreated AML who are eligible for non-intensive chemotherapy.
Continuation Cohort (Monotherapy Cohort):

To assess the safety of PF-04449913 administered as monotherapy in the Japanese 
MF patient who has been treated with PF-04449913 in Study B1371013 and without
documented objective progression of disease and with continuous clinical benefit at 
the time the patient discontinued from Study B1371013.
Endpoints:
Monotherapy Cohort:
Primary Endpoint

First-cycle dose-limiting toxicities (DLTs); Type, incidence, severity [graded by the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE), Version 4.0], timing, seriousness, and relatedness of adverse events; vital 
signs and laboratory test abnormalities.
Secondary Endpoints

PK parameters of PF-04449913;

Potential biomarkers of target modulation, response or resistance to PF-04449913 in 
Japanese patients with advanced hematologic malignancies;


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
Objective disease response as assessed using the response criteria for the hematologic 
disease under study.
Combination Cohorts 1 and 2 (Unfit and Fit Patients):
Primary Endpoint

First-cycle DLTs; Type, incidence, severity (graded by NCI CTCAE, Version 4.0), 
timing, seriousness, and relatedness of adverse events; vital signs and laboratory test 
abnormalities.
Secondary Endpoints

PK parameters of PF-04449913 with: (i) LDAC, and (ii) cytarabine/daunorubicin 
(7:3) combinations;

Potential biomarkers of target modulation, response or resistance to PF-04449913 in 
combination with chemotherapy in Japanese patients with previously untreated AML 
or high-risk MDS; 

Objective disease response, as assessed using the appropriate response criteria for 
AML or MDS.

Survival status (only Combination Cohort 1)
Expansion Cohort of LDAC combination for efficacy (Unfit Patients):
Primary Endpoint

DMR rate
Secondary Endpoints

Type, incidence, severity (graded by NCI CTCAE, Version 4.0), timing, seriousness, 
and relatedness of adverse events; vital signs and laboratory test abnormalities;

OS;

Objective disease response, as assessed using the appropriate response criteria for 
AML or MDS; complete remission (CR) rate; duration of response; time to response;

PK and Potential biomarkers of target modulation, response or resistance to 
PF-04449913 in combination with LDAC in Japanese patients with previously 
untreated AML or high-risk MDS.


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Combination Cohort 3 (Azacitidine Combination):
Primary Endpoint

First-cycle DLTs; Type, incidence, severity (graded by NCI CTCAE, Version 4.0), 
timing, seriousness, and relatedness of adverse events; vital signs and laboratory test 
abnormalities.
Secondary Endpoints

PK parameters of PF-04449913 and azacitidine;

OS;

Potential biomarkers of target modulation, response or resistance to PF-04449913 in 
combination with azacitidine in Japanese patients with previously untreated AML 
who are eligible for non-intensive chemotherapy; 

Objective disease response, as assessed using the appropriate response criteria for 
AML; duration of response; time to response.
Continuation Cohort (Monotherapy Cohort):

Type, severity (graded by NCI CTCAE, Version 4.0), timing, seriousness, and 
relatedness of adverse events; laboratory test abnormalities.
Efficacy-related data will not be collected in this cohort.
Overall Study Design:
This is an open-label, multi-center, Phase 1 study of PF-04449913 in Japanese patients. 
PF-04449913 will be administered orally as a single agent in up to 15 patients with select 
advanced hematologic malignancies (Monotherapy Cohort), or in combination with LDAC 
(Combination Cohort 1, unfit patients) or cytarabine and daunorubicin (7:3) (Combination 
Cohort 2, fit patients) in up to a total of 12 (6 in Cohort 1 and 6 in Cohort 2) previously 
untreated patients with AML or high-risk MDS. PF-04449913 will be administered in 
combination with LDAC in a total of 15 patients with previously untreated AML or high-risk 
MDS (Expansion Cohort of LDAC combination for efficacy, unfit patients). PF-04449913 
will also be administered in combination with azacitidine in a total of 6 patients with 
previously untreated AML who are eligible for non-intensive chemotherapy (Combination 
Cohort 3, Azacitidine Combination). PF-04449913 will be administered as a single agent in 1 
Japanese MF patient who has been treated in Study B1371013 and on the study treatment at 
the time of the study discontinuation [Continuation Cohort (Monotherapy Cohort)].


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Monotherapy Cohort:
The monotherapy cohort will evaluate the safety and tolerability of PF-04449913 
administered as a single agent once daily continuously. Cycle 1 will be preceded by a single 
lead-in dose of PF-04449913 administered on Day -5 (lead-in period) in order to characterize 
the single-dose PK of PF-04449913 prior to initiation of continuous dosing in the first cycle 
of treatment. From Cycle 1/Day 1 onwards, PF-04449913 will be administered continuously 
once daily, in 28-day cycles.
A standard 3+3 dose escalation design will be used to evaluate the tolerability of PF-
04449913 with 3-6 patients per dose level. Two dose levels of PF-04449913 (Dose Level 1: 
50 mg once daily (QD) and Dose Level 2: 100 mg QD) will, in the first instance, be 
investigated in sequential cohorts of patients. Intermediate (such as 80 mg QD) or lower dose 
levels (such as 25 mg) may be explored at any time during the study if this is clinically and 
scientifically warranted. Study centers will receive a notification if additional dose levels are 
explored.
The DLT evaluation period includes the PK lead-in period, and the first cycle of treatment. 
Dose escalation to the 100 mg QD dose level will occur if <1/3 or <2/6 patients at the 50 mg 
QD dose level experience dose-limiting toxicities (DLT) during the first cycle of treatment.  
If 1 patient experiences a DLT event in the first 3 patients, an additional 3 patients will be 
enrolled to give a total of 6 patients in the 100 mg QD cohort. If 1 of the 6 patients 
experiences a DLT by the end of Cycle 1, the tolerability of the 100 mg QD dose level in the 
monotherapy cohort will be deemed confirmed, and the study will proceed to the 
combination cohort.  If 2 or more of the 6 patients treated at 100 mg QD in the monotherapy 
cohort experience a DLT by the end of Cycle 1, an intermediate dose level (80 mg QD) may 
be explored in the monotherapy cohort prior to proceeding with the combination cohort. If 
two or more of the 3 or 6 patients treated at 50 mg QD in the monotherapy cohort 
experiences a DLT by the end of Cycle 1, the dose escalation will be terminated, and a lower 
dose may be explored.
As of 7 August 2014, it was decided by the study team that a lower dose level (25 mg QD) 
will be explored in the study, since evaluation of PD data at the 25 mg QD dose is 
scientifically warranted.  Up to 3 patients will be enrolled at the 25 mg dose level.  DLT 
evaluation will be performed on this dose level, however, it will not be used for the dose 
escalation decision, or for the determination of whether or not to proceed with the 
combination cohort.  The Sponsor will discuss with the Investigator to confirm that there is 
no safety issue for patients enrolled at this dose level.
Treatment with PF-04449913 may continue for up to 12 cycles or until disease progression 
or relapse, patient withdrawal, or unacceptable toxicity occurs (whichever is first).  Patients 
who complete 12 cycles of treatment will be deemed to have completed the study.  However, 
patients who complete 12 cycles of study treatment who demonstrate clinical benefit with 
manageable toxicity, and are willing to continue receiving the study treatment, may be given 
the opportunity to do so following agreement between the Investigator and Sponsor, and 


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pending study drug availability.  If treatment continues beyond 12 cycles, study procedures 
should continue to be performed as per Table 1 (See Schedule of Activities).
The study may at any time evaluate additional dose levels of single-agent PF-04449913 
based upon the emerging data from the ongoing pre-clinical and clinical studies, following 
discussion between the Investigators and the Sponsor.
Combination Cohorts:
The combination cohorts will evaluate the safety and tolerability of PF-04449913 at the 
starting dose of 100 mg once daily continuously administered in combination with 3 different 
chemotherapy regimens.
Combination Cohort 1 (Unfit Patients):
In this cohort, patients who are “unfit for intensive chemotherapy” based on predefined 
criteria (See Inclusion Criteria) will receive PF-04449913 once daily continuously in 
combination with LDAC over 28 day cycles. 
A total of 6 patients will be treated in this cohort and followed up for DLT evaluation. The 
DLT evaluation period includes the first cycle of treatment.  If ≤ 1 of the 6 patients 
experiences a DLT by the end of Cycle 1, the tolerability of the combination will be deemed 
confirmed.  If 2 or more of the 6 patients experience a DLT by the end of Cycle 1, additional 
lower dose levels may be tested, applying identical criteria to those outlined above with 
respect to DLT events.
Treatment with PF-04449913 in combination with LDAC may continue for up to 12 cycles 
or until disease progression or relapse, patient refusal, or unacceptable toxicity occurs 
(whichever is first).  Unfit patients who complete 12 cycles of study treatment will be 
deemed to have completed the study.  However, patients who complete the 12 cycles of study 
treatment and demonstrate clinical benefit with manageable toxicity, and are willing to 
continue receiving the study treatment (monotherapy with PF-04449913 or combination 
therapy), may be given the opportunity to do so following agreement between the 
Investigator and Sponsor, and pending study drug availability. If treatment continues beyond 
12 cycles, study procedures should continue to be performed as listed in Table 2 (Schedule of 
Activities). This cohort includes survival follow-up.
Expansion Cohort of LDAC combination for efficacy (Unfit Patients):
In this cohort, patients who are “unfit for intensive chemotherapy” based on predefined 
criteria (See Inclusion Criteria) will receive PF-04449913 once daily continuously in 
combination with LDAC over 28-day cycles. 
A total of 15 patients will be treated in this cohort and DMR rate will be evaluated. 
Treatment with PF-04449913 in combination with LDAC may continue until disease 
progression or relapse, patient refusal, or unacceptable toxicity occurs (whichever is first).  
All patients will be followed for survival every 8 weeks up to 2 years from the first dose of 


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the last patient enrolled in the study, or until death, end of the study, or patient withdrawal of 
consent, whichever comes first, regardless of initiation of new cancer therapy (follow-up on 
survival status will no longer be required after Protocol Amendment 8).
Combination Cohort 2 (Fit Patients):
In this cohort, patients defined as “fit for intensive chemotherapy” based on pre-defined 
criteria (See Inclusion Criteria) will receive PF-04449913 once daily continuously in 
combination with daunorubicin and cytarabine during induction and consolidation. For the 
first induction cycle only, PF-04449913 will commence on Day -3 and will then be given 
once daily continuously for the duration of treatment. Following completion of induction and 
consolidation, single-agent PF-04449913 may be given to eligible patients as maintenance 
therapy for a maximum of 6 cycles. 
A total of 6 patients will be treated in this cohort and followed up for DLT evaluation. If 1 
of the 6 patients experiences a DLT event by the end of Induction Cycle 1, the tolerability of 
the combination will be confirmed.  If 2 or more of the 6 patients experience a DLT by the 
end of Induction Cycle 1, additional lower dose levels may be tested using identical criteria 
to those outlined above with respect to DLT events.
Treatment will continue until disease progression or relapse, patient refusal, or unacceptable 
toxicity (whichever is first).  Fit patients who complete induction, consolidation and 6 cycles 
of maintenance with PF-04449913 will be deemed to have completed the study treatment.  
However, patients who complete the 6 cycles of maintenance and demonstrate clinical 
benefit with manageable toxicity, and are willing to continue receiving single-agent PF-
04449913, may be given the opportunity to do so following agreement between the 
Investigator and Sponsor, and pending study drug availability. If treatment continues beyond 
the 6 cycles of maintenance, study procedures should continue to be performed as listed in 
Table 3 (Schedule of Activities).
Combination Cohort 3 (Azacitidine Combination):
In this cohort, patients with previously untreated AML and eligible for non-intensive 
chemotherapy will receive PF-04449913 once daily continuously at the starting dose of 
100 mg in combination with azacitidine over 28 day cycles.
A total of 6 patients will be treated in this cohort and followed up for DLT evaluation.  The 
DLT evaluation period includes the first cycle of treatment.  If ≤1 of the 6 patients 
experiences a DLT by the end of Cycle 1, the tolerability of the combination will be deemed 
confirmed.  If 2 or more of the 6 patients experience a DLT by the end of Cycle 1, the 
investigator and the sponsor will review all available safety data and discuss the next steps.
Since responses to azacitidine may require 4-6 cycles of administration to emerge, treatment 
with the study drug combination should be continued for at least 6 cycles, or until death, 
unacceptable toxicity, or patient refusal (whichever is first).  If documentation of disease 
progression occurs within the first 6 cycles of study treatment, the patient SHOULD NOT be 


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withdrawn from study treatment following agreement between the Investigator and Sponsor
if, in the Investigator’s judgment, the patient is still likely to receive clinical benefit.
Treatment with the study drug combination should be continued beyond 6 cycles of treatment 
until objective disease progression or relapse (unless according to the Investigator there is 
reasonable evidence of clinical benefit, eg, HI [hematologic imiprovement], to justify 
continuation on treatment following agreement between the Investigator and Sponsor), death, 
unacceptable toxicity, or patient refusal (whichever is first).  All patients will be followed for 
survival every 12 weeks up to 3 years from the first dose of the last patient enrolled in the 
study, or until death, end of the study, or patient withdrawal of consent, whichever comes 
first, regardless of initiation of new cancer therapy.
Continuation Cohort (Monotherapy Cohort):
PF-04449913 at the same dose as the patient was taking in Study B1371013 will be orally 
administered once daily continuously as a single agent over 28 day cycles in 1 Japanese MF 
patient who has been treated in Study B1371013 and without documented objective 
progression of disease and with continuous clinical benefit at the time the patient 
discontinued from Study B1371013.
In this cohort, the patient receiving PF-04449913 will continue to receive study treatment 
until the time of disease progression, unacceptable toxicity, death, withdrawal of consent or 
termination of the study by Sponsor, whichever comes first. The patient may continue 
PF-04449913 treatment after objective progression of disease has been determined if the 
patient continues to experience clinical benefit, in the opinion of the investigator, and 
following discussion with the Sponsor.


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Figure 1.
Schematic of Study Design
SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
The Assessments section of the protocol contains detailed information relating to each 
assessment required for compliance with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the 
Schedule of Activities table as necessary, in order to conduct evaluations or assessments 
required to ensure patient well-being and safety.


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Table 1.
Monotherapy Cohort: Single-Agent PF-04449913 in Select Hematologic Malignancies
Screening
Lead-in 
PK 
Period14
Cycle 1 (28-day Cycle)
Even-
Numbered 
Cycles*
Odd-
Numbered 
Cycles*
Protocol Activity
Within 
28 Days 
Prior to
Study 
Entry
Day
-5**
Day 
1
Day
5
(1 
day)
Day
8
(1 
day)
Day 
15
(1 
day)
Day
21
(1 
day)
Day
1
(2 
days)
Day
15
(2 
days)
Day
1
(2 
days)
Day 
15
(2 
days)
End of Txt/
Withdrawal
Post-Txt 
Follow-
Up18
Baseline documentation
Informed Consent1
X
Medical/Oncologic History2
X
ECOG Performance Status3
X
X
X
X
X
Safety
Labs/Measurements
Vital Signs (BP and pulse) ***
X
X
X
X
X
X
X
X
X
X
Physical Examination4***
X
X
X
X
X
X
X
CBC (Complete Blood Count) with 
differential5***
X
X
X
X
X
X
X
X
X
X
X
Blood Chemistry6***
X
X
X
X
X
X
X
X
X
X
X
Urinalysis with micro7***
X
X
X
X
X
X
X
X
X
PT/PTT (or aPTT)/INR***
X
X
X
X
X
X
X
X
Pregnancy Test8 
X
X
X
X
X
Triplicate 12-lead ECG9
X
X
X
X
X
X
X
X
X
Other Clinical Assessments
Adverse Event (AE)10
X
X
X
X
X
X
X
X
X
X
X
X
Prior/Concomitant Medications 
and Treatments11
X
X
X
X
X
X
X
Drug Compliance12
X
X
Study Treatments
PF-04449913 Dosing13
X
X
X
X
Special Laboratory Studies
Blood samples for PF-04449913 
PK14
X
X
X
X
X
X
X
Bone marrow aspirate and/or 
biopsy for clinical staging and 
pharmacodynamic (PD) biomarker 
analysis 15 (5 days)
X
X
X


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Screening
Lead-in 
PK 
Period14
Cycle 1 (28-day Cycle)
Even-
Numbered 
Cycles*
Odd-
Numbered 
Cycles*
Protocol Activity
Within 
28 Days 
Prior to
Study 
Entry
Day
-5**
Day 
1
Day
5
(±1 
day)
Day
8
(±1 
day)
Day 
15
(±1 
day)
Day
21
(±1 
day)
Day
1
(±2 
days)
Day
15
(±2 
days)
Day
1
(±2 
days)
Day 
15
(±2 
days)
End of Txt/
Withdrawal
Post-Txt 
Follow-
Up18
Immunophenotyping and 
Cytogenetics16
X
X
X
For CML Patients: mutation status 
and PCR for BCR-ABL20
X
X
X
For Non-CML patients: mutation 
status21
X
Blood samples for PD 
biomarkers17
X
X
X
Normal Skin Punch Biopsy19
(±7day)
X
X
* For Cycles >7, only a Day 1 assessment is required.
** Days -5 should be considered Baseline for all assessments (except when the assessments are required only at screening). There is no Day 0 in the study.
*** If assessment obtained within 48 hours of scheduled time points, it need not be repeated.
1.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures. Must be obtained additional Informed consent form for confirmation of 
patient’s willingness to continue participation in the study at the end of Cycle 1.
2.
Medical History: To be collected within 28 days prior to first dose of PF-04449913.  Includes oncology history, history of other diseases (active or resolved), and 
concomitant illnesses.  During study treatment, any new or worsened conditions since baseline should be reported on the Adverse Event CRF.  Include information on 
prior regimens, dosing, and duration of administration as well as a description of the best response observed and treatment failure based on appropriate Disease Specific 
Guidelines.
3.
ECOG performance scale is provided in Appendix 1.
4.
Physical Examination includes major body systems as well as measurement of spleen and liver size to assess extramedullary disease (EMD).  Weight must be recorded 
at Screening and on Day 1 of each cycle.  Height need not be recorded following the first measurement.
5.
CBC (Complete Blood Count): WBC (White Blood Cell) with differential, hemoglobin, and platelet count.  Additional hematology tests may be performed as clinically 
indicated.  
6.
Blood Chemistry: Total bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase (LDH), total protein, albumin, sodium, potassium, magnesium, chloride, 
calcium, phosphorus, BUN or Urea, creatinine, uric acid, glucose, creatine kinase.  These tests may be repeated as clinically indicated.  
7.
Urinalysis: For pH, specific gravity, protein, glucose, ketones, red and white blood cells, leukocyte esterase, casts, crystals and nitrite (microscopic urinalysis).  
Additional urinalysis may be performed as clinically indicated.
8.
Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL will be performed on 
two occasions prior to commencing study therapy, once at the start of screening, once at the baseline visit, and immediately before investigational product 
administration.  Pregnancy tests will be routinely repeated at every cycle during the active treatment period, at the end of study therapy, and additionally whenever a 
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menstrual cycle is missed, or when pregnancy is otherwise suspected.  Additional pregnancy tests may be undertaken if requested by IRB/IECs, or if required by local 
regulations.
9.
Triplicate 12-lead ECGs: At each time point 3 consecutive supine 12-lead ECGs will be performed approximately 2 minutes apart to determine the mean QTcF interval.  
ECGs will be collected as follows: a) at Screening; b) On Day-5, at pre-dose and 1, 4, and 24 hrs post-dose; c) On Cycle 1/Day 1, at pre-dose and 1 hr post-dose; d) On 
Cycle 1/Day 8 at 1 hr post-dose; e) On Cycle 1/Day 15 at 1 hr post-dose; f) On Cycle 1/Day 21, at pre-dose and 1, 2, 4, and 24 hours following the dose of PF-
04449913; g) For every subsequent cycle on Day 1 at 1 hr post-dose and h) at the End of Treatment visit.  Refer to PK/ECG collection time points.
10. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.0. Patients must be followed for AEs 
for 28 days after the last treatment administration or until all drug-related toxicities have resolved, whichever is later; or earlier than 28 days should the patient 
commence another anticancer therapy in the meantime. For SAEs, the active reporting period to Pfizer or its designated representative begins from the time that the 
patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or receiving 
investigational product, through and including 28 calendar days after the last administration of the investigational product.  Serious adverse events occurring to a patient 
after the active reporting period has ended should be reported to the Sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator 
believes have at least a reasonable possibility of being related to study drug are to be reported to the Sponsor.
11. Concomitant Medications and Treatments: Every concomitant medication and treatment required by the patient within 28 days prior to study drug treatment and during 
the trial (and up to 28 days following last treatment administration or until initiation of another oncologic treatment) and the reason for its administration must be 
recorded on the CRF.
12. Drug Compliance: All PF-04449913 bottles including any unused tablets and patient dosing diaries will be returned for assessing compliance and drug accountability on 
Day 1 of each cycle.
13. PF-04449913 Dosing: A single dose of PF-04449913 will be administered on Day -5 (lead-in period), and PF-04449913 will then be given continuously orally, once 
daily in 28- day cycles. 
14. PF-04449913 PK: Blood samples for PF-04449913 PK will be collected a) during the lead-in Period on Day -5, at pre-dose and at 0.5, 1, 2, 4, 8, 24, 48, 72, and 120 hrs
(1 day)  post-dose (i.e., pre-dose on Cycle 1/Day 1); b) On Cycle 1 on Day 1, Day 8 and Day 15, at pre-dose and 1 hr post-dose (matched with the ECG); c) On 
Cycle 1/ Day 21 at pre-dose and at 0.5, 1, 2, 4, 8, and 24 hrs post-dose; d) For Cycles 2, 3, and 4 on Day 1 at pre-dose and 1 hr post-dose (matched with the ECGs).
15. A bone marrow aspirate and/or biopsy (5 days of nominal date) will be collected for local clinical staging.  
Time Points for Bone Marrow Sampling: For AML and CML AP (accelerated phase)/BC (blast crisis) patients these will be collected at a) screening, b) every even 
cycle on Day 1 and c) at End of Treatment and at investigators discretion.  For all other diseases these will be collected at screening and Day 1 of Cycle 2, 6 and 10 (and 
every 4 cycles), End of Treatment and at investigators discretion.  If a bone marrow aspirate and/or biopsy has been collected within 28 days (excluding the screening 
sample) it need not be repeated. For centralized biomarker assessments, bone marrow aspirate will be collected at a) screening; b) at End of Treatment/Withdrawal. With 
sponsor approval, the screening bone marrow need not be performed based on the patient characteristics (eg, dry tap or inevaluable) or a bone marrow performed prior 
to the screening period may be used for study inclusion.  
16. Quantitative immunophenotyping and cytogenetics on blood and/or bone marrow will be conducted for all patients at the same time as any scheduled or unscheduled 
bone marrow aspirate and/or biopsy as well as at screening (if a bone marrow is not performed the assessments should be performed using blood), End of Treatment, 
and at the investigator’s discretion.  
17. Blood samples for PD biomarkers: Blood will be collected a) on Cycle 1/Day 1 at pre-dose; b) on Cycle 1/Day 21 at pre-dose; c) at End of Treatment.
18. Follow-up Visit: At least 28 days, and no more than 35 days, after discontinuation of treatment (up to 42 days after the last dose of study drug if treatment was stopped 
for prolonged myelosupression) patients will return to undergo review of concomitant medications and assessment for resolution of any treatment-related toxicity.  
Patients continuing to experience toxicity at this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or 
determination, in the clinical judgment of the Investigator, that no further improvement is expected.
19. A normal skin punch biopsy will be collected at screening and on Cycle 1/Day 21 (7 days of nominal date).  Both biopsies should be obtained from approximately the 
same area of the body.  


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20. For all CML patients, mutation analyses will be conducted on blood and/or bone marrow samples at screening only. Quantitative PCR for BCR-ABL will be conducted 
on blood and/or bone marrow samples at the same time as any scheduled or unscheduled bone marrow aspirate and/or biopsy as well as at screening (if a bone marrow 
is not performed the assessments should be performed using blood), End of Treatment, and at the investigator’s discretion.  
21. For all non-CML patients mutation analysis is required within 6-months of start of the lead-in period. If not been performed within 6 months the mutation analysis must 
be performed on blood or bone marrow at screening. 
22.
 
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Table 2.
Combination Cohort 1: PF-04449913 + LDAC in Unfit Patients with AML or High-Risk MDS 
Screening
Cycle 1 (28-day Cycle)
Even-Numbered 
Cycle*
Odd-Numbered 
Cycle*
Protocol Activity
Within 28 Days 
Prior to Study 
Entry
Day 
1
Day 
2
Day 
3
Day 
10
Day 21 
(2 
day)
Day 1 
(2 
days)
Day 15 
(2 
days)
Day 1 
(2 
days)
Day 15 
(2 
days)
End of Txt/
Withdrawal
Post-Txt 
Follow-
Up23
Baseline documentation
Informed Consent1
X
Medical/Oncologic History2
X
ECOG Performance Status3
X
X
X
X
X
Safety Labs/Measurements
Vital Signs (BP and pulse) **
X
X
X
X
X
X
X
X
X
Physical Examination4**
X
X
X
X
X
X
X
CBC (Complete Blood Count) with 
differential5 **
X
X
X
X
X
X
X
X
X
Blood Chemistry6**
X
X
X
X
X
X
X
X
X
Urinalysis with micro7 **
X
X
X
X
X
PT/PTT (or aPTT)/INR**
X
X
X
X
X
Pregnancy Test8
X
X
X
X
X
Triplicate 12-lead ECG9
X
X
X
X
X
X
X
X
Other Clinical Assessments
Adverse Event (AE)10
X
X
X
X
X
X
X
X
X
X
X23
Prior/Concomitant Medications and 
Treatments11
X
X
X
X
X
X
X
X
X
X
X
X23
Recording of red blood cell and platelet 
transfusions21
X
X
X
X
X
X
X
X
X
X
X
Drug Compliance12
X
X
X
X
X
X
X
X
X
X
Survival Follow-up13
X13
Study Treatments
PF-04449913 Dosing14
Days 3 to 28
Days 1 to 28
Days 1 to 28
LDAC Dosing15
Days 1 to 10
Days 1 
to 10
Days 1 
to 10
Special Laboratory Studies
Blood samples for PF-04449913 PK16
X
X
X
X
X
Blood samples for LDAC PK17
X
X
Blood samples for PD biomarkers18
X
X
X
X
Normal Skin Punch Biopsy24 (7 day)
X
X


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Screening
Cycle 1 (28-day Cycle)
Even-Numbered 
Cycle*
Odd-Numbered 
Cycle*
Protocol Activity
Within 28 Days 
Prior to Study 
Entry
Day 
1
Day 
2
Day 
3
Day 
10
Day 21 
(±2 
day)
Day 1 
(±2 
days)
Day 15 
(±2 
days)
Day 1 
(±2 
days)
Day 15 
(±2 
days)
End of Txt/
Withdrawal
Post-Txt 
Follow-
Up23
Bone marrow for clinical and 
pharmacodynamic (PD) analysis19
(±7 days) 
X
X (C6 
and 
C12)
X (C3 
and C9)
X
Immunophenotyping and 
Cytogenetics20
X
X (C6 
and 
C12)
X (C3 
and C9)
X
* For Cycles >7, only a Day 1 assessment is required
** If assessment obtained within 48 hours of Cycle 1/Day 1 and following scheduled time points, it need not be repeated.
1.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures. Must be obtained additional Informed consent form for confirmation of 
patient’s willingness to continue participation in the study at the end of Cycle 1.
2.
Medical History: To be collected within 28 days prior to first dose.  Includes oncology history, full history of AML/MDS prior therapy (include dosing and duration of 
therapy) with best response, FAB subtype at initial presentation (for AML only), cytogenetics, mutation history, and prior and concomitant illnesses.  
3.
ECOG performance scale is provided in Appendix 1.
4.
Physical Examination includes examination of major body systems as well as measurement of spleen and liver size to assess extramedullary disease (EMD)  Weight 
must be recorded at Screening and on Day 1 of each cycle.  Height need not be recorded after the first measurement.
5.
CBC (Complete Blood Count): WBC (White Blood Cell) with differential, hemoglobin and platelet count.  These hematology tests may be repeated as clinically 
indicated.    For patients with MDS only, all platelet, absolute neutrophil and hemoglobin values observed during the 28-day screening period should be captured in the 
CRF.
6.
Blood Chemistry: Total bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase (LDH), total protein, albumin, sodium, potassium, magnesium, chloride, 
calcium, phosphorus, BUN or Urea, creatinine, uric acid, glucose, creatine kinase.  These chemistry tests may be repeated as clinically indicated.
7.
Microscopic urinalysis: For pH, specific gravity, protein, glucose, ketones, red and white blood cells, leukocyte esterase, casts, crystals and nitrite.  These urine tests 
may be repeated as clinically indicated.  
8.
Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with a sensitivity of at least 25 mIU/mL will be performed 
on two occasions prior to starting study therapy, once at the start of screening and once at the baseline visit, immediately before investigational product administration.  
Pregnancy tests will also be routinely repeated at every cycle during the active treatment period, at the end of study therapy and additionally whenever one menstrual 
cycle is missed or when potential pregnancy is otherwise suspected. Additional pregnancy tests may also be undertaken if requested by IRB/IECs or if required by local 
regulations.
9.
Triplicate 12-lead ECGs: At each time point, 3 consecutive supine 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTc interval.  
ECGs will be collected: a) Screening; b) Cycle 1/Day 1 at pre-dose; c) Cycle 1/Day 3 at pre-dose, 1 and 4 hour post-dose; d) Cycle 1/Day 10 at pre-dose and 1, 2, and 
4 hrs post-dose; e) Cycle 1/Day 21 at pre-dose and 1 and 4 hrs post-dose; f) In Cycles 2, 3, 4 and 5, on Day 1 at 1 hr post-dose and g) End of Treatment.  Refer to 
PK/ECG collection time points.
10.
Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.0.  Patients must be followed for AEs 
for 28 days after the last treatment administration or until all drug-related toxicities have resolved, whichever is later; or earlier than 28 days should the patient 
commence another anticancer therapy in the meantime.  For SAEs, the active reporting period to Pfizer or its designated representative begins from the time that the 
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Page 23
patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last administration of the investigational product.  Serious adverse events occurring 
to a patient after the active reporting period has ended should be reported to the Sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to study drug are to be reported to the Sponsor.  
11.
Concomitant Medications and Treatments: Every concomitant medication and treatment required by the patient within 28 days prior to study drug treatment and during 
the trial (and up to 28 days following last treatment administration or until initiation of another oncologic treatment) and the reason for its administration must be 
recorded on the CRF.
12.
Drug compliance: All PF-04449913 bottles including any unused tablets and patient dosing diaries will be returned for assessing compliance and drug accountability on
Day 1 of each cycle.  
13.
Survival follow-up post treatment: All patients will be followed for survival by site visit, phone or letter, regardless of initiation of new cancer therapy.
14.
PF-04449913 Dosing: For Cycle 1 only, PF-04449913 will start on Day 3, and will then be given continuously orally, once daily in 28-day cycles.  All subsequent 
cycles of PF-04449913 will start on Day 1 of each cycle, and be dosed as above.  PF-04449913 will be administered in the morning at approximately the same time as 
the first LDAC subcutaneous injection on days these agents are dosed together.  On days that PF-04449913 is dosed alone, PF-04449913 will be administered in the 
morning at approximately the same time each day.  
15.
LDAC Dosing: LDAC will be administered at a dose of 20 mg SC BID (morning and evening; approximately 12 hrs apart) for 10 consecutive days, starting on Day 1 
of each cycle. 
16.
Blood samples for PF-04449913 PK will be collected on: a) Cycle 1/Day 3 at pre-dose and 0.5 (30 min), 1, and 4 hrs post-dose; b) Cycle 1/Day 10 and Day 21 at pre-
dose and 0.5 (30 min), 1, 2, 4, 6 and 24 hrs post-dose; c) In Cycles 2, 3, 4 and 5 on Day 1 at pre-dose and 1 hr post-dose.  All samples will be collected relative to PF-
04449913 dosing.  Refer to PK/ECG collection time points.
17.
Blood samples for LDAC PK will be collected on: a) Cycle 1/Day 2, at pre-dose and 0.25 (15 min), 0.5 (30 min), 1, 2, 4 and 6 hrs post-dose following the AM 
subcutaneous injection; b) On Cycle 1/Day 10, at pre-dose and 0.25 (15 min), 0.5 (30 min), 1, 2, 4 and 6 hrs post-dose following the AM subcutaneous injection.  All 
samples will be collected relative to LDAC dosing.  Refer to PK/ECG collection time points.
18.
Blood samples for PD biomarkers will be collected on: a) Cycle 1/Day 1 at pre-LDAC dose; b) Cycle 1/Day 2 at 1 hr post LDAC-dose; c) Cycle 1/Day 21 at pre PF-
04449913-dose and d) End of Treatment 
19.
Type of Bone Marrow Sample: For all patients, a bone marrow aspirate and/or a biopsy sample is required and will be used for local clinical staging.  Only aspirates 
are required from all patients, and biopsies are optional unless required for clinical staging (e.g., dry tap).  All aspirate collections are mandatory unless in the
clinical judgment of the investigator, aspirate collection is inappropriate in which case following discussion with the sponsor collection may not be required.
Time Points for Bone Marrow Sampling: Bone marrow evaluations are required within 14 days of screening period (maximum window allowed is -42 days from 
study entry), and on Cycle 3/Day 1 (±7 days) and every third cycle (Cycle 6/Day 1, Cycle 9/Day 1, Cycle 12/Day 1), and within 14 days of achieving initial 
hematologic recovery in the peripheral blood (defined as ANC>1000/μL and platelets≥100,000/μL), End of Treatment and at investigators discretion.If 
hematologic recovery bone marrow has been performed within 14 days of next scheduled bone marrow evaluation, then it does not need to be repeated. For centralized 
biomarker assessments, bone marrow aspirate will be collected at a) screening; b) at End of Treatment/Withdrawal. 
20.
Quantitative immunophenotyping (to include MDR-1 [CD243] and ABCG-2 [CDw338] where possible) and cytogenetics will be conducted for all patients using any 
scheduled or unscheduled bone marrow samples collected during study participation. 
21.
All red blood cell and platelet transfusions, including date of each transfusion and the number of red blood cell units transfused will be recorded while on treatment. 
Note that number of units not number of bags must be recorded.  For patients with high-risk MDS, the transfusion history must be provided for 8-weeks prior to the 
start of study treatment.
22.
 
23.
Follow-up Visit: At least 28 days, and no more than 35 days following discontinuation of treatment (up to 42 days after the last dose of study drug if treatment was 
stopped for prolonged myelosupression) patients require review of concomitant medications and assessment for resolution of any treatment related toxicity. Patients 
continuing to experience toxicity at this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or 
determination, in the clinical judgment of the Investigator, that no further improvement is expected.
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24.
A normal skin punch biopsy will be collected at screening and on Cycle 1/Day 21 (7 days of nominal date).  Both biopsies should be obtained from approximately the 
same area of the body.
Table 3.
Expansion Cohort of LDAC combination for efficacy: PF-04449913 + LDAC in Unfit Patients with AML or High-
Risk MDS
Screening
Cycle 1 (28-day Cycle)
Even-Numbered 
Cycle
Odd-Numbered 
Cycle
Protocol Activity
Within 28 Days 
Prior to Study 
Entry
Day 
1
Day 
2
Day 
3
Day 
10
Day 21 
(2 
days)
Day 1 
(2 
days)
Day 15 
(2 
days)
Day 1 
(2 
days)
Day 15 
(2 
days)
End of Txt/
Withdrawal22
Post-Txt 
Follow-
Up23
Baseline documentation
Informed Consent1
X
Medical/Oncologic History2
X
ECOG Performance Status3
X
X
Safety Labs/Measurements
Vital Signs (BP and pulse)**
X
X
X
X
According to local clinical practice
Physical Examination4**
X
X
X
X
According to local clinical practice
CBC (Complete Blood Count) with 
differential5**
X
X
X
X
According to local clinical practice
Blood Chemistry6**
X
X
X
X
According to local clinical practice
Urinalysis with micro7**
X
X
According to local clinical practice
PT/PTT (or aPTT)/INR**
X
X
According to local clinical practice
Pregnancy Test8
X
X
X
X
X
Triplicate 12-lead ECG9
X
X
X
According to local clinical practice
Other Clinical Assessments
Adverse Event (AE)10
X
X
X
X
X
X
X
X
X
X
X23
Prior/Concomitant Medications and 
Treatments11
X
X
X
X
X
X
X
X
X
X
X
X23
Recording of red blood cell and platelet 
transfusions12
X
X
X
X
X
X
Drug Compliance13
X
X
X
X
X
X
X
X
X
X
Disease progression post treatment14
New anti-cancer therapies since 
discontinuation of study treatment14
Survival Assessment14
Study Treatments
PF-04449913 Dosing15
Days 1 to 28
Days 1 to 28
Days 1 to 28


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Screening
Cycle 1 (28-day Cycle)
Even-Numbered 
Cycle∗
Odd-Numbered 
Cycle∗
Protocol Activity
Within 28 Days 
Prior to Study 
Entry
Day 
1
Day 
2
Day 
3
Day 
10
Day 21 
(±2 
days)
Day 1 
(±2 
days)
Day 15 
(±2 
days)
Day 1 
(±2 
days)
Day 15 
(±2 
days)
End of Txt/
Withdrawal22
Post-Txt 
Follow-
Up23
LDAC Dosing16
Days 1 to 10
Days 1 
to 10
Days 1 
to 10
Special Laboratory Studies
Blood samples for PF-04449913 PK17
X (C6)
X (C3)
Blood samples for PD biomarkers18
X
X
X
Bone marrow for clinical and 
pharmacodynamic (PD) analysis19
(±7 days) 
X
According to local clinical practice (at least every 6 
months)
Immunophenotyping and 
Cytogenetics20
X
* For Cycles >7, only a Day 1 assessment is required.
** If assessment obtained within 48 hours of Cycle 1/Day 1 and following scheduled time points, it need not be repeated.
1.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.
2.
Medical History: To be collected within 28 days prior to first dose.  Includes oncology history, full history of AML/MDS prior therapy (include dosing and duration of 
therapy) with best response, FAB subtype at initial presentation (for AML only), cytogenetics, mutation history, and prior and concomitant illnesses.  
3.
ECOG performance scale is provided in Appendix 1. This assessment is not required after Protocol Amendment 8.
4.
Physical Examination includes examination of major body systems as well as measurement of spleen and liver size to assess extramedullary disease (EMD).  Weight 
must be recorded at Screening and on Day 1 of each cycle.  Height need not be recorded after the first measurement. After Protocol Amendment 8, these assessments 
will be conducted according to local clinical practice and the data is not required to be reported in CRF (AE must be reported in CRF if any observation is considered 
as AE).
5.
CBC (Complete Blood Count): WBC (White Blood Cell) with differential, hemoglobin and platelet count.  These hematology tests may be repeated as clinically 
indicated.  For patients with MDS only, all platelet, absolute neutrophil and hemoglobin values observed during the 28-day screening period should be captured in the 
CRF. After Protocol Amendment 8, these assessments will be conducted according to local clinical practice and the data is not required to be reported in CRF (AE 
must be reported in CRF if any observation is considered as AE).
6.
Blood Chemistry: Total bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase (LDH), total protein, albumin, sodium, potassium, magnesium, chloride, 
calcium, phosphorus, BUN or Urea, creatinine, uric acid, glucose, creatine kinase.  These chemistry tests may be repeated as clinically indicated. After Protocol 
Amendment 8, these assessments will be conducted according to local clinical practice and the data is not required to be reported in CRF (AE must be reported in CRF 
if any observation is considered as AE).
7.
Microscopic urinalysis: For pH, specific gravity, protein, glucose, ketones, red and white blood cells, leukocyte esterase, casts, crystals and nitrite.  These urine tests 
may be repeated as clinically indicated. After Protocol Amendment 8, these assessments will be conducted according to local clinical practice and the data is not 
required to be reported in CRF (AE must be reported in CRF if any observation is considered as AE).
8.
Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with a sensitivity of at least 25 mIU/mL will be performed 
on two occasions prior to starting study therapy, once at the start of screening and once at the baseline visit, immediately before investigational product administration.  
Pregnancy tests will also be routinely repeated at every cycle during the active treatment period, at the end of study therapy and additionally whenever one menstrual 
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cycle is missed or when potential pregnancy is otherwise suspected. Additional pregnancy tests may also be undertaken if requested by IRB/IECs or if required by local 
regulations. If the in-clinic study visits cannot be conducted due to COVID-19-related reasons, this assessment may be performed at a local clinic. Local laboratory 
reference ranges and lab accreditation need to be collected. Records of local laboratory tests and lab accreditation should be retrieved and kept in the site medical 
records and relevant data from the local clinic entered in the CRF.
9.
Triplicate 12-lead ECGs: At each time point, 3 consecutive supine 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTc interval.  
ECGs will be collected: a) Screening; b) Cycle 1/Day 1 at pre-dose, 1 and 4 hour post-dose; c) Cycle 1/Day 10 at 1 and 4 hour post-dose; d) In Cycles 2 and 3, on 
Day 1 at 1 hour post-dose and e) End of Treatment.  Refer to PK/ECG collection time points. After Protocol Amendment 8, these assessments will be conducted 
according to local clinical practice and the data is not required to be reported in CRF (AE must be reported in CRF if any observation is considered as AE).
10.
Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.0.  Patients must be followed for AEs 
for 28 days after the last treatment administration or until all drug-related toxicities have resolved, whichever is later; or earlier than 28 days should the patient 
commence another anticancer therapy in the meantime.  For SAEs, the active reporting period to Pfizer or its designated representative begins from the time that the 
patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last administration of the investigational product.  SAEs occurring to a patient after 
the active reporting period has ended should be reported to the Sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator 
believes have at least a reasonable possibility of being related to study drug are to be reported to the Sponsor.  If the in-clinic study visits cannot be conducted due to 
COVID-19-related reasons, this assessment should be conducted by phone or video contact and based on the test results from a local clinic if applicable.
11.
Concomitant Medications and Treatments: Every concomitant medication and treatment required by the patient within 28 days prior to study drug treatment and during 
the trial (and up to 28 days following last treatment administration or until initiation of another oncologic treatment) must be reviewed. If the in-clinic study visits 
cannot be conducted due to COVID-19-related reasons, this review should be conducted by phone or video contact. After Protocol Amendment 8, these data are not 
required to be recorded on the CRF.
12.
All red blood cell and platelet transfusions, including date of each transfusion and the number of red blood cell units transfused will be recorded while on treatment. 
Note that number of units not number of bags must be recorded.  For patients with high-risk MDS, the transfusion history must be provided for 8-weeks prior to the 
start of study treatment. If the in-clinic study visits cannot be conducted due to COVID-19-related reasons, this review should be conducted by phone or video contact. 
After Protocol Amendment 8, these data are not required to be recorded on the CRF.
13.
Drug compliance: All PF-04449913 bottles including any unused tablets and patient dosing diaries will be returned for assessing compliance and drug accountability on
Day 1 of each cycle.  If the in-clinic study visits cannot be conducted due to COVID-19-related reasons, this review of dosing compliance should be conducted by 
phone or video contact.
14.
Disease progression post treatment, new anti-cancer therapies since discontinuation of study treatment and Survival Assessment: All patients will be followed every 8 
weeks starting from the last dose of study medication to confirm survival status and collect information on any new anti-cancer therapies initiated.  All patients will be 
followed for survival every 8 weeks up to 2 years from the first dose of the last patient enrolled in the study, or until death, end of the study, or patient withdrawal of 
consent, whichever comes first, regardless of initiation of new cancer therapy.  For patients refusing to return to the site, a telephone follow-up call is acceptable.
Post-treatment disease progression including the data for disease assessment recorded in the source documents will be collected until initiation of new anti-cancer 
therapies. For patients in DMR, disease assessment and corresponding lab data (neutrophil counts, platelets and peripheral/bone marrow blasts %) will be collected if 
available from the source documents. After Protocol Amendment 8, these follow-up assessments are not required.
15.
PF-04449913 Dosing: PF-04449913 will start on Day 1 of each cycle, and be given continuously orally, once daily in 28-day cycles.  PF-04449913 will be 
administered in the morning at approximately the same time as the first LDAC subcutaneous injection on days these agents are dosed together.  On days that PF-
04449913 is dosed alone, PF-04449913 will be administered in the morning at approximately the same time each day.  
16.
LDAC Dosing: LDAC will be administered at a dose of 20 mg SC BID (morning and evening; approximately 12 hrs apart) for 10 consecutive days, starting on Day 1 
of each cycle. If the in-clinic study visits cannot be conducted due to COVID-19-related reasons, LDAC administration may be skipped only once. In such case, the 
safety assessments should be performed by phone or video contact, and/or by utilizing the test results from a local clinic if applicable. If 2 or more consecutive skips 
are required, the investigator and the Sponsor should have a consultation to determine the necessity of the study treatment discontinuation.


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17.
Blood samples for PF-04449913 PK will be collected on: a) Cycle 3/Day 1 at pre-dose and b) Cycle 6/Day 1 at pre-dose (i.e. the same dates as bone marrow aspirates 
for biomarker assessments).
18.
Blood samples for PD biomarkers will be collected on: a) Cycle 1/Day 1 at pre LDAC-dose; b) Cycle 1/Day 2 at 1 hr post LDAC-dose; c) Cycle 1/Day 21 at pre PF-
04449913-dose and d) End of Treatment. After Protocol Amendment 8, these assessments are not required.
19.
Type of Bone Marrow Sample: For all patients, a bone marrow aspirate and/or a biopsy sample is required and will be used for local clinical staging.  Only aspirates 
are required from all patients, and biopsies are optional unless required for clinical staging (e.g., dry tap).  All aspirate collections are mandatory unless in the 
clinical judgment of the investigator, aspirate collection is inappropriate in which case following discussion with the sponsor collection may not be required.
Time Points for Bone Marrow Sampling: Bone marrow evaluations are required within 14 days of screening period (maximum window allowed is -42 days from 
study entry), and on Cycle 3/Day 1 (±7 days) and every third cycle (Cycle 6/Day 1, Cycle 9/Day 1, Cycle 12/Day 1, etc.), and within 14 days of achieving initial 
hematologic recovery in the peripheral blood (defined as ANC>1000/μL and platelets≥100,000/μL), End of Treatment and at investigators discretion. If 
hematologic recovery bone marrow has been performed within 14 days of next scheduled bone marrow evaluation, then it does not need to be repeated. For centralized 
biomarker assessments, bone marrow aspirate will be collected at the timing of bone marrow assessment for disease assessment (after consent obtained). After Protocol 
Amendment 8, bone marrow evaluation for clinical assessment will be conducted according to local clinical practice (at least every 6 months) but bone marrow samples 
are not required to be submitted for centralized biomarker assessments. 
20.
Quantitative immunophenotyping (to include MDR-1 [CD243] and ABCG-2 [CDw338] where possible) and cytogenetics will be conducted for all patients using any 
scheduled or unscheduled bone marrow samples collected during study participation. After Protocol Amendment 8, these assessments are not required.
21.
 
22.
End of Treatment: Obtain these assessments if not completed in the last week (last 3 months for BM assessments, unless the patient is coming off study treatment for 
disease progression).
23.
Follow-up Visit: At least 28 days, and no more than 35 days following discontinuation of treatment (up to 42 days after the last dose of study drug if treatment was 
stopped for prolonged myelosuppression) patients require review of concomitant medications and assessment for resolution of any treatment related toxicity. Patients 
continuing to experience toxicity at this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or 
determination, in the clinical judgment of the Investigator, that no further improvement is expected.
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Table 4.
Combination Cohort 2: PF-04449913 + Cytarabine/Daunorubicin in Fit Patients with AML or High-Risk MDS 
Screening
Induction
Consolidation
Maintenance
Lead-
in (first 
cycle 
only)
Up to 2 Induction Cycles 
(28-day cycle)
2-4 Consolidation Cycles
(28-day cycle)***
Maximum of 6
Maintenance 
Cycles
(28-day cycle)
Protocol Activity
Within 28 
Days Prior 
to Study 
Entry
Day
-3 *
Da
y 1
Da
y 3
Day 
10
(1 
days)
Day 
21
(2 
days)
Da
y 1
Da
y 5
Day 
10
(1 
days)
Day 
21
(2 
days)
Day 1 (2 days)
End of 
Txt/
Withdra
wal
Post-Txt 
Follow-
Up24
Baseline documentation
Informed Consent1
X
Medical/Oncologic History2
X
ECOG Performance Status3
X
X
X
X
X
X
Safety Labs/Measurements
Vital Signs (BP and pulse) **
X
X
X
X
X
X
Physical Examination4**
X
X
X
X
X
X
X
X
X
X
CBC (Complete blood count) with 
differential5 **
X
X
X
X
X
X
X
X
X
X
X
X
Blood Chemistry6 **
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis with micro7 **
X
X
X
X
X
X
PT/PTT (or aPTT)/INR**
X
X
X
X
X
X
Pregnancy test8
X
X
X
X
X
Triplicate 12-lead ECG9
X
X
X
X
X
X
ECHO or MUGA scan21
X
Other Clinical Assessments
Adverse Event (AE)10
X
X
X
X
X
X
X
X
X
X
X
X
Prior/Concomitant Medications
and Treatments11
X
X
X
X
X
X
X
X
X
X
X
X
X
Recording of red blood cell and 
platelet transfusions22
X
X
X
X
X
X
X
X
X
X
X
X
Drug Compliance12
X
X
X
X
X
X
X
X
X
X
X


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Screening
Induction
Consolidation
Maintenance
Lead-
in (first 
cycle 
only)
Up to 2 Induction Cycles 
(28-day cycle)
2-4 Consolidation Cycles
(28-day cycle)***
Maximum of 6
Maintenance 
Cycles
(28-day cycle)
Protocol Activity
Within 28 
Days Prior 
to Study 
Entry
Day
-3 *
Da
y 1
Da
y 3
Day 
10
(±1 
days)
Day 
21
(±2 
days)
Da
y 1
Da
y 5
Day 
10
(±1 
days)
Day 
21
(±2 
days)
Day 1 (±2 days)
End of 
Txt/
Withdra
wal
Post-Txt 
Follow-
Up24
Study Treatments
PF-04449913 Dosing13
Days -3 to 28
Days 1 to 28
Days 1 to 28
Daunorubicin Dosing14
Days 1 to 
3
Cytarabine Dosing15
Days 1 to 
7
Days 1, 3,
and 5
Special Laboratory Studies
Blood samples for PF-04449913 
PK16
X
X
X
X
X
Blood samples for Daunorubicin 
PK17
X
Blood samples for Cytarabine PK17
X
Blood samples for PD 
biomarkers18
X
X
X
X
X
X
Normal Skin Punch Biopsy25(±  
7day)
X
X
Bone marrow for clinical staging 
and for PD biomarker analysis (±7 
days)19
X
X
X
X
X
Immunophenotyping and 
Cytogenetics20
X
X
X
X
X
* There is no Day 0.  
** If assessment obtained within 48 hours of Cycle 1/Day 1 and following scheduled time points, it need not be repeated.
***Patients with CR/CRi must receive a minimum of 2 consolidation cycles, but no more than 4 consolidation cycles, to be eligible for maintenance therapy.
1.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures. Must be obtained additional Informed consent form for confirmation of 
patient’s willingness to continue participation in the study at the end of Induction Cycle 1.
2.
Medical History: To be collected within 28 days prior to first dose.  Includes oncology history, full history of AML/MDS prior therapy (include dosing and duration of 
therapy) with best response, FAB subtype at initial presentation (for AML only), cytogenetics and mutation history and prior and concomitant illnesses.  
3.
ECOG performance scale is provided in Appendix 1.
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4.
Physical Examination includes examination of major body systems as well as measurement of spleen and liver size to assess extra-medullary disease (EMD).  Weight 
must be recorded at Screening and Day 1 of each cycle.  Height need not be recorded after the first measurement.
5.
CBC (Complete blood count): WBC (White blood cell) with differential, hemoglobin and platelet count.  Additional hematology tests may be performed as clinically 
indicated.    For patients with MDS only, all platelet, absolute neutrophil and hemoglobin values observed during the 28-day screening period should be captured in the 
CRF.
6.
Blood Chemistry: Total bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase (LDH), total protein, albumin, sodium, potassium, magnesium, chloride, 
calcium, phosphorus, BUN or Urea, creatinine, uric acid, glucose, creatine kinase.  These chemistry tests may be repeated as clinically indicated.  
7.
Microscopic urinalysis: For pH, specific gravity, protein, glucose, ketones, red and white blood cells, leukocyte esterase, casts, crystals and nitrite.  These urine tests 
may be repeated as clinically indicated. 
8.
Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL will be performed on 
two occasions prior to starting study therapy   once at the start of screening and once at the baseline visit, immediately before investigational product administration.  
Pregnancy tests will also be routinely repeated at every cycle during the active treatment period, at the end of study therapy and additionally whenever one menstrual 
cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by IRB/IECs or if required by local 
regulations.
9.
Triplicate 12-lead ECGs: At each time point, 3 consecutive supine 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTc interval.  
ECGs will be collected at:
a) Screening; b) Induction Cycle 1 Lead-in Day -3 at pre-dose and 1 hr post PF-04449913 dose; c) Induction Cycle 1/Day 10 at 1 and 4 hrs post-PF-04449913 dose; d) 
If a second induction cycle is administered, then ECG should be collected on Day 1 and Day 10 at 1 hr post-dose; e) Consolidation cycles on Day 1 at 1 hr post-PF-
04449913 dose in first 2 cycles; f) Maintenance cycles on Day 1 at 1 hr post-PF-04449913 dosing in first 2 cycles and g) End of Treatment.  Refer to PK/ECG 
collection time points.
10. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.0.  Patients must be followed for AEs 
for 28 days after the last treatment administration or until all drug-related toxicities have resolved, whichever is later; or earlier than 28 days should the patient be 
commenced on another anti-cancer therapy in the meantime.  For SAEs, the active reporting period to Pfizer or its designated representative begins from the time that 
the patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last administration of the investigational product.  Serious adverse events occurring 
to a patient after the active reporting period has ended should be reported to the Sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to study drug are to be reported to the Sponsor.  
11. Concomitant Medications and Treatments: Every concomitant medication and treatment required by the patient within 28 days prior to study drug treatment and during 
the trial (and up to 28 days following last treatment administration or until initiation of another oncologic treatment) and the reason for its administration must be 
recorded on the CRF.
12. Drug compliance: All PF-04449913 bottles including any unused tablets and patient dosing diaries will be returned for assessing compliance and drug accountability on 
Day 1 of each cycle.
13. PF-04449913 Dosing:  PF-04449913 will be started at Day-3 for the first cycle of induction only, and given continuously from Day -3 onwards as described below.  For 
all other cycles, PF-04449913 will start on Day 1 of each cycle and will be given orally once daily in the morning at approximately the same time of day for all 3 phases 
(induction, consolidation and maintenance) in 28-day cycles.  Where possible, PF-04449913 will be administered together with daunorubicin IV injection during 
induction and the morning cytarabine IV infusion start during consolidation.
14. Daunorubicin Dosing (Induction only):  Daunorubicin will be given at a dose of 60 mg/m2 as an IV in combination with cytarabine and PF-04449913, on Days 1-3 of 
induction Cycle 1.  Induction chemotherapy may be repeated for one additional cycle if an unsatisfactory clinical response is observed and there are no signs of cardiac 
toxicity.  If clinical signs of cardiac dysfunction are observed, a repeat MUGA/ECHO should be performed, and must demonstrate a LVEF 45% to receive a second 
course of induction chemotherapy.  If a second cycle of induction therapy is required, it may start prior to Day 28 of induction Cycle 1 but not earlier than 
Cycle 1/Day 21.  Dose must be recalculated if the weight changes by >10%.  
15. Cytarabine Dosing: Separate cytarabine dosing and schedules will be used for Induction and Consolidation and administered using institutional guidelines:                
Induction: Cytarabine will be administered (in parallel to daunorubicin) at a dose of 100 mg/m2 by continuous IV infusion for 7 days on Days 1-7 of induction Cycle 1.  


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If a second cycle of induction therapy is indicated by the treating physician and the patient does not have resistant disease, it may start prior to Day 28 of induction 
Cycle 1 but no earlier than Cycle 1/Day 21.  Dose must be recalculated if the weight changes by >10%.                                                                                                            
Consolidation: Single-agent cytarabine will be administered at a dose of 1g/m2 IV infused over 3 hours, given Q12 hours (morning and evening) on Days 1, 3 and 5. 
Consolidation cytarabine will be repeated every 28 days for 4 cycles unless the patient relapses, unacceptable toxicity or patient withdrawal. Dose must be recalculated 
if the weight changes by >10%.  
16. Blood samples for PF-04449913 PK will be collected on:
a) Induction Cycle 1 Lead-in Day -3 at pre-dose and 1 hr post-PF-04449913 dose; b) Induction Cycle 1/Day 3 at pre-dose, 0.5 (30 min), 1, 6, and 24 hrs post-PF-
04449913 dose; c) Induction Cycle 1/Day 10 at pre-dose, 0.5 (30 min), 1, 4, 6, and 24 hrs post-PF-04449913 dose; d) Consolidation cycles on Day 1 at 1 hr post-PF-
04449913 dose in first 2 cycles; e) Maintenance cycles on Day 1 at 1 hr post-dose in first 2 cycles. All samples will be collected relative to PF-04449913 dosing.  Refer 
to PK/ECG collection time points.
17. Blood samples for Cytarabine and Daunorubicin PK: 
Daunorubicin: Day 3 (Induction Cycle 1 only) at pre-dose, 0.25 (15 min, mid-infusion), 0.5 (30 min, immediately prior to the end of infusion), 1, 4, 6, 24 hrs post 
administration of daunorubicin. All samples will be collected relative to daunorubicin dosing.  Refer to PK/ECG collection time points.
Cytarabine: Day 3 (Induction Cycle 1 only), at pre-dose, 6 and 24 hours after the start of cytarabine infusion. All samples will be collected relative to cytarabine
dosing. Refer to PK/ECG collection time points.
18. Blood samples for PD biomarkers will be collected on: a) Day -3 of first induction cycle at pre-dose; b) Day 3 of first induction cycle at 1 hr post-dose; c) Day 10 of 
first induction cycle at 1 hr post-dose; d) Day 1 of first consolidation cycle at 1 hr post-dose; e) Day 10 of first consolidation cycle at pre-dose and f) End of Treatment. 
All collections are relative to PF-04449913 dosing.
19. Type of Bone Marrow Sample: For all patients a bone marrow aspirate and/or a biopsy sample is required and will be used for local clinical staging. Only aspirates 
are required of all patients, and biopsies are optional unless required for clinical staging (e.g., dry tap).  All aspirate collections are mandatory unless in the 
clinical judgment of the investigator, aspirate collection is inappropriate in which case following discussion with the sponsor collection may not be required.                       
Time Points for Bone Marrow Sampling: For screening: An aspirate and biopsy obtained within 14 days of screening period (maximum window allowed is -42 days 
from study entry) is acceptable for patient eligibility and PD biomarker assessment, but if not available it will need to be obtained as part of the screening procedures.
•
Induction: the bone marrow samples will be collected during both Induction cycles. There is only an allowed window of +7 days (i.e., Day 21-Day 28).  Bone 
marrow evaluations may be repeated at Investigator discretion as required for clinical staging anytime prior to next cycle of chemotherapy.
•
Consolidation: If a patient enters consolidation with a CRi (post-induction), the bone marrow evaluation must be repeated within 14 days if initial hematologic 
recovery is achieved in the peripheral blood (defined as ANC>1000/μL and platelets≥100,000/μL). Bone marrow evaluation is required D21 (±7 days) of the 
final cycle of consolidation.  If hematologic recovery bone marrow has been performed within 14 days of next scheduled bone marrow evaluation it need not be 
repeated. Additional bone marrow evaluations may be repeated at Investigator discretion as required for clinical staging anytime prior to next cycle of 
chemotherapy. 
•
Maintenance: A bone marrow is required on Day 1 (±7 days) every third cycle from start of maintenance therapy (i.e., Cycles 3 and 6 of the maintenance cycle).
For centralized biomarker assessments, bone marrow aspirate will be collected at a) screening; b) at End of Treatment/Withdrawal. 
20. Quantitative immunophenotyping (to include MDR-1 [CD243] and ABCG-2 [CDw338] where possible) and cytogenetics will be conducted locally for all patients using 
any scheduled or unscheduled bone marrow samples collected during study participation.  
21. Should be repeated before Induction Cycle 2 if signs of cardiac toxicity are observed and as clinically indicated thereafter.
22. All red blood cell and platelet transfusions, including date of each transfusion and number of red blood cell units transfused will be recorded while on treatment.  Note 
that number of units not number of bags must be recorded.  For patients with high-risk MDS, the transfusion history is required to be provided for 8-weeks prior to start 
of study treatment.
23.
 
  
24. Follow-up Visit: At least 28 days, and no more than 35 days, after discontinuation of treatment (up to 42 days after the last dose of study drug if treatment was stopped 
for prolonged myelosupression) patients require review of concomitant medications and assessment for resolution of any treatment related toxicity. Patients continuing 
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to experience toxicity at this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the 
clinical judgment of the Investigator, that no further improvement is expected.
25. A normal skin punch biopsy will be collected at screening and on Cycle 1/Day 21 (7 days of nominal date).  Both biopsies should be obtained from approximately the 
same area of the body.


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Table 5.
Combination Cohort 3: PF-04449913 + Azacitidine in Patients with previously untreated AML who are eligible for 
non-intensive chemotherapy
Screening
Cycle 1 (28-day cycle)
Cycle 2 (28-day cycle)
Cycles 3
(28-day cycles)
End of Txt/
Withdrawal25
Post-Txt 
Follow-Up26
Protocol Activity
Within 28 
Days 
Prior to 
Study 
Entry
Day 1
Day 2
Day 7
Day 
21
Day 1
(3 days)
Day 15
(3 days)
Day 1
(3 days)
Baseline documentation
Informed Consent1
X
Medical History2
X
ECOG Performance Status3
X
X
X
X
X
Disease Classification4
X
Safety Labs/Measurements
Vital Sign (BP and pulse)**
X
X
X
X
X
Physical Examination5**
X
X
X
X
X
CBC (Complete Blood 
Count) with differential 6**
X
X
X
X
X
X
X
X
Blood Chemistry7**
X
X
X
X
X
X
X
X
Urinalysis8**
X
X
X
X
X
Coagulation9**
X
X
X
X
X
X
X
Pregnancy test10
X
X
X
X
X
Triplicate 12 - lead ECG11
X
X
X
X
X
X 
X
X
Study Treatment
PF-04449913 Dosing12
Oral Daily Continuous Dosing (For Cycle 1 only PF-04449913 dosing will start on Day 2)
Azacitidine Dosing13
SC injection or IV Days 1-7 (After Cycle 1, 3 days window applicable to each 
dose)
Drug Compliance14
X
X
X
X
X 
X
X
X
Clinical Staging
Bone Marrow15
X
X15
X
Bone marrow 
immunophenotyping and 
Cytogenetics16
X
X
X
Other Clinical Assessments
Adverse Event Monitoring17
X
X
X
Review Prior/Concomitant 
Treatments18
X
X
X
X
Recording of red blood cell 
and platelet transfusions19
X
X
X


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Screening
Cycle 1 (28-day cycle)
Cycle 2 (28-day cycle)
Cycles ≥3
(28-day cycles)
End of Txt/
Withdrawal25
Post-Txt 
Follow-Up26
Protocol Activity
Within 28 
Days 
Prior to 
Study 
Entry
Day 1
Day 2
Day 7
Day 
21
Day 1
(±3 days)
Day 15
(±3 days)
Day 1
(±3 days)
Disease progression post 
treatment20
X
New anti cancer therapies 
since discontinuation of study 
treatment20
X
Survival Assessment20
X
PK Sampling
Blood Samples for PK 
evaluation21
X
X
X
X
X 
Biomarker Assessments
Blood samples for 
biomarkers22
X
X
X
Bone marrow aspirate for 
biomarker analysis23
X
X
(Cycle 4 only)
X
** If assessment obtained within 3 days of Cycle 1/Day 1 and following scheduled time points, it need not be repeated.
1.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures. Must be obtained additional Informed consent form for confirmation of 
patient’s willingness to continue participation in the study at the end of Cycle 1.
2.
Medical History: Includes oncology history, full history of AML prior therapy (include dosing and duration of therapy) with best response, FAB subtype at initial 
presentation, cytogenetics and mutation history and prior and concomitant illnesses.
3.
ECOG: See Appendix 1.
4.
Disease Classification: AML by WHO.  Prognostic system using 2017 European Leukemia Net (ELN) criteria.
5.
Physical Examination: Examination of major body systems as well as measurement of spleen and liver size to assess extra-medullary disease (EMD).  Weight must be 
recorded at Screening and Day 1 of each cycle.  Height need not be recorded after the first measurement at screening.
6.
CBC (Complete Blood Count): WBC (White Blood Cell) with differential, hemoglobin and platelet count.  These hematology tests may be repeated as clinically 
indicated. The list of required laboratory tests is provided in Secton 7.1.3.
7.
Blood Chemistry: The list of required laboratory tests is provided in Section 7.1.3.
8.
Urinalysis: The list of required laboratory tests is provided in Section 7.1.3.
9.
Coagulation: The list of required laboratory tests is provided in Section7.1.3.
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10. Pregnancy Tests: For female patients of childbearing potential, a serum or urine pregnancy test, with a sensitivity of at least 25 mIU/mL will be performed on two 
occasions prior to starting study therapy, once at the start of screening and once at the baseline visit, immediately before investigational product administration.  
Pregnancy tests will also be routinely repeated at every cycle during the active treatment period, at the end of study therapy and additionally whenever one menstrual 
cycle is missed or when potential pregnancy is otherwise suspected. Additional pregnancy tests may also be undertaken if requested by IRB/IECs or if required by 
local regulations.   
11. ECG: See Table 11 for detailed ECG Schedule. 
12. PF-04449913 Dosing: Treatment will be administered in 28-day cycles (cycle duration may be extended to allow for toxicity resolution).  PF-04449913 will be 
administered once daily continuously, in the morning at approximately the same time each day.  For Cycle 1 only PF-04449913 dosing will start on Day 2 to 
accommodate PK samples collection for DDI assessment.  In all subsequent cycles PF-04449913 administration will start on Day 1.  
13. Azacitidine Dosing: Azacitidine will be administered subcutaneously or IV on Days 1-7 of each 28-day cycle (After Cycle 1, 3 days window applicable to each 
dose).  The next cycle start can be delayed to allow for toxicity resolution.
14. Drug Compliance: All PF-04449913 bottles including any unused tablets and patient dosing diaries will be returned to the clinic for compliance assessment and drug 
accountability.  
15. Bone Marrow Assessments for Clinical Staging.

Type of Bone Marrow Sample: For all patients, a bone marrow aspirate and/or a biopsy sample are required at screening and will be used for clinical staging.  
For screening, samples taken prior to consent but within the 28-day window prior to fist dose can be used and need not be repeated.  Only bone marrow 
aspirates are performed for disease evaluation and biopsies are optional unless required for clinical staging (eg, dry tap). All aspirate collections are 
mandatory unless in the clinical judgment of the investigator, aspirate collection is inappropriate in which case following discussion with the sponsor collection 
may not be required.

Timepoints for Bone Marrow Sampling:
Bone marrow assessment must be completed at screening (within 28 days of first dose).  However, if progression is suspected during the screening period an 
additional BM sample should be collected prior first dose of study drug to confirm eligibility.  Subsequent BM samples to be collected on C4D1 (±7 days), and 
every 3 cycles afterwards (C7D1, C10D1, C13D1 and so on ±7 days), at the EOT, and as clinically indicated. If hematologic recovery bone marrow has been 
performed within 14 days of next scheduled bone marrow evaluation it need not be repeated.
16. Bone Marrow Immunophenotyping and Cytogenetics: Quantitative immunophenotyping (to include MDR-1 [CD243] and ABCG-2 [CDw338] where possible) and 
cytogenetics will be conducted on all patients using any scheduled or unscheduled bone marrow samples collected during study participation.  Please see Footnote 
15 for details on bone marrow samples collection schedule.  
17. Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.0.  Patients must be followed for 
AEs for 28 days after the last treatment administration or until all drug-related toxicities have resolved, whichever is later; or earlier than 28 days should the patient 
commence another anticancer therapy in the meantime.  For SAEs, the active reporting period to Pfizer or its designated representative begins from the time that the 
patient provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last administration of the investigational product.  Serious adverse events occurring 
to a patient after the active reporting period has ended should be reported to the Sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to study drug are to be reported to the Sponsor.
18. Concomitant Medications and Treatments: Every concomitant medication and treatment required by the patient within 28 days prior to study drug treatment and 
during the trial (and up to 28 days following last treatment administration or until initiation of another oncologic treatment) and the reason for its administration must 
be recorded on the CRF.
19. Red Blood Cells and Platelets Transfusion Recording: Transfusion history up to 8 weeks prior to the start of study treatment should be recorded.  All red blood cell 
and platelet transfusions, including date of each transfusion and number of red blood cell and platelet units transfused will be recorded while on treatment.  Note that 
number of units, not number of bags, must be recorded.


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20. Disease progression post treatment, new anti-cancer therapies since discontinuation of study treatment and Survival Assessment: All patients will be followed every 
12 weeks starting from the last dose of study medication to confirm survival status and collect information on any new anti-cancer therapies initiated.  All patients 
will be followed for survival every 12 weeks up to 3 years from the first dose of the last patient enrolled in the study, or until death, end of the study, or patient 
withdrawal of consent, whichever comes first, regardless of initiation of new cancer therapy.  For patients refusing to return to the site, a telephone follow-up call is 
acceptable. Post-treatment disease progression including the data for disease assessment recorded in the source documents will be collected until initiation of new 
anti-cancer therapies. For patients in remission, disease assessment and corresponding lab data (neutrophil counts, platelets and peripheral/bone marrow blasts %) will 
be collected if available from the source documents.
21. Blood samples for PK Evaluation: See detailed information in Table 11 for PK timepoints.
22. Blood samples for Biomarker Profiling: Blood samples for biomarkers profiling will be collected on C1D1 (pre-dose), C2D1 (pre-dose), and EOT.
23. Bone Marrow Aspirates for Biomarker Analysis: A bone marrow aspirate for biomarker assessments must be collected at screening, C4D1, and EOT.  All bone 
marrow aspirate collections are mandatory unless in the clinical judgment of the Investigator aspirate collection is inappropriate in which case following discussion 
with the Sponsor collection may not be required. Collection of an aspirate BM sample for biomarker analysis should also occur when the BM for clinical response 
assessment is repeated.  Samples will be analyzed centrally.
 
25. End of Treatment: Obtain these assessments if not completed in the last week (last 3 months for BM assessments, unless the patient is coming off study treatment for 
disease progression).
26. Follow-up Visit: At least 28 days, and no more than 35 days following discontinuation of treatment (up to 42 days after the last dose of study drug if treatment was 
stopped for prolonged myelosupression) patients require review of concomitant medications and assessment for resolution of any treatment related toxicity. Patients 
continuing to experience toxicity at this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or 
determination, in the clinical judgment of the Investigator, that no further improvement is expected.
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Table 6.
Continuation Cohort (Monotherapy Cohort): Single-Agent PF-04449913 in Myelofibrosis Patient
Screening
Cycle 1 
(28-day Cycle)
Cycles 4, 7, 10 and 
thereafter every 3 cycles
Protocol Activity
Within 28 Days 
Prior to 
Cycle 1 Day 1
Day 1
Day 1
(2 days)
End of Txt/
Withdrawal
Post-Txt Follow- Up12
Baseline documentation
Informed Consent 1
X
Medical/Oncologic History 2
X
Safety Labs/Measurements
Height and Weight3***
X
X
X
CBC (Complete Blood Count) with 
differential4***
X
X
X
Pregnancy Test 5
X
X
X
Triplicate 12-lead ECG6
X
X
X
Others (ex. Vital signs, ECOG 
Performance Status, Blood 
Chemistry, Coagulation, Urinalysis)
According to local clinical practice
Other Clinical Assessments
Adverse Event (AE) 7
X
Concomitant Medications and 
Treatments8
X
Recording of red blood cell and 
platelet transfusions9
X
Drug Compliance10
X
X
X
Study Treatment
PF-04449913  Dosing11
X
X
*** If assessment obtained within 48 hours of scheduled time points, it need not be repeated.
In the event that the in-clinic study visits cannot be conducted due to COVID-19-related reasons, the study visits every 3 cycles may be skipped only once. In such case, the safety 
assessments should be performed by phone or video contact, and/or by utilizing the test results from a local clinic if applicable. If 2 or more consecutive skips are required, the 
investigator and the Sponsor should have a consultation to determine the necessity of the study treatment discontinuation.
1.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.
2.
Medical History: Includes oncology history, prior and concomitant illnesses. Ongoing adverse events which had occurred in the previous study and any new or worsened 
conditions since baseline during study treatment should be reported on the Adverse Event CRF.
3.
Weight and Hight: Weight must be recorded at Baseline, thereafter on Day 1 of every 3 cycles and at End of Treatment.  Height must be recorded at Baseline only. If the in-
clinic study visits cannot be conducted due to COVID-19-related reasons, weight tests may be performed at a local clinic. Local laboratory reference ranges and lab 
accreditation need to be collected. Records of local laboratory tests and lab accreditation should be retrieved and kept in the site medical records and relevant data from the 
local clinic entered in the CRF.


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4.
CBC (Complete Blood Count): To be collected at Cycle 1 Day 1 (pre-treatment), thereafter on Day 1 of every 3 cycles and at the End of Treatment.  Refer to Section 7.1.3
for a list of assessments. Additional hematology tests may be performed as clinically indicated. If the in-clinic study visits cannot be conducted due to COVID-19-related 
reasons, this assessment may be performed at a local clinic. Local laboratory reference ranges and lab accreditation need to be collected. Records of local laboratory tests and 
lab accreditation should be retrieved and kept in the site medical records and relevant data from the local clinic entered in the CRF.
5.
Serum/Urine Pregnancy Test: Pregnancy tests will be collected at Cycle 1 Day 1 (pre-treatment), thereafter routinely repeated at every cycle during the active treatment 
period, at End of Treatment, and additionally whenever a menstrual cycle is missed, or when pregnancy is otherwise suspected.  Additional pregnancy tests may be 
undertaken if requested by IRB/IECs, or if required by local regulations. If the in-clinic study visits cannot be conducted due to COVID-19-related reasons, this assessment 
may be performed at a local clinic. Local laboratory reference ranges and lab accreditation need to be collected. Records of local laboratory tests and lab accreditation should 
be retrieved and kept in the site medical records and relevant data from the local clinic entered in the CRF.
6.
Triplicate 12-lead ECGs: At each time point 3 consecutive supine 12-lead ECGs will be performed approximately 2 minutes apart to determine the mean QTcF interval.  
ECGs will be collected as follows: On Cycle 1/Day 1 at pre-dose and thereafter on Day 1 at 1 hr post-dose of every 3 cycles and at the End of Treatment.  If the in-clinic 
study visits cannot be conducted due to COVID-19-related reasons, this assessment may be performed at a local clinic. Local laboratory reference ranges and lab 
accreditation need to be collected. Records of local laboratory tests and lab accreditation should be retrieved and kept in the site medical records and relevant data from the 
local clinic entered in the CRF.
7.
Adverse Event (AE) Assessments: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.0. Ongoing events which had occurred in 
the previous study and any new or worsened conditions since baseline during study treatment should be reported on the Adverse Event CRF. Patients must be followed for 
AEs for 28 days after the last treatment administration or until all drug-related toxicities have resolved, whichever is later; or earlier than 28 days should the patient 
commence another anticancer therapy in the meantime. For SAEs, the active reporting period to Pfizer or its designated representative begins from the time that the patient 
provides informed consent, which is obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or receiving 
investigational product, through and including 28 calendar days after the last administration of the investigational product.  Serious adverse events occurring to a patient after 
the active reporting period has ended should be reported to the Sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have 
at least a reasonable possibility of being related to study drug are to be reported to the Sponsor. If the in-clinic study visits cannot be conducted due to COVID-19-related 
reasons, this assessment should be conducted by phone or video contact and based on the test results from a local clinic if applicable.
8.
Concomitant Medications and Treatments: Every concomitant medication and treatment required by the patient within 28 days prior to Cycle 1 Day 1 and during the trial 
(and up to 28 days following last treatment administration or until initiation of another oncologic treatment) and the reason for its administration must be recorded on the 
CRF. If the in-clinic study visits cannot be conducted due to COVID-19-related reasons, this review should be conducted by phone or video contact.
9.
All red blood cell and platelet transfusions, including date of each transfusion and the number of red blood cell units transfused will be recorded while on treatment. Note that 
number of units not number of bags must be recorded.  If the in-clinic study visits cannot be conducted due to COVID-19-related reasons, this review should be conducted by 
phone or video contact.
10.
Drug compliance: All PF-04449913 bottles including any unused tablets and patient dosing diaries will be returned for assessing compliance and drug accountability on Day 
1 of each cycle. If the in-clinic study visits cannot be conducted due to COVID-19-related reasons, this review of dosing compliance should be conducted by phone or video 
contact.
11.
PF-04449913 Dosing: PF-04449913 will be given continuously orally, once daily in 28-day cycles. The starting dose will be the same as the dose at the time the patient 
discontinued from Study B1371013.
12.
Follow-up Visit: At least 28 days, and no more than 35 days following discontinuation of treatment (up to 42 days after the last dose of study drug if treatment was stopped 
for prolonged myelosupression) patients require review of concomitant medications and assessment for resolution of any treatment-related toxicity. Patients continuing to 
experience toxicity at this point following discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical 
judgment of the Investigator, that no further improvement is expected.


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PK/ECG collection time points:
Table 7.
Monotherapy Cohort: Single-Agent PF-04449913 in Select Hematologic Malignancies
PK Lead-in Period
Cycle 1
Study Days
Day -5
Day -4
Day -
3
Day -2
Day 1 (1)
Day 8 (1)
Day 15 (1)
PF-04449913 
Dosing




Hour
0
(pre-dose)
0.5
1
2
4
8
24
48
72
120a
1
0
(pre-dose)
1
0
(pre-dose)
1
Blood samples for 
PF-04449913 PK















Triplicate 12-lead 
ECG








a.
The 120 hr time point is also the pre-dose (0 hour) time point for Cycle 1/Day 1. 
Patients should be hospitalized on Day -5 and Day -4 in PK Lead-in Period for full PK sample collection.
Cycle 1
Cycle 2-4
Study Days
Day 21 (1)
Day 
22
Day 1 (2)
PF-04449913 Dosing



Hour
0
(pre-dose)
0.5
1
2
4
8
24 a
0
(pre-dose)
1
Blood samples for 
PF-04449913 PK









Triplicate 12-lead ECGb






a.
The 24 hr time point for Cycle 1/Day 21 is the pre-dose time point on Cycle 1/Day 22.
b.
After Cycle 4, for every subsequent cycle on Day 1 at 1 hr post-dose.
Patients should be hospitalized on Cycle 1/Day 21 and Day 22 for full PK sample collection.


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Table 8.
Combination cohort 1: PF-04449913 + LDAC in Unfit Patients with AML or High-Risk MDS
Cycle 1 (28 day Cycle)
Study Days
Day 1
Day 2
Day 3
PF-04449913 
Dosing

LDAC Dosing



Hour
0
(pre-dose)
0.5
1
4
0
(pre-dose)
0.25
0.5
1
2
4
6
0
0.5
1
4
Blood samples for 
PF-04449913 PKa




Blood samples for 
LDAC PKb







Triplicate 12-lead 
ECG




a.
All samples will be collected relative to PF-04449913 dosing.  
b.
All samples will be collected relative to LDAC dosing.
Cycle 1 (28 day Cycle)
Cycle 2-5
Study Days
Day 10
Day 
11
Day 21 (2)
Day 
22
Day 1 (2)
PF-04449913 
Dosing





LDAC Dosing


Hour
0
(pre-
dose)
0.25
0.5
1
2
4
6
24a
0
(pre-
dose)
0.5
1
2
4
6
24a
0
(pre-
dose)
1
Blood samples for 
PF-04449913 PKb
















Blood samples for 
LDAC PKc







Triplicate 12-lead 
ECG








a.
The 24 hr time point for Cycle 1/Day 10 is the pre-dose time point on Cycle 1/Day 11 and the 24 hr time point for Cycle 1/Day 21 is the pre-dose time point on Cycle 
1/Day 22.  
b.
All samples will be collected relative to PF-04449913 dosing.  
c.
All samples will be collected relative to LDAC dosing.
Patients should be hospitalized on Cycle 1/Day 2 and 3, Cycle 1/Day 10 and 11, and Cycle 2/Day 21 and 22 for full PK sample collection.


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Table 9.
Expansion Cohort of LDAC combination for efficacy: PF-04449913 + LDAC in Unfit Patients with AML or High-
Risk MDS
Cycle 1 (28 day Cycle)
Cycle 2 (28 day Cycle)
Study Days
Day 1
Day 10
Day 1 (2)
PF-04449913
Dosing



LDAC Dosing



Hour
0
(pre-dose)
1
4
1
4
0
(pre-dose)
1
Blood samples 
for PF-04449913 
PKa
(C3 and C6 
only)
Triplicate 12-lead 
ECGb





(C2-3 only)
a.
Blood samples for PF-04449913 PK will be collected on the same days as the collection of bone marrow aspirates for biomarker assessments.
b.
Triplicate 12-lead ECGs: At each time point, 3 consecutive supine 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTc 
interval.  ECGs will be collected: prior to blood sample collection, such that the blood sample is collected at the appropriate time. All ECG timepoints are 
in reference to dosing of PF-04449913.


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Table 10.
Combination cohort 2: PF-04449913 + Cytarabine/Daunorubicin in Fit Patients with AML or High-Risk MDS
Induction 
Consoli
dation
Maint
enace
Cycle 1 (28 day Cycle)
First
2 cycle
First 
2 
cycle
Study Days
Day -3
Day 3
Day 
4
Day 10
Day 
11
Day 1
Day 1
PF-04449913 
Dosing







Daunorubicin 
Dosing

Cytarabine 
Dosing



Hour
0
(pre-
dose
1
0
(pre-
dose
0.25
0.5
1
4
6
24a
0
(pre-
dose
0.25
0.5
1
2
4
6
24a
1
1
Blood samples 
for PF-
04449913 PKb















Blood samples 
for 
Daunorubicin 
PKc







Blood samples 
for Cytarabine 
PK



Triplicate 12-
lead ECGd






a.
The 24 hr time point for Cycle 1/Day 3 is the pre-dose time point on Cycle 1/Day 4 and the 24 hr time point for Cycle 1/Day 10 is the pre-dose time point on Cycle 1/Day 
11.  
b.
All samples will be collected relative to PF-04449913 dosing.  
c.
All samples will be collected relative to daunorubicin dosing.  Cycle 1/Day 3: 0 hour (pre-dose), 0.25 hour (mid-infusion), 0.5 hour (immediately prior to the end of 
infusion).
d.
If a second induction cycle is administered, then ECG should be collected on Day 1 and Day 10 at 1 hr post-dose.
Patients should be hospitalized on Cycle 1/Day 3 and 4, and Cycle 1/Day 10 and 11 for full PK sample collection.


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Table 11.
Combination cohort 3: PF-04449913 + Azacitidine in Patients with previously untreated AML who are eligible for 
non-intensive chemotherapy
Study Days
Screening
Cycle 1, Day 1
Cycle 
1   Day 2
Cycle 1, Day 7&21 (azacitidine samples 
taken only on C1D7)
Cycle 2  Day 1
(PK samples taken 
only on C3D1 and 
C5D1)
EOT
Houra
0a
0.25
0.5
1
2
6
1
4
0a,c
0.25
0.5
1
2
4
6
24
0a
1
4
0
PF-
04449913 PK 
Samples
X
X
X
X
X
X
X
X
X
X
X
Azacitidine 
PK Samples
X
X
X
X
X
X
X
X
X
X
X
Triplicate 12-
lead ECGb
X
X
X
X
X
X
Xd
X
Xd
X
a.
PK sample collection: In all instances, “0 hour” represents a pre-dose collection.  The PK sample should be collected within 30 minutes prior to the first dose 
administration and within 15 minutes prior to the subsequent dose administrations.  Patients should be reminded not to take their study drug prior to arriving at 
the clinic on protocol scheduled visits.  The PK time points for each compound (Azacitidine and PF-04449913) are in reference to their respective dosing times.
b.
Triplicate 12 lead ECGs: At each time point, 3 consecutive supine 12 lead ECGs will be performed approximately 2 minutes apart to determine mean QTc 
interval.  ECGs will be collected: prior to blood sample collection, such that the blood sample is collected at the appropriate time.  All ECG timepoints are in 
reference to dosing of PF-04449913.
c.
The 24 hr time points for Cycle 1/Day 7 and Cycle 1/Day 21 are the pre-dose time points on Cycle 1/Day 8 and Cycle 1/Day 22, respectively.
d.
For patients without any medical history of cardiac disease or cardiac observation during the study, ECGs at 0 and 4 hours on Day 1 of Cycle 7 and thereafter may 
be omitted. However, if a moderate/strong CYP3A4/5 inhibitor or TdP drug will be initiated, the guidance provided in Section 7.1.5 requiring additional ECG 
monitoring before and after starting the medication must be followed for all patients. 


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TABLE OF CONTENTS
PROTOCOL SUMMARY...............................................................................................7
LIST OF TABLES.........................................................................................................50
LIST OF FIGURES .......................................................................................................52
APPENDICES ...............................................................................................................52
1. INTRODUCTION .....................................................................................................53
1.1. Indication.......................................................................................................53
1.2. Background and Rationale ............................................................................53
1.2.1. Malignancy, Stem Cells, and the Hedgehog (Hh) Signaling Pathway
...............................................................................................................53
1.2.2. The Role of Hh in Myeloid Malignancies........................................54
1.2.3. Role of Hh Pathway Activation in Myelodysplastic Syndrome 
(MDS) and Acute Myeloid Leukemia (AML).......................................55
1.2.4. Rationale for Combination Therapy of PF-04449913 in Patients with 
AML and MDS ......................................................................................56
1.2.4.1. Rationale for Intensive Chemotherapy Combinations with 
PF-04449913 ...........................................................................57
1.2.4.2. Rationale for LDAC and PF-04449913 Combinations...58
1.2.4.3. Rationale for azacitidine and PF-04449913 Combinations
.................................................................................................58
1.2.4.4. Rationale for Assessment of the Drug-Drug Interaction 
(DDI) Potential between PF-04449913 and Coadministered 
Drugs .......................................................................................58
1.2.5. Summary of Product Profile.............................................................59
1.2.5.1. Properties of PF-04449913..............................................59
1.2.5.2. Properties of Cytarabine (Cytosine Arabinoside, Ara-C)60
1.2.5.3. Properties of Daunorubicin .............................................60
1.2.5.4. Properties of Azacitidine.................................................61
1.2.6. PF-04449913 Preclinical Safety Data...............................................61
1.2.7. PF-04449913 Preclinical Pharmacokinetics Data ............................63
1.2.8. Summary of Safety, Efficacy and PK data in Patients with Selected 
Myeloid Malignancies and Solid Tumors..............................................63
1.2.8.1. Safety and Efficacy Summary in Patients with Select 
Myeloid Malignancies and Solid Tumors ...............................64
1.2.8.2. Clinical PK Summary......................................................70


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1.2.8.3. Clinical PD Summary......................................................72
1.2.9. Rationale for the Starting Dose and the Highest Dose of PF-
04449913 in This Trial ..........................................................................72
1.2.10. Summary of Benefit-Risk Assessment...........................................73
2. STUDY OBJECTIVES AND ENDPOINTS.............................................................74
2.1. Objectives......................................................................................................74
2.2. Endpoints.......................................................................................................77
3. STUDY DESIGN ......................................................................................................79
3.1. Study Overview.............................................................................................79
3.1.1. Monotherapy Cohort.........................................................................79
3.1.2. Combination Cohorts........................................................................80
3.1.3. Continuation Cohort (Monotherapy Cohort)....................................82
3.2. DLT Definition..............................................................................................83
4. PATIENT SELECTION............................................................................................84
4.1. Inclusion Criteria...........................................................................................85
4.1.1. Monotherapy Cohort.........................................................................85
4.1.2. Combination Cohort 1, Expansion Cohort of LDAC combination for 
efficacy and Combination Cohort 2 (Unfit and Fit Patients).................88
4.1.3. Combination Cohort 3 (Azacitidine Combination) ..........................90
4.1.4. Continuation Cohort (Monotherapy Cohort)....................................92
4.2. Exclusion Criteria..........................................................................................92
4.2.1. Monotherapy Cohort.........................................................................92
4.2.2. Combination Cohort 1, Expansion Cohort of LDAC combination for 
efficacy and Combination Cohort 2 (UnFit and Fit Patients)................94
4.2.3. Combination Cohort 3 (Azacitidine Combination) ..........................96
4.2.4. Continuation Cohort (Monotherapy Cohort)....................................98
4.3. Life Style Guidelines.....................................................................................98
4.4. Sunlight Exposure .........................................................................................99
4.5. Sponsor Qualified Medical Personnel...........................................................99
5. STUDY TREATMENTS...........................................................................................99
5.1. Allocation to Treatment ................................................................................99
5.2. Drug Supplies..............................................................................................100
5.2.1. Dosage Form(s) and Packaging......................................................100


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5.2.1.1. PF-04449913.................................................................100
5.2.1.2. Daunorubicin.................................................................100
5.2.1.3. Cytarabine .....................................................................100
5.2.1.4. Azacitidine ....................................................................100
5.2.2. Preparation and Dispensing............................................................100
5.3. Administration.............................................................................................100
5.3.1. General Guidelines .........................................................................100
5.3.1.1. Study Treatment Duration in the Monotherapy Cohort 101
5.3.1.2. Study Treatment Duration in the Combination Cohorts101
5.3.1.3. Study Treatment Duration in the Continuation Cohort 
(Monotherapy Cohort)...........................................................102
5.3.2. PF-04449913 Administration .........................................................102
5.3.3. PF-04449913 in Combination with LDAC (Combination Cohort 1 
and Expansion Cohort of LDAC combination for efficacy: Unfit 
Patients) ...............................................................................................103
5.3.4. PF-04449913 in Combination with Cytarabine/Daunorubicin 
(Combination Cohort 2: Fit Patients)...................................................104
5.3.4.1. Induction........................................................................104
5.3.4.2. Consolidation ................................................................105
5.3.4.3. Maintenance ..................................................................106
5.3.5. PF-04449913 in Combination with Azacitidine (Combination Cohort 
3) ..........................................................................................................108
5.3.6. Continuation Cohort (Monotherapy Cohort)..................................109
5.3.7. Post End-of-Treatment Follow-up..................................................109
5.3.8. Food Requirements.........................................................................109
5.3.9. Recommended Dose Modifications [Monotherapy Cohort, 
Combination Cohort 1 and Expansion Cohort (Unfit Patients), 
Combination Cohort 2 (Fit Patients) and Continuation Cohort 
(Monotherapy Cohort)]........................................................................109
5.3.9.1. Additional Guidance for Intra-Patient Dose Modification 
[Monotherapy Cohort, Combination Cohort 1 and Expansion 
Cohort (Unfit Patients), Combination Cohort 2 (Fit Patients)
and Continuation Cohort (Monotherapy Cohort)].................114
5.3.10. Recommended Dose Modifications [Combination Cohort 3 
(Azacitidine Combination)] .................................................................115


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5.3.10.1. Dose Interruptions for Azacitidine and PF-04449913
[Combination Cohort 3 (Azacitidine Combination)] ............116
5.3.10.2. Dose Delays for Azacitidine and PF-
04449913 [Combination Cohort 3 (Azacitidine Combination)]
...............................................................................................117
5.3.10.3. Dose Reductions for Azacitidine and PF-
04449913 [Combination Cohort 3 (Azacitidine Combination)]
...............................................................................................118
5.3.11. Recommended Dose Modifications for PF-04449913 QTcF 
Prolongation and Drug Class Related AEs [Monotherapy Cohort, 
Combination Cohort 1 (Unfit Patients), Combination Cohort 2 (Fit 
Patients), Combination Cohort 3 (Azacitidine Combination)] ............121
5.3.12. Compliance...................................................................................124
5.4. Drug Storage and Drug Accountability.......................................................125
5.4.1. PF-04449913 ..................................................................................125
5.4.2. Cytarabine.......................................................................................125
5.4.3. Daunorubicin ..................................................................................125
5.4.4. Azacitidine......................................................................................125
5.5. Concomitant Medication(s).........................................................................126
5.5.1. Other Prohibited or Restricted Concomitant Medications..............127
5.5.1.1. Combination Cohort 3 (Azacitidine Combination).......127
5.5.1.2. Continuation Cohort (Monotherapy Cohort).................128
5.5.2. Other Anti-Cancer or Experimental Drugs.....................................128
5.5.3. Prophylactic Medications ...............................................................129
5.5.3.1. Tumor Lysis Syndrome (TLS) Prophylaxis..................129
5.5.3.2. Infection Prophylaxis ....................................................129
5.5.3.3. Blood Product, Mucosal, Ocular and Nutritional Support
...............................................................................................130
5.5.4. Supportive care...............................................................................131
5.5.5. Hematopoietic Growth Factors (excluding the Continuation Cohort)
.............................................................................................................131
5.5.6. Anti-Diarrheal, Anti-Emetic Therapy.............................................131
5.5.7. Surgery............................................................................................131
6. STUDY PROCEDURES .........................................................................................131
6.1. Screening.....................................................................................................132


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6.2. Study Period ................................................................................................132
6.3. Follow-up Visit ...........................................................................................132
6.4. Patient Withdrawal......................................................................................132
7. ASSESSMENTS......................................................................................................133
7.1. Safety Assessment.......................................................................................133
7.1.1. Pregnancy Testing ..........................................................................134
7.1.2. Adverse Events...............................................................................134
7.1.3. Laboratory Safety Assessment .......................................................134
7.1.4. Vital Signs and Physical Examination............................................135
7.1.5. Triplicate (12-Lead) ECG...............................................................135
7.1.6. Cardiac Testing (MUGA/ECHO)...................................................137
7.2. PK Assessments (excluding the Continuation Cohort)...............................137
7.3. Blood samples for PK analysis (excluding the Continuation Cohort) ........137
7.3.1. Monotherapy cohort........................................................................137
7.3.2. Combination Cohort 1 and Expansion Cohort of LDAC combination 
for efficacy (Unfit Patients, PF-04449913 + LDAC) ..........................138
7.3.3. Combination Cohort 2 (Fit Patients, PF-04449913 + 
Cytarabine/Daunorubicin)....................................................................138
7.3.4. Combination Cohort 3 (PF-04449913 + Azacitidine) ....................138
7.4. PD Assessments (excluding the Continuation Cohort)...............................139
7.4.1. PD Sample Collections...................................................................139
7.4.1.1. Blood Sample Collections.............................................139
7.4.1.2. Normal Skin Biopsies [Monotherapy Cohort, 
Combination Cohort 1 (Unfit Patients) and Combination 
Cohort 2 (Fit Patients)]..........................................................139
7.4.1.3. Bone Marrow Sample Collections ................................139
7.5. Disease Response Assessment (excluding the Continuation Cohort).........140
7.5.1. Response Criteria............................................................................140
7.5.2. Bone Marrow..................................................................................140
7.5.3. Immunophenotyping, Cytogenetics and Mutation Analysis ..........141
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8. ADVERSE EVENT REPORTING .........................................................................142
8.1. Adverse Events............................................................................................142
8.2. Reporting Period .........................................................................................143
8.3. Definition of an Adverse Event...................................................................143
8.4. Medication Errors........................................................................................144
8.5. Abnormal Test Findings..............................................................................145
8.6. Serious Adverse Events...............................................................................145
8.6.1. Protocol-Specified Serious Adverse Events...................................146
8.6.2. Potential Cases of Drug-Induced Liver Injury................................146
8.7. Hospitalization ............................................................................................147
8.8. Severity Assessment....................................................................................148
8.9. Causality Assessment..................................................................................149
8.10. Exposure During Pregnancy......................................................................149
8.11. Occupational Exposure .............................................................................150
8.12. Withdrawal Due to Adverse Events (Refer to the Section Patient 
Withdrawal)...................................................................................................151
8.13. Eliciting Adverse Event Information ........................................................151
8.14. Reporting Requirements............................................................................151
8.14.1. Serious Adverse Event Reporting Requirements .........................151
8.14.2. Non-Serious Adverse Event Reporting Requirements .................151
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ....152
9. DATA ANALYSIS/STATISTICAL METHODS...................................................152
9.1. Analysis Sets ...............................................................................................152
9.2. Sample Size Determination.........................................................................153
9.3. Efficacy Analysis (excluding the Continuation Cohort).............................153
9.4. Analysis of Other Endpoints (excluding the Continuation Cohort)............154
9.4.1. Analysis of PK................................................................................154
9.4.1.1. PK Analysis of PF-04449913, Cytarabine/Ara-C, 
Daunorubicin, and Azacitidine..............................................154
9.4.1.2. Evaluation of Drug-Drug Interaction Potential.............155
9.4.1.3. Combination Cohort 3: PF-04449913 and Azacitidine.155
9.4.1.4. Population PK Analysis or PK/PD Modeling ...............156
9.4.1.5. Statistical Analysis of Biomarker Endpoints ................156


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9.5. Safety Analysis............................................................................................156
9.5.1. Analysis of Adverse Events............................................................156
9.5.2. Analysis of ECG.............................................................................157
9.6. Data Safety Monitoring Committee............................................................158
10. QUALITY CONTROL AND QUALITY ASSURANCE.....................................158
11. DATA HANDLING AND RECORD KEEPING .................................................158
11.1. Case Report Forms/Electronic Data Record .............................................158
11.2. Record Retention.......................................................................................159
12. ETHICS .................................................................................................................160
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 160
12.2. Ethical Conduct of the Study ....................................................................160
12.3. Patient Information and Consent...............................................................160
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...............................................................................................................161
13. DEFINITION OF END OF TRIAL.......................................................................161
14. SPONSOR DISCONTINUATION CRITERIA....................................................161
15. PUBLICATION OF STUDY RESULTS..............................................................161
15.1. Communication of Results by Pfizer ........................................................161
15.2. Publications by Investigators ....................................................................162
16. REFERENCES ......................................................................................................164
LIST OF TABLES
Table 1.
Monotherapy Cohort: Single-Agent PF-04449913 in Select Hematologic 
Malignancies...............................................................................................17
Table 2.
Combination Cohort 1: PF-04449913 + LDAC in Unfit Patients with AML 
or High-Risk MDS......................................................................................21
Table 3.
Expansion Cohort of LDAC combination for efficacy: PF-04449913 + 
LDAC in Unfit Patients with AML or High-Risk MDS ............................24
Table 4.
Combination Cohort 2: PF-04449913 + Cytarabine/Daunorubicin in Fit 
Patients with AML or High-Risk MDS......................................................28
Table 5.
Combination Cohort 3: PF-04449913 + Azacitidine in Patients with 
previously untreated AML who are eligible for non-intensive 
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Table 6.
Continuation Cohort (Monotherapy Cohort): Single-Agent PF-04449913 in 
Myelofibrosis Patient..................................................................................37
Table 7.
Monotherapy Cohort: Single-Agent PF-04449913 in Select Hematologic 
Malignancies...............................................................................................39
Table 8.
Combination cohort 1: PF-04449913 + LDAC in Unfit Patients with AML 
or High-Risk MDS......................................................................................40
Table 9.
Expansion Cohort of LDAC combination for efficacy: PF-04449913 + 
LDAC in Unfit Patients with AML or High-Risk MDS ............................41
Table 10.
Combination cohort 2: PF-04449913 + Cytarabine/Daunorubicin in Fit 
Patients with AML or High-Risk MDS......................................................42
Table 11.
Combination cohort 3: PF-04449913 + Azacitidine in Patients with 
previously untreated AML who are eligible for non-intensive 
chemotherapy..............................................................................................43
Table 12.
Summary of Plasma Pharmacokinetic Parameters Following Single and 
Multiple Oral Doses of PF-04449913 in Select Hematological 
Malignancies (Study B1371001)................................................................71
Table 13.
Recommended Dose Modification Criteria for Treatment-Related Toxicity 
[Monotherapy Cohort, Combination Cohort 1 and Expansion Cohort (Unfit 
Patients), Combination Cohort 2 (Fit Patients) and Continuation Cohort 
(Monotherapy Cohort)].............................................................................112
Table 14.
PF-04449913 Dose Levels (All Cohorts) .................................................115
Table 15.
LDAC Dose Levels (Combination Cohort 1 and Expansion Cohort only)
..................................................................................................................115
Table 16.
Cytarabine Dose Levels in Consolidation Cycles (Combination Cohort 2 
only)..........................................................................................................115
Table 17
Available Dose Levels (Combination Cohort 3) ......................................118
Table 18
Recommended Dose Modifications for Hematologic Toxicities .............119
Table 19
Recommended Dose Modifications for Non-Hematologic Toxicities.....120
Table 20.
Recommended PF-04449913 Dose Modifications for mean QTcF
(mQTcF) Prolongation..............................................................................123
Table 21
Recommended Dose Modifications for PF-04449913 in Case of Drug 
Class Related AEs.....................................................................................124
Table 22
Suggested Antimicrobial Agents and Doses.............................................130
Table 23.
Summary of Biomarker Assessments.......................................................140


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LIST OF FIGURES
Figure 1.
Schematic of Study Design.........................................................................16
Figure 2.
Mechanism of Hh Signaling.......................................................................54
Figure 3
Schematic of Study Design.........................................................................83
Figure 4.
Overview of Combination Cohort 2 (Fit Patients) Treatment Plan..........104
Figure 5.
Treatment Flow Diagram for Combination Cohort 2 (Fit Patients) .........108
APPENDICES
Appendix 1. ECOG Performance Status......................................................................170
Appendix 2. Table of French-American-British (FAB) classification of Acute Myeloid 
Leukemia ................................................................................................171
Appendix 3. WHO Classification of Myelodysplastic Syndromes (MDS).................172
Appendix 4. Diagnostic Criteria for Chronic Myelomonocytic Leukemia (CMML)*173
Appendix 5. Response Criteria and Progression Definitions for Myelodysplasia and 
CMML....................................................................................................174
Appendix 6. 2008 WHO Diagnostic Criteria for Primary Myleofibrosis*..................176
Appendix 7. Response Criteria and Progession Definitions for Myleofibrosis...........177
Appendix 8. Response Criteria and Progression Definitions for Acute Myeloid 
Leukemia ................................................................................................178
Appendix 9. Response Criteria and Progression Definitions for Chronic Myeloid 
Leukemia ................................................................................................180
Appendix 10. Doxorubicin Equivalent ........................................................................183
Appendix 11. List of drugs with known risk of Torsade de Pointes ...........................184
Appendix 12. Strong and Moderate CYP3A4/5 Inhibitors..........................................186
Appendix 13. Strong and Moderate CYP3A4/5 Inducers ...........................................190


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1. INTRODUCTION
PF-04449913 is a novel small molecule inhibitor of the Sonic Hedgehog (Hh) signaling 
pathway being developed for the treatment of hematologic malignancies and solid tumors.  
This Phase 1 study is designed to evaluate the safety, tolerability, efficacy, PK and PD of 
PF-04449913 administered orally as a single agent in Japanese patients with select advanced 
hematologic malignancies, in combination with intensive chemotherapy (cytarabine and 
daunorubicin) or low-dose cytarabine (LDAC) in patients with previously untreated AML or 
high-risk MDS, or in combination with azacitidine in previously untreated AML patients 
who are eligible for non-intensive chemotherapy.  PF-04449913 is administered as a single
agent in 1 Japanese MF patient who has been treated in Study B1371013. Forty-nine patients 
will be enrolled in this study at maximum.
1.1. Indication
Hematologic malignancies, including acute myeloid leukemia (AML) and high-risk 
myelodysplastic syndrome (MDS).
1.2. Background and Rationale
1.2.1. Malignancy, Stem Cells, and the Hedgehog (Hh) Signaling Pathway
A milestone in understanding cancer as a developmental problem is the identification of 
cancer stem cells that self-renew, reinitiate tumor development, and give rise to tumor bulk.  
This may ultimately contribute to tumor resistance and metastatic spread, and impact overall 
survival.  Standard chemotherapy, radiotherapy, and a range of targeted therapies can reduce 
tumor bulk, but are less effective at targeting cancer stem cells.  The key challenge has been 
to identify the molecular mechanisms that maintain and support cancer stem cell self-renewal 
and survival.
Hh and Gli signaling (Hh-Gli) are critical pathways in animal patterning and cell terminal 
differentiation during embryogenesis, and may play a key role in human malignancies when 
aberrantly activated.  After birth, the Hh pathway is repressed in the majority of cells but is 
activated during tissue repair and in self-renewing populations.  Hh signaling is initiated 
when Hh binds to the Patched (PTCH) transmembrane protein and inactivates its function, 
which in the absence of Hh, is to inhibit SMO signal transduction.  Following deactivation of 
PTCH in response to the binding of Hh ligand, the seven-transmembrane protein 
Smoothened (SMO), which is normally held in an inactive state by PTCH, is released and 
activates a signaling cascade that regulates the Gli family of transcription factors (Figure 2).  
The Gli family of genes encodes proteins that act either as transcriptional repressors (in the 
absence of Hh), or as transcriptional activators (in the presence of Hh) of genes controlled by 
the Hh pathway.  Several proteins modulate the ratio of Gli activator (GliA) to Gli repressor 
(GliR) activity and in so doing determine the level of active cellular Hh ligand (Figure 2).
Since its original description, the Hh pathway has received increasing attention as a 
pleiotropic oncogenic pathway, and its aberrant activity has been implicated in both 
hematopoietic and solid tumor malignancies utilizing a range of different mechanisms, 
including direct cell cycle and anti-angiogenic effects (Thomas BJ, 2005; Straface G et al, 


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2008). 1, 2  Given that these cell types and mechanisms are unrelated in their developmental 
origin, site, and function, a common dependence of cancer stem cells on Hh-Gli signaling for 
survival and self-renewal, paralleling its roles in normal development and homeostasis, could 
underlie its widespread involvement in human cancers (Altaba AR, 2008). 3  An important 
caveat is that the Hh signaling pathway is dispensable for adult hematopoetic stem cell 
function (Gao J et al, 2009). 4
Figure 2.
Mechanism of Hh Signaling
1.2.2. The Role of Hh in Myeloid Malignancies  
Aberrant Hh signaling has been described in a variety of different human lymphoid and 
myeloid leukemias, and leukemia stem cells.  The expression levels of PTCH, SMO and 
GLI1 were found to be elevated in several leukemic cell lines (Bai LY et al, 2008) 5. PTCH 
and SMO were found to be expressed in Jurkat T-ALL cells, and Shh and GLI1 expression 
were identified in human promyelocytic leukemia (HL-60) and KG-1 cell lines (Kobune M et 
al, 2009). 6 Patient-derived AML samples have been shown to express Gli-1 in proportion to 
the number of CD34+ blast cells (Jamieson C et al, 2011). 7 In addition, Hh signaling is up-
regulated in several subtypes of human AML cells, including primary CD34+ leukemic cells 
and cytokine-responsive CD34+ cell lines such as Kasumi-1, Kasumi-3, and TF-1.  Inhibition 
of Hh signaling induced apoptosis following 48 h of exposure, although these CD34+ cell 
lines exhibited resistance to cytarabine.  These data were confirmed by reverse transcription-


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polymerase chain reaction (RT-PCR) for Hh pathway components, and a GLI-responsive 
reporter assay (Kobune M et al, 2009). 6 Finally, upregulation of Hh pathway components 
has been observed in chemoresistant AML cell lines in vitro, and pharmacological inhibition 
of the Hh pathway resulted in decreased multi-drug resistance (MDR-1) or P-glycoprotein 
(P-gp) expression in these cells (Queiroz KCS et al, 2010). 8
Given the central role of Hh signaling in cell differentiation, Hh inhibition represents a 
mechanistically novel approach, with the potential to eliminate the leukemia stem cells 
(LSC) population and to abrogate tumor proliferation in at least a subset of CD34+ lymphoid 
and myeloid hematopoietic malignancies.
1.2.3. Role of Hh Pathway Activation in Myelodysplastic Syndrome (MDS) and Acute 
Myeloid Leukemia (AML)
MDS and AML comprise a group of myeloid neoplasms, whose common feature is a stem-
cell-derived clonal myelopoiesis with altered proliferation and differentiation. AML is 
generally a disease of older individuals, and is uncommon prior to the age of 40. The average 
age of diagnosis of AML is 67 years.  It is estimated that there will be 12,950 new cases and 
9,050 deaths from AML in the United States in 2011 (American Cancer Society: Cancer 
Facts and Figures 2011). 9 It is estimated that there will be 3,400 new cases of AML in Japan 
(Mattson-Jack Epi data 2012). Similarly, the onset of MDS before age 50 is rare, and the 
estimated annual incidence of MDS is similar for different regions; United States (3.3 per 
100,000 persons), England and Wales (3.6 per 100,000), Germany (4.1 per 100,000) and 
France (3.2 per 100,000) (Rollison DE et al, 2008). 10 It is estimated that annual incidence 
rate of MDS is 2.7 per 100,000 in Japan (Investigation by Japan Ministry of Health, Labour 
and Welfare). Genetic and functional studies have demonstrated that AML and MDS develop 
as a result of the acquisition of genetic and epigenetic alterations resulting in abnormal cell 
differentiation and dysregulated self-renewal.  
In 2001, the WHO (World Health Organization) committee modified the FAB (French-
American-British) system (Appendix 2) by lowering the level of myeloblasts required for the 
diagnosis of AML to >20%.  The revised MDS 2008 WHO criteria (Appendix 3) made 
additional adjustments, classifying adult-onset primary MDS into six subcategories including 
RAEB-2 (defined as 5-19% circulating peripheral blasts or 10-19% bone marrow blasts).  
The estimated risk of leukemic transformation from RAEB-2 (also referred to as high-risk 
MDS) to AML is more than 50%; thus most patients with MDS RAEB-2 are treated with 
AML-type therapies (Tefferi A et al, 2009). 11
In addition to the evidence described in Section 1.2.2, further data supporting the importance 
of aberrant Hh pathway activation in leukemia is derived from patients enrolled in the 
completed SMO inhibitor monotherapy hematology trial (B1371001).  Preliminary data from 
this study suggests that the mechanism of action of Hh inhibition in leukemia may involve 
the mobilization of blast cells from the bone marrow to the peripheral blood, with subsequent 
expansion and differentiation to leukemia stem cells (Jamieson C et al, 2011). 7  Fiedler W et 
al (ASH 2011) 12 examined untreated AML patient samples and identified GLI2 gene 
expression as a negative prognostic indicator that correlated with FLT3 mutation status. In 


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addition, the clinical outcome of patients correlated with Hh pathway expression, suggesting 
that aberrant Hh pathway activity may be a relevant therapeutic target.
Given the central role that Hh signaling plays in cell differentiation through impacting both 
the LSC population and the surrounding stromal microenvironment or niche supporting these 
cells, Hh inhibition in combination with chemotherapy represents a mechanistically attractive 
approach to assist with the elimination of the residual LSC population in AML and MDS that 
persists following standard chemotherapy regimens, and is likely to contribute to recurrence. 
1.2.4. Rationale for Combination Therapy of PF-04449913 in Patients with AML and 
MDS
Patients with AML and MDS have few treatment options yielding durable remissions, 
especially in older patients.  Although treatment regimens and outcomes for patients with 
AML may differ between younger and older adults, induction chemotherapy with cytarabine 
and an anthracycline has been a standard treatment for newly diagnosed AML over the past 
20 years.  Complete remissions can be achieved in 50-80% of adult patients <60 years old 
with de novo AML, when treated with continuous infusion cytarabine and anthracycline, 
depending on the patient’s prognostic factors.  However, only 20-40% of patients who
achieve a remission have prolonged leukemia-free survival (Stone RM et al, 1993; Bishop 
JF, 1997; Mayer RJ, 1994). 13, 14, 15
While there is no clear dividing line when considering age in AML, in many studies, ’older 
adults" have been defined as >60 years of age.  Outcomes for AML patients worsen with age, 
as overall survival rates decrease as age increases (Schiller G et al, 1997). 16  Most trials of 
older patients with newly diagnosed AML have reported CR (complete remission) rates of 
between 40 and 60 percent (Applebaum FR et al, 2006; Juliusson G et al, 2009; Lowenberg 
B et al, 2009; Lowenberg B et al, 1998; Estey E et al, 2007; Ferrara F et al, 1998; Leoni F et 
al, 1997; Juliusson G et al, 2003; Vey N et al, 2004; Gardin C et al 2007). 17, 18, 19, 20, 21, 22, 23, 
24, 25, 26  This may in part be due to the fact that older patients are often ineligible for intensive 
chemotherapy due to co-morbidities, and thus are treated with less aggressive approaches 
that result in lower frequencies of durable response rates.  These patients also more 
commonly have adverse prognostic factors including central nervous system involvement of 
the leukemia, systemic infection at diagnosis, elevated white blood cell count 
(>100,000/mm3), treatment-induced AML, a history of MDS or another antecedent 
hematological disease (AHD), or express the progenitor cell antigen CD34 and/or the P-
glycoprotein (MDR1 gene product), both of which result in a more unfavorable outcome 
(Myint H et al, 1992; Geller RB et al, 1990; Campos L et al, 1992). 27, 28, 29 Taken together 
these data indicate that therapeutic options for these patients are limited, and less toxic 
therapies with more durable responses are urgently required. 
One option for these patients may be to combine with an agent that targets the residual cancer 
stem cells which may persist following standard chemotherapy.  Given the central role of Hh 
signaling in cell differentiation through modulating the LSC population and surrounding 
stromal microenvironment supporting and nourishing these cells, Hh inhibition in 
combination with chemotherapy represents a mechanistically attractive approach to eliminate 
the LSC population in MDS and AML.  In addition, it has been demonstrated that Hh 


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signaling maintains chemo-resistance in myeloid leukemia cells (Queiroz KCS et al, 2010).8
Finally, the clinical activity observed with PF-04449913 monotherapy in AML and MDS 
(Section 1.2.8.1) suggests that these diseases may be Hh pathway dependent.  Thus, the 
rationale for this combination, is that patients with previously untreated AML and MDS will 
have increased efficacy with acceptable accompanying safety profiles when PF-04449913 is 
added to standard 7:3 induction chemotherapy (fit patients), or used in combination with 
LDAC in patients unable to tolerate intensive chemotherapy. 
1.2.4.1. Rationale for Intensive Chemotherapy Combinations with PF-04449913
Fit patients are defined as those having an ECOG (Eastern Cooperative Oncology Group) 
performance status less than 2 and having a lack of specific co-morbidities (Kantarjian H et 
al, 2006).30  For these patients, standard intensive induction therapy is often a reasonable 
option, resulting in CR rates averaging 50% and rates of death from aplasia or indeterminate 
causes below 15% (Applebaum FR et al, 2006; Estey E, 2007).31, 21  Induction therapy 
generally comprises 3 days of an anthracycline (eg, daunorubicin 45-60 mg/m2 or an 
alternative anthracycline at equivalent dose) and 7 days of cytarabine (100-200 mg/m2
continuous IV).  Both American (Rowe JM et al, 2004; Anderson JE et al, 2002)32, 33 and 
European (Gardin C et al, 2007)26 cooperative group studies have found that the choice of 
anthracycline (daunorubicin or idarubicin) is of little consequence, assuming equitoxic doses 
are administered.  In addition, protocols that have substituted other anthracyclines, evaluated 
increased doses of cytarabine or daunorubicin, or added a third or fourth drug, have not 
shown significantly improved response rates.  Specifically, attempts to improve responses 
with potentially non-cross-resistant drugs have not been successful (eg, fludarabine, 
etoposide, topotecan, thioguanine, mitoxantrone) (Arlin Z et al, 1990; MacCallum PK et al,
1993; Buchner T et al, 1999; Ho AD et al, 1998; Feldman EJ et al, 1993; Estey EH et al,
2001; Russo et al, 2005; Bishop JF et al, 1990; Hann IM et al, 1997).34, 35, 36, 37, 38, 39, 40, 41 ,42  
As such, there is no conclusive evidence to recommend one "7+3" regimen over another 
(Kolitz JE et al, 2006).43  Depending on dose, schedule, and patient selection criteria, most 
regimens evaluated have similar response rates and share common toxicities (Atallah E et al,
2007; Mandelli F et al, 2009; Lowenberg B et al, 2009).44, 45, 19  Thus, a reasonable induction 
regimen for patients who are medically fit is seven days of continuous infusion of 
cytarabine (Ara-C, 100 mg/m2 per day) plus three days of daunorubicin (60 mg/m2 per day) 
(Larson R et al, 2011).46  
The AML 14 trial is being used in this study as a reference for intensive chemotherapy 
response rates (Burnett AK et al, 2009).47  The Burnett trial enrolled 1273 patients, 
predominantly aged over 60 years (although younger patients were allowed) with AML and 
High-risk MDS.  The overall response rate across all arms was 62% (complete remission 
54%, complete remission without platelet/neutrophils recovery 8%); 5-year survival was 
12%, and no benefits were observed in either dose escalation schedule.  
To determine whether the addition of an Hh inhibitor can increase intensive chemotherapy 
response rates with an accompanying acceptable safety profile, PF-04449913 will be 
administered once daily and continuously starting on Day -3, prior to the commencement of 
cytotoxic therapy.  This schedule is consistent with other mobilizing/cytotoxic combination 


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studies, and will allow cells time to transit from the marrow to the peripheral blood 
compartment (Fierro FA et al, 2009).48
1.2.4.2. Rationale for LDAC and PF-04449913 Combinations
Less aggressive therapies are often required for unfit older patients with poor performance
status (as defined by Kantarjian H et al, 2006). 30 Low-dose Ara-C (LDAC) is commonly 
used in this patient population (Dohner H et al, 2010). 49  Data obtained from a large trial 
comparing LDAC (given at the dose of 20 mg twice daily for 10 days on a 28-day cycle) to 
hydroxyurea, showed LDAC CR rates of 18% with an OS of 6 months (Burnett AK et al, 
2007). 50  Based on the above data, LDAC offers significant therapeutic advantages over best 
supportive care in patients who cannot tolerate intensive chemotherapy and have few clinical 
options.  For the purposes of this trial and in order to maintain consistency with the above 
data, LDAC will be given at a dose of 20 mg administered SC twice daily for 10 days every 
28 days. PF-04449913 will be added to these agents to determine if the combination regimen 
is adequately tolerated and can improve on the efficacy response rates and survival of stand-
alone LDAC chemotherapy.
1.2.4.3. Rationale for azacitidine and PF-04449913 Combinations
In a randomised Phase 3 trial to compare azacitidine with standard therapy in untreated non-
Japanese elderly AML patients (>30% bone marrow blast), azacitidine showed a clinically 
meaningful prolongation of OS [mOS: 10.4 mo (95%CI (confidential interval): 8.0, 12.7) vs 
6.5 mo (95%CI: 5.0, 8.6), HR (hazard ratio): 0.85 (95%CI: 0.69, 1.03), log-rank p-value 
(one-side) = 0.1009], although it did not reach the statistically significant difference.  
CR/CRi (CR with incomplete blood count recovery) rate were 27.8% for azacitidine and 
25.1% for standard therapy. 51  Based on this study result, azacitidine has been approved in 
Europe for the indication of AML in addition to MDS. 52  Also, in National Comprehensive 
Cancer Network (NCCN) Guidelines, Ver. 2 (2016) 53  azacitidine is recommended as a 
standard medication for treatment of elderly patients with AML not indicated for intensive 
chemotherapy, and is also positioned as a standard treatment in the United States.  In Japan, 
azacitidine has been approved as a drug for treatment of MDS in the FAB classification 
[including AML accompanying multilineage dysplasia by the WHO classification (AML-
MLD)], and the safety profile thereof in Japanese patients with AML-MLD (499 subjects, 
13.70%) was confirmed to be not notably different from that of non-Japanese patients in a 
drug use investigation of azacitidine conducted in 3642 subjects. 54  Furthermore, the 
regimens used in the standard treatment group of the above-mentioned phase 3 study 
comparing azacitidine monotherapy and standard therapy were also a standard therapy for 
treatment of AML in Japan, and compared to those regimens, azacitidine demonstrated a 
clinically-meaningful improvement, and thus, should also be appropriate as a control drug to 
be used in Japan.
1.2.4.4. Rationale for Assessment of the Drug-Drug Interaction (DDI) Potential between 
PF-04449913 and Coadministered Drugs
PF-04449913 is extensively metabolized by CYP3A4 (99.8%) in human liver microsomes 
and hepatocytes.  Cytarabine is metabolized to a uracil derivative, arabinofuranosyl uracil in 
the liver and kidneys.  Daunorubicin hydrochloride is extensively metabolized in the liver 


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and other tissues, producing daunorubicinol, the major metabolite which has anti-neoplastic 
activity.  For azacitidine, the exact route of elimination and metabolic fate is not known in 
humans.  One of the pathways of elimination for azacitidine appears to be deamination by 
cytidine deaminase principally located in the liver but also in granulocytes, the intestinal 
epithelium, and whole blood (Vidaza® USPI [US Prescribing Information]).  The potential 
for a DDI is considered low for each of these agents, as enzyme systems other than CYP3A4 
may be involved in the metabolism of these drugs.  Since it is required to assess the DDI 
potential in humans when drugs are dosed in combination, a DDI assessment has been 
implemented for cytarabine and daunorubicin in the ongoing global Phase 1B/2 study
(B1371003) and for azacitidine in the global Phase 1b/2 study (B1371012) with the Western 
population.  In this study, potential DDI in Japanese patients will be evaluated. 
1.2.5. Summary of Product Profile
1.2.5.1. Properties of PF-04449913  
PF-04449913 is a potent and selective inhibitor of the Hh signaling pathway through binding 
to its target, SMO.  PF-04449913 inhibited the binding of a known comparator inhibitor of 
SMO with an IC50 of 4 nM.  In addition, in a Shh-induced Gli-Luciferase reporter assay, PF-
04449913 inhibited the Hh pathway activity with an IC50 of 3 nM.  Using human aortic 
adventitial fibroblasts, Shh stimulation for 48 hours induced a 300% increase in endogenous 
Gli1 levels, assessed using quantitative PCR; PF-04449913 at 100 nM inhibited 75% of the 
ligand-induced Gli1 levels.  PF-04449913 was also evaluated in mouse 3T3-L1 
preadipocytes, a cell line that forms triglycerides through a mechanism activated by insulin 
and antagonized by Shh.  In this model, PF-04449913 (50 nM) reproducibly antagonized 
Shh, restoring 60% of lipid production relative to control cultures induced with insulin alone. 
In the PTCH/P53 medulloblastoma mouse model of Hh pathway-driven tumors, PF-
04449913 inhibited pathway activation (Gli1 expression) and produced rapid and complete 
tumor regression.  Preclinical PK/PD modeling using this model suggests a target human 
dose of 15 mg/day is projected to yield at least 50% of tumor Gli1 mRNA inhibition from 
baseline levels and approximately 20% of skin Gli1 mRNA suppression.  
PF-04449913 has been shown pre-clinically to have activity in imatinib-resistant CML blast 
crisis disease.  Patient derived CD34+ imatinib resistant blast crisis CML cells 
xenotransplanted into immunocompromised mice treated with PF-04449913 alone or in 
combination with dasatinib reduced primary leukemic tumor burden.  In addition, treatment 
with PF-04449913 reduced leukemic tumor formation in secondary recipients, suggesting 
that PF-04449913 is able to inhibit the LSC population that supports tumor propagation.  
Importantly, this was verified in CML T315I mutants, which are resistant to treatment with 
standard TKI therapy such as Imatinib. Similar studies are currently on-going in AML 
patient derived samples.
For more details on the pre-clinical data with PF-04449913, refer to the Investigator’s 
Brochure (IB).


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1.2.5.2. Properties of Cytarabine (Cytosine Arabinoside, Ara-C)
Cytarabine (1--D-Arabinofuranosylcytosine) is an anti-neoplastic synthetic nucleoside 
which differs from the normal nucleosides cytidine and deoxycytidine in that the sugar 
moiety is arabinose rather than ribose or deoxyribose.  It is approved for use in combination 
with other approved anticancer drugs for remission induction in acute non-lymphocytic 
leukemia of adults and children. 
Common side effects of cytarabine include bone marrow suppression, Ara-C syndrome 
(fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and 
malaise) and infections.  Additional side effects include anorexia, nausea, vomiting, diarrhea, 
oral or anal ulcerations, hepatic dysfunction, fever, rash, bleeding and thrombophlebitis.  At 
high doses it may cause neurological disorders.  For details of the safety of cytarabine, please 
refer to the Japanese Package Inserts. 
For induction therapy of acute non-lymphocytic leukemia and high-risk MDS, the usual 
cytarabine dose in combination with other anticancer drugs (including daunorubicin, see 
below) is 100-200 mg/m2/day on Days 1-7 by continuous IV infusion.  Cytarabine is then 
given at higher doses for consolidation therapy (1-3 g/m2) Q12 hours on Days 1, 3 and 5 for 
2-4 cycles. 63, 64, 65  It is also commonly used at low-doses (LDAC) as single-agent in patients 
unfit for intensive chemotherapy.
1.2.5.3. Properties of Daunorubicin
Daunorubicin has anti-mitotic and cytotoxic activity through a number of proposed 
mechanisms of action.  Daunorubicin forms complexes with DNA (deoxyribonucleic acid)
by intercalation between base pairs inhibiting topoisomerase II activity, therefore inhibiting 
polymerase activity and altering regulation of gene expression, as well as producing free 
radical damage to DNA.  Daunorubicin hydrochloride in combination with other approved 
anticancer drugs (including cytarabine) is indicated for remission induction in acute non-
lymphocytic leukemia (myelogenous, monocytic, erythroid) of adults.  In the treatment of 
adult acute non-lymphocytic leukemia, daunorubicin hydrochloride, used as a single-agent, 
has produced complete remission rates of 40-50%, and in combination with cytarabine, has 
produced complete remission rates of 53-65%.
Side effects of daunorubicin include local tissue necrosis if there is extravasation during 
administration.  Myocardial toxicity manifested in its most severe form by potentially fatal 
congestive heart failure may occur either during therapy or months to years after termination 
of therapy.  In adult patients, the incidence of myocardial toxicity increases after a total 
cumulative dose is administered exceeding 400 to 550 mg/m2.  Severe myelosuppression 
occurs when used in therapeutic doses; this may lead to infection or hemorrhage.  Other side 
effects include reversible alopecia, contact dermatitis and urticaria.  For patients with AML 
and high-risk MDS, induction chemotherapy consisting of 1 or 2 cycles of daunorubicin 
hydrochloride 45-90 mg/m2/day IV on Days 1, 2, and 3 in combination with cytosine 
arabinoside (see above) is commonly given.  For details of the safety of daunorubicin, please 
refer to the Japanese Package Inserts.


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1.2.5.4. Properties of Azacitidine
Azacitidine is a chemical analogue of the cytosine nucleoside whose mechanism of action 
involves inhibition of DNA methyltransferase at low doses, causing hypomethylation of 
DNA, and direct cytotoxicity in abnormal hematopoietic cells in the bone marrow through its 
incorporation into DNA and ribonucleic acid (RNA) at high doses, resulting in cell death.  
Azacitidine was approved for the treatment of all subtypes of MDS according to the FAB 
classification in Japan.
Main adverse reactions associated with azacitidine treatment include neutropenia (including 
febrile neutropenia), thrombocytopenia, leukopenia , haemoglobin decreased, constipation, 
erythropenia, injection site reaction (including erythemas, rash, pruritus, induration),
haematocrit decreased, lymphopenia, malaise, pyrexia, alanine aminotransferase (ALT) 
increased, anorexia, ALP increased, aspartate aminotransferase (AST) increased, blood 
albumin decreased.  For details of the safety of azacitidine, please refer to the Japanese 
Package Inserts.
1.2.6. PF-04449913 Preclinical Safety Data
In the 1-month rat toxicity study, the primary target organs included the kidney and bone 
(epiphyseal growth plate); the no observed adverse effect level (NOAEL) was 10 mg/kg/day 
(Day 29, male and female combined, free Cmax of 97 ng/mL and free Cave of 40 ng/mL).  In 
the 1-month dog toxicity study, the primary target organ was the kidney; the NOAEL was 
1 mg/kg/day (Day 29, free Cmax of 28 and 14 ng/mL and free Cave of 6 and 2.5 ng/mL, in 
males and females, respectively).
Kidney Effects: The kidney was identified as a target organ in both rat and dog toxicity 
studies. 
In the rat 10-day study, kidney injury was dose-dependent.  Microscopically, severe hyaline 
droplet deposition along with degeneration/necrosis, karyomegaly and vacuolation was 
observed in the kidneys of all animals given 500 mg/kg/day.  Similar changes of lower 
severity were observed microscopically at 50 mg/kg/day, without clinical evidence. 
In the 1-month rat toxicity study, the microscopic changes were similar to those reported in 
the 10-day rat study and were also dose dependent.  Regeneration of tubule cells in the 
cortical region was moderate in 1/10 males and 8/10 females, with the remaining animals in 
the 50 mg/kg/day group exhibiting minimal to slight regenerative changes.  These 
microscopic changes correlated with significant increases in serum creatinine levels, a 
decrease in urinary pH and the presence of inflammatory cells and granular casts in the urine.  
Evidence from both the rat and dog 1-month toxicity study suggested that the kidney changes 
are reversible as determined by histological examination.  
Bone Effects: Bone changes were limited to the 50 mg/kg/day group in the 1-month rat 
toxicity study.  Changes in femur and sternum were characterized by slight to moderate 
epiphysis alterations and decreased medullary trabeculae.  The epiphyseal chondrocytes were 
decreased in number and disorganized in appearance.  These changes persisted throughout 


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the 1-month recovery phase.  The changes in the epiphyseal growth plate are consistent with 
inhibiting the Hh pathway in growing bone (Kimura H et al, 2008) 55 and chondrogenesis 
(Amando K et al, 2008). 56
Cardiovascular Effects: The hERG (human ether- à -go-go-related gene) binding IC50 for PF-
04449913 was 3.1 uM.  PF-04449913 produced dose related changes in electrocardiogram 
parameters in a single dose cardiovascular safety pharmacology study in dogs at 5 and 
30 mg/kg.  At 5 mg/kg, a small (5 msec) but statistically significant increase in QT 
measurement corrected by heart rate (QTc) occurred 7 to 14 hour post-dose, where the peak 
free plasma concentration was 276 ng/mL.  At 30 mg/kg, statistically significant increases in 
heart rate (10 bpm) and QRS, QT and QTc were observed.  Of note, the statistically 
significant increases in heart rate at 30 mg/kg coincided with episodes of emesis, and 
therefore were most likely due to the emetic effect.  There were no statistical or remarkable 
changes in cardiovascular parameters in dogs treated with 1 mg/kg PF-04449913.
Other Findings: 

Hematologic
There were no histopathologic correlates suggestive of changes in normal bone marrow. 

Gastrointestinal
In a 7-day repeat dose toxicity study in dogs up to 100 mg/kg/day there were observations of 
emesis and liquid stool.  In the 1-month toxicity study in dogs, vomiting and 
discolored/liquid feces was observed at 5 mg/kg.  

Phototoxic
PF-04449913 absorbs light with a peak absorbance observed at 204 and 280 nm.  For the 
UVA-UVB/visible range important for phototoxic potential (290 nm-700 nm), PF-04449913 
absorbs light at 290 nm; the tail of the large absorbance peak at 280 nm.  The molar 
extinction coefficient for PF-04449913 at 290 nm is 9,622 L/mol/cm.  
Impact of preclinical safety findings on patient management:
Based on the pre-clinical safety studies, the kidney could be a target organ of toxicity in 
humans.  However, given the ability to monitor for changes in kidney function and 
reversibility of the effects in both animal species this suggests that this is a manageable risk 
for PF-04449913.  Renal function and potentially related adverse events have been closely 
monitored in the B1371001 and B1371002 studies, and no gross adverse renal effects have 
been identified in patients to date.
The pre-clinical data suggest there is a potential for PF-04449913 to induce QT prolongation 
in humans.  Electrocardiograms (ECGs) and vital signs and potentially related adverse events 
are closely being monitored in the ongoing dose-escalation Phase 1 studies with PF-


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04449913 administered as single-agent to patients with hematologic malignancies or solid 
tumors. 
PF-04449913 has the potential to be phototoxic.  Guidelines for the prevention of excessive 
sunlight exposure will be implemented in the study (Section 4.4).
Bone changes occurred only in the growth plate of the growing bone of the rat and did not 
occur in the closed plate of the dog therefore these effects are not a risk for adult patients 
where the epiphyseal growth plate is also closed.
1.2.7. PF-04449913 Preclinical Pharmacokinetics Data 
In humans, PF-04449913 has been projected to have an oral bioavailability of 55%, a steady 
state volume of distribution of 2.7 L/kg, a systemic plasma clearance of 1.03 mL/min/kg, and 
an elimination half-life of 30 hours.  PF-04449913 exhibited high plasma protein binding 
with a fraction unbound of 0.091 in humans.  All primary metabolites observed in-vitro and 
in-vivo appeared to be formed via oxidative metabolism, indicating that this is likely the 
major route of clearance of PF-04449913.  CYP3A4 appeared to be the major enzyme 
mediating PF-04449913 metabolism (~99.8%).  The contributions from the other ten P450s 
evaluated in the metabolism of PF-04449913 were negligible.  In rats, 6.88% and 10.7% of 
the administered dose was eliminated unchanged from urine and bile, respectively.
In-vitro data indicate that PF-04449913 has minimal potential to inhibit all the major human 
CYP enzymes with IC50 values greater than 30 M (11,232 ng/mL) for CYP1A2, 2C8, 2C9, 
2C19, 2D6 and 3A4.  PF-04449913 does not inhibit the metabolic activity of CYP3A in a 
time dependent manner.  PF-04449913 was evaluated in-vitro to determine if it is a substrate 
for human P-glycoprotein (P-gp) in monolayer Madine-Darby Canine Kidney cells 
transfected with human Multi-drug Resistance gene.  The resulting polarized efflux ratio was 
14.9.  In the presence of a combination of P-gp inhibitors, the efflux ratio reduced to unity.  
These data collectively suggest the involvement of P-gp in attenuating the absorptive 
transport of PF-04449913.
For more details about the ADME of PF-04449913 refer to the IB.
1.2.8. Summary of Safety, Efficacy and PK data in Patients with Selected Myeloid 
Malignancies and Solid Tumors
As of 29 January 2020, 7 clinical studies have been conducted in cancer patients.  Four (4) 
studies in cancer patients have completed (B1371001, B1371002, B1371003 and B1371013),
and 3 studies are ongoing (B1371005, B1371012 and B1371019).

B1371001: A Phase 1 dose-escalation, single-agent study in patients with select 
advanced hematologic malignancies.  Forty-seven patients were dosed.  This study
has completed.

B1371002: A Phase 1 dose-escalation, single-agent study in patients with advanced 
solid tumors.  Twenty-three patients were dosed.  This study has completed.


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
B1371003: A Phase 1b/2 study of glasdegib in combination with low-dose cytarabine 
(Ara-C), decitabine, or intensive chemotherapy (cytarabine/daunorubicin), in patients 
with acute myeloid leukemia or high-risk myelodysplastic syndrome.  Two hundred
fourty six (246) patients were dosed. This study has completed.

B1371005: A Phase 1 dose-finding study of single-agent glasdegib in Japanese 
patients with select advanced hematologic malignancies, or glasdegib in combination 
with intensive chemotherapy (cytarabine and daunorubicin), low-dose cytarabine
(LDAC) or azacitidine in patients with previously untreated AML or high-risk MDS.  
Fourty five (45) patients have been enrolled and treated in this ongoing study.

B1371012: A Phase 1b/2 study of glasdegib in combination with azacitidine versus p
in patients with previously untreated Intermediate-2 or High-Risk MDS, AML with 
20% to 30% blasts and multi-lineage dysplasia, and CMML.  Seventy-two (72) 
patients have been enrolled and treated in this ongoing study.

B1371013: A Phase 2 study of single-agent glasdegib versus placebo in patients with 
primary or secondary myelofibrosis who have been previously treated with a Janus 
kinase inhibitor.  Twenty-one (21) patients were enrolled and treated. This study has 
completed.

B1371019: A Phase 3 study of glasdegib versus placebo in combination with 
intensive chemotherapy (cytarabine/daunorubicin) or azacitidine, in patients with 
previously untreated acute myeloid leukemia. Seven hundred seventeen (717) 
patients have been enrolled and treated in this ongoing study. Following planned 
interim analyses for the Non-Intensive and Intensive study cohorts, Pfizer accepted 
the External Data Monitoring Committee’s (EDMC) conclusion of futility that in this 
trial the combination arms (azacitidine + glasdegib and cytarabine/daunorubicin + 
glasdegib, respectively) would not meet the primary objective of improving overall 
survival with respect to azacitidine and cytarabine/daunorubicin alone.
1.2.8.1. Safety and Efficacy Summary in Patients with Select Myeloid Malignancies and 
Solid Tumors
1.2.8.1.1. B1371001: Patients with Select Myeloid Malignancies
A total of 47 patients were screened and assigned to treatment.  All treated patients were 
analyzed for PK and safety.  All treated patients except 1 patient in the 80 mg group were 
included in the efficacy analysis.  The majority (28/47 patients, 59.6%) of patients were 
male.  The mean age was 69 years (range from 25 to 89 years). The diagnoses of enrolled 
patients included:  AML (28 patients, 59.6%), CML (5 patients, 10.6%), CMML (1 patient, 
2.1%), MDS (6 patients, 12.8%), and MF (7 patients, 14.9%). The median duration of 
treatment with PF-04449913 for AML patients, CML patients, CMML patients, MDS 
patients, and MF patients was 64.5 days (range: 5-261 days), 36.0 days (range: 1-280 days), 
54.0 days (range: 54-54 days), 153.0 days (range: 36-537 days), and 182.0 days (range: 44-
371 days) respectively.


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Out of the 41 DLT evaluable patients, 2 patients (1 patient each in the 80 mg and the 600 mg 
groups) experienced DLTs during Cycle 1.  One patient in the 80 mg group experienced non-
hematologic DLTs of hypoxia and pleural effusion. In response to the hypoxia, which was 
also considered as a Serious Adverse Event (SAE), dosing with the study drug was 
interrupted temporarily, and the dose reduced.  The patient also received a blood transfusion.  
One patient in the 600 mg group experienced a non-hematologic DLT of peripheral oedema 
which was also considered an SAE.  In response to the SAE, the study drug was stopped 
temporarily.  All the 3 DLTs experienced by the 2 patients were Grade 3 in severity and 
considered to be related to the study drug.  Six patients were not evaluable for DLTs as they 
took less than 80% of the planned dose in Cycle 1 for reasons other than study drug related 
non-hematologic and hematologic toxicities (except prolonged myelosuppression), including 
1 patient who received the lead in dose but developed CNS (central nervous system) disease 
progression during the lead-in period, and thus did not start the Cycle 1/Day 1 dose.
The majority of treatment-related adverse events (AEs) reported were Grades 1 to 3 in 
severity.  The most frequently reported treatment-related AE was dysgeusia 
(27.7%).Treatment-related Grade 3 events included: decreased appetite (n = 5), weight 
decreased (n = 2), nausea, vomiting, fatigue, mucosal inflammation (n = 1 each). The only 
treatment related Grade 3 AE reported in >2 patients included decreased appetite (5 patients).  
Three treatment-related Grade 4 AEs were reported.  No treatment-related Grade 5 AEs were 
reported.  One Grade 1 and 4 Grade 2 treatment-related AEs of prolonged ECG QT were 
reported. 
Grade 3 laboratory test results independent of causality included: lymphocytes (n = 16), 
platelets (n = 8), WBCs (n = 8), haemoglobin (n = 10), neutrophils (n = 3), ALT (n = 1), 
alkaline phosphatase (n = 2), total bilirubin, hypokalemia, hyponatremia (n = 4 each), 
hyperglycemia (n = 3), hypoalbuminemia, hypocalcemia and hypophosphatemia (n = 1 
each).  Grade 4 laboratory test results independent of causality included: platelets (n = 33), 
neutrophils (n = 26), WBCs (n = 15), lymphocytes (n = 6), hemoglobin (n = 4), bicarbonate 
(n = 1).
QTc AEs were observed in the B1371001 study. Three patients (1 patient in the 400 mg 
group and 2 patients in the 600 mg group) had a post-baseline maximum QTcF interval (QTc 
interval using Fridericia’s correction formula) of 500 msec and 6 patients (1 from the 5 mg 
group and 5 from the 600 mg group) had a maximum QTcF increase from baseline of 60 
msec. All these events were non-symptomatic in nature.
Although the evaluation of efficacy was not the primary objective of this study, patients were 
evaluated for disease specific efficacy endpoints and the best overall responses, duration of 
response, TTP and PFS were derived.  A total of 4 MDS/CMML patients (4/7 patients: 3/6 
MDS patients and 1/1 CMML patient, 57.1%) achieved stable disease or better, among 
whom 2 patients (2/7 patients, 28.6%) showed hematologic improvement.  For the 7 MF 
patients, 2 patients achieved clinical improvement.  For patients with AML (28 patients), 1 
patient (3.6%) had morphologic complete remission with incomplete blood count recovery, 4 
patients (14.3%) had partial remission with incomplete blood count recovery, and 4 patients 
(14.3%) had minor response.  Treatment failures occurred in 7 patients (25%) due to resistant 


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disease.  Clinical benefit (CR + CRi+ PR + PRi+ stable disease + MR) was shown in 16 
patients (57.1%), including 7 patients (25%) with stable disease.  Among the 2 patients with 
CML-AP/BC, 1 patient had a partial cytogenetic response.  None of the patients with CML-
CP had a cytogenetic response.  Out of the 46 patients evaluated for efficacy, 2 out of 7 
MDS/CMML patients (28.6%), 2 out of 7 MF patients (28.6%) and 9 out of 28 AML patients 
(32.1%) had an OR.  No CML patients had an OR.
1.2.8.1.2. B1371002: Patients with Solid Tumors
A total of 23 patients were screened and received study treatment. Nine (39.1%) females and 
14 (60.9%) males were assigned to study treatment; the majority of the patients were white 
(18/23, 78.3%). The median age was 61.0 years, ranging from 27 to 76 years. The diagnoses 
of enrolled patients included: adenocarcinoma of the cervix, basal cell carcinoma, 
chondrosarcoma, malignant hepatic neoplasm, leiomyosarcoma, malignant fibrous 
histiocytoma, metastatic malignant melanoma, small cell lung cancer, malignant tongue 
neoplasm, dermatofibrosarcoma, signet-ring cell carcinoma, primitive neuroectodermal 
tumour (PNET), non-small cell lung cancer and desmoplastic small round cell tumour 
(DSRCT) (1/23 each, 4.3%); extraskeletal chondrosarcoma (2/23, 8.7%); and pancreatic 
carcinoma [7/23 (including pancreatic carcinoma, metastatic pancreatic carcinoma and 
adenocarcinoma pancreas), 30.4%].
Four patients each were assigned to PF-04449913 80 mg and 160 mg treatment, respectively.
One patient in PF-04449913 160 mg cohort did not receive 80% of the planned PF-04449913
dose during Cycle 1 for reasons other than safety problems, therefore was not evaluable for
assessment of DLT and was thus replaced. No patients in PF-04449913 80 mg and 160 mg 
cohorts experienced DLTs. A total of 7 patients were assigned to PF-04449913 320 mg 
treatment, among whom, 1 patient was not evaluable for DLT. A total of 8 patients were 
assigned to PF-04449913 640 mg treatment, among whom, 2 patients were not evaluable for 
assessment of DLT. Of the first 3 DLT-evaluable patients treated at 640 mg QD, 1 patient 
developed a DLT and thus the cohort was expanded to include 3 additional patients, of whom 
another patient developed a DLT. Thus the maximum administered dose was achieved at 
640 mg QD and the MTD was estimated at 320 mg QD.
All patients experienced at least 1 Treatment-Emergent Adverse Events (TEAE during) the 
study, and 87% of the patients reported treatment-related TEAEs. The most frequently 
reported treatment-related AEs were dysgeusia (65.2%), fatigue (52.2%), decreased appetite 
(34.8%), nausea (34.8%) and dizziness (30.4%). The majority of treatment-related AEs 
reported were Grade 1 and 2 in severity. No Grade 3 treatment-related AEs were reported in 
2 patients. Grade 3 treatment-related AEs included fatigue, increased ALT, increased AST, 
decreased appetite, dehydration, hyponatraemia, hypophosphataemia, dizziness and syncope
reported in 1 patient each. No Grades 4 and 5 treatment-related AEs were reported in the 
study.
Grade 3 laboratory test results independent of causality included: lymphopenia (n = 3),
hyponatremia (n = 5), increased AST and hypophosphatemia (n = 2 each), and hypocalcemia, 
hyperglycemia, increased ALT, increased total bilirubin and increased alkaline phosphatase 


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(n = 1 each). Grade 4 laboratory test results independent of causality included: lymphopenia , 
hypokalemia, hypocalcemia and hyperglycemia (n = 1 each).
Although the evaluation of efficacy was not the primary objective of this study, patients were
evaluated for best overall response according to RECIST version 1.1. Of the 23 patients
enrolled, 8 (34.8%) patients had a best overall response of objective disease progression and 
8 (34.8%) achieved disease stabilization. Among the 8 patients with disease stabilization, 3 
had stable disease lasting more than 6 months (1 patient with DSRCT, 1 patient with 
pancreatic cancer and 1 patient with extraskeletal myxoid chondrosarcoma). No patients 
achieved a complete response or partial response.
In summary, PF-04449913 appears to be safe and well-tolerated to date, with signs of clinical 
efficacy observed in all the hematologic malignancies studied (AML, MDS, CML and MF), 
with the exception of CMML.  Several patients with aggressive malignancies remained on 
trial for prolonged durations; some exhibited cellular differentiation as determined by flow 
cytometry.  On-target AEs (including alopecia and dysgeusia) were observed at multiple dose 
levels in both studies.  Taken together, the data support testing PF-04449913 as a 
combination therapy in patients with AML and MDS for whom there are limited available 
therapeutic options. 
1.2.8.1.3. B1371003: Patients with AML or high-risk MDS
As of July 2015, B1371003 Phase 1b enrollment of AML or High-Risk MDS patients for 
Arms A and B (unfit) and Arm C (fit) was completed and 52 patients were enrolled in this 
portion. In this portion, the median age was 70.0 (27-85 years).  The majority of the patients 
were White (82.7%).  The diagnoses included AML in 45 patients (Arm A = 20; Arm B = 5; 
Arm C = 20) and MDS in 7 patients (Arm A = 3; Arm B = 2; Arm C = 2).  
In Arm A (LDAC + PF-04449913), twenty three patients were enrolled. Seventeen (17) 
patients received a starting PF-04449913 dose of 100 mg and 6 patients of 200 mg QD. No 
DLTs were observed. The most frequently reported treatment-related AEs in patients who 
received LDAC + PF-04449913 100 mg included nausea (35.3%), diarrhoea and neutropenia 
(29.4% each), and muscle spasms and dysgeusia (23.5% each).  Grade 3 treatment-related 
TEAEs reported were anaemia (17.6%), fatigue (11.8%) and diarrhoea, stomatitis, abdominal 
pain, enterocolitis, impaired gastric emptying, oral disorder, febrile neutropenia, 
thrombocytopenia, backpain, pneumonia and hyperuricaemia (5.9% each). Grade 4 
treatment-related TEAEs reported were neutropenia (29.4%), febrile neutropenia and 
thrombocytopenia (11.8% each), cardiac failure congestive (5.9%).  Two on-study deaths 
were reported, one due to acute respiratory distress syndrome and one to acute myocardial 
infarction; both deaths were considered not related to PF-04449913 as per Sponsor 
assessment.
In Arm B (Decitabine + PF-04449913) 7 patients were enrolled. Four (4) patients received 
PF-04449913 100 mg and 3 patients received PF-04449913 200 mg.  No DLTs were 
reported. The most frequently reported treatment-related AEs in patients who received 
Decitabine + PF-04449913 100 mg were nausea (75.0%), diarrhoea, thrombocytopenia, and 
neutropenia (50.0% each). No Grade 3 treatment-related TEAEs were reported.  Grade 4 


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treatment related TEAEs were neutropenia and thrombocytopenia (50.0% each).  No 
treatment-related deaths have been reported. This arm will not be evaluated in the Phase 2 
portion of Study B1371003.
In Arm C (Cytarabine/Daunorubicin + PF-04449913), 22 fit patients were enrolled. Sixteen 
patients received a starting PF-04449913 dose of 100 mg QD and 6 patients of 200 mg.  The 
most frequently reported treatment-related AEs in patients who received 
Cytarabine/Daunorubicin + PF-04449913 100 mg included nausea (81.3%), diarrhoea, 
febrile neutropenia and muscle spasms (43.8% each), dysgeusia (37.5%), stomatitis, 
headache, fatigue and pyrexia (31.3% each), constipation, dyspepsia, vomiting, anaemia, 
neutropenia, white blood cell count decreased, hypocalcaemia, hypokalaemia and alopecia 
(25% each).  Grade 3 treatment-related TEAEs reported in more than 1 patient were febrile 
neutropenia (43.8%), anaemia (25.0%) and pyrexia (12.5%). Grade 4 treatment-related 
TEAEs reported in more than 1 patient were white blood cell count decreased (25.0%), 
thrombocytopenia and leukopenia (12.5% each).  No treatment-related deaths have been 
reported.  A DLT of Grade 4 polyneuropathy was reported at the 100 mg dose level and 
treatment was permanently discontinued.
Phase 2 consists of 2 components: Phase 2 randomized component in unfit patients (P2 
Unfit) enrolled to receive either LDAC in combination with PF-04449913 or LDAC alone, 
and Phase 2 single arm component in fit patients (P2 Fit) who received PF-04449913 in 
combination with cytarabine/daunorubicin.  As of Jan 2017, data were available for 132
patients in the P2 Unfit randomized portion of the study, and 71 patients in the P2 Fit arm.  
The primary analysis of OS was conducted after 92 OS events observed. As a result, 
statistically and clinically significant improvement of OS prolongation in LDAC +
PF-04449913 arm was observed (mOS for LDAC + PF-04449913 was 8.3 months vs 4.9 
months for LDAC alone; stratified HR of 0.537 [80% CI: 0.407, 0.708]; 1-sided stratified
log-rank p-value 0.0017) (data cut off: 13 Apr 2016). This result was consistent with the 
updated analysis in the CSR (mOS 8.8 months vs 4.9 months; stratified HR=0.513 (80% CI: 
0.394, 0.666; stratified p=0.0004) (data cut off, hereafter: 3 Jan 2017). CR and DMRa rates 
based on derived response for PF-04449913 + LDAC were 17.0% (15/88) and 34.1% (30/88) 
versus 2.3% (1/44) and 6.8% (3/44) for LDAC alone, respectively. The safety profile of 
PF-04449913 100 mg combined with LDAC and LDAC alone was tolerable and 
manageable: The most commonly-reported AEs in the PF-04449913 100 mg+LDAC arm 
were cytopenia and gastrointestinal disorder. Cytopenias were not accompanied by higher 
rates of infections or bleeding as compared to the LDAC alone arm. SAEs of febrile 
neutropenia (28.6% versus 17.1%) and pneumonia (22.6% versus 17.1%) were more frequent 
in the PF-04449913 100 mg+LDAC arm than in the LDAC alone arm. In contrast, SAE of
                                                
a Disease Modifying Response (DMR) rate includes Complete Remission (CR), CR with incomplete 
blood count recovery (CRi), Morphologic Leukemia-Free State (MLFS), marrow CR (mCR) and 
Partial Remission (PR) (Appendix 5 and Appendix 8).


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sepsis (3.6% versus 12.2%) was less frequently reported for the PF-04449913+LDAC arm 
versus the LDAC alone arm.
In P2 Fit arm (cytarabine/daunorubicin + PF-04449913), the primary analyses were planned 
for patients age ≥55 years old. For the primary endpoint, 22 (36.7%) patients achieved CR 
based on derived response for patients 55 years old. For OS of the secondary endpoint, the 
estimated mOS was 14.7 months for patients 55 years old. The safety profile of 
PF-04449913 100 mg combined with cytarabine/daunorubicin for patients in the P2 Fit arm 
was tolerable and manageable. The most frequently reported AEs (50%) in the P2 Fit arm 
were diarrhoea, febrile neutropenia, nausea and hypokalaemia.


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1.2.8.1.4. Phase 1b/2 to Evaluate the Safety and Tolerability of PF-04449913 in 
Combination with Azacitidine in Patients with Previously Untreated Intermediate-2 or 
High-Risk Myelodysplastic Syndrome, Acute Myeloid Leukaemia with 20%-30% Blasts 
and Multi-Lineage Dysplasia, and Chronic Myelomonocytic Leukaemia (B1371012)
As of 2 September 2015, 10 patients have received 100 mg QD PF-04449913 + azacitidine 
75 mg/m2 day given subcutaneously for 7 consecutive days every 28 days. The primary 
diagnosis was MDS (n = 6), AML (n = 3) and CMML (n = 1). As of the time of reporting (15 
July 2015), only 6 patients had received study treatment.  The most frequently reported 
treatment-related TEAEs in 20% patients were fatigue (50.0%) and constipation (33.3%).  
The Grade 3 treatment-related TEAEs were hypophosphataemia, anaemia and febrile 
neutropenia (16.7% each). Grade 4 treatment-related TEAEs reported were neutropenia and 
thrombocytopenia (16.7% each). No Grade 5 treatment-related TEAEs were reported.
For additional details on the safety, tolerability and efficacy of PF-04449913 please refer to 
the current IB.
1.2.8.2. Clinical PK Summary 
1.2.8.2.1. B1371001: Patients with Selected Myeloid Malignancies
Data following single and multiple dosing of PF-04449913 from study B1371001 in patients 
with selected hematologic malignancies are summarized for all cohorts tested (5, 10, 20, 40, 
80, 120, 180, 270, 400, and 600 mg QD).
PF-04449913 was rapidly absorbed following oral dosing with a median Tmax of PF-
04449913 ranged from 1-2 hours following a single dose and 1-4 hours following multiple 
dosing.  The geometric mean t½ for PF-04449913 ranged from 17.4 to 34.3 hours (Table 12) 
across the various dose levels; however, at most dose levels, the half-life was ~ 24 hours.  
The geometric mean CL/F ranged from 5.63 to 12.7 L/hour following a single dose and 5.33 
to 13.3 L/hour following multiple dosing.  PF-04449913 accumulated following repeated 
dosing with a median Rac ranging from 1.2 to 2.5.  This was consistent with the observed t½, 
as the predicted Rac is in agreement with the estimated Rac.  The median linearity ratio (Rss) 
ranged from 0.76 to 2.1, with the ratio being close to unity for most of the tested dose levels.


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Table 12.
Summary of Plasma Pharmacokinetic Parameters Following Single and Multiple Oral Doses of PF-04449913 in 
Select Hematological Malignancies (Study B1371001)
Parameter 
(Units)
Parameter Statistics by Dose Level
5 mg QD
n=3
10 mg QD
n=3
20 mg QD
n=4
40 mg QD
n=4
80 mg QD
n=8
120 mg QD
n=3
180 mg QD
n=3
270 mg QD
n=5
400 mg QD
n=9
600 mg QD
n=5
Cycle 1 Lead-in Day (Single Dose)
N
3
3
4
4
8a
3
3
5
9a
5
Cmax (ng/mL)
32.9 (3.0)
59.0 (21)
247 (47)
313 (51)
746 (56)
1418 (22)
1409 (79)
1534 (72)
3714 (30)
4527 (64)
Tmax (hr)
2.0
(1.0-4.0)
2.0
(1.2-2.0)
1.0
(1.0-2.0)
1.0
(1.0-1.0)
2.0
(1.0-4.0)
2.0
(1.3-4.0)
2.0
(1.1-4.0)
2.0
(1.0-4.1)
2.0
(1.3-4.5)
2.0
(1.1-4.0)
AUCinf (ng•hr/mL)
657(19)
786 (23)
3548 (50)
3614 (38)
8755 (64)
14430 (35)
21280 (64)
25110
(109)
67720 (19)
86620 (58)
CL/F (L/hr)
7.61 (19)
12.7 (23)
5.63 (50)
11.1 (37)
9.13 (64)
8.33 (36)
8.48 (64)
10.8 (110)
5.90 (19)
6.93 (58)
Vz/F (L)
262 (32)
455 (41)
265 (62)
367 (38)
292 (71)
316 (52)
210 (92)
359 (143)
185 (50)
191 (78)
t1/2 (hr)
25.1 (9.6)
25.1 (4.3)
34.3 (14)
23.3 (4.2)
23.3 (8.1)
26.5 (4.0)
17.4 (3.3)
23.6 (5.5)
23.9 (14)
19.6 (4.7)
Cycle 1/Day 21 (Multiple Dose)
N
3
3
3
3
5
3
4c
2
6
4
Cmax (ng/mL)
45.4 (12)
75.0 (30)
249 (35)
565 (83)
871 (35)
1621 (10)
2069 (41)
1504
4989 (7.0)
6413 (65)
Tmax (hr)
2.2
(1.0-4.0)
1.0
(1.0-2.0)
0.92
(0.92-1.0)
1.0
(1.0-2.0)
1.3
(1.0-2.0)
2.2
(2.0-6.1)
1.1
(1.0-2.0)
3.1
4.0
(1.1-4.2)
3.2
(2.2-4.6)
AUCtau b(ng•hr/mL)
583 (10)
753 (27)
2566 (13)
6134 (61)
7482 (46)
22520 (13)
23060 (47)
22990
70430 (24)
71710 (51)
CL/F (L/hr)
8.57 (9.0)
13.3 (27)
7.79 (13)
6.52 (62)
10.7 (46)
5.33 (13)
7.81 (48)
11.8
5.68 (24)
8.36 (51)
Cavg (ng/mL)
24.3 (9.0)
31.4 (27)
107 (13)
256 (61)
312 (46)
940 (13)
961 (48)
960
2933 (24)
2986 (51)
Cmin (ng/mL)
14.7 (15)
18.9 (14)
54.7 (46)
162 (107)
116 (48)
360 (115)
408 (42)
428
1113 (44)
1641 (59)
Ctrough (ng/mL)d
15.1 (17)
18.9 (14)
67.8 (48)
170 (121)
120 (53)
495 (56)
485 (86)
428
1291 (42)
1871 (57)
Rac
1.4
(1.3-1.7)
1.6
(1.1-1.8)
1.6
(1.6-1.9)
2.4
(2.3-3.0)
1.4
(1.1-2.2)
2.5
(1.5-3.4)
1.4
(0.8-2.0)
1.5
1.2
(1.0-2.8)
1.4
(1.1-1.6)
Rss
0.91
(0.79-0.98)
1.1
(0.70-1.2)
0.76
(0.71-1.2)
1.6
(1.5-2.2)
0.97
(0.75-1.7)
2.1
(0.91-2.1)
1.0
(0.5-1.4)
1.0
0.86
(0.76-2.1)
0.97
(0.72-1.1)
Geometric mean (geometric %CV) for all except: median range for Tmax, Rss and Rac, and arithmetic mean (SD) for t½.  Geometric (%CV) not reported for n2.
Abbreviations:  %CV = percent coefficient of variation, N/n = number of patients, PK = pharmacokinetic(s), QD = once daily, SD = standard deviation
a.   For AUCinf, t½., CL/F and Vz/F, the number of patients with PK parameters available on Cycle 1/Lead-in for the 80-mg and 400-mg dose groups were 7 and 8 
      respectively.
b.   For Cycle 1/Day 21 (multiple dose), tau was 24 hours.
c.   Patient 10011010 was dose reduced from 270 mg to 180 mg in Cycle 1.  This patient’s PK parameters are reported under 180 mg for Cycle 1/Day 21.
d.  The number of patients with Ctrough data at 20 mg, 400 mg and 600 mg were 4, 7, and 3 respectively.


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1.2.8.2.2. B1371010: Food Effect and Drug Interaction Study
The effect of food on single dose PF-04449913 plasma PK and the effect of multiple dose 
ketoconazole on the single dose PF-04449913 plasma PK in healthy subjects were evaluated 
in study B1371010.  The safety and tolerability of a single dose of PF-04449913 in healthy 
subjects when administered alone and with ketoconazole or with food were also assessed. 
Following PF-04449913 administration under fed conditions, PF-04449913 AUCinf and Cmax 
decreased ~13% and 34%, respectively, as compared to administration under overnight 
fasted conditions.  Following administration of ketoconazole 400 mg once daily for 7 days, 
PF-04449913 AUCinf and Cmax increased by ~140% and 40%, respectively, as compared to 
PF-04449913 administered alone.  Generally, a single dose of PF-04449913 200 mg was well 
tolerated when administered alone under fasted or fed conditions and with ketoconazole in 
healthy subjects.
1.2.8.2.3. B1371002: Patients with Solid Tumors
PF-04449913 exhibited similar PK properties in solid tumor patients as in those with 
hematological malignancies. PF-04449913 was rapidly absorbed following oral dosing with a 
median Tmax of 1-2 hr after single and multiple dose administration. Following attainment of 
Cmax, PF-04449913 plasma concentrations showed a bi-exponential decline. The mean 
terminal half-life (estimated following the Day 25 dose) ranged from 16 to 21 hours. In 
general, low to moderate inter-individual variability were observed in Cmax and AUC 
following single and multiple dose administration.
Overall, PF-04449913 exhibited similar PK properties in both hematological and solid tumor 
patients with drug exposure increasing with dose both after single and multiple dosing.
1.2.8.3. Clinical PD Summary
Analysis of Hh pathway gene expression changes in surrogate tissue (skin) in samples 
collected from both the B1371001 and B1371002 studies indicated >80% down regulation of 
the expression of the Hh pathway gene GLI1 at doses of 80 mg or higher.  To investigate PD 
data at doses lower than 80 mg, lower dose levels (such as 25 mg) may be explored at any 
time during the B1371005 study.  Evaluation of circulating cytokine modulation 
demonstrated a post-treatment decrease in IL-8 and IL-10 in one MF patient who responded 
to treatment in B1371001, although limited conclusions can be drawn due to the small 
number of samples available for analysis. No consistent changes in cytokine levels were 
identified in patients treated in the B1371002 trial.
1.2.9. Rationale for the Starting Dose and the Highest Dose of PF-04449913 in This 
Trial
The Phase 1 study of single-agent PF-04449913 in select hematologic malignancies 
(B1371001) in Western patients has been completed. A total of 47 patients were treated at 
doses ranging between 5-600 mg daily.  This study has identified the MTD as 400 mg QD in 
Western patients, and it was decided that the appropriate recommended phase 2 dose (RP2D) 
for PF-0449913 would be 200 mg or less, based on the following factors:


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
Doses of PF-04449913 up to 200 mg are safe and well-tolerated following prolonged 
administration (most patients tolerated study drug for a minimum of 3 cycles in the 
dose range of 5-180 mg). Three patients (1 patient in the 400 mg group and 2 patients 
in the 600 mg group) had a post-baseline maximum QTcF interval of 500 msec;

The most commonly reported treatment-related AEs have been grade 1 and 2, 
suggesting that PF-04449913 is generally well-tolerated.  Most frequently reported 
treatment-related AEs include gastrointestinal-related events (weight loss, nausea, 
and diarrhea), dysgeusia, and muscle cramps;

Clinical responses have been observed in 16 patients (including 5 patients with AML) 
with doses of PF-04449913 as low as 10 mg QD, with the majority of responses 
observed at 80 mg QD;

Linear dose-dependent PK have been observed at all doses of PF-04449913 for which 
data are available, suggesting that exposures of PF-04449913 are predictable;

GLI1 (a biomarker of Hh pathway signaling activation) expression is down-regulated 
by ≥80% at doses of 80 mg QD or more in surrogate (skin) tissue, suggesting that at 
the 100 mg dose, there will be adequate target modulation.
Following this, the healthy volunteer study to assess the effect of azoles on PF-04449913 
exposures, indicated that there was up to a 140% increase in AUCinf.  For patients with AML 
who are frequently treated with azoles, the RP2D in Western patients was conservatively 
selected as 100 mg to accommodate the use of azoles given the plateau in Hh pathway 
modulation and the clinical signals observed over a wide dose range. 
In this study, the starting dose has been established at 50 mg which is one-half of the 
Western RP2D (100 mg QD). And the highest dose level has been set at 100 mg QD which is 
the Western RP2D (100 mg QD). 
Complete information for PF-04449913 may be found in the Single Reference Safety 
Document, which for this study is the Investigator’s Brochure.  For the purpose of this study, 
the Single Reference Safety Document for cytarabine, daunorubicin and azacitidine are the 
Japanese Package Inserts for each product.
1.2.10. Summary of Benefit-Risk Assessment
Based on the pre-clinical data available to date, the safety profile of PF-04449913 is 
characterized by manageable and reversible toxicities (mainly renal and effects on the QTc 
interval).  PF-04449913 was well tolerated in the two phase 1 studies (B1371001, B1371002)
with adverse events reported mostly as mild to moderate in severity.  In the patients with 
hematological malignancies (B1371001), the most frequently reported treatment-related AE 
was dysgeusia (27.7%).  In the patients with solid tumors (B1371002), the most frequently 
reported treatment-related AEs were dysgeusia (65.2%), fatigue (52.2%), decreased appetite 
(34.8%), nausea (34.8%) and dizziness (30.4%).  The clinical activity observed with single-


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agent PF-04449913 in AML and MDS patients suggests that there may be Hh signaling 
dependence in these diseases.
In the Phase 1b component of study B1371003, 7 patients have been treated with 
PF-04449913 in combination with the hypomethylating agents (HMA) decitabine.  Overall, 
the combination appears to be safe and tolerable, suggesting that a combination of 
PF-04449913 with the HMA azacitidine will show similar safety and tolerability.  
Preliminary evidence of clinical activity of the decitabine/PF-04449913 combination has also 
been observed in 5 patients achieving a response; in particular 1 patient with AML and 
1 patient with MDS achieved prolonged CR or marrow CR (mCR), respectively. 66
Furthermore, in the P2 Unfit Arm of this study, the primary anlysis of the primary endpoint 
OS, which was conducted after 92 OS events had been observed, showed a statistically and 
clinically significant prolongation of survival in  the PF-04449913 + LDAC combination 
therapy arm than LDAC monotherapy arm (mOS: 8.3 months vs 4.9 months, stratified HR
0.537 [80% CI: 0.407, 0.708], one-sided p-value of 0.0017 by stratified log-rank test, data 
cutoff: 13 Apr 2016).
Based on the available clinical data, the safety profile of PF-04449913 as a single agent 
administered on a once daily continuous dosing regimen is characterized by manageable and 
potentially reversible toxicities that are generally mild to moderate in severity.  The key 
observed toxicities in the clinical studies are dysgeusia, decreased appetite, and alopecia. 
Small but significant increases in the QTc interval have been reported in animal and clinical 
studies with PF-04449913 so specific dosing requirements and additional monitoring may 
apply (refer to section 5.3.11 and Table 20). Concomitant administration of PF-04449913 
with moderate/strong CYP3A4/5 inhibitors (Appendix 12) are not permitted and drugs with 
known risk of Torsade de Pointes (TdP) (Appendix 11) is not recommended due to the 
potential for drug-drug interaction to prolong the QTc interval.
The results of the nonclinical toxicity and safety pharmacology studies, together with the 
clinical experience obtained to date with PF-04449913 support the hypothesis that an Hh 
inhibitor in combination with chemotherapy may represent an attractive therapeutic approach 
to eliminate the leukemia stem cell population in MDS and AML.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
This study includes six cohorts: 1) a monotherapy cohort to evaluate the tolerability and 
safety of PF-04449913 administered orally as a single agent to Japanese patients with select 
advanced hematologic malignancies, 2) two combination cohorts of Japanese patients with 
previously untreated AML or high-risk MDS assessing the tolerability and safety of the 
following two combination regimens: (i) LDAC plus PF-04449913 in the unfit patient 
population for patients who are unable to receive intensive chemotherapy (Combination 
Cohort 1, unfit patients), and (ii) cytarabine/daunorubicin (7:3) plus PF-04449913 in the fit 
patient population for patients who are able to receive intensive chemotherapy (Combination 
Cohort 2, fit patients), 3) expansion cohort of LDAC combination for efficacy in which 


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PF-04449913 is administered with LDAC in 15 Japanese patients with previously untreated 
AML or high-risk MDS, 4) one combination cohort to evaluate the tolerability and safety of 
PF-04449913 administered in combination with azacitidine to 6 Japanese patients with 
previously untreated AML who are eligible for non-intensive chemotherapy, and 5) a 
continuation cohort (monotherapy cohort) in which PF-04449913 is administered as a single 
agent in 1 Japanese MF patient who has been treated in Study B1371013. The study 
objectives for each cohort are outlined below. A total of up to 49 patients will be treated 
across all six cohorts.
Monotherapy Cohort:
Primary Objective

To determine the safety and tolerability of PF-04449913 administered as 
monotherapy in Japanese patients with select advanced hematologic malignancies.
Secondary Objectives

To evaluate the pharmacokinetics (PK) of PF-04449913 as monotherapy in Japanese 
patients with select advanced hematologic malignancies;

To evaluate the pharmacodynamics (PD) of PF-04449913 as monotherapy in 
Japanese patients with select advanced hematologic malignancies;

To assess preliminary evidence of clinical efficacy of PF-04449913 administered as 
monotherapy in Japanese patients with select advanced hematologic malignancies.
Combination Cohorts 1 and 2 (Unfit and Fit Patients):
Primary Objective

To determine the safety and tolerability of PF-04449913 administered in combination 
with Low-dose Ara-C (LDAC) (Combination Cohort 1, unfit patients), or 
cytarabine/daunorubicin (7:3) (Combination Cohort 2, fit patients) to Japanese 
patients with previously untreated AML, or high-risk MDS.
Secondary Objectives

To evaluate the PK of PF-04449913 and potential drug-drug interaction (DDI) 
between PF-04449913 and LDAC (Combination Cohort 1, unfit patients) or 
cytarabine/daunorubicin (7:3) (Combination Cohort 2, fit patients) administered to 
Japanese patients with previously untreated AML or high-risk MDS;

To evaluate the PD of PF-04449913 administered in combination with LDAC 
(Combination Cohort 1, unfit patients) or cytarabine/daunorubicin (7:3) (Combination 
Cohort 2, fit patients) to Japanese patients with previously untreated AML or high-
risk MDS;


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
To assess preliminary evidence of clinical efficacy (including disease-specific 
measures) of PF-04449913 administered in combination with LDAC (Combination 
Cohort 1, unfit patients) or cytarabine/daunorubicin (7:3) (Combination Cohort 2, fit 
patients) to Japanese patients with previously untreated AML or high-risk MDS.
Expansion Cohort of LDAC combination for efficacy (Unfit Patients):
Primary Objective

To evaluate the efficacy (DMR rate) of PF-04449913 administered in combination 
with LDAC to Japanese patients with previously untreated AML or high-risk MDS.
Secondary Objectives

To evaluate the safety of PF-04449913 administered in combination with LDAC to 
Japanese patients with previously untreated AML or high-risk MDS;

To evaluate the efficacy (including OS) of PF-04449913 administered in combination 
with LDAC to Japanese patients with previously untreated AML or high-risk MDS;

To evaluate the PK and PD of PF-04449913 administered in combination with LDAC 
to Japanese patients with previously untreated AML or high-risk MDS.
Combination Cohort 3 (Azacitidine Combination):
Primary Objective

To determine the safety and tolerability of PF-04449913 administered in combination 
with azacitidine in Japanese patients with previously untreated AML who are eligible 
for non-intensive chemotherapy.
Secondary Objectives

To evaluate the PK of PF-04449913 and azacitidine when administered to Japanese 
patients with previously untreated AML who are eligible for non-intensive 
chemotherapy;

To evaluate the PD of PF-04449913 administered in combination with azacitidine to 
Japanese patients with previously untreated AML who are eligible for non-intensive 
chemotherapy;

To assess any preliminary evidence of clinical efficacy including OS of PF-04449913 
administered in combination with azacitidine to Japanese patients with previously 
untreated AML who are eligible for non-intensive chemotherapy.


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Continuation Cohort (Monotherapy Cohort):

To assess the safety of PF-04449913 administered as monotherapy in the Japanese 
MF patient who has been treated with PF-04449913 in Study B1371013 and without 
documented objective progression of disease and with continuous clinical benefit at 
the time the patient discontinued from Study B1371013.
2.2. Endpoints
Monotherapy Cohort:
Primary Endpoint

First-cycle dose-limiting toxicities (DLTs); Type, incidence, severity [graded by the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE), Version 4.0], timing, seriousness, and relatedness of adverse events; vital 
signs and laboratory test abnormalities.
Secondary Endpoints

PK parameters of PF-04449913;

Potential biomarkers of target modulation, response or resistance to PF-04449913 in 
Japanese patients with advanced hematologic malignancies;

Objective disease response as assessed using the response criteria for the hemotologic 
disease under study.
Combination Cohorts 1 and 2 (Unfit and Fit Patients):
Primary Endpoint

First-cycle DLTs; Type, incidence, severity (graded by NCI-CTCAE, Version 4.0), 
timing, seriousness, and relatedness of adverse events; vital signs and laboratory test 
abnormalities.
Secondary Endpoints

PK parameters of PF-04449913 with: (i) LDAC, and (ii) cytarabine/daunorubicin 
(7:3) combinations;

Potential biomarkers of target modulation, response or resistance to PF-04449913 in 
combination with chemotherapy in Japanese patients with previously untreated AML 
or high-risk MDS; 

Objective disease response, as assessed using the appropriate response criteria for 
AML or MDS.


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
Survival status (only Combination Cohort 1)
Expansion Cohort of LDAC combination for efficacy (Unfit Patients):
Primary Endpoint

DMR rate
Secondary Endpoints

Type, incidence, severity (graded by NCI CTCAE, Version 4.0), timing, seriousness, 
and relatedness of adverse events; vital signs and laboratory test abnormalities;

OS;

Objective disease response, as assessed using the appropriate response criteria for 
AML or MDS; complete remission (CR) rate; duration of response; time to response;

PK and potential biomarkers of target modulation, response or resistance to 
PF-04449913 in combination with LDAC in Japanese patients with previously 
untreated AML or high-risk MDS.
Combination Cohort 3 (Azacitidine Combination):
Primary Endpoint

First-cycle DLTs; Type, incidence, severity (graded by NCI CTCAE, Version 4.0), 
timing, seriousness, and relatedness of adverse events; vital signs and laboratory test 
abnormalities.
Secondary Endpoints

PK parameters of PF-04449913 and azacitidine;

OS;

Potential biomarkers of target modulation, response or resistance to PF-04449913 in 
combination with azacitidine in Japanese patients with previously untreated AML 
who are eligible for non-intensive chemotherapy; 

Objective disease response, as assessed using the appropriate response criteria for 
AML; duration of response; time to response
Continuation Cohort (Monotherapy Cohort):

Type, severity (graded by NCI CTCAE, Version 4.0), timing, seriousness, and 
relatedness of adverse events; laboratory test abnormalities.


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Efficacy-related data will not be collected in this cohort.
3. STUDY DESIGN
3.1. Study Overview
This is an open-label, multi-center, Phase 1 study of PF-04449913 in Japanese patients. 
PF-04449913 will be administered orally as a single agent in up to 15 patients with select 
advanced hematologic malignancies (Monotherapy Cohort), or in combination with LDAC 
(Combination Cohort 1, unfit patients) or cytarabine and daunorubicin (7:3) (Combination 
Cohort 2, fit patients) in up to 12 previously untreated patients with AML or high-risk MDS. 
PF-04449913 will be administered in combination with LDAC in a total of 15 patients with 
previously untreated AML or high-risk MDS (Expansion Cohort of LDAC combination for 
efficacy, unfit patients). PF-04449913 will be also administered in combination with 
azacitidine in a total of 6 patients with previously untreated AML who are eligible for non-
intensive chemotherapy (Combination Cohort 3, Azacitidine Combination). PF-04449913 
wii be administered as a single agent in 1 Japanese MF patient who has been treated in Study 
B1371013 and on the study treatment at the time of the study discontinuation [Continuation 
Cohort (Monotherapy Cohort)].
3.1.1. Monotherapy Cohort
The monotherapy cohort will evaluate the safety and tolerability of PF-04449913 
administered as a single agent once daily continuously. Cycle 1 will be preceded by a single 
lead-in dose of PF-04449913 administered on Day -5 (lead-in period) in order to characterize 
the single-dose PK of PF-04449913 prior to initiation of continuous dosing in the first cycle 
of treatment. From Cycle 1/Day 1 onwards, PF-04449913 will be administered continuously 
once daily, in 28-day cycles.
A standard 3+3 dose escalation design will be used to evaluate the tolerability of PF-
04449913 with 3-6 patients per dose level. Two dose levels of PF-04449913 (Dose Level 1: 
50 mg QD and Dose Level 2: 100 mg QD) will, in the first instance, be investigated in 
sequential cohorts of patients. Intermediate (such as 80 mg QD) or lower dose levels (such as 
25 mg) may be explored at any time during the study if this is clinically and scientifically 
warranted.  Study centers will receive a notification if additional dose levels are explored.
The DLT evaluation period includes the PK lead-in period, and the first cycle of treatment. 
Dose escalation to the 100 mg QD dose level will occur if <1/3 or <2/6 patients at the 50 mg 
QD dose level experience dose-limiting toxicities (DLT) during the first cycle of treatment.  
If 1 patient experiences a DLT event in the first 3 patients, an additional 3 patients will be 
enrolled to give a total of 6 patients in the 100 mg QD cohort. If 1 of the 6 patients 
experiences a DLT by the end of Cycle 1, the tolerability of the 100 mg QD dose level in the 
monotherapy cohort will be deemed confirmed, and the study will proceed to the 
combination cohort. If 2 or more of the 6 patients treated at 100 mg QD in the monotherapy 
cohort experience a DLT by the end of Cycle 1, an intermediate dose level (80 mg QD) may 
be explored in the monotherapy cohort prior to proceeding with the combination cohort. If 
two or more of the 3 or 6 patients treated at 50 mg QD in the monotherapy cohort 


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experiences a DLT by the end of Cycle 1, the dose escalation will be terminated, and a lower 
dose may be explored.
As of 7 August 2014, it was decided by the study team that a lower dose level (25 mg QD) 
will be explored in the study, since evaluation of PD data at the 25 mg QD dose is 
scientifically warranted.  Up to 3 patients will be enrolled at the 25 mg dose level.  DLT 
evaluation will be performed on this dose level, however, it will not be used for the dose 
escalation decision, or for the determination of whether or not to proceed with the 
combination cohort.  The Sponsor will discuss with the Investigator to confirm that there is 
no safety issue for patients enrolled at this dose level.
Treatment with PF-04449913 may continue for up to 12 cycles or until disease progression 
or relapse, patient withdrawal, or unacceptable toxicity occurs (whichever is first).  Patients 
who complete 12 cycles of treatment will be deemed to have completed the study.  However, 
patients who complete 12 cycles of study treatment who demonstrate clinical benefit with 
manageable toxicity, and are willing to continue receiving the study treatment, may be given 
the opportunity to do so following agreement between the Investigator and Sponsor, and 
pending study drug availability.  If treatment continues beyond 12 cycles, study procedures 
should continue to be performed as per Table 1 (See Schedule of Activities).
The study may at any time evaluate additional dose levels of single-agent PF-04449913 
based upon the emerging data from the ongoing pre-clinical and clinical studies, following 
discussion between the Investigators and the Sponsor.
3.1.2. Combination Cohorts 
The combination cohorts will evaluate the safety and tolerability of PF-04449913 at the 
starting dose of 100 mg once daily continuously administered in combination with 3 different 
chemotherapy regimens. 
Combination Cohort 1 (Unfit Patients):
In this cohort, patients who are “unfit for intensive chemotherapy” based on predefined 
criteria (See Inclusion Criteria) will receive PF-04449913 once daily continuously in 
combination with LDAC over 28 day cycles.
A total of 6 patients will be treated in this cohort and followed up for DLT evaluation. The 
DLT evaluation period includes the first cycle of treatment.  If ≤ 1 of the 6 patients 
experiences a DLT by the end of Cycle 1, the tolerability of the combination will be deemed 
confirmed.  If 2 or more of the 6 patients experience a DLT by the end of Cycle 1, additional 
lower dose levels may be tested, applying identical criteria to those outlined above with 
respect to DLT events.
Treatment with PF-04449913 in combination with LDAC may continue for up to 12 cycles 
or until disease progression or relapse, patient refusal, or unacceptable toxicity occurs 
(whichever is first).  Unfit patients who complete 12 cycles of study treatment will be 
deemed to have completed the study.  However, patients who complete the 12 cycles of study 


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treatment and demonstrate clinical benefit with manageable toxicity, and are willing to
continue receiving the study treatment (monotherapy of PF-04449913 or combination 
therapy), may be given the opportunity to do so following agreement between the 
Investigator and Sponsor, and pending study drug availability. If treatment continues beyond 
12 cycles, study procedures should continue to be performed as listed in Table 2 (Schedule of 
Activities). This cohort includes survival follow-up.
Expansion Cohort of LDAC combination for efficacy (Unfit Patients):
In this cohort, patients who are “unfit for intensive chemotherapy” based on predefined 
criteria (See Inclusion Criteria) will receive PF-04449913 once daily continuously in 
combination with LDAC over 28-day cycles. 
A total of 15 patients will be treated in this cohort and DMR rate will be evaluated. 
Treatment with PF-04449913 in combination with LDAC may continue until disease 
progression or relapse, patient refusal, or unacceptable toxicity occurs (whichever is first). 
All patients will be followed for survival every 8 weeks up to 2 years from the first dose of 
the last patient enrolled in the study, or until death, end of the study, or patient withdrawal of 
consent, whichever comes first, regardless of initiation of new cancer therapy (follow-up on 
survival status will no longer be required after Protocol Amendment 8).
Combination Cohort 2 (Fit Patients):
In this cohort, patients defined as “fit for intensive chemotherapy” based on pre-defined 
criteria (See Inclusion Criteria) will receive PF-04449913 once daily continuously in 
combination with daunorubicin and cytarabine during induction and consolidation. For the 
first induction cycle only, PF-04449913 will commence on Day -3 and will then be given 
once daily continuously for the duration of treatment. Following completion of induction and 
consolidation, single-agent PF-04449913 may be given to eligible patients as maintenance 
therapy for a maximum of 6 cycles. 
A total of 6 patients will be treated in this cohort and followed up for DLT evaluation. If 1 
of the 6 patients experiences a DLT event by the end of Induction Cycle 1, the tolerability of 
the combination will be confirmed.  If 2 or more of the 6 patients experience a DLT by the 
end of Induction Cycle 1, additional lower dose levels may be tested using identical criteria 
to those outlined above with respect to DLT events.
Treatment will continue until disease progression or relapse, patient refusal, or unacceptable 
toxicity (whichever is first).  Fit patients who complete induction, consolidation and 6 cycles 
of maintenance with PF-04449913 will be deemed to have completed the study treatment.  
However, patients who complete the 6 cycles of maintenance and demonstrate clinical 
benefit with manageable toxicity, and are willing to continue receiving single-agent PF-
04449913, may be given the opportunity to do so following agreement between the 
Investigator and Sponsor, and pending study drug availability. If treatment continues beyond 
6 cycles of maintenance, study procedures should continue to be performed as listed in 
Table 4 (Schedule of Activities).


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Combination Cohort 3 (Azacitidine Combination):
In this cohort, patients with previously untreated AML and eligible for non-intensive 
chemotherapy will receive PF-04449913 once daily continuously at the starting dose of 
100 mg in combination with azacitidine over 28 day cycles.
A total of 6 patients will be treated in this cohort and followed up for DLT evaluation.  The 
DLT evaluation period includes the first cycle of treatment.  If ≤1 of the 6 patients 
experiences a DLT by the end of Cycle 1, the tolerability of the combination will be deemed 
confirmed.  If 2 or more of the 6 patients experience a DLT by the end of Cycle 1, the 
investigator and the sponsor will review all available safety data and discuss the next steps.
Since responses to azacitidine may require 4-6 cycles of administration to emerge, treatment 
with the study drug combination should be continued for at least 6 cycles, or until death, 
unacceptable toxicity, or patient refusal (whichever is first).  If documentation of disease 
progression occurs within the first 6 cycles of study treatment, the patient SHOULD NOT be 
withdrawn from study treatment following agreement between the Investigator and Sponsor
if, in the Investigator’s judgment, the patient is still likely to receive clinical benefit.
Treatment with the study drug combination should be continued beyond 6 cycles of treatment 
until objective disease progression or relapse (unless according to the Investigator there is 
reasonable evidence of clinical benefit, eg, HI [hematologic imiprovement], to justify 
continuation on treatment following agreement between the Investigator and Sponsor), death, 
unacceptable toxicity, or patient refusal (whichever is first).  All patients will be followed for 
survival up to 3 years from the first dose of the last patient enrolled in the study, or until 
death, end of the study, or patient withdrawal of consent, whichever comes first, regardless 
of initiation of new cancer therapy.
3.1.3. Continuation Cohort (Monotherapy Cohort)
PF-04449913 at the same dose as the patient was taking in Study B1371013 will be orally 
administered once daily continuously as a single agent over 28 day cycles in 1 Japanese MF 
patient who has been treated in Study B1371013 and without documented objective 
progression of disease and with continuous clinical benefit at the time the patient 
discontinued from Study B1371013. 
In this cohort, the patient receiving PF-04449913 will continue to receive study treatment 
until the time of disease progression, unacceptable toxicity, death, withdrawal of consent or 
termination of the study by Sponsor, whichever comes first. The patient may continue PF-
04449913 treatment after objective progression of disease has been determined if the patient 
continues to experience clinical benefit, in the opinion of the investigator, and following 
discussion with the Sponsor. Refer to Appendix 7 for the definition of disease progression.


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Figure 3
Schematic of Study Design
3.2. DLT Definition
DLTs will be classified according to CTCAE version 4.0.
In the Monotherapy Cohort, the DLT observation period will be from Day -5 to Day 28 of 
Cycle 1.
In Combination Cohort 1 (combination with LDAC, unfit patients) and Combination Cohort 
3 (combination with azacitidine) the DLT observation period will be from Day 1 to Day 28 
of Cycle 1; 


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In Combination Cohort 2 (combination with daunorubicin and cytarabine, fit patients) the 
DLT observation period will be from Day -3 to Day 21 or to Day 28 of the first induction 
cycle depending on when the next chemotherapy cycle is started (ie, anytime between 
Days 21 and 28). 
Any of the following adverse events will be a DLT if considered by the Investigator to be 
possibly related to single-agent PF-04449913 (monotherapy cohort), to PF-04449913 in 
combination with chemotherapy (Combination Cohorts 1 and 2), or PF-04449913 in 
combination with azacitidine (Combination Cohorts 3):
1. Grade 3 non-hematologic toxicity (uncontrolled despite optimal medical 
management [eg, nausea, vomiting, and diarrhea]), excluding Grade 3 infection,
fever (including febrile neutropenia), infusion related adverse events, electrolyte 
abnormalities and ALT/AST elevation that returns to Grade 1 or baseline within 
7 days.  Note: Allergic reactions that necessitate discontinuation of study drug will 
not be considered a DLT unless considered possibly related to PF-04449913.

In an asymptomatic patient, Grade 3 QTc prolongation (QTc ≥ 501 msec) will first 
require repeat testing, re-evaluation by a qualified person, and correction of reversible 
causes such as electrolyte abnormalities, concomitant medications that may cause 
QTc prolongation, or hypoxia for confirmation.  If, after correction of any reversible 
causes, the Grade 3 prolongation persists, then the event should be considered a DLT.
2. Prolonged myelosuppression that lasts longer than 42 days from the point of 
detection, defined as absolute neutrophil count (ANC) <500/L or platelet count <10 
x 109/L with a normal bone marrow (<5% blasts and no evidence of disease or 
dysplasia).
3. Inability to deliver at least 80% of the planned study doses for all agents in a 
combination due to non-hematologic toxicities.
4. Delay of >28 days in receiving the next scheduled cycle due to persisting 
non-hematologic toxicities.
Patient replacement
Patients who receive less than 80% of the planned dose of any of the study drugs in the first 
cycle of treatment for reasons other than treatment-related toxicities are not evaluable for 
DLT, and should be replaced to adequately assess the safety of study treatments. At the time 
of dose escalation and when proceeding to the next cohort, Sponsor will discuss with 
Investigator to confirm there is no safety issue of patients who are not evaluable for DLT and 
replaced.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 


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appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient.  
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before patients are included in the study. 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
4.1.1. Monotherapy Cohort
1. Patients with selected advanced hematologic malignancies who are refractory, resistant or 
intolerant to prior therapies.  Eligible patients are limited to 1. Myelodysplastic 
Syndrome (any MDS International Prognostic Scoring System or IPSS score), 2. 
Myleofibrosis, 3. Chronic Myelomonocytic Leukemia (CMML), 4. CML T315I mutants, 
5. CML in whom the T315I mutation is not present (any phase; must have received at 
least one prior treatment), 6. Acute Myeloid Leukemia (AML).
2. Patients with CML:
a.
Must have a confirmed diagnosis as evidenced by the presence of the BCR-ABL 
translocation [t(9;22)] by fluorescence in situ hybridization (FISH), cytogenetics, 
or quantitative polymerase chain reaction (QPCR) for chronic myeloid leukemia 
in either chronic, accelerated or blast phase. 
b. Non-T315I CML must have received at least one prior therapy.
c.
May be resistant or intolerant as defined by: 

In CML-CP, primary resistance is defined as failure to achieve a complete 
hematologic response (CHR) following 3 months on therapy; failure to 
achieve any cytogenetic response (CyR) following 6 months on therapy, 
failure to achieve a major cytogenetic response following 12 months on 
therapy, or failure to achieve a complete cytogenetic response following 
18 months on therapy;

Secondary resistance is defined as a loss of CHR (defined by leukocytosis 
confirmed with at least one WBC>15K not felt to be due to a secondary 
cause); loss of a MCyR (defined by ≥30% increase in the number of 
metaphases); or disease progression to AP or BP;

In CML-AP or CML-BP, resistance is defined as the failure to achieve a 
hematologic response, an increasing WBC, or an overt disease progression. 


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
Intolerance for all phases is defined as discontinuation of prior therapy due to 
adverse events at the lowest approved dose or if a patient can only tolerate prior 
therapy at less than the lowest approved dose.

In addition, for all phases (except patients with T315I mutations), patients are eligible 
in the case of unsatisfactory clinical response to the initial course of TKI, but who do 
not meet the definition for refractory, resistant or intolerant (eg, a CML CP patient 
who rapidly progresses on primary therapy, but does not meet the criteria for primary 
resistance because they have not been on TKI for 3 months; or patients with 
co-morbid diseases who cannot tolerate TKI therapy).

To be considered in chronic phase, all the following must be met:

<15% blasts in peripheral blood and bone marrow; 

<30% blasts and promyelocytes in peripheral blood or bone marrow; 

<20% basophils in peripheral blood; 

Platelets 100 x 109/L; 

No EMD other than spleen or liver.

To be considered in accelerated phase, one or more of the following must be met: 

15% blasts in peripheral blood;

30% blasts + promyelocytes in peripheral blood;

20% basophils in peripheral blood;

Platelet count 100 x 109/L unrelated to therapy; 

Clonal evolution.

To be considered in blast phase, either one of the following criteria must be met:

30% blasts in peripheral blood or bone marrow, or

Extramedullary disease. 
3. All anti-cancer treatments should be discontinued as follows:

Anagrelide should be discontinued 7 days prior to first dose of investigational 
product;


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
Dasatinib should be discontinued from 1 day (24 hrs) prior to first dose of 
investigational product;

Nilotinib should be discontinued from 3 days (72 hrs) prior to first dose of 
investigational product;

Imatinib should be discontinued from 4 days (96 hrs) prior to first dose of 
investigational product; 

Bosutinib should be discontinued from 4 days (96 hrs) prior to the first dose of 
investigational product; 

Ponatinib should be discontinued from 7 days (168 hrs) prior to the first dose of 
investigational product;

All other anti-cancer treatments should be discontinued 2 weeks from first dose 
of investigational product, e.g., chemotherapy (including intrathecal), 
radiotherapy, cytokines, investigational agents, or hormones.
4. Age 20 years old.
5. ECOG performance status of 0, 1, or 2.
6. Patients who have previously received an autologous stem cell transplant are eligible 
provided that the transplant occurred more than 30 days prior to study entry and if the 
patient has recovered from transplant associated toxicities prior to study entry.
7. Patients with a history of allogeneic stem cell transplant are eligible for study 
participation provided that the transplant was greater than 60 days prior to first dose of 
investigational product and the patient has recovered from transplant-associated toxicities 
prior to first dose of investigational product.
8. Adequate organ function as defined by the following criteria:

Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤3
x upper limit of normal (ULN), or AST and ALT ≤5 x ULN if liver function 
abnormalities are due to underlying malignancy;

Total serum bilirubin ≤2 x ULN (except patients with documented Gilbert’s 
syndrome);

Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 mL/min as 
calculated using the method standard for the institution. 
9. Serum/urine pregnancy test (for females of childbearing potential) that is negative at 
screening and immediately prior to initiation of treatment (first dose).  


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Male and female patients of childbearing potential must agree to use a highly effective 
method of contraception throughout the study and for at least 180 days after the last dose 
of assigned treatment.  Female patients are of childbearing potential if, in the opinion of 
the investigator, she is biologically capable of having children and is sexually active. 
Female patients with permanent sterilization or post-menopausal are not considered as 
childbearing potential. (Post-menopausal is defined medically confirmed post-
menopausal status defined as spontaneous cessation of regular menses for at least 12 
consecutive months with no alternative physiological causes.)  Male patients are of 
childbearing potential if, in the opinion of the investigator, he is biologically capable of 
having children and is sexually active.  
10. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or legal representative) has been informed of all pertinent aspects of the study.
11. Willingness and ability to comply with the study scheduled visits, treatment plans, 
laboratory tests and other procedures.
4.1.2. Combination Cohort 1, Expansion Cohort of LDAC combination for efficacy and 
Combination Cohort 2 (Unfit and Fit Patients)
1. Patients with AML or RAEB-2 High-Risk MDS who are newly diagnosed according to 
the WHO 2008 Classification and previously untreated.  Eligible patients with MDS, as 
well as eligible patients with AML arising from an antecedent hematologic disease 
(AHD) or MDS may have had one prior regimen with commercially-available agent(s)  
(eg, azacitidine or decitabine) for the treatment of their prior hematologic disease.  The 
patients may not have had any prior therapy for their AML. 
2. AML patients include de-novo AML, AML evolving from MDS or other AHD and AML 
after previous cytotoxic therapy or radiation (secondary AML).

For a diagnosis of AML, a bone marrow blast count of 20% or more is required. 

For AML defined by cytogenetic aberrations t(8;21), inv(16) or t(16;16) and some 
cases of erythroleukemia the proportion of bone marrow blasts may be <20%.

In AML FAB M6a (erythroid leukemia) 20% of non-erythroid cells in the bone 
marrow must be leukemic blasts and ≥50% of the cells are erythroid precursors.

In AML with monocytic or myelomonocytic differentiation, monoblasts and 
promonocytes, but not abnormal monocytes, are counted as blast equivalents.
3. For a diagnosis of high-risk Myelodysplastic Syndrome RAEB-2 the patient must have 
10-19% bone marrow blasts.
4. Age:

≥20 years old for patients enrolled in Combination Cohort 2 (Fit Patients);


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
≥55 years old for patients enrolled in Combination Cohort 1 and Expansion Cohort of 
LDAC combination for efficacy (Unfit Patients).
5. ECOG Performance Status 0, 1, or 2.
6. Patients with AML or High-Risk MDS who have one or more of the criteria below are 
considered unfit for intensive chemotherapy and are eligible for Combination Cohort 1
and Expansion Cohort of LDAC combination for efficacy (Unfit Patients):

Age ≥75 years;

ECOG Performance Status of 2;

Serum creatinine >1.3 mg/dL;

Severe cardiac disease (eg, LVEF <45% by multi-gated acquisition [MUGA] or 
echocardiography [ECHO] at screening).
7. Patients with AML or high-risk MDS and have none of the following criteria are 
considered fit for intensive chemotherapy and are only eligible for Combination Cohort 2
(Fit Patients):

Age ≥75 years;

ECOG Performance Status of 2;

Serum creatinine >1.3 mg/dL;

Severe cardiac disease (eg, LVEF <45% by MUGA or ECHO at screening).
8. Adequate Organ Function as defined by the following:

Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3 x 
upper limit of normal (ULN), or AST and ALT ≤ 5 x ULN if liver function 
abnormalities are due to underlying malignancy;

Total serum bilirubin ≤2 x ULN (except patients with documented Gilbert’s 
syndrome);

Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥ 60 mL/min as 
calculated using the method standard for the institution.
9. All anti-cancer treatments (unless specified) should be discontinued 2 weeks from first 
dose of investigational product, for example: targeted chemotherapy, radiotherapy, 
investigational agents, hormones, anagrelide or cytokines. 


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
For control of rapidly progressing leukemia, hydroxyurea or leukopheresis may be 
used before and for up to 1 week after first dose of PF-04449913;

Patients with controlled CNS leukemia (documented by two consecutive assessments 
of zero blast count in cerebrospinal fluid), and who are still receiving intrathecal (IT) 
therapy at study entry are considered eligible, and will continue to receive IT therapy.
10. Resolved acute effects of any prior therapy to baseline severity or Grade 1 CTCAE 
except for AEs not constituting a safety risk by investigator judgement.
11. Serum/urine pregnancy test (for females of childbearing potential) that is negative at 
screening and immediately prior to initiation of treatment (first dose).  
Male and female patients of childbearing potential must agree to use a highly effective 
method of contraception throughout the study and for at least 180 days after the last dose 
of assigned treatment.  Female patients are of childbearing potential if, in the opinion of 
the investigator, she is biologically capable of having children and is sexually active. 
Female patients with permanent sterilization or post-menopausal are not considered as 
childbearing potential. (Post-menopausal is defined medically confirmed post-
menopausal status defined as spontaneous cessation of regular menses for at least 12 
consecutive months with no alternative physiological causes.)  Male patients are of 
childbearing potential if, in the opinion of the investigator, he is biologically capable of 
having children and is sexually active.  
12. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or legal representative) has been informed of all pertinent aspects of the study.
13. Willingness and ability to comply with the study scheduled visits, treatment plans, 
laboratory tests and other procedures. 
4.1.3. Combination Cohort 3 (Azacitidine Combination)
1. Patients with AML who are newly diagnosed according to the WHO 2008 Classification 
and previously untreated.  Eligible patients with AML arising from an antecedent 
hematologic disease (AHD) may have had one prior regimen with commercially-
available agent(s) (eg, azacitidine or decitabine) for the treatment of their prior 
hematologic disease.  The patients may not have had any prior therapy for their AML. 
2. AML patients include de-novo AML, AML evolving from MDS or other AHD and AML 
after previous cytotoxic therapy or radiation (secondary AML).

For a diagnosis of AML, a bone marrow blast count of 20% or more is required. 

For AML defined by cytogenetic aberrations t(8;21), inv(16) or t(16;16) and some 
cases of erythroleukemia the proportion of bone marrow blasts may be <20%.


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
In AML FAB M6a (erythroid leukemia) 20% of non-erythroid cells in the bone 
marrow must be leukemic blasts and ≥50% of the cells are erythroid precursors.

In AML with monocytic or myelomonocytic differentiation, monoblasts and 
promonocytes, but not abnormal monocytes, are counted as blast equivalents.
3. AML patients who are eligible for non-intensive chemotherapy per investigator’s 
judgement.
4. 20 years old.
5. ECOG Performance Status 0, 1, or 2.
6. Adequate Organ Function as defined by the following:

Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤3 x 
upper limit of normal (ULN), or AST and ALT ≤5 x ULN if liver function 
abnormalities are due to underlying malignancy;

Total serum bilirubin ≤2 x ULN (except patients with documented Gilbert’s 
syndrome);

Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 mL/min as 
calculated using the method standard for the institution.
7. All anti-cancer treatments (unless specified) should be discontinued 2 weeks from first 
dose of investigational product, for example: targeted chemotherapy, radiotherapy, 
investigational agents, hormones, anagrelide or cytokines. 

For control of rapidly progressing leukemia, hydroxyurea or leukopheresis may be 
used before and for up to 1 week after first dose of PF-04449913

Patients with controlled CNS leukemia (documented by two consecutive assessments 
of zero blast count in cerebrospinal fluid), and who are still receiving intrathecal (IT) 
therapy at study entry are considered eligible, and will continue to receive IT therapy.
8. Resolved acute effects of any prior therapy to baseline severity or Grade 1 CTCAE 
except for AEs not constituting a safety risk by investigator’s judgement.
9. Serum/urine pregnancy test (for females of childbearing potential) that is negative at 
screening and immediately prior to initiation of treatment (first dose).  
Male and female patients of childbearing potential must agree to use a highly effective 
method of contraception throughout the study and for at least 180 days after the last dose 
of assigned treatment.  Female patients are of childbearing potential if, in the opinion of 
the investigator, she is biologically capable of having children and is sexually active. 
Female patients with permanent sterilization or post-menopausal are not considered as 


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childbearing potential. (Post-menopausal is defined medically confirmed post-
menopausal status defined as spontaneous cessation of regular menses for at least 12 
consecutive months with no alternative physiological causes.)  Male patients are of 
childbearing potential if, in the opinion of the investigator, he is biologically capable of 
having children and is sexually active.  
10. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or legal representative) has been informed of all pertinent aspects of the study.
11. Willingness and ability to comply with the study scheduled visits, treatment plans, 
laboratory tests and other procedures. 
4.1.4. Continuation Cohort (Monotherapy Cohort)
1. Patient receiving the study treatment with PF-04449913 in Study B1371013 without 
documented objective progression of disease and with continuous clinical benefit at the
time the patient discontinued from Study B1371013.
2. Patient tolerating the study drug.
3. Serum/urine pregnancy test (for females of childbearing potential) that is negative 
immediately prior to initiation of treatment (first dose).  
Male and female patients of childbearing potential must agree to use a highly effective 
method of contraception throughout the study and for at least 180 days after the last dose 
of assigned treatment.  Female patients are of childbearing potential if, in the opinion of 
the investigator, she is biologically capable of having children and is sexually active. 
Female patients with permanent sterilization or post-menopausal are not considered as 
childbearing potential. (Post-menopausal is defined medically confirmed post-
menopausal status defined as spontaneous cessation of regular menses for at least 12 
consecutive months with no alternative physiological causes.)  Male patients are of 
childbearing potential if, in the opinion of the investigator, he is biologically capable of 
having children and is sexually active.
4. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or legal representative) has been informed of all pertinent aspects of the study.
5. Willingness and ability to comply with the study scheduled visits, treatment plans, 
laboratory tests and other procedures.
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the study: 
4.2.1. Monotherapy Cohort
1. Patient has undergone a donor lymphocyte infusion (DLI) in the prior 30 days;


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2. Patient is known to be refractory to platelet or packed red blood cell transfusions per 
Institutional Guidelines;
3. Patient with active malignancy with the exception of basal cell carcinoma, non-melanoma 
skin cancer or carcinoma-in-situ cervical. Other prior or concurrent malignancies will be 
considered on a case-by case basis; 

Patients with controlled CNS leukemia (documented by two consecutive assessments 
of zero blast count in cerebrospinal fluid), and who are still receiving IT therapy at 
first dose of investigational product are considered eligible, and will continue to 
receive IT therapy.
4. Any one of the following currently or in the previous 6 months: myocardial infarction, 
congenital long QT syndrome, Torsades de Pointes or clinically significant ventricular 
arrhythmias.
5. QTc interval >470 msec using Fridericia’s correction formula (QTcF).
6. Patient has an active, life threatening, or clinically significant uncontrolled systemic 
infection.
7. Patients with active central nervous system (CNS) involvement of the leukemia.  
8. Active graft-versus-host disease, other than Grade 1 skin involvement.
9. Patients taking immunosuppressants for GVHD or any other medical conditions 
(including but not limited to: steroids, cyclosporine, tacrolimus, methotrexate or 
mycophenolate mofetil) within 14 days prior to first dose of investigational product.
10. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness or with active Hepatitis B or -C infection.
11. Known malabsorption syndrome or other condition that may impair absorption of study 
medication (e.g., gastrectomy or lap band).
12. Prior or concurrent anti-cancer treatment with a Hh inhibitor or concurrent treatment with 
other investigational or approved oncology agents.
13. Concurrent administration of herbal preparations.
14. Current use or anticipated need for food or drugs that are strong/moderate CYP3A4/5 
inhibitors, including their administration within 7 days prior to first dose of 
investigational product.  
15. Current use or anticipated need for drugs that are known strong/moderate CYP3A4/5 
inducers, including their administration within 7 days prior to first dose of investigational 
product. 


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16. Current use or anticipated need for drugs that are P-glycoprotein inhibitors/inducers, 
including their administration within 7 days prior to first dose of investigational product.
17. Chronic systemic corticosteroid treatment, although topical applications, inhaled sprays, 
eye drops, local injections of corticosteroids and systemic steroids required for acute 
medical interventions are allowed.
18. Current drug or alcohol abuse.
19. Other severe acute or chronic medical or psychiatric condition, including recent (within 
the past year) or active suicidal ideation or behavior, or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
20. Patients who are investigational site staff members directly involved in the conduct of the 
study and their family members, site staff members otherwise supervised by the 
Investigator, or patients who are Pfizer employees directly involved in the conduct of the 
study.
21. Pregnant females; breastfeeding females; males and females of childbearing potential 
who are unwilling or unable to use two (2) highly effective methods of contraception as 
outlined in this protocol for the duration of the study and for at least 180 days after last 
dose of investigational product. 
4.2.2. Combination Cohort 1, Expansion Cohort of LDAC combination for efficacy and 
Combination Cohort 2 (UnFit and Fit Patients)
1. Acute Promyelocytic Leukemia (APL) patients with t(15;17) or patients with a t(9;22) 
cytogenetic translocation for any component of the study.
2. Hyperleukocytosis (leukocytes ≥30 x 109/L) at study entry.  These patients may be 
treated with hydroxyurea or receive leukopheresis treatment according to routine 
practice, and enrolled in the study when the leukocyte count falls below 30 x 109/L.
3. Patients known to be refractory to platelet or packed red cell transfusions per Institutional 
Guidelines, or a patient who refuses blood product support.
4. Patients with active malignancy with the exception of basal cell carcinoma, 
non-melanoma skin cancer, cervical carcinoma-in-situ.  Other prior or concurrent 
malignancies will be considered on a case-by-case basis.

Patients with controlled CNS leukemia (documented by two consecutive assessments 
of zero blast count in cerebrospinal fluid), and who are still receiving IT therapy at 
first dose of investigational product are considered eligible, and will continue to 
receive IT therapy.


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5. For Combination Cohort 2 (Fit Patients):

LVEF <45% by ECHO or MUGA scan;

Cumulative anthracycline dose equivalent of ≥190 mg/m2 of doxorubicin. (Refer to 
Appendix 10)
6. Any one of the following currently or in the previous 6 months: myocardial infarction, 
congenital long QT syndrome, Torsades de Pointes or clinically significant ventricular 
arrhythmias.
7. QTc interval >470 msec using Fridericia’s correction formula (QTcF).
8. Patients with an active, life threatening or clinically significant uncontrolled systemic 
infection.
9. Patients with known active uncontrolled central nervous system (CNS) leukemia.
10. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness or active Hepatitis B or C infection.
11. Known malabsorption syndrome or other condition that may impair absorption of study 
medication (eg, gastrectomy or lap band).
12. Major surgery or radiation within 4 weeks of starting the study treatment.
13. Prior treatment with:

a Hh inhibitor at any time;

an investigational agent for the treatment of an antecedent hematologic disease 
(AHD).
14. Prior treatment with cytarabine (Combination Cohort 1 and Expansion Cohort of LDAC 
combination for efficacy, Unfit Patients only).
15. The presence of hypersensitivity to cytarabine (not including drug fever or exanthema) 
and daunorubicin (Combination Cohort 2, Fit Patients only).
16. Concurrent treatment with any investigational or approved oncology agents (unless 
specified in the protocol).
17. Concurrent administration of herbal preparations.
18. Current use or anticipated need for food or drugs that are strong/moderate CYP3A4/5 
inhibitors, including their administration within 7 days prior to first dose of 
investigational product.  


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19. Current use or anticipated need for drugs that are known strong/moderate CYP3A4/5 
inducers, including their administration within 7 days prior to first dose of investigational 
product.  
20. Current use or anticipated need for drugs that are P-glycoprotein inhibitors/inducers, 
including their administration within 7 days prior to first dose of investigational product.
21. Current drug or alcohol abuse.
22. Other severe acute or chronic medical or psychiatric condition, including recent (within 
the past year) or active suicidal ideation or behavior, or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
23. Patients who are investigational site staff members directly involved in the conduct of the 
study and their family members, site staff members otherwise supervised by the 
Investigator, or patients who are Pfizer employees directly involved in the conduct of the 
study.
24. Pregnant females; breastfeeding females; males and females of childbearing potential 
who are unwilling or unable to use two (2) highly effective methods of contraception as 
outlined in this protocol for the duration of the study and for at least 180 days after last 
dose of investigational product.
4.2.3. Combination Cohort 3 (Azacitidine Combination)
1. Acute Promyelocytic Leukemia (APL) patients with t(15;17) or patients with a t(9;22) 
cytogenetic translocation for any component of the study.
2. Hyperleukocytosis (leukocytes ≥30 x 109/L) at study entry.  These patients may be 
treated with hydroxyurea or receive leukopheresis treatment according to routine 
practice, and enrolled in the study when the leukocyte count falls below 30 x 109/L.
3. Patients known to be refractory to platelet or packed red cell transfusions per Institutional 
Guidelines, or a patient who refuses blood product support.
4. Patients with active malignancy with the exception of basal cell carcinoma, 
non-melanoma skin cancer, cervical carcinoma-in-situ.  Other prior or concurrent 
malignancies will be considered on a case-by-case basis.

Patients with controlled CNS leukemia (documented by two consecutive assessments 
of zero blast count in cerebrospinal fluid), and who are still receiving IT therapy at 
first dose of investigational product are considered eligible, and will continue to 
receive IT therapy.


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5. Any one of the following currently or in the previous 6 months: myocardial infarction, 
congenital long QT syndrome, Torsades de Pointes or clinically significant ventricular 
arrhythmias.
6. QTc interval >470 msec using the Fridericia correction (QTcF).
7. Patients with an active, life threatening or clinically significant uncontrolled systemic 
infection.
8. Patients with known active uncontrolled CNS leukemia.
9. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness or active Hepatitis B or C infection.
10. Known malabsorption syndrome or other condition that may impair absorption of study 
medication (eg, gastrectomy or lap band) and inability or unwillingness to swallow 
tablets or capsules.
11. Major surgery or radiation within 4 weeks of starting the study treatment.
12. Prior treatment with:

A Hh inhibitor at any time;

An investigational agent for the treatment of an antecedent hematologic disease 
(AHD).
13. The presence of hypersensitivity to azacitidine or mannitol.
14. Concurrent administration of herbal preparations.
15. Current use or anticipated need for food or drugs that are strong/moderate CYP3A4/5 
inhibitors, including their administration within 7 days prior to first dose of 
investigational product.  
16. Current use or anticipated need for drugs that are known strong/moderate CYP3A4/5 
inducers, including their administration within 7 days prior to first dose of investigational 
product.  
17. Current use or anticipated need for drugs that are P-glycoprotein inhibitors/inducers, 
including their administration within 7 days prior to first dose of investigational product.
18. Current drug or alcohol abuse.
19. Other severe acute or chronic medical or psychiatric condition, including recent (within 
the past year) or active suicidal ideation or behavior, or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 


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judgment of the investigator, would make the patient inappropriate for entry into this 
study.
20. Patients who are investigational site staff members directly involved in the conduct of the 
study and their family members, site staff members otherwise supervised by the 
Investigator, or patients who are Pfizer employees directly involved in the conduct of the 
study.
21. Pregnant females; breastfeeding females; males and females of childbearing potential 
who are unwilling or unable to use two (2) highly effective methods of contraception as 
outlined in this protocol for the duration of the study and for at least 180 days after last 
dose of investigational product.
4.2.4. Continuation Cohort (Monotherapy Cohort)
1. Pregnant females; breastfeeding females; males and females of childbearing potential 
who are unwilling or unable to use two (2) highly effective methods of contraception as 
outlined in this protocol for the duration of the study and for at least 180 days after last 
dose of investigational product.
4.3. Life Style Guidelines
All male and female patients who, in the opinion of the investigator, are biologically capable 
of having children and are sexually active, must agree to use two (2) highly effective 
methods of contraception consistently and correctly for the duration of the active treatment 
period and for at least 180 days after the last dose of investigational product.  The 
investigator, in consultation with the patient, will select the most appropriate method of 
contraception for the individual patient from the permitted list of contraception methods, and 
instruct the patient in their consistent and correct use.  The investigator, at each study visit, 
will confirm and document consistent and correct use.  If the in-clinic study visits cannot be 
conducted due to COVID-19-related reasons, this review of contraception methods should be 
conducted by phone or video contact. In addition, the investigator will instruct the patient to 
call immediately if the selected birth control methods are discontinued or if pregnancy is 
known or suspected.  
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:
1. Established use of oral, inserted, injected* or implanted* hormonal methods of 
contraception are allowed provided the patient remains on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
2. Correctly placed copper containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a spermicide* (ie, foam, gel, film, 
cream, suppository).


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4. Male sterilization with appropriately confirmed absence of sperm in the post-
vasectomy ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy.
      *Not commercially available in Japan
4.4. Sunlight Exposure
Patients will be advised to report any reaction to sun exposed skin.  In addition, special 
precautions will be taken to limit any potential photo irritation effect, by minimizing the 
patients’ exposure to light including high intensity UVb sources such as tanning beds, 
tanning booths and sunlamps.  Patients should be advised to apply sunscreen/sunblock daily.
4.5. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the team SharePoint site.
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study number, 
contact information for the investigational site and contact details for a help desk in the event 
that the investigational site staff cannot be reached to provide advice on a medical question 
or problem originating from another healthcare professional not involved in the patients 
participation in the study.  The help desk number can also be used by investigational staff if 
they are seeking advice on medical questions or problems, however it should only be used in 
the event that the established communication pathways between the investigational site and 
the study team are not available.  It is therefore intended to augment, but not replace the 
established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study.  The help desk 
number is not intended for use by the patient directly and if a patient calls that number they 
will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
Treatment allocation will be performed centrally by the Sponsor for all patient cohorts. 
Following full assessment and determination that the patient meets all eligibility criteria, the 
investigator or designee will fax or email a complete Registration Form to the designated 
Sponsor study team member.  For the combination cohorts, attribution to the fit or unfit 
patient category will be based on the patient’s characteristics by the Investigator and 
confirmed by the Sponsor. The Sponsor will assign a patient identification number, which 
will be used on all Case Report Form (CRF) pages and other trial-related documentation or 
correspondence referencing that patient and fax of email to the site.
No patient shall receive study drug until the Investigator or designee has received the 
following information from the Sponsor: confirmation of the patient’s enrollment.


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5.2. Drug Supplies
Upon site activation, study centers will receive a supply of PF-04449913 or azacitidine free 
of charge by Pfizer.  Re-supplies of PF-04449913 or azacitidine will be made during the 
course of the study based on need.
Commercially available cytarabine and daunorubicin will be used in the study and sourced 
by the sites. 
The study monitor should be contacted for any issues related to drug supplies.
5.2.1. Dosage Form(s) and Packaging
5.2.1.1. PF-04449913
PF-04449913 is formulated in tablets containing 10 mg, 25 mg, and 100 mg of study 
medication.  Supplies will be labeled according to local regulatory requirements.  The tablets 
are packaged in high-density polyethylene (HDPE) bottles, with protection from moisture 
and should be handled with care.  Site personnel must ensure that patients clearly understand 
the directions for self-medication.  Patients should be given sufficient supply to last until 
their next study visit.  Patients should be instructed to keep their medication in the bottles 
provided and not transfer it to any other containers.
5.2.1.2. Daunorubicin
Commercially available daunorubicin will be used.  Refer to the local package insert or 
Institutional Guidelines for detailed formulation, preparation and dispensing information.
5.2.1.3. Cytarabine
Commercially available cytarabine will be used.  Refer to the local package insert or 
Institutional Guidelines for detailed formulation, preparation and dispensing information.
5.2.1.4. Azacitidine
Upon site activation, Pfizer will provide a supply of azacitidine for clinical use.  Refer to the 
local package insert for detailed formulation, preparation and dispensing information.
5.2.2. Preparation and Dispensing
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.
5.3. Administration
5.3.1. General Guidelines
In the monotherapy cohort, PF-04449913 administered as a single agent will be evaluated.  
In the combination cohort, three different PF-04449913 combinations (with LDAC for the 
unfit patient population, with cytarabine/daunorubicin for the fit patient population, and with 
azacitidine for the azacitidine patient population) will be evaluated. In the Continuation 


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Cohort, PF-04449913 continuously administered as a single agent will be evaluated for 
safety. Patients should be instructed to take their medication at approximately the same time 
each day and to not take more than the prescribed dose at any time.
Study drugs are administered in cycles.  Bone marrow evaluations are performed at specified 
times to determine clinical response and treatment progression decisions within the trial
(except for the Continuation Cohort). 
5.3.1.1. In the combination cohorts, all patients should be weighed within 72 hours prior 
to dosing for every cycle to ensure they did not experience either a weight loss or gain 
>10% from the prior weight used to calculate the amount of cytarabine, daunorubicin 
required, or azacitidine for dose preparation.  Decision to recalculate cytarabine,
daunorubicin, or azacitidine dose based on the weight obtained at each cycle can be in 
accordance with institutional practice for changes in weight of 10% or less; however, if 
the patient experienced either a weight loss or gain of >10%, the amount of cytarabine,
daunorubicin, or azacitidine required for study drug preparation and administration 
must be recalculated using this most recent weight obtained.Study Treatment Duration 
in the Monotherapy Cohort
Treatment with PF-04449913 may continue for up to 12 cycles or until disease progression 
or relapse, patient withdrawal, or unacceptable toxicity occurs (whichever comes first). 
However, patients who complete 12 cycles of study treatment demonstrating clinical benefit 
with manageable toxicity, and are willing to continue receiving the study treatment, may be 
given the opportunity to do so upon agreement between Investigator and Sponsor and 
pending study drug availability.  
5.3.1.2. Study Treatment Duration in the Combination Cohorts
Combination Cohort 1 (Unfit Patients):
Study treatment (LDAC plus PF-04449913) may continue for up to 12 cycles or until disease 
progression or relapse, patient refusal, or unacceptable toxicity occurs (whichever comes 
first). However, patients who complete 12 cycles of study treatment, demonstrate clinical 
benefit with manageable toxicity, and are willing to continue receiving the treatment 
(monotherapy of PF-04449913 or combination therapy), may be given the opportunity to do 
so following discussion and agreement between the Investigator and Sponsor, and pending 
confirmation of study drug availability. 
Expansion Cohort of LDAC combination for efficacy (Unfit Patients):
Study treatment (LDAC plus PF-04449913) may continue until disease progression or 
relapse, patient refusal, or unacceptable toxicity occurs (whichever comes first). 
Combination Cohort 2 (Fit Patients):
Study treatment may continue until patient refusal, or the patient develops unacceptable 
toxicity or demonstrates either resistant disease during induction (ie, the bone marrow blast 


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count is greater than or equal to the screening bone marrow blast count), or disease 
progression/relapse after induction but before maintenance (see Appendix 5 and Appendix 8)

Patients with residual disease following the first induction (ie, persistent leukemia on 
bone marrow exam [ie, lower blast counts than the screening bone marrow but still 
>5% blasts and not meeting a complete response]) are candidates for a second cycle 
of induction if re-induction criteria are met;

In addition, following completion of the induction and consolidation, PF-04449913 
single agent may be given to eligible patients as maintenance treatment for a 
maximum of 6 cycles. However, patients who complete the maintenance treatment 
period and who demonstrate clinical benefit with manageable toxicity, and who are 
willing to continue receiving PF-04449913 single agent, may be given the 
opportunity to do so following agreement between Investigator and Sponsor, and 
pending confirmation of study drug availability.
Combination Cohort 3 (Azacitidine Combination):
Since responses to azacitidine may require 4-6 cycles of administration to emerge, treatment 
with the study drug combination should be continued for at least 6 cycles, or until death, 
unacceptable toxicity, or patient refusal (whichever is first).  If documentation of disease 
progression occurs within the first 6 cycles of study treatment, the patient SHOULD NOT be 
withdrawn from study treatment following agreement between the Investigator and Sponsor 
if, in the Investigator’s judgment, the patient is still likely to receive clinical benefit.
Treatment with the study drug combination should be continued beyond 6 cycles of treatment 
until objective disease progression or relapse (unless according to the Investigator there is 
reasonable evidence of clinical benefit, eg, HI [hematologic improvement], to justify 
continuation on treatment following agreement between the Investigator and Sponsor), death, 
unacceptable toxicity, or patient refusal (whichever is first).
5.3.1.3. Study Treatment Duration in the Continuation Cohort (Monotherapy Cohort)
In this cohort, the patient receiving PF-04449913 will continue to receive study treatment 
until the time of disease progression, unacceptable toxicity, death, withdrawal of consent or 
termination of the study by Sponsor, whichever comes first. The patient may continue PF-
04449913 treatment after objective progression of disease has been determined if the patient 
continues to experience clinical benefit, in the opinion of the investigator, and following 
discussion with the Sponsor. Refer to Appendix 7 for the definition of disease progression.
5.3.2. PF-04449913 Administration
PF-04449913 will be administered once daily and orally on a continuous basis for all 
patients.  A cycle is defined as 28 days unless the cycle is prolonged due to toxicity per 
Section 5.3.9 and Section 5.3.10.  PF-04449913 will be administered without adjustment for 
body size and with plenty of water.  Tablets must not be crushed or cut; they must be 
swallowed whole and not chewed.  Patients should be instructed to self-administer their
medication in the morning at approximately the same time each day and to not take more 


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than the prescribed dose at any time.  The patient will be reminded not to take their dose at 
home on clinic days but to bring their bottle into clinic so that PF-04449913 may be 
administered as described in the schedule of activities. 
If a patient misses a day’s dose entirely, they must be instructed not to “make it up” the next 
day.  If a patient vomits anytime after taking a dose, they must be instructed not to “make it 
up,” but to resume subsequent doses the next day as prescribed.  If a patient inadvertently 
takes 1 extra dose during a day, the patient should not take the next dose of PF-04449913.
If the in-clinic study visits cannot be conducted due to COVID-19-related reasons, 
arrangements to send investigational product and dosing diary to patient’s home via the third 
courier may be implemented. Participants must provide verbal consent for providing the 
contact details for shipping purposes. The verbal consent should be documented in the source 
document. Tracking record including temperature logs of shipments (eg. Lot number, receipt 
record by the participant and/or study drug status at the time of receipt, etc.) and the chain of 
custody of the study medication must be kept in the Investigational Product Accountability 
Log (IPAL) and/or the participant’s medical records.
Patients should return all unused or partially used bottles of investigational product and 
dosing diaries at the next in-clinic visit.
5.3.3. PF-04449913 in Combination with LDAC (Combination Cohort 1 and Expansion 
Cohort of LDAC combination for efficacy: Unfit Patients) 

PF-04449913 will be commenced on Day 3 of Cycle 1 for PK assessment purposes 
(for Combination Cohort 1) or Day 1 of Cycle 1 (for Expansion Cohort) and 
thereafter given once daily and continuously for 28-day cycles (starting on Day 1 for 
all other cycles);

PF-04449913 will be administered in the morning at approximately the same time as 
the first LDAC subcutaneous injection on days these agents are dosed together.  On 
days that PF-04449913 is dosed alone, PF-04449913 will be administered in the 
morning at approximately the same time each day;

LDAC will be given at a dose of 20 mg (not adjusted for the patients weight) 
subcutaneously (SC) twice daily (morning and evening; approximately 12 hrs apart) 
on Days 1-10 days of the 28 day cycles.

If the in-clinic study visits cannot be conducted due to COVID-19-related reasons, 
LDAC administration may be skipped only once. In such case, the safety assessments 
should be performed by phone or video contact, and/or by utilizing the test results 
from a local clinic if applicable. If 2 or more consecutive skips are required, the 
investigator and the Sponsor should have a consultation to determine the necessity of 
the study treatment discontinuation.


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5.3.4. PF-04449913 in Combination with Cytarabine/Daunorubicin (Combination 
Cohort 2: Fit Patients)
In this cohort, treatment consists of 3 distinct phases: induction, consolidation and 
maintenance.  All patients must meet specific criteria to enter each phase and will be required 
to wait the full 28 days of each cycle before progressing (Figure 4).  The only exception is 
for receiving the second cycle of induction which, if needed, can occur as early as Day 21 of 
induction Cycle 1.
Patients may require placement of a central venous catheter prior to initiation of therapy per 
institutional guidelines.
Figure 4.
Overview of Combination Cohort 2 (Fit Patients) Treatment Plan
5.3.4.1. Induction
Patients will participate in their first induction therapy for a total of 28 days.  However, if a 
patient requires a second cycle of induction therapy due to residual leukemia or investigator 


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opinion, this second course may start as soon as possible following the Cycle 1/Day 21 bone 
marrow evaluation. If the induction cycle(s) extends longer than 28 days, dosing with PF-
04449913 should continue daily in the absence of PF-04449913-related toxicity that would 
prevent dosing.
The intensive chemotherapy doses will be unaltered for both induction cycles regardless of 
toxicity or response (see Section 5.3.1 for dose adjustments based on body weight changes).    
For the first induction cycle only, PF-04449913 will be started on Day -3 and will then be 
given once daily and continuously for the duration of the treatment.  Daunorubicin will be 
given on Days 1 through 3 once daily at a dose of 60 mg/m2/day by IV together with 
cytarabine on Days 1 through 7 at a dose of 100 mg/m2/day by continuous intravenous 
infusion (CIV).  Where possible, daunorubicin should be given as close as possible to the 
administration of PF-04449913.  Daunorubicin and cytarabine should be administered per 
institutional guidelines.
The second induction cycle may be delayed up to an additional 28 days from Day 28 of the 
previous cycle to allow the patient to recover from any severe reversible hematologic or non-
hematologic drug related toxicity.  Treatment with PF-04449913 should continue during any 
delay before the start of the second cycle of induction in the absence of significant PF-
04449913-related toxicity that would prevent dosing.  The second cycle of induction should 
not be performed if the patient has clinically significant cardiotoxicity (LVEF <45%) and in 
this case the patient should be discontinued from treatment.
The bone marrow may be repeated at the Investigator’s discretion as required for clinical 
staging at any time prior to the next cycle of chemotherapy.
The following rules apply for progression from induction to consolidation (Figure 5): 

Patients who successfully obtain a CR or CRi after induction are eligible to enter the 
consolidation phase of the trial 28 days from the start of the last induction cycle;

Patients with residual leukemia at the end of induction Cycle 1 may be treated with a 
second cycle of induction therapy.  If after the second cycle of induction the patient 
still shows signs of residual or resistant leukemia, they must be discontinued from 
treatment and followed as described in Section 5.3.7;

Patients with resistant leukemia after the first and/or second course of induction will 
be discontinued from treatment and followed as described in Section 5.3.7.
5.3.4.2. Consolidation
Patients achieving a CR or CRi after the completion of induction therapy are eligible to begin 
consolidation.  Post-remission therapy will consist of two to four courses of cytarabine at a 
dose of 1 g/m2 administered as a 3 hour IV infusion Q12hrs (2 g/m2/day) on Days 1, 3 and 5 
of a 28-day cycle (see Section 5.3.1 for dose adjustments based on body weight changes).    
Cytarabine may be interrupted or delayed as clinically indicated.  However, cytarabine may
be dose reduced in the next cycle only, based on the worst toxicity experienced in the 


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previous cycle (Table 13 and Table 16). PF-04449913 will continue to be given once daily in 
the morning continuously in 28-day cycles, where possible at the same with chemotherapy 
infusion start.  
Patients can remain on the study for a minimum of two, but not more than four, courses of 
consolidation if they do not progress during consolidation treatment.  If a patient enters 
consolidation with a CRi (post induction) assessment but then achieves hematologic recovery 
in the peripheral blood (defined as ANC >1000/µL and platelets ≥100,000/µL), the bone 
marrow evaluation should be repeated within 14 days of the hematologic recovered blood 
counts observation. Bone marrow examinations may be performed at any time throughout 
consolidation as clinically indicated to confirm the patient has not relapsed.  At a minimum a 
bone marrow evaluation is required Day 21 of the final consolidation cycle to confirm 
response before going on to maintenance therapy.
The start of subsequent consolidation cycles may be delayed from the end of the previous 
cycle to allow for recovery from reversible hematologic or non-hematologic drug-related 
toxicities. If the consolidation cycle(s) extends longer than 28 days, dosing with PF-
04449913 should continue daily in the absence of PF-04449913-related toxicity that would 
prevent dosing.
The following rules apply for progression from consolidation to the maintenance treatment 
phase and will be based on the results of the bone marrow evaluation conducted during the 
last consolidation cycle:

If a patient demonstrates a CR/CRi at the end of two or three consolidation cycles, 
and are not candidates for additional consolidation therapy, they are eligible to 
proceed to maintenance therapy;

If a patient completes four cycles of consolidation and has a CR/CRi at the end of the 
4th cycle, they are eligible to proceed to maintenance therapy;

Patients who initially obtained a CR/CRi but no longer meet this definition may be 
eligible to continue with maintenance following consultation between Investigator 
and Sponsor;

Patient requiring more than two dose reductions of cytarabine will be withdrawn from 
treatment unless otherwise agreed between the Investigator and the Sponsor.
5.3.4.3. Maintenance
Patients are eligible for maintenance therapy if they have:

Completed the induction phase;

Completed at least 2, but not more than 4 cycles of consolidation;

Maintained a CR/CRi through the end of consolidation;


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
Maintenance begins at the end of consolidation (following Day 28 of the last 
consolidation cycle) and consists of PF-04449913 administered orally once daily 
continuously in the morning as monotherapy in 28-day cycles.  Maintenance will 
continue for a maximum of six cycles after the completion of consolidation; 
thereafter, all patients will discontinue treatment (unless demonstrating clinical 
benefit and upon agreement between the Investigator and Sponsor). 
Patients unable to maintain their CR/CRi while on maintenance may still be eligible to 
continue on maintenance therapy based on investigator Input and Sponsor approval.  If a 
patient demonstrates unequivocal disease progression or unacceptable toxicity, they must be 
discontinued from treatment and followed as described in Section 5.3.7. 


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Figure 5.
Treatment Flow Diagram for Combination Cohort 2 (Fit Patients)
5.3.5. PF-04449913 in Combination with Azacitidine (Combination Cohort 3)

Azacitidine will be administered SC or IV daily at a dose of 75 mg/m2/day on Days 
1-7 of each 28-day cycle (After Cycle 1, 3 days window applicable to each dose).

PF-04449913 will be orally administered daily and continuously.  In Cycle 1 only, 
administration of PF-04449913 will commence on Day 2 of the cycle (C1D2) to 
allow azacitidine alone PK sample collection.  The starting dose will be 100 mg.


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
Recommended dose modifications are discussed in Section 5.3.10.
5.3.6. Continuation Cohort (Monotherapy Cohort)

PF-04449913 will be commenced on Day 1 of Cycle 1 and orally administered once 
daily and continuously in 28-day cycles. The starting dose will be the same as the 
dose at the time the patient discontinued from Study B1371013.

Dose modifications are discussed in Section 5.3.9.
5.3.7. Post End-of-Treatment Follow-up 
In all study cohorts, at least 28 days, and no more than 35 days, after discontinuation of 
treatment (up to 42 days after the last dose of study drug if treatment was stopped for 
prolonged myelosuppression) patients require review of concomitant medications and 
assessment for resolution of any treatment related toxicity. Patients continuing to experience 
toxicity at this point following discontinuation of treatment will continue to be followed at 
least every 4 weeks until resolution or determination, in the clinical judgment of the 
Investigator, that no further improvement is expected.  In Combination Cohort 1 (unfit 
patients), all patients will be followed for survival by site visit, phone or letter, regardless of 
initiation of new cancer therapy. In Expansion Cohort of LDAC combination for efficacy
(unfit patients) and Combination Cohort 3 (Azacitidine Combination), all patients will be 
followed for survival every 8 weeks up to 2 years (for Expansion Cohort of LDAC 
combination for efficacy) or 12 weeks up to 3 years (for Combination Cohort 3) from the 
first dose of the last patient enrolled in the study, or until death, end of the study, or patient 
withdrawal of consent, whichever comes first, regardless of initiation of new cancer therapy.  
For patients refusing to return to the site, a telephone follow-up call is acceptable. After 
Protocol Amendment 8, follow-up on survival status will no longer be required in Expansion 
Cohort of LDAC combination for efficacy (unfit patients).
5.3.8. Food Requirements 
In all study cohorts, only in Cycle 1 PF-04449913 will be administered with plenty of water 
on an empty stomach ie, patients should refrain from food and beverages (except for water) 
where possible for at least two hours before and two hours after dosing throughout treatment 
administration. From Cycle 2 onwards, PF-04449913 can be administered with or without 
food. In the Expansion Cohort of LDAC combination for efficacy and Continuation Cohort, 
PF-04449913 may be administered with or without food in Cycle 1 and thereafter.
5.3.9. Recommended Dose Modifications [Monotherapy Cohort, Combination Cohort 1 
and Expansion Cohort (Unfit Patients), Combination Cohort 2 (Fit Patients) and 
Continuation Cohort (Monotherapy Cohort)]
Every effort should be made to administer the study treatments at the planned dose and 
schedule.
In the event of study treatment related toxicity, dosing may be delayed and/or dose reduced 
as described below in Table 13.  In the event of multiple toxicities, dose modification should 


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be based on the worst toxicity observed.  Patients are to be instructed to notify Investigators 
at the first occurrence of any adverse symptom.
Dose modifications may occur in three ways:
1.
Within a cycle: dose interruption/reduction until adequate recovery during a given 
treatment cycle. 

PF-04449913 (All Cohorts):

Doses of PF-04449913 that are held or missed during any cycle due to PF-
04449913-related toxicities will not be made up (eg. cycles will not be 
prolonged beyond the 28th calendar day in order to make up any missed PF-
04449913 doses during the cycle);

PF-04449913 may be dose reduced during any cycle. However, for patients
who are enrolled into the 25 mg dose level in the monotherapy cohort, PF-
04449913 dose reduction is not allowed.

Backbone chemotherapy (Combination Cohort 1, Expansion Cohort and 
Combination Cohort 2 only):

No dose-reductions are permitted in Cycle 1 for any of the backbone 
chemotherapeutic agents;  

After Cycle 1, if a toxicity is attributed to the backbone chemotherapy and not 
to PF-04449913, chemotherapeutics may be delayed or reduced (see Table 13
and Table 15) (while PF-04449913 dosing should be continued);

Missed doses of backbone chemotherapy (LDAC, cytarabine/daunorubicin) can 
be made up if the Investigator considers it appropriate according to standard 
practice.
2.
Between cycles: next cycle administration may be postponed due to toxicity in the 
previous cycle. 

A cycle may be extended to a maximum of 56 days for non-hematologic 
toxicity, or to a maximum of 70 days if due to hematologic toxicity.  PF-
04449913 dosing should continue if observed toxicity is not deemed related to 
PF-04449913;

If a treatment interruption continues beyond Day 28 of the current cycle for any 
agent, then the day when full treatment (all agents in the combination) is 
restarted will be counted as Day 1 of the next cycle for all agents.
3.
In the next cycle: dose reduction based on worst toxicity in the previous cycle. 


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For all drug combinations:
A study treatment related continuous treatment interruption or delay of >28 days for non-
hematologic toxicity OR >42 days for prolonged myelosuppression defined as ANC <500/L 
or platelet count <10 x109/L in a normal bone marrow with <5% blasts and no evidence of 
disease or dysplasia, will result in permanent discontinuation from treatment, unless the 
patient is demonstrating clinical benefit as agreed by the Investigator and Sponsor 
(Table 13). 


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Table 13.
Recommended Dose Modification Criteria for Treatment-Related Toxicity 
[Monotherapy Cohort, Combination Cohort 1 and Expansion Cohort (Unfit 
Patients), Combination Cohort 2 (Fit Patients) and Continuation Cohort
(Monotherapy Cohort)]
Drug
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
PF-04449913
Non Hematologic 
Continue 
at the 
same dose 
level.
Continue at the 
same dose level. 
If persistent (at 
least 7 days) and 
not responding to 
optimal medical 
management, 
withhold dose 
until toxicity is 
grade 1, then 
resume treatment 
at the same dose 
level or reduce the 
dose by 1 level at 
the discretion of 
the investigator.
Withhold dose 
until toxicity is 
grade 1, or has 
returned to 
baseline, then 
resume 
treatment at the 
same dose level  
or reduce the 
dose by 1 level 
at the discretion 
of the 
investigator.
(Nausea, 
vomiting or 
diarrhea must 
persist at Grade 
3 or 4 despite 
maximal 
medical therapy 
to require dose 
modification).
Withhold dose until 
toxicity is grade 1, 
or has returned to 
baseline, then 
reduce the dose by 1 
level and resume 
treatment, or 
discontinue at the 
discretion of the 
investigator.
(Nausea, vomiting 
or diarrhea must 
persist at Grade 3 or 
4 despite maximal 
medical therapy to 
require dose 
modification).
PF-04449913
Hematologic -
myelosuppression 
lasting 42 days
If ANC <500/L or platelet count <10 x109/L for 42 days in a normal 
bone marrow with <5% blasts and no evidence of disease or dysplasia, 
withhold dose until toxicity is grade 2, or has returned to baseline, then 
reduce the dose by 1 level and resume treatment, or discontinue at the 
discretion of the investigator.
PF-04449913
Hematologic -
prolonged  
myelosuppression 
lasting >42 days
If ANC <500/L or platelet count <10 x109/L in a normal bone marrow 
with <5% blasts and no evidence of disease or dysplasia for >42 days, 
discontinue treatment
PF-04449913
Delay of more than 
28 days for non-
hematologic toxicity 
Discontinue treatment


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Drug
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
LDAC 
Non Hematologic 
Continue 
at the 
same dose 
level.
Continue at the 
same dose level. 
If persistent (at 
least 7 days) and 
not responding to 
optimal medical 
management, 
withhold dose 
until toxicity is 
grade 1, then 
resume treatment 
at the same dose 
level or reduce the 
dose by 1 level at 
the discretion of 
the investigator.
Withhold dose 
until toxicity is 
grade 1, or has 
returned to 
baseline, then 
resume 
treatment at the 
same dose level 
or reduce the 
dose by 1 level 
at the discretion 
of the 
investigator 
(Nausea, 
vomiting or 
diarrhea must 
persist at Grade 
3 or 4 despite 
maximal 
medical therapy 
to require dose 
modification).
Withhold dose until 
toxicity is grade 1, 
or has returned to 
baseline, then 
reduce the dose by 1 
level and resume 
treatment, or 
discontinue at the 
discretion of the 
investigator.
(Nausea, vomiting 
or diarrhea must 
persist at Grade 3 or 
4 despite maximal 
medical therapy to 
require dose 
modification).
LDAC
Hematologic -
myelosuppression 
lasting 42 days
If ANC <500/L or platelet count <10 x109/L for 42 days in a normal 
bone marrow with <5% blasts and no evidence of disease or dysplasia, 
withhold dose until toxicity is grade 2, or has returned to baseline, then 
resume treatment at same dose level or reduce the dose by 1 level and 
resume treatment, or discontinue at the discretion of the investigator.
LDAC
Hematologic -
prolonged  
myelosuppression 
lasting >42 days
If ANC <500/L or platelet count <10 x109/L in a normal bone marrow 
with <5% blasts and no evidence of disease or dysplasia for >42 days, 
discontinue treatment
LDAC
Delay of more than 
28 days for non-
hematologic toxicity 
Discontinue treatment
Induction
Cytarabine/Daunorubicin
Non Hematologic 
and Hematologic 42 
days
No dose modification permitted for either agent.
Induction
Cytarabine/Daunorubicin
Hematologic -
prolonged  
myelosuppression 
lasting >42 days
If ANC <500/L or platelet count <10 x109/L in a normal bone marrow 
with <5% blasts and no evidence of disease or dysplasia for >42 days, 
discontinue treatment
Induction
Cytarabine/Daunorubicin
Delay of more than 
28 days for non-
hematologic toxicity 
Discontinue treatment


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Drug
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Consolidation
Cytarabine
Non Hematologic 
Continue 
at the 
same dose 
level.
Continue at the 
same dose level. 
Withhold dose 
until toxicity is 
grade 1, or has 
returned to 
baseline, then 
resume 
treatment at the 
same dose level 
or reduce the 
dose by 1 level 
at the discretion 
of the 
investigator 
(Nausea, 
vomiting or 
diarrhea must 
persist at Grade 
3 or 4 despite 
maximal 
medical therapy 
to require dose 
modification).
Withhold dose until 
toxicity is grade 1, 
or has returned to 
baseline, then 
reduce the dose by 1 
level and resume 
treatment, or 
discontinue at the 
discretion of the 
investigator.
(Nausea, vomiting 
or diarrhea must 
persist at Grade 3 or 
4 despite maximal 
medical therapy to 
require dose 
modification).
Consolidation
Cytarabine
Hematologic -
prolonged  
myelosuppression 
lasting >42 days
If ANC <500/L or platelet count <10 x109/L in a normal bone marrow 
with <5% blasts and no evidence of disease or dysplasia for >42 days, 
discontinue treatment
Consolidation
Cytarabine
Hematologic -
myelosuppression 
lasting 42 days
If ANC <500/L or platelet count <10 x109/L for 42 days in a normal 
bone marrow with <5% blasts and no evidence of disease or dysplasia, 
withhold dose until toxicity is grade 2, or has returned to baseline, then 
resume treatment at same dose level or reduce the dose by 1 level and 
resume treatment, or discontinue at the discretion of the investigator.
Consolidation
Cytarabine
Delay of more than 
28 days for non-
hematologic toxicity 
Discontinue treatment
5.3.9.1. Additional Guidance for Intra-Patient Dose Modification [Monotherapy 
Cohort, Combination Cohort 1 and Expansion Cohort (Unfit Patients), Combination 
Cohort 2 (Fit Patients) and Continuation Cohort (Monotherapy Cohort)]
All dose reductions or interruptions will be at the discretion of the treating physician based 
on the known toxicities of each study drug.  If no clear attribution can be determined, it is 
recommended to initially dose reduce PF-04449913 according to Table 14, followed by dose 
reduction of the chemotherapy as clinically indicated. 
Once a patient has a dose reduction for a study drug-related toxicity, the dose will not be 
re-escalated.  Patients requiring dose reductions exceeding the doses listed in Table 14-
Table 16 will be withdrawn from treatment. 
Recommended dose levels for individual agents are listed in below.


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Table 14.
PF-04449913 Dose Levels (All Cohorts)
Dose Level
PF-04449913 Dose Levels QD (mg)
1
100
-1
50 
-2
25
Table 15.
LDAC Dose Levels (Combination Cohort 1 and Expansion Cohort only)
Dose Level
LDAC Dose Levels Q12hrs (mg)
1
20 (starting dose level)
-1
15
-2
10
Table 16.
Cytarabine Dose Levels in Consolidation Cycles (Combination Cohort 2 
only)
Dose Level
Cytarabine Dose Levels Q12hrs (mg/m2)
1
1000 (starting dose level)
-1
750
-2
500
No dose modification is permitted for Daunorubicin (Combination Cohort 2). 
5.3.10. Recommended Dose Modifications [Combination Cohort 3 (Azacitidine 
Combination)]
Every effort should be made to administer the study drug treatment according to the planned 
dose and schedule.  This section, package insert or institutional guideline for dose 
modification of azacitidine should be followed.
In the event of significant toxicity, dosing may be interrupted, delayed and/or reduced as 
outlined below.  In the event of multiple toxicities, dose modification should be based on the 
worst toxicity observed.  Patients must be instructed to notify investigators at the first 
occurrence of any adverse symptom/s.
Dose modifications may occur in three ways:

Within a cycle: Dosing interruption until adequate recovery followed by dose 
reduction (if required) of PF-04449913 during a given treatment cycle.  Azacitidine 
dosing interruption is not allowed within a cycle unless there is an unexpected or
unacceptable study drug combination related toxicity or Grade 3 non-hematologic 
toxicity.

Between cycles: The next treatment cycle may be delayed if toxicity from the 
preceding cycle persists. If a treatment interruption continues beyond Day 28 of the 
current cycle for any agent, then the day when full treatment (all agents in the 
combination) is restarted will be counted as Day 1 of the next cycle for all agents.


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
In the next cycle: Dose reduction may be required based on toxicities experienced in 
the previous cycle.
A study treatment related continuous treatment interruption or delay of >28 days (21 days in 
case of azacitidine related) for non-hematologic toxicity OR >42 days for prolonged 
myelosuppression defined as ANC <500/L or platelet count <10 x109/L in a normal bone 
marrow with <5% blasts and no evidence of disease or dysplasia, will result in permanent 
discontinuation from treatment, unless the patient is demonstrating clinical benefit as agreed 
by the Investigator and Sponsor (Table 18 and Table 19).
5.3.10.1. Dose Interruptions for Azacitidine and PF-04449913 [Combination Cohort 3 
(Azacitidine Combination)]
Azacitidine
Azacitidine dose interruption is not allowed within a cycle unless there is an unacceptable or 
unexpected study drug combination related toxicity or Grade 3 non-hematologic toxicity.  
In this case azacitidine dosing may be resumed following the dose modifications listed in
Table 18 and Table 19. 
After Cycle1, each dose of azacitidine will be allowed to be shifted by a plus or minus 3 day 
window.
Patients experiencing Grade 3 non-hematologic toxicities should have their azacitidine 
treatment interrupted regardless of when it occurs in the cycle until the toxicity returns to 
baseline. If the toxicity prolongs >21 days from when the next cycle is due to start or it 
becomes severe, azacitidine treatment will be discontinued permanently.
Appropriate follow up assessments should be implemented until adequate recovery occurs as 
assessed by the Investigator.  The criteria that must be met prior to resuming treatment with 
azacitidine are outlined in Section 5.3.10.2.
Azacitidine administration should not be interrupted if PF-04449913 dosing is interrupted for 
toxicity.
PF-04449913
Patients experiencing Grade 3 or persisting (at least 7 days not responding to optimal 
medical management) Grade 2 non-hematologic toxicities or myelosuppression defined as 
ANC <500/L or platelet count <10 x109/L in a normal bone marrow with <5% blasts and no 
evidence of disease or dysplasia potentially attributable to PF-04449913 should have their 
PF-04449913 treatment interrupted regardless of when it occurs in the cycle until the toxicity 
recovers to Grade 1or less (for non-hematologic), Grade 2 or less (for hematologic) or 
baseline. 


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Appropriate follow-up assessments should be implemented until adequate recovery occurs.  
The criteria that must be met prior to resuming treatment with PF-04449913 are described in 
Section 5.3.10.2.
Depending on when the adverse event resolved, treatment interruption may lead to the patient 
missing all subsequent planned doses of PF-04449913 within the cycle.  If the AE leading to
treatment interruption recovers within the same cycle, re-commencement of dosing in that 
cycle is allowed.  PF-04449913 doses omitted for toxicity will not be replaced within that 
cycle (eg, cycles will not be prolonged beyond the 28 days in order to make up for any 
missed PF-04449913 doses during that cycle). 
The need for a dose reduction at the time of treatment resumption should be based on the 
criteria outlined in Section 5.3.10.3, unless specifically agreed otherwise following 
discussion between the Investigator and the Sponsor.
5.3.10.2. Dose Delays for Azacitidine and PF-04449913 [Combination Cohort 3 
(Azacitidine Combination)]
Azacitidine
Hematologic toxicitity is defined as below:

Patients without reduced baseline counts (defined as an absolute neutrophil count (ANC) 
1,500/L, white blood cells 3,000/L and platelets 75,000/L prior to the first cycle): 

Hematologic toxicitity is defined as: the lowest count for the previous cycle showed 
ANC <1,000/L or platelets <50,000/L.

Patients with reduced baseline counts (defined as ANC <1,500/L, white blood cells 
<3,000/L or platelets <75,000/L prior to the first cycle):

Hematologic toxicitity is defined as: any parameters of ANC, white blood cells or 
platelets decreases to 50% of baseline or below.
For each case, at the start of each new cycle, re-treatment with azacitidine may not occur 
until the Neutrophil and Platelet Recovery Parameters described below are met:
Counts (lowest count) + [0.5 × (baseline count – lowest count)]
PF-04449913
PF-04449913 treatment should be interrupted for toxicities described in Section 5.3.10.1. Re-
commencement of treatment with PF-04449913 may not occur until the recovery parameters 
described below are met:

Hematologic toxicities have returned to baseline or ≤ Grade 2 severity, provided that 
patietns recovered from myelosuppression (defined as ANC <500/L or 


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platelets <10 x 109/L in a normal bone marrow with <5% blasts and no evidence of 
disease or dysplasia) within 42 days and re-treatment can occur safely as per the 
Investigator’s judgment.

Non-hematologic toxicities have returned to baseline or ≤ Grade 1 severity within ≤28 
days of dose interruption or delay.
If these conditions are met, PF-04449913 may be resumed (see Section 5.3.10.3 for toxicities
requiring dose reduction at the time of treatment resumption). 
If myelosuppression (defined as ANC <500/L or platelets <10 x 109/L in a normal bone 
marrow with <5% blasts and no evidence of disease or dysplasia) prolongs for >42 days or 
non-hematologic toxicities need >28 days of dose interruption or dalay, permanent 
discontinuation of treatment with PF-04449913 should be considered.
5.3.10.3. Dose Reductions for Azacitidine and PF-04449913 [Combination Cohort 3 
(Azacitidine Combination)]
Following dosing interruption or cycle delay due to toxicity, the azacitidine and/or PF-
04449913 dose may need to be reduced when treatment is resumed.
Dose reduction of azacitidine and/or PF-04449913 by 1 or if necessary, 2 dose levels will be 
allowed depending on the type and severity of toxicity encountered (Table 17).  Patients 
requiring more than 2 dose reductions of azacitidine should permanently discontinue both 
azacitidine and PF-04449913.  NOTE: In the specific situations where clinical benefit is 
observed, PF-04449913 can be reduced below 50 mg QD upon Sponsor approval.  All dose 
modifications/adjustments must be clearly documented in the CRF. 
Once the PF-04449913 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. 
Once the azacitidine dose has been reduced for a given patient, subsequent cycles should be 
administered at that dose level.  If dose re-escalation could be acceptable (ex. a patient 
undergoes two cycles at a reduced dose without recurrent hematologic toxicity), dose re-
escalation to the next higher dose level could be considered following discussion and 
agreement between the Investigator and Sponsor.
Table 17
Available Dose Levels (Combination Cohort 3)
Azacitidine (mg/m2/day)
PF-04449913 (mg QD)
75 (100%)
100
50% of current dose
75
33% of current dose
50
25 *
* NOTE: If clinical benefit is observed, PF-04449913 may be reduced below 50 mg QD following Sponsor approval.


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Recommended dose modifications for treatment-related hematologic toxicities are outlined in
Table 18.
Table 18
Recommended Dose Modifications for Hematologic Toxicities
Toxicity
Azacitidine dose at Start of 
Subsequent Cycle 
PF-044499133
regardless of when it occurs 
in the cycle
Hematologic toxicity 1, 2
Recovery4 within 14 days from when 
the next cycle is due to start 
(corresponding to recovery before or 
on Day 42 of the current cycle)
No change 
-
Hematologic toxicity 1, 2
Recovery4 after 14 days from when 
the next cycle is due to start 
(corresponding to recovery after Day 
42 of the current cycle)
Without reduced baseline counts1
Decrease to 50% of the current dose
With reduced baseline counts2
Bone 
marrow 
cellularity 
Dose in the 
Subsequent Cycle
>50%
No change
15%-50%
Decrease to 50% of 
the current dose if 
recovery4 after 21 
days from when 
the next cycle is 
due to start
<15%
Decrease to 33% of 
the current dose if 
recovery4 after 21 
days from when 
the next cycle is 
due to start
-
Hematologic - 42 days prolongation 
of myelosuppression5
-
Withhold dose until toxicity is 
grade 2, or has returned to 
baseline, then reduce the dose 
by 1 level and resume 
treatment, or discontinue at the 
discretion of the investigator.
Hematologic - >42 days prolongation 
of myelosuppression5
Permanently discontinue
Permanently discontinue 
1. For patients without reduced baseline counts (defined as ANC 1,500/L, white blood cells 3,000/L and platelets 
75,000/L prior to the first cycle): hematologic toxicity is defined as: ANC <1,000/L or platelets <50,000/L.
2. For patients with reduced baseline counts (defined as ANC <1,500/L, white blood cells <3,000/L or platelets 
<75,000/L prior to the first cycle): hematologic toxicity is defined as: more than one parameter of ANC, white blood 
cells or platelets decreases to 50% of baseline or below. 
3. PF-04449913 treatment should be interrupted for myelosuppression (defined as ANC <500/L or platelet count <10 
x109/L in a normal bone marrow with <5% blasts and no evidence of disease or dysplasia) regardless of when it occurs.
4. Counts (lowest count) + [0.5 × (baseline count – lowest count)]


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5. Myelosuppression is defined as ANC <500/L or platelet count <10 x109/L in a normal bone marrow with <5% 
blasts and no evidence of disease or dysplasia
Recommended dose modifications for treatment-related non-hematologic toxicities 
(excluding QTc prolongation) are outlined in Table 19.
Table 19
Recommended Dose Modifications for Non-Hematologic Toxicities
Toxicity 
(NCI CTCAE version 4.0)
Azacitidine dose at Start of 
Subsequent Cycle Based on Worst 
Toxicity Observed in the Previous 
Cycle
PF-04449913
regardless of when it occurs in 
the cycle
Renal Toxicity
Serum creatinine or BUN 
2x baseline value and 
>ULN
Azacitidine may be re-started at the 
next cycle when values have returned 
to baseline or normalized 
Reduce to 50% of the current dose
In case of Grade 2;
Continue at the same dose level. 
If persistent (at least 7 days) and 
not responding to optimal medical 
management, withhold dose until 
toxicity is grade 1, then resume 
treatment at the same dose level or 
reduce the dose by 1 level at the 
discretion of the investigator.
In case of Grade 3;
Withhold dose until toxicity is 
grade 1, or has returned to 
baseline, then resume treatment at 
the same dose level or reduce the 
dose by 1 level at the discretion of 
the investigator.
In case of Grade 4;
Withhold dose until toxicity is 
grade 1, or has returned to 
baseline, then reduce the dose by 1 
level and resume treatment, or 
discontinue at the discretion of the 
investigator.
Permanently discontinue if the 
continuous treatment interruption 
or delay of >28 days.
Serum bicarbonate levels 
<20 mEq/L (venous)
Reduce to 50% of the current dose
No Change
Other Non-Hematologic Toxicities (Excluding QTc Prolongation, Muscle Spasms and Myalgia)
Grade 1 toxicity
No change
Continue at the same dose level.


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Toxicity 
(NCI CTCAE version 4.0)
Azacitidine dose at Start of 
Subsequent Cycle Based on Worst 
Toxicity Observed in the Previous 
Cycle
PF-04449913
regardless of when it occurs in 
the cycle
Grade 2 toxicity
No change
Continue at the same dose level. 
If persistent (at least 7 days) and 
not responding to optimal medical 
management, withhold dose until 
toxicity is grade 1, then resume 
treatment at the same dose level or 
reduce the dose by 1 level at the 
discretion of the investigator.
Permanently discontinue if the 
continuous treatment interruption 
or delay of >28 days.
≥ Grade 3 toxicity
Azacitidine should be interrupted 
regardless of when it occurs in the 
cycle. Azacitidine could be resumed 
when grade of the toxicity returns to 
baseline within 21 days from when the 
next cycle is due to start and ONLY if 
as per investigator judgment there will 
be a patient’s clinical benefit to justify 
continuation of treatment
Nausea, vomiting, or diarrhea must 
persist at ≥ Grade 3 despite 
maximal appropriate medical
therapy to require dose 
modification
In case of Grade 3;
Withhold dose until toxicity is 
grade 1, or has returned to 
baseline, then resume treatment at 
the same dose level or reduce the 
dose by 1 level at the discretion of 
the investigator.
In case of Grade 4;
Withhold dose until toxicity is 
grade 1, or has returned to 
baseline, then reduce the dose by 1 
level and resume treatment, or 
discontinue at the discretion of the 
investigator.
Permanently discontinue if the 
continuous treatment interruption 
or delay of >28 days
5.3.11. Recommended Dose Modifications for PF-04449913 QTcF Prolongation and 
Drug Class Related AEs [Monotherapy Cohort, Combination Cohort 1 (Unfit Patients), 
Combination Cohort 2 (Fit Patients), Combination Cohort 3 (Azacitidine 
Combination)]
QTcF Interval Monitoring and Management: Patients should be closely monitored for 
potential cardiovascular symptoms.  Appropriate monitoring should include clinical 
examinations, vital signs, routine ECGs, and AE monitoring. In case of QTc prolongation, 
concomitant conditions such as electrolyte imbalances, hypoxia, or use of medications affecting 
the QT interval should be ruled out or corrected. In case of clinically significant toxicities, PF-


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04449913 administration should be interrupted and the dose reduced as indicated in Table 20
(PF-04449913 Dose Modifications for mean QTcF (mQTcF) Prolongation). 
Concomitant administration of PF-04449913 with moderate/strong CYP3A4/5 inhibitors       
(Appendix 12) is not permitted.  And concomitant administration of PF-04449913 with drugs 
with known risk of Torsade de Pointes (TdP) (Appendix 11) is not recommended due to the  
potential for drug-drug interaction to prolong the QTc interval. However, if it is medically 
necessary for patients to use these medications please refer to Section 7.1.5 for details on 
required assessments and monitoring procedures (excluding the Expansion Cohort of LDAC 
combination for efficacy). 
All protocol specified QTcF prolongation-related exclusion criteria must be followed. 
Investigators must be aware of the QTcF-prolonging potential of all medications that patients
on study at their site 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 during the study. In the event 
that the QTcF interval is prolonged beyond 480 ms (CTCAE v.4.03 Grade 2), the protocol 
Recommended PF-04449913 Dose Modifications for mean QTcF (mQTcF) Prolongation-
Table 20 must be referenced and actioned. Throughout the study additional ECG and cardiac 
consultation should be obtained if clinically indicated.


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Table 20.
Recommended PF-04449913 Dose Modifications for mean QTcF (mQTcF)
Prolongation
CTCAE v 4.03
Electrocardiogram 
QT corrected (QTc) 
interval prolonged *
Grade  1
Grade 2
Grade 3**
Grade 4
450-480 msec
481-500 msec
ı 501 msec at least 
two separate ECGs
QTc >= 501 or >60 
msec change from 
baseline and Torsade 
de pointes or 
polymorphic 
ventricular 
tachycardia or 
signs/symptoms of 
serious arrhythmia
*The  severity of QTc prolongation assessment is to be done by calculating  a mean QT of 3 consecutive ECGs 
performed approximately 2 minutes (but no longer than 5 minutes) apart  by using the Fridericia  correction method 
(mQTcF).
** If mQTcF is ı 501 msec continuous ECG monitoring and cardiology consultation are required.
Grade
Category
Requirement
1
2
3
4
ECG monitoring
Continuous ECG monitoring and cardiology consultation  
for  mQTcF  ı 501 msec  
x
x
Initial PF-04449913 
action
Discontinue and do not re-challenge.
x
Interrupt treatment
x
x
Continue at same level
x
General management
Assess for and correct electrolyte abnormalities.
x
x
x
x
Withhold any concomitant medications if possible that 
may cause QTc prolongation.
x
x
x
Resume PF-04449913 
dosing
At prior dose if mQTcF returns to İ470 msec and to 
within 20 msec of baseline in 7 days and  if no prior
dose interruption related to mQTcF prolongation has
occurred
x
x
At one lower dose level if mQTcF returns to İ470msec 
and to within 20 msec of baseline between 7-14 days. 
and if no prior dose interruption related to mQTcF
prolongation has occurred
x
x
At one lower dose level if mQTcF returns to İ470
msec and to within 20 msec of baseline in 14 days if one  
prior dosing interruption related to mQTcF prolongation 
has occurred
x
Management after 
dose resumed
An ECG should be repeated and mQTcF re-assessed
approximately 7 days after PF-04449913 
dosing resumption following interruption for a mQTcF
prolongation
x
x
Discontinue PF-
04449913 
permanently
The mQTcF prolongation does not return toİ470 msec
and to within 20 msec of baseline after 14 days
x
x
The Grade ı 2 mQTcF prolongation recurs after one
dose reduction related to mQTcF prolongation
x
x
The Grade ı3 mQTcF prolongation recurs after one  
prior dosing interruption related to mQTcF prolongation 
has occurred
x
If at any time during the 14 day window that PF-
04449913 is stopped due to QTcF prolongation the 
patient has a confirmed mean QTcF interval >515 msec 
or becomes symptomatic 
x
x


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Recommended dose modifications for PF-04449913 in case of drug class related AEs are 
outlined in Table 21.
Table 21
Recommended Dose Modifications for PF-04449913 in Case of Drug Class
Related AEs
Muscle Spasms or 
Myalgia
Grade 1
Grade 2
Grade 3
PF-04449913
Continue at same dose level.
Administer oral rehydration 
solutions containing 
electrolytes.
Consider other appropriate 
interventions (eg, anti-
spasmodics) as per 
institutional guidelines.
Evaluate levels of: CK, Vit 
B6, Vit D, ferritin, transferin 
and electrolytes (Na, K, Mg, 
Ca and P).
If CK is elevated, evaluate 
urine and serum myoglobin, 
CK isoenzymes, and plasma 
creatinine.
Continue at same dose level.
Administer oral re-hydration 
salts containing electrolytes.
Consider other appropriate 
interventions (eg, anti-
spasmodics) as per 
institutional guidelines.
Evaluate levels of: CK, Vit 
B6, Vit D, ferritin, transferin 
and electrolytes (Na, K, Mg, 
Ca and P).
If CK is elevated, evaluate 
urine and serum myoglobin, 
CK isoenzymes, and plasma 
creatinine.
If event persists, hold dose 
until resolution to Grade ≤1.
Upon resolution, restart at 
prior dose, or for prolonged 
muscle spasms, consider 
reducing dose by one dose 
level.
Hold dose.
Administer oral re-hydration 
salts containing electrolytes.
Consider other appropriate 
interventions (eg, anti-
spasmodics) as per institutional 
guidelines.
Evaluate levels of: CK, Vit B6, 
Vit D, ferritin, transferin and 
electrolytes (Na, K, Mg, Ca and 
P).
If CK is elevated, evaluate urine 
and serum myoglobin, CK 
isoenzymes, and plasma 
creatinine.
Upon resolution to Grade ≤1, 
restart study treatment at next 
lower dose level.
If the event does not resolve 
within 3 weeks to Grade ≤1, at 
the discretion of the Investigator 
the dose may be restarted at the 
next lower dose level or the 
patient may be permanently 
discontinued from study 
treatment. 
In the event of alopecia or dysgeusia, investigator discretion should be applied with respect to dose interruption and/or dose 
reduction of PF-04449913 as preliminary analysis of available clinical data suggests that these events are not dose 
dependent.
5.3.12. Compliance
For PF-04449913, patients will maintain diaries to include missed or changed doses, or 
significantly delayed doses. Patients are required to return all bottles and unused study 
medications at each cycle and at end of treatment for compliance assessment and drug 
accountability.  The number of tablets returned by the patient at the end of the cycle will be 
counted, documented and recorded.


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For medications administered in the study site (cytarabine, daunorubicin, and azacitidine in 
Combination Cohorts) the site will complete the required dosage Preparation Record.  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.  This may be used in place of the Preparation Record after 
approval from the Pfizer monitor.
5.4. Drug Storage and Drug Accountability 
Investigators and site staff are reminded to check temperatures daily and ensure that 
thermometers are working correctly as required for proper storage of investigational 
products.  This includes thermometers for both room storage and refrigerator storage.  Any 
temperature excursions should be reported immediately. 
5.4.1. PF-04449913
PF-04449913 should be stored as described on the drug label with protection from moisture.  
Patients should be instructed to keep their medication in its original container.  Returned 
medication should be stored separately from medication that needs to be dispensed.
The investigator, or an approved representative (eg, pharmacist), will ensure that all trial drug 
is stored in a secured area, under recommended storage conditions provided in the Study 
Manual and in accordance with applicable regulatory requirements.  Under no circumstances 
should the investigator or other site personnel supply trial drug to other investigators, 
patients, or clinics, or allow supplies to be used other than directed by this protocol without 
prior authorization from Pfizer.  Pfizer may supply drug accountability forms that must be 
used or may approve use of standard institution forms.  In either case, the forms must 
identify the investigational product, and account for its disposition on a patient-by-patient 
basis, including specific dates and quantities.  The forms must be signed by the individual 
who dispensed the drug, and copies must be provided to Pfizer.
Adequate records documenting receipt, use, return, loss or other disposition of PF-04449913 
must be kept.  PF-04449913 tablets must be used according to the protocol directions.  The 
reason for missed dose should be entered on the CRF. 
5.4.2. Cytarabine
Cytarabine will be stored in accordance with the drug label and institutional guidelines.
5.4.3. Daunorubicin
Daunorubicin will be stored in accordance with the drug label and institutional guidelines.
5.4.4. Azacitidine
Azacitidine will be stored in accordance with the drug label and institutional guidelines.


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5.5. Concomitant Medication(s)
Concomitant treatment considered necessary for the patient’s well-being may be given at 
discretion of the treating physician.
Every concomitant medication, blood products, and intervention (eg, paracentesis) required 
by the patient within 28 days prior to study drug treatment and during the trial (and up to 
28 days following last treatment administration or until initiation of another oncologic 
treatment) and the reason for its administration, must be recorded on the CRF (After Protocol 
Amendment 8, these data are not required to be recorded on the CRF in the Expansion 
Cohort of LDAC combination for efficacy).  
The following information is based on results from in vitro studies with PF-04449913 and a 
drug-drug interaction study with a strong CYP3A4/5 inhibitor in healthy subjects.  

CYP3A4/5 Inhibitors: In vitro studies with human liver microsomes and 
recombinant CYP enzymes indicated that PF-04449913 metabolism is primarily 
mediated by the drug-metabolizing enzyme CYP3A4/5.  Clinically, there is 
likelihood that PF-04449913 plasma concentrations may be increased in the presence 
of co-administered inhibitors of the CYP3A4/5 enzymes.  In a healthy volunteer 
study, ketoconazole, a potent CYP3A4/5 inhibitor, produced a 2.4-fold increase in 
plasma exposure and a 1.4-fold increase in peak plasma concentration of PF-
04449913.  Therefore a potential exists for drug-drug interactions with 
CYP3A4/5 inhibitors, and the use of strong/moderate CYP3A4/5 inhibitors are not 
permitted (unless approved by Sponsor) from 7 days prior to first dose of 
investigational product until study treatment discontinuation (eg, aprepitant, 
clarithromycin, cimetidine, ciprofloxacin, cyclosporine, diltiazem, erythromycin,
tofisopam, verapamil, fluconazole, itraconazole, ketoconazole, and voriconazole). 
During this period, food, beverages, and herbal preparations which inhibit CYP3A4/5
are not permitted (eg, grapefruit juice). A comprehensive list of strong/moderate 
CYP3A4/5 inhibitors is provided in Appendix 12 of the protocol. These 
requirements/lists may be updated based on emerging data;

CYP3A4/5 Inducers: PF-04449913 metabolism may be induced when taking 
CYP3A4/5 inducers, resulting in reduced plasma concentrations. The impact of 
CYP3A4/5 inducers on PF-04449913 pharmacokinetics has not been studied in the 
clinic.  Therefore co-administration of PF-04449913 in combination with any of the 
following and other strong/moderate CYP3A4/5 inducers is not permitted (unless 
approved by Sponsor) from 7 days prior to first dose of investigational product until 
study treatment discontinuation (eg, avasimibe, mitotane, phenytoin, enzalutamide, 
semagacestat, bosentan, genistein, thioradazine, nafcillin, modafinil, carbamazepine, 
phenobarbital, phenytoin, rifampin, rifabutin, rifapentine). During this period, food, 
beverages, and herbal preparations which induce CYP3A4 are not permitted (eg, St. 
John’s Wort).  A comprehensive list of strong/moderate CYP3A4/5 inducers is
provided in Appendix 13 of the protocol. These requirements/lists may be updated 
based on emerging data;


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
In vitro studies have indicated that PF-04449913 is a substrate for P-gp.  Therefore, 
dosing of PF-04449913 in combination with P-gp inhibitors (eg, cyclosporine, 
erythromycin, itraconazole, ketoconazole, quinidine, tacrolimus and verapamil) and 
P-gp inducers (eg, St. John’s Wort) is not permitted (unless approved by Sponsor) 
from 7 days prior to first dose of investigational product until the completion of all 
PK samples. These requirements/list may be updated based on emerging data;

Immunosuppressants (including but not limited to cyclosporine, tacrolimus, 
methotrexate, or mycophenolate mofetil) are not permitted from 14 days prior to first 
dose of investigational product until treatment discontinuation;

Drugs with known risk of Torsade de Pointes: PF-04449913 has been shown to 
have the potential to prolong the QTc interval in pre-clinical studies and at doses 
>200 mg.  While the PF-04449913 dose evaluated in this study is 100 mg, the 
concomitant administration of PF-04449913 and drugs with a known risk of Torsade 
de pointes should be avoided whenever possible. A list of such drugs is provided in 
Appendix 11 of the protocol. Use of these drugs is not recommended unless there are 
no alternatives. If a TdP drug is to be initiated in addition to PF-04449913 the 
guidance provided in Section 7.1.5 requiring additional ECG monitoring before, 
during and after starting the medication (excluding the Expansion Cohort of LDAC 
combination for efficacy), electrolyte monitoring (including correction and re-
checking values) and dose modifications for QT prolongation per Table 20 must be 
followed.

QT prolonging medications (without a risk of TdP) should be avoided whenever 
possible.

Concomitant administration of multiple moderate/strong CYP3A4/5 inhibitors,TdP 
drugs, and/or QT prolonging medications (without a risk of TdP) is not recommended 
and must be discussed with the Sponsor Medical Monitor.

Prior or concurrent treatment with a Hh inhibitor or concurrent treatment with other 
investigational agents not specified in the protocol is not permitted;

Use of Oral anticoagulant (ie, warfarin) is strongly discouraged if alternate 
medication (eg, low molecular weight heparin) can be substituted.  Warfarin is a 
CYP3A4 substrate and drug interactions causing variability in INR are possible.  If 
oral anticoagulants are needed, frequent monitoring of the INR is recommended and 
the dosage of oral anticoagulant should be adjusted as needed.
5.5.1. Other Prohibited or Restricted Concomitant Medications 
5.5.1.1. Combination Cohort 3 (Azacitidine Combination)
The following medications are not allowed during the active study treatment period:


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
Hydroxyurea (except for the use before and for up to 1 week after first dose of PF-
04449913 for control of rapidly progressing leukemia) or other anti-cancer agents 
(eg, tacrolimus, hormones, cytokines, etc.);

Immunosuppressant agents (eg, cyclosporine); 
The following medications have use restrictions during the active study treatment period:

Aspirin in doses exceeding 300 mg per day is not permitted.
5.5.1.2. Continuation Cohort (Monotherapy Cohort)
The following medications have restrictions on use or dose during the study treatment period: 

Aspirin in doses exceeding 150 mg per day is not permitted. 

Topical androgen therapies for condition unrelated to MF are permitted; other 
androgens are not permitted.
The following medications and surgical/medical procedures are prohibited during study 
treatment:

Hematopoietic growth factor receptor agonists [eg, erythropoietin (Epo), granulocyte 
colony stimulating factor (GCSF), romiplostim, and eltrombopag]. 

Moderate or high-dose steroids (eg, >10 mg QD prednisone);

Androgens (eg, fluoxymesterone);

Focal irradiation;

Allogeneic peripheral stem cell or bone marrow transplantation;

Splenectomy;

Investigational agents;

Other treatments routinely used to treat MF. 
5.5.2. Other Anti-Cancer or Experimental Drugs
No additional anticancer therapy (including herbal supplements) will be permitted while 
patients are receiving study therapy.  All anti-cancer treatments (unless specified) should be 
discontinued 2 weeks from first dose of investigational product, for example, targeted 
chemotherapy, radiotherapy, investigational agents, hormones, anagrelide, or cytokines. 

Patients with controlled CNS leukemia (documented by two consecutive assessments 
of zero blast count in cerebrospinal fluid), and who are still receiving IT therapy at 
first dose of investigational product are considered eligible, and will continue to 
receive IT therapy.


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5.5.3. Prophylactic Medications
Patients with high circulating blasts counts may receive hydroxyurea or leukopheresis to 
reduce their blast count for up to 1 week in Cycle 1 after the first dose of PF-04449913 of the 
study.  Continuation of hydroxyurea or leukopheresis after that time period must be approved 
by the Sponsor.
Renal function abnormalities should be treated aggressively and corrected.  Patients should 
be adequately hydrated and receive anti-nephrotoxic medications and antimicrobial 
prophylaxis according to institutional practice.
5.5.3.1. Tumor Lysis Syndrome (TLS) Prophylaxis
Optimal management of the TLS should involve preservation of renal function as well as 
prevention of dysrhythmias and neuromuscular irritability.  Patients should be managed 
according to institutional practice and guidelines.  In addition, the following practice is 
recommended:

Ensure adequate IV hydration.

Reduce uric acid levels with allopurinol or rasburicase.

Correct hyperkalemia, hypocalcemia, and hyperphosphatemia.
5.5.3.2. Infection Prophylaxis
Patients should be managed according to institutional practice and guidelines. In addition, the 
following practice is recommended:

Extremely careful hand washing by all members of health care team is encouraged. 

Diet should exclude raw fruits, vegetables, and unprocessed foods per institutional 
guidelines.

Prophylaxis with antimicrobial agents is strongly recommended for all patients as 
indicated in the following table when absolute neutrophil count (ANC) <500/L.  
Specific anti-microbial agents are prohibited per protocol because of their ability to 
inhibit CYP3A, resulting in a high-risk for a drug-drug interaction with PF-04449913.  
These include ketoconazole, itraconazole, voriconazole, clarithromycin, 
erythromycin, fluconazole and ciprofloxacin.  Nephrotoxic agents (eg, gentamicin) 
should be avoided if possible.

For Unfit Patients (Combination Cohort 1 and Expansion Cohort of LDAC 
combination for efficacy): Antimicrobial prophylaxis is indicated during all 
cycles when ANC is <500/L and stopped when the ANC ≥500/L and the 
patient is afebrile.


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For Fit Patients (Combination Cohort 2): Antimicrobial prophylaxis should start 
at the initiation of induction chemotherapy.  Treatment with all agents may be 
stopped when ANC is ≥500/L for 3 consecutive days and the patient is afebrile. 
During consolidation and maintenance, antimicrobial prophylaxis is indicated 
when ANC is <500/L during all cycles and stopped when the ANC ≥500/L and 
the patient is afebrile.

Antimicrobial agents may be chosen at the discretion of local institutional 
guidelines; however, in the table below the following agents are suggested to 
decrease the potential for a drug-drug interaction with PF-04449913. These 
agents are not mandatory and the following table should only be used as a 
guideline, other agents may be used as long as not prohibited as described in 
Section 5.5.
Table 22
Suggested Antimicrobial Agents and Doses
AGENT
DOSE
ROUTE
Capsofungin
Or
Micafungin
Or
Amphotericin B 
(Fungizone/
AmBisome)
70 mg loading dose on Day 1 followed by 50 mg q 24h
150 mg per day (treatment of esophageal candidiasis)
Or
50 mg per day (prophylaxis of Candida infections in HSCT recipients)
Please refer to dosing instructions on drug label
IV
IV
IV
Acyclovir
Or
Valacyclovir
800 mg q 12h
Or
250 mg/m2 q 12h
500 mg q 24h
PO 
Or 
IV
PO
Management of neutropenic infections should follow institutional guidelines. 
5.5.3.3. Blood Product, Mucosal, Ocular and Nutritional Support
Administration of blood products, mucosal, ocular and nutritional support should be 
consistent with institutional guidelines.  The following are suggested:

Red blood cell and platelet transfusions may be utilized throughout the study as 
clinically indicated.

The hemoglobin should be maintained at a safe level (eg, hemoglobin >8-
10 grams/dL), especially in severely thrombocytopenic patients or those with co-
morbid diseases.


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
Efforts should be made to maintain the platelet counts above 10 x109/L in 
asymptomatic patients.  In the presence of fever or hypertension, platelet transfusion 
to 20 x109/L is recommended.  In the presence of active hemorrhage or suspected 
gastrointestinal bleeding, platelet transfusion to a minimum count of 50 x109/L is 
recommended.

For patients receiving cytarabine consolidation therapy, ocular prophylaxis consisting 
of combined dexamethasone and diclofenac eye drops should be instituted to prevent 
ocular toxicity.
5.5.4. Supportive care 
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and institutional guidelines.
In the Continuation Cohort, the use of red blood cell and platelet transfusions, low-dose 
aspirin and/or non-therapeutic doses of steroids will be permitted at any time. 
5.5.5. Hematopoietic Growth Factors (excluding the Continuation Cohort)
Primary prophylactic use of granulocyte-colony stimulating factors/granulocyte-macrophage 
colony stimulating factors is not permitted during Cycle 1 in the Monotherapy Cohort, 
Cycle 1 for the Unfit populations, during Induction cycle(s) for the Fit populations, and 
Cycle 1 in the Combination Cohort 3 (Azacitidine Combination), but they may be used to 
treat treatment-emergent complicated neutropenia as indicated by institutional guidelines. 57
Erythropoietin may be used at the investigator’s discretion for the supportive treatment of 
emergent anemia (Erythropoietin is not allowed in the Combination Cohort 3 [Azacitidine 
Combination]) but prophylactic use is discouraged.
5.5.6. Anti-Diarrheal, Anti-Emetic Therapy
Primary prophylaxis of diarrhea, nausea and vomiting is permitted at the investigator’s 
discretion.  The choice of the prophylactic drug is at investigator discretion assuming the 
drug is not contraindicated as described in Section 5.5.  
5.5.7. Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and PF-04449913 required to minimize the risk 
of impaired wound healing and bleeding has not been determined.  Stopping PF-04449913 is 
recommended at least 1 week prior to elective surgery.  Postoperatively, the decision to 
reinitiate PF-04449913 treatment should be based on a clinical assessment of satisfactory 
wound healing and recovery from surgery.
6. STUDY PROCEDURES 
Study entry is defined as the first day of the lead-in PK period (Cycle 1/Day -5) in the 
Monotherapy Cohort, Cycle 1/Day 1 in the Combination Cohort 1 and the Expansion Cohort 


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(unfit patients) and Combination Cohort 3 (Azacitidine Combination), Cycle 1/Day -3 in the 
Combination Cohort 2 (fit patients) and Cycle 1/Day 1 in the Continuation Cohort.
6.1. Screening
For screening procedures, refer to the Schedule of Activities and Assessments section.
6.2. Study Period
For treatment period procedures, refer to the Schedule of Activities and Assessments section.
6.3. Follow-up Visit
For follow-up procedures, refer to the Schedule of Activities and Assessments section.
6.4. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be
withdrawn at the discretion of the investigator or sponsor for safety or behavioral reasons, or 
the inability of the patient to comply with the protocol required schedule of study visits or 
procedures at a given study site.  
Reasons for withdrawal of study treatment may include:

Need for treatment delay or continuous interruption for >28 days due to ongoing 
study treatment-related non-hematologic toxicity (or >42 days for prolonged study 
treatment related myelosuppression) unless the patient is demonstrating clinical 
benefit as agreed by the investigator and sponsor;

Need for more dose reductions than allowed in Sections 0 and 5.3.10.3;

Objective disease progression or relapse according to the response criteria for each 
hematologic diseases (Appendix 5 through Appendix 9);

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment;

Study terminated by Sponsor;

Death.


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Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by Sponsor;

Lost to follow-up;

Refusal for further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  In any circumstance, every effort should be made to document patient outcome, if 
possible.  The investigator should inquire about the reason for withdrawal, request the patient 
to return all unused investigational product(s), request the patient to return for a final visit, if 
applicable, and follow-up with the patient regarding any unresolved adverse events (AEs).
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further study specific evaluations should be performed, and no additional 
data should be collected.  The sponsor may retain and continue to use any data collected 
before such withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.  
The study team will be informed of these incidents in a timely fashion.
7.1. Safety Assessment
Safety assessments will include collection of AEs, SAEs, vital signs and physical 
examination, triplicate ECG (12-lead), laboratory assessments (including bone marrow 
assessments, cytogenetics and immunophenotyping) and verification of concurrent 
medications and interventions. In the Expansion Cohort of LDAC combination for efficacy,
safety assessments will include assessment of AEs and SAEs, and all other safety 
assessments will be performed per local clinical practice after Protocol Amendment 8. In the 
Continuation Cohort, safety assessments will include collection of AEs, SAEs, weight, 
triplicate ECG (12-lead), Complete Blood Count with differential, verification of concurrent 
medications and interventions and other safety assessments that might be performed 
according to local clinical practice.


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7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed on two occasions (one occasion for the 
Continuation Cohort) prior to starting study therapy - once at the start of screening
(excluding the Continuation Cohort) and once at the baseline visit, immediately before 
investigational product administration.  Following a negative pregnancy result at screening, 
appropriate contraception defined in Section 4.3 must be commenced and a further negative 
pregnancy result will then be required at the baseline visit before the patient may receive the 
investigational product.  Pregnancy tests will also be routinely repeated at every cycle during 
the active treatment period, at the end of study therapy and additionally whenever one 
menstrual cycle is missed or when potential pregnancy is otherwise suspected.  In the case of 
a positive hCG test, the patient will be withdrawn from study medication but may remain in 
the study.  
Additional pregnancy tests may also be undertaken if requested by IRB/IECs or if required 
by local regulations.
7.1.2. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by the 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
version 4.0) timing, seriousness, and relatedness.
Adverse events that occur during the study, including baseline signs and symptoms, will be 
recorded on the adverse events CRF page.
7.1.3. Laboratory Safety Assessment
Haematology and blood chemistry will be drawn at the time points described in the Schedule 
of Activities and analyzed at local laboratories.
After Protocol Amendment 8, the timings and items of these assessments will be determined 
according to local clinical practice in the Expansion Cohort of LDAC combination for 
efficacy.
Hematology
Chemistry
(excluding the 
Continuation 
Cohort)
Urinalysis
(excluding the Continuation Cohort)
Coagulation 
tests
(excluding the 
Continuation 
Cohort)
Hemoglobin
ALT
Microscopic urinalysis: pH, specific gravity, 
protein, glucose, ketones, red and white blood 
cells, leukocyte esterase, casts, crystals and nitrite.
PTT (or aPTT)
Platelets
AST
INR
WBC
Alk Phos
PT
(Monotherapy
Cohort, 
Combination 
Cohort 1,
Expansion 


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Hematology
Chemistry
(excluding the 
Continuation 
Cohort)
Urinalysis
(excluding the Continuation Cohort)
Coagulation 
tests
(excluding the 
Continuation 
Cohort)
Cohort and 
Combination 
Cohort 2 only)
Neutrophils
Sodium
Lymphocytes
Potassium
Monocytes
Magnesium
Eosinophils
Chloride
Basophils
Calcium
Blast Count
Total Bilirubin
BUN or Urea
Creatinine
Uric Acid
Glucose
Albumin
Total Protein
Phosphorus
LDH
Creatine kinase
CO2 (Combination 
Cohort 3 only) if 
possible
7.1.4. Vital Signs and Physical Examination
Vital signs will include blood pressure (sitting or supine but same position should be used for 
each assessment when possible) and heart rate.  Patients will have a physical exam (PE) 
including an examination of major body systems, measurement of spleen and liver size to 
assess extramedullary disease (EMD), weight, assessment of ECOG status.  If PE obtained 
within 48 hours of previous assessments, the evaluation need not be repeated.  Height will be 
measured at baseline only.  Weight must be recorded at Screening and Day 1 of each cycle
(in the Continuation Cohort, at Screening and thereafter Day 1 of every 3 cycles, and at the 
End of Treatment). In the Continuation Cohort, only height and weight should be assessed 
and recorded.
After Protocol Amendment 8, these assessments will be conducted according to local clinical 
practice and the data is not required to be reported in CRF (AE must be reported in CRF if 
any observation is considered as AE) in the Expansion Cohort of LDAC combination for 
efficacy.
7.1.5. Triplicate (12-Lead) ECG
Triplicate 12-lead (with a 10-second rhythm strip) tracing in the supine position will be 
performed for all ECGs.  It is preferable that the machine used has a capacity to calculate the 
standard intervals automatically.  The acceptable mean on treatment upper limit of QTc 
interval will be using the Fridericia (QTcF) correction methods.  At each time point three 


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consecutive ECGs will be performed approximately 2 minutes (but no longer than 5 minutes) 
apart, to determine the mean QTcF intervals.  
After Protocol Amendment 8, these assessments will be conducted according to local clinical 
practice and the additional ECG monitoring will be required when abnormal findings are 
observed as described below. The ECG data is not required to be reported in CRF (AE must 
be reported in CRF if any observation is considered as AE).
If Grade 3 mean QTcF (mQTcF) prolongation (mQTcF501 msec) occurs, continuous ECG 
monitoring and cardiology specialist evaluation and guidance are required (excluding the 
Expansion Cohort of LDAC combination for efficacy).
The acceptable mean on treatment upper limit of QTcF interval is 480 msec.  If any patient 
has a mean pre- or post-dose QTcF value >480 msec, please refer to Table 20 of the protocol 
for detailed instructions on management of QTcF prolongation and handling dose delays and 
dose modifications for PF-04449913.
If a moderate/strong CYP3A4/5 inhibitor or TdP drug will be initiated in addition to PF-
04449913 the following guidance must be followed: 

Prior to the start of a moderate/strong CYP3A4/5 inhibitor or TdP drug:

ECGs pre-PF-04449913 dose, 1 and 4 hours post- PF-04449913 dose

Follow dose modifications for QT prolongation (Table 20)

After starting a moderate/strong CYP3A4/5 inhibitor or TdP drug: ECGs on Day 
2 or 3 and on Day 5, 6, or 7:

ECGs pre- PF-04449913 dose, 1 and 4 hours post- PF-04449913 dose

Follow dose modifications for QT prolongation (Table 20)

Perform additional ECG testing as appropriate

Perform routine electrolyte monitoring (Ca, K, Cl, Mg), implement timely 
electrolyte correction, followed by appropriate re-checking of values  
When there is an urgent need to start a moderate/strong CYP3A4/5 inhibitor or TdP drug, 
administration of these medications should not be delayed, the Investigator should consider 
temporarily interrupting PF-04449913 dosing and should implement these additional 
monitoring procedures as soon as it is reasonably possible.
When matched with PK sampling, all efforts should be made to perform the ECGs before 
each PK sample drawing such that the PK sample is collected at the nominal time (ie, the 
timing of the PK collections over rides the timing of the ECG collections).  A 15-min 
window for each ECG collection is allowed around the nominal ECG time point.


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7.1.6. Cardiac Testing (MUGA/ECHO)
For all fit patients in Combination Cohort 2, an ECHO or MUGA scan is required at 
screening.  If the left ventricular ejection fraction (LVEF) is 45%, the patient may proceed 
to their first induction therapy.  If LVEF <45%, the patient will be considered unfit according 
to the definition provided in Section 4.1.2 and may be eligible for treatment with LDAC.  If a 
second cycle of induction chemotherapy is indicated, a second MUGA or ECHO is required 
prior to initiating the second cycle if clinically indicated (eg, patient exhibiting signs of 
cardiac failure).  If the second MUGA or ECHO demonstrates a LVEF of <45%, the patient 
is not eligible to receive additional induction chemotherapy and study treatment will be 
discontinued.
7.2. PK Assessments (excluding the Continuation Cohort)
As noted in the Schedule of Activities, blood samples for PF-04449913 concentrations will 
be collected at approximately the same time as the PD samples and ECGs whenever possible 
(even accounting for scheduling changes). 
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, samples obtained within 10% of the nominal time (eg, 6 minutes of a 
60 minute sample) will be considered protocol compliant, and the exact time of the sample 
collection noted on the CRF.  The pre-dose PK sample should be collected within 15 minutes 
prior to administration of the drug (unless the drug is being administered for the very first 
time).  If a scheduled blood sample collection cannot be completed for any reason, the 
missed sample time may be re-scheduled with agreement of clinical investigators, patient and 
sponsor.
PK samples will be assayed for PF-04449913, cytarabine/Ara-U, daunorubicin/ 
daunorubicinol and azacitidine using a validated analytical method in compliance with Pfizer 
standard operating procedures.  Details regarding the collection, processing, storage and 
shipping of the blood samples will be provided in the lab manual.
PK blood draws should be collected from a location other than any study drug infusion site.
7.3. Blood samples for PK analysis (excluding the Continuation Cohort)
7.3.1. Monotherapy cohort
PF-04449913:
Blood samples (1.5 mL whole blood sufficient to provide a minimum of 0.6 mL of plasma) 
will be collected for PK analysis of PF-04449913 for all cohorts as outlined in the Schedule 
of Activities (Table 1): during the lead-in period on Day -5, in Cycle 1 on Day 1, Day 8, Day 
15 and Day 21.  PK samples will also be collected on Day 1 in Cycle 2, 3, and 4.  The PK 
assessments during Cycle 1 may be repeated if the PK sampling is missed for any reason or if 
the PK data collected are deemed inevaluable by the Sponsor. 


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7.3.2. Combination Cohort 1 and Expansion Cohort of LDAC combination for efficacy
(Unfit Patients, PF-04449913 + LDAC)
PF-04449913:
Blood samples (1.5 mL whole blood sufficient to provide a minimum of 0.6 mL of plasma) 
will be collected for PK analysis of PF-04449913 as outlined in the Schedule of Activities
(Table 2 for Combination Cohort 1 and Table 3 for Expansion Cohort of LDAC combination 
for efficacy).  
Cytarabine (Combination Cohort 1 only):
Blood samples (2 mL whole blood sufficient to provide a minimum of 1 mL of plasma) will 
be collected for PK analysis of LDAC/Ara-U as outlined in the Schedule of Activities
(Table 2). 
7.3.3. Combination Cohort 2 (Fit Patients, PF-04449913 + Cytarabine/Daunorubicin)
PF-04449913:
Blood samples (1.5 mL whole blood sufficient to provide a minimum of 0.6 mL of plasma) 
will be collected for PK analysis of PF-04449913 as outlined in the Schedule of Activities
(Table 4).
Daunorubicin/Daunorubicinol:
Blood samples (2 mL whole blood sufficient to provide a minimum of 1 mL of plasma) will 
be collected for PK analysis of daunorubicin/daunorubicinol as outlined in the Schedule of 
Activities (Table 4).
Cytarabine:
Blood samples (2 mL whole blood sufficient to provide a minimum of 1 mL of plasma) will 
be collected for PK analysis of cytarabine/Ara-U as outlined in the Schedule of Activities
(Table 4).
7.3.4. Combination Cohort 3 (PF-04449913 + Azacitidine)
PF-04449913:
Blood samples (1.5 mL whole blood sufficient to provide a minimum of 0.6 mL of plasma) 
will be collected for PK analysis of PF-04449913 as outlined in the Schedule of Activities
(Table 11).
Azacitidine:
Blood samples (2 mL whole blood sufficient to provide a minimum of 1 mL of plasma) will 
be collected for PK analysis of azacitidine (and possibly metabolites) as outlined in the 
Schedule of Activities (Table 11).


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7.4. PD Assessments (excluding the Continuation Cohort)
Biomarker assessments will be used to help understand the in vivo mechanism of action of
PF-04449913, as well as potential mechanisms of resistance.  Such results may help in the 
future development of this drug as a single-agent and/or in combination with the agents 
under investigation in this protocol.  PD biomarker assessments will be performed on all 
patients enrolled in this study.  These assessments may include the following; (i) evaluation 
of Hh pathway genes and proteins, (ii) circulating protein levels, and (iii) molecular analysis 
of somatic mutations and translocations with a known frequency of occurrence in the AML 
and MDS populations.  Additional PD biomarkers may also be included, based on emerging 
data on Hh pathway biology.  A brief description of the types and frequencies of sample 
collection is provided below and summarized in Table 23. For collection timepoints, refer to 
the Schedule of Activities and Assessments section.
7.4.1. PD Sample Collections
7.4.1.1. Blood Sample Collections
Approximately 6 mL of blood will be collected from all patients for circulating protein and 
gene expression analysis at the time points indicated in the Schedule of Activities. When 
possible, PD blood collections will be matched with PK sample collections for PK/PD 
evaluations.  Full details regarding collection, processing, storage and shipping of all PD 
biomarker samples will be provided in the lab manual. 
7.4.1.2. Normal Skin Biopsies [Monotherapy Cohort, Combination Cohort 1 (Unfit 
Patients) and Combination Cohort 2 (Fit Patients)]
Normal skin punch biopsies will be obtained from all patients in Monotherapy Cohort, 
Combination Cohort 1 and Combination Cohort 2 at screening and Cycle 1/Day 21 (7 day 
of nominal time on Day 21).  Skin samples should be taken from the same area of the body.  
Skin samples will be analyzed for treatment-related changes in the RNA transcript levels of 
Hh pathway-regulated genes (eg, Gli1, Gli2) and potentially other signaling pathways.  When 
possible, PD skin sample collections will be matched with PK sample collections for PK/PD 
evaluations. Samples will be processed and shipped as described in the Lab Manual. 
7.4.1.3. Bone Marrow Sample Collections
Bone marrow aspirates (approximately 2 mL) will be analyzed for genetic abnormalities 
frequently associated with AML.  These genetic abnormalities include known mutations in 
the genes such as NPM1, CEBPA, FLT3, RUNX1, IDH1, IDH2, KIT, K-Ras, N-Ras and 
WT1.  Additional genes with mutations known to be associated with AML and MDS may 
also be evaluated if feasible. Treatment-related changes in the RNA transcript levels of Hh 
pathway-regulated genes (eg, Gli1, Gli2) and potentially other signaling pathways may be 
analyzed in the Expansion Cohort of LDAC combination for efficacy (unfit patients). 
Methylation profiling and leukemia stem cell gene expression signature(s) may also be 
performed to identify candidate epigenetic markers in the Combination Cohort 3.


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All bone marrow samples will be prepared according to the study Lab Manual.  All bone 
marrow samples (aspirates) will be collected as outlined in the Schedule of Activities. When 
possible, PD sample collection timing will be matched with PK sample collection.  
After Protocol Amendment 8, PD sample collection are not required in the Expansion Cohort 
of LDAC combination for efficacy.
Table 23.
Summary of Biomarker Assessments
Assay
Source
Mutational Analysis
Epigenetic Analysis (Combination Cohort 3 only)
Leukemia stem cell gene expression Analysis
(Combination Cohort 3 only)
Bone marrow aspirate 
Circulating Protein Analysis
Peripheral blood and serum
Expression of Hh family genes
Peripheral blood, serum and skin biopsy
Bone marrow aspirate (Expansion Cohort 
of LDAC combination for efficacy only)
7.5. Disease Response Assessment (excluding the Continuation Cohort)
7.5.1. Response Criteria 
Monotherapy Cohort:
Assessment of response will be made using response criteria for selected hematologic 
diseases, each having specific clinical response criteria (Appendix 4 through Appendix 8). 
The response criteria for CML are derived from Faderl et al 199958 and Cohen et al 200559. 
Response criteria for CMML/MDS, MF and AML are derived and defined by the disease 
specific International Working Groups and World Health Organizations (WHO) Guidelines. 
Combination Cohorts:
Assessment of response will be made using response criteria for MDS and AML derived and 
defined by the disease specific International Working Groups and World Health 
Organizations (WHO) Guidelines (Appendix 5 and Appendix 8).
7.5.2. Bone Marrow
Bone marrow aspirate and/or biopsy will be collected for clinical staging and for PD 
biomarker assessments as outlined in the Schedule of Activities.  If a bone marrow aspirate 
and/or biopsy has been collected within 28 days (excluding the screening sample), it does not 
need to be repeated.  With the Sponsor’s approval, a bone marrow does not need to be 
performed based on the patient characteristics, or a bone marrow performed prior to 
screening may be used for study inclusion.
After Protocol Amendment 8, bone marrow samples are not required to be submitted for PD
assessments in the Expansion Cohort of LDAC combination for efficacy.


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7.5.3. Immunophenotyping, Cytogenetics and Mutation Analysis
For all patients, quantitative immunophenotyping and cytogenetics on blood and/or bone 
marrow must be collected at the same time as any scheduled or unscheduled bone marrow 
aspirate and/or biopsy, at End of Treatment and at investigators discretion. For all CML 
patients quantitative PCR for BCR-ABL will be conducted on blood and/or bone marrow at 
the same time as any scheduled or unscheduled bone marrow aspirate and/or biopsy and at 
investigators discretion, mutation analyses will be performed at screening only. If a bone 
marrow assessment is not performed a blood sample must be used for the clinical 
assessments (immunophenotyping, cytogenetics, mutation analyses).
After Protocol Amendment 8, these assessments are not required in the Expansion Cohort of 
LDAC combination for efficacy.
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections.
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
CCI


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AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as a SAE.  To 
assist in the determination of case seriousness further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a patient after the active 
reporting period has ended should be reported to the Sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to study drug are to be reported to the Sponsor.

AEs (serious and non-serious) should be recorded on the CRF from the time the 
patient has taken at least one dose of study treatment through the patient’s last visit
(for Combination Cohort 3 and Expansion Cohort of LDAC combination for efficacy, 
28 days after the last administration of the investigational product). In the 
Continuation Cohort, ongoing adverse events which had occurred in the previous 
study should also be recorded on the CRF; 

If a patient begins a new anticancer therapy, the AE reporting period for non-serious 
AEs ends at the time the new treatment is started.  Death must be reported if it occurs 
during the SAE reporting period after the last dose of investigational product, 
irrespective of any intervening treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;


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
Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasations;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure;
Worsening of signs and symptoms of the malignancy under study should be reported as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error case report form (CRF) which is a specific version of the adverse event (AE) page, and 
on the SAE form when appropriate.  In the event of medication dosing error, the sponsor 
should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the adverse 
event (AE) page and, if applicable, any associated adverse event(s) are captured on an 
adverse event (AE) CRF page. 


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8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with CTCAE grade 5 (refer to the Section 
on Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes the 
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Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol specified SAEs in this study.  All SAEs will be reported by the 
Investigator as described in previous sections and will be handled as SAEs in the safety 
database (refer to the Section 8.14.1 SAE Reporting Requirements). 
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values ≥3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin value ≥2 X UNL with no evidence 
of hemolysis and an alkaline phosphatase value ≤2 X ULN or not available;

For patients with preexisting ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above:

For patients with pre-existing AST or ALT baseline values above the normal range,
AST or ALT ≥2 times the baseline values and ≥3 X ULN, or ≥8 X ULN (whichever 
is smaller);
Concurrent with

For patients with pre-existing values of total bilirubin above the normal range: Total 
bilirubin level increased from baseline by an amount of at least 1 X ULN or if the 
value reaches ≥3 X ULN (whichever is smaller).
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, creatine kinase, 
total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time 


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(PT)/ international normalized ratio (INR), and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug 
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected.  Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted.  All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for liver function test (LFT) abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
Law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);


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
Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
If required on the AE CRFs, the investigator will use the following definitions of severity in 
accordance with CTCAE Version 4.0 (Publish Date:  May 28, 2009, 
http://ctep.cancer.gov/reporting/ctc.html) to describe the maximum intensity of the AE.  If 
the event is serious, the CTCAE grade reported in the AE CRF must be consistent with the 
description of CTCAE grade included in the narrative section of the SAE report. 
GRADE
Clinical Description of Severity
0
No Change from Normal or Reference Range (This grade is not included in the 
Version 4.0 CTCAE document but may be used in certain circumstances.)
1
MILD Adverse Event
2
MODERATE Adverse Event
3
SEVERE Adverse Event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO Adverse Event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example headache may be severe (interferes significantly with 
patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs listed above.


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8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship in the CRF, as appropriate, and 
report such an assessment in accordance with the serious adverse reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (refer to the Section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product", 
this should be clearly documented on study records.  
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant women (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on a Serious Adverse Event (SAE) Report Form 
and Exposure During Pregnancy (EDP) supplemental form, regardless of whether an SAE 
has occurred.  In addition, the investigator must submit information regarding environmental 
exposure to a Pfizer product in a pregnant woman (eg, a patient reports that she is pregnant 
and has been exposed to a cytotoxic product by inhalation or spillage) using the EDP 
supplemental form.  This must be done irrespective of whether an AE has occurred and 
within 24 hours of awareness of the exposure.  The information submitted should include the 


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anticipated date of delivery (see the below for information related to termination of 
pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
the termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, 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 as SAEs follows:

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator will provide the study patient with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The Investigator must document in the source 
documents that the patient was given the Pregnant Partner Release of Information Form to 
provide to his partner.
8.11. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an adverse event.
An occupational exposure is reported to the drug safety unit within 24 hours of Investigator’s 
awareness, using the SAE Report form, regardless of whether there is an associated AE/SAE. 
Since the information does not pertain to a patient enrolled in the study, the information is 
not reported on a CRF, however a copy of the completed SAE Report form is maintained in 
the investigator site file.


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8.12. Withdrawal Due to Adverse Events (Refer to the Section Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.
When a patient withdraws because of a SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This timeframe 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding, and occupational exposure cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 


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term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by Pfizer.  
The SAP may modify the plans outlined in the protocol; however, any major modifications 
of the primary endpoint definition and/or its analysis will also be reflected in a protocol 
amendment.  Unless otherwise stated, the monotherapy cohort and the combination cohorts 
will be analyzed separately. The data from the Continuation Cohort will not be analyzed and 
will be presented in the form of patient data listings separately from the other cohorts.
The primary analysis will be performed after disease assessment on Cycle 9/Day 1 for the 
last (15th) patient treated in Expansion Cohort of LDAC combination for efficacy. The timing
of the primary analysis is estimated to be after approximately 19 months after the first dose 
for the first patient in Expansion Cohort of LDAC combination for efficacy, assuming the 
enroll speed as 15 patients per year.    
The final analysis will be performed after all patients have died or after the last patient last
visit, whichever occurs first. Further analyses could be performed, if necessary.
9.1. Analysis Sets 
In this study, analysis sets are defined as below although the patients enrolled in the 
Expansion Cohort of LDAC combination for efficacy are excluded from DLT-evaluable
analysis set and the patient enrolled in the Continuation Cohort is excluded from all of these 
analysis sets except the safety analysis set. The patient enrolled in the Continuation Cohort is
included in the safety analysis set if the patient receives at least one dose of study 
medication.
1. Safety analysis set:
The safety analysis set includes all enrolled patients who receive at least one dose of 
study medication.
2. Full analysis set:
The full analysis set includes all enrolled patients who receive at least one dose of study 
medication on or after Cycle 1/Day 1 (Induction Cycle/Day 1 for fit patients in the 
Combination Cohort 2).
3. DLT-evaluable analysis set:


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The per protocol analysis set includes all enrolled patients who receive at least one dose 
of study medication and who do not have major treatment deviations during first cycle
(DLT observation period).  Patients with major treatment deviations during the DLT 
observation period are not evaluable for the DLT assessment and will be replaced as 
needed. Major deviations include, but are not limited to, administration of less than 80% 
of the planned dose during the DLT observation period of PF-04449913 or any 
component of the combination therapy [LDAC for Combination Cohort 1 (Unfit 
Patients), cytarabine/daunorubicin for Combination Cohort 2 (Fit Patients), and 
azacitidine for Combination Cohort 3 (Azacitidine Combination)] for reasons other than
drug related toxicity.
4. PK analysis sets:
The PK concentration population is defined as all treated patients who have at least 1 
concentration of any of the study drugs.  The PK parameter analysis population is defined 
as all treated patients who have at least one of the PK parameters of interest of any of the 
study drugs.
5. QTc-evaluable analysis set:
The QTc-evaluable dataset is defined as all patients who have baseline and at least one 
triplicate ECG assessment after having at least one PF-04449913 dose on study.
9.2. Sample Size Determination
Cohorts excluding the Expansion Cohort of LDAC combination for efficacy
No statistical sample size determination was performed.  The number of patients to be 
enrolled in the study depends on the observed safety profile within the cohorts. The total 
expected number of patients is estimated to be 34 patients. 
The Expansion Cohort of LDAC combination for efficacy
The total expected number of patients is estimated to be 15 patients.
A one stage design with 15 patients provides 80.8% power with a one-sided type I error rate 
of 0.05 to test the null hypothesis that the true investigator-reported DMR rate is 6.8% vs the 
alternative hypothesis that the investigator-reported DMR rate is 34.1%. The study would be 
considered positive if 4 responses are observed. The null DMR rate and the alternative DMR 
rate are based on the result of the analysis based on the derived response for B1371003 CSR 
(P2 Unfit, data cut off: 3 Jan 2017).  
9.3. Efficacy Analysis (excluding the Continuation Cohort)
Disease response will be presented in the form of patient data listings that include, but are not 
limited to, malignancy type, tumor response at each visit, and best overall response. In 
addition, disease progression date, date of first disease response, and last disease assessment 
date will be listed.


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In Combination Cohort 1 (unfit patients), survival follow-up data will be presented in the 
form of patient data listings and summary table as needed. The listings include, but are not 
limited to, malignancy type, event date, event day from first dose, type, reason for censoring 
and age (≤60 vs >60 years).
In Expansion Cohort of LDAC combination for efficacy (unfit patients), the DMR rate will 
be estimated for patients in the full analysis set. DMR includes CR, CRi, morphologic 
leukemia-free status (MLFS), marrow CR (mCR) and PR (Appendix 5 and Appendix 8). CR 
rate and median OS will also be estimated. The time-to-event endpoints including OS, 
duration of response and time to response, will be presented in the form of patient data 
listings, respectively. The listings include, but are not limited to, event date, event day from 
first dose, type, reason for censoring, AML/MDS risk, European Leukemia Net (ELN) 
cytogenetic risk and age (ӊ60 vs >60 years).
In Combination Cohort 3 (Azacitidine Combination), the time-to-event endpoints including 
OS, duration of response and time to response, will be presented in the form of patient data 
listings, respectively. The listings include, but are not limited to, event date, event day from 
first dose, type, reason for censoring, ELN cytogenetic risk and age (≤60 vs >60 years).
OS is defined as the time from the date of first dose of study drug to the date of death due to 
any cause.  Patients last known to be alive will be censored at the date of last contact.
Duration of response is the time from the date of first documentation of a CR/CRi and DMR
to the date of first documentation of relapse after CR/CRi and DMR or death due to any 
cause.  Duration of response data will be censored on the date of the last adequate response 
assessment for patients who do not have an event (relapse or death).  
Time to response is the time from the date of first dose of study drug to the date of first 
documentation of a CR or CRi and DMR.
9.4. Analysis of Other Endpoints (excluding the Continuation Cohort)
9.4.1. Analysis of PK
9.4.1.1. PK Analysis of PF-04449913, Cytarabine/Ara-C, Daunorubicin, and Azacitidine
Standard plasma PK parameters including the observed maximum plasma concentration 
(Cmax), time to maximum plasma concentration (Tmax), and area under the plasma 
concentration versus time curve (AUC) for each drug (and metabolite if relevant), will be 
estimated using non-compartmental analysis. If data permit or if considered appropriate, 
minimum plasma concentration (Cmin), average plasma concentration (Cave), area under the 
plasma concentration versus time curve to infinity (AUCinf), terminal elimination half-life 
(t1/2), oral plasma clearance (CL/F, CL), apparent volume of distribution (Vd/F, Vd), 
accumulation ratio (Rac) will be estimated.  Descriptive statistics will be provided for these 
PK parameters in tabular form (n, mean, SD, CV, median, minimum, maximum, geometric 
mean and its associated CV) by analyte, dose, administration route, cycle and day.


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For drug concentrations, individual values and descriptive statistics (n, mean, SD, CV, 
median, minimum, maximum, geometric mean and its associated CV) will be presented by 
dose, cycle, day of assessment, and nominal time in tabular form.  Individual patient and 
median profiles of the concentration-time data will be plotted by dose, cycle and day using 
nominal times.  Median profiles will be presented on both linear-linear and log-linear scales. 
9.4.1.2. Evaluation of Drug-Drug Interaction Potential 
9.4.1.2.1. Combination Cohort 1 (Unfit Patients): PF-04449913 and LDAC
The primary PK parameters, AUC and Cmax, will be utilized to estimate the effect of 
coadministration of PF-04449913 and LDAC on the PK of either PF-04449913 or LDAC. 
The geometric mean ratios and its 90% confidence intervals (if data permit) for the PK 
parameters will be used for assessment of the extent of interaction for PF-04449913 in 
presence of LDAC and PF-04449913 alone.  
PF-04449913 AUC and Cmax when administered alone (Cycle 1/Day 21) will be compared to 
Cycle 1 Day 10 AUC and Cmax, when administered in combination with LDAC.  A similar 
assessment will be performed to determine the effect of PF-04449913 on Ara-C. The AUC 
and Cmax on Cycle 1/Day 2 when LDAC is administered alone will be compared to Cycle 1 
Day 10 AUC and Cmax when administered in combination with PF-04449913.
9.4.1.2.2. Combination Cohort 2 (Fit Patients): PF-04449913 and
Cytarabine/Daunorubicin
The primary PK parameters, AUC and Cmax, will be utilized to estimate the effect of 
coadministration of PF-04449913 and cytarabine/daunorubicin on the PK of PF-04449913.  
The geometric mean ratios and its 90% confidence intervals (if data permit) for the PK 
parameters will be used for assessment of the extent of interaction for PF-04449913 in 
presence of cytarabine/daunorubicin and PF-04449913 alone.  
PF-04449913 AUC and Cmax when administered alone (Induction Cycle Day 10) will be 
compared to Induction Cycle Day 3 AUC and Cmax, when administered in combination with 
cytarabine/daunorubicin.  The effect of PF-04449913 on cytarabine/daunorubicin will not be 
conducted within the study due to the inability to dose cytarabine/daunorubicin alone.
9.4.1.3. Combination Cohort 3: PF-04449913 and Azacitidine
The primary PK parameters, AUC and Cmax, will be utilized to estimate the effect of 
co-administration of PF-04449913 and azacitidine on the PK of either PF-04449913 or 
azacitidine.  The geometric mean ratios and their 90% confidence intervals (if data permit) 
for the PK parameters will be used for assessment of the extent of interaction for PF-
04449913+ azacitidine vs. PF-04449913 alone.  A similar assessment will be conducted for 
PF-04449913 + azacitidine vs. azacitidine alone.
PF-04449913 AUC and Cmax when administered alone (Cycle 1/Day 21) will be compared to 
Cycle 1/Day 7 AUC and Cmax, when administered in combination with azacitidine.  A similar 
assessment will be performed to determine the effect of PF-04449913 on azacitidine.  The 
AUC and Cmax on Cycle 1/Day 1 when azacitidine is administered alone will be compared to 


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Cycle 1/Day 7 AUC and Cmax when azacitidine is administered in combination with PF-
04449913.
9.4.1.4. Population PK Analysis or PK/PD Modeling
PK and PD data from this study may be analyzed using compartmental or mixed-effect 
modeling approaches and may also be pooled with other study results.  PK/PD modeling may 
be attempted to investigate any causal relationship between PF-04449913 exposure and 
biomarkers or significant safety endpoints. The results of these analyses, if performed, may 
be reported separately.
9.4.1.5. Statistical Analysis of Biomarker Endpoints
PD biomarkers will be assessed separately for blood, serum, normal skin biopsies and the 
bone marrow samples.  In each case, summaries of baseline levels, changes from baseline
(where appropriate), and mutation status will be reported. Summary statistics may include 
the mean and standard deviation, median, %CV and minimum/maximum levels of biomarker 
measures or frequency statistics, as appropriate. Data from biomarker assays will be 
analyzed using graphical methods and descriptive statistics such as linear regression, 
Wilcoxon and ranked sum. The statistical approach may examine correlations of biomarker 
results with pharmacokinetic parameters and measures of anti tumor efficacy.
Due to the exploratory nature of the proposed biomarkers, the data analysis will be conducted 
with the goal of identifying biomarkers with the strongest concordance to clinical outcome, 
encompassing both safety and efficacy. Candidate biomarkers will be validated in 
subsequent trials. 
9.5. Safety Analysis
Summaries and analyses of safety parameters will include all patients in the safety analysis 
sets. However, safety data from the patient enrolled in the Continuation Cohort will be 
separately presented in the form of patient data listings.
For Combination Cohort 1 and Expansion Cohort, the pooled analysis will be considered in 
addition to separated analysis for each cohort.
9.5.1. Analysis of Adverse Events
Dose Limiting Toxicity (DLT) is the primary endpoint of the study.  For each cohort, DLTs 
will be summarized by MedDRA preferred term.
Adverse Events
Adverse Events (AEs) will be graded by the investigator according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 and coded using the Medical 
Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries will be on 
Treatment Emergent Adverse Events, those with initial onset or increasing in severity after 
the first dose of study medication.  The number and percentage of patients who experienced 
any AE, serious AE (SAE), treatment related AE, and treatment related SAE will be 


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summarized according to worst toxicity grades.  The summaries will present AEs both on the 
entire study period and by cycle (Cycle 1 and Cycles beyond 1). 
Laboratory Test Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay.  For 
laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal or not done. 
9.5.2. Analysis of ECG
The analysis of ECG results will be based on patients in the safety analysis set with both 
baseline and on-treatment ECG data.  All ECGs obtained during the study will be evaluated 
for safety. 
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis (duplicate ECGs will also be averaged and single ECGs used if 
necessary).  Any data obtained from ECGs repeated for safety reasons after the nominal 
time-points will not be averaged along with the preceding triplicates.  Interval measurements 
from repeated ECGs will be included in the outlier analysis as individual values obtained at 
unscheduled time points.
Data will be summarized and listed for QT, HR, RR, PR, QRS and QTcF by treatment arm
and cohort.  Individual QTc intervals will be listed by treatment arm, cohort and time point.  
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute QTc value and changes from baseline in QTc by treatment 
arm, cohort and time point.  For each patient and by treatment, the maximum increase from 
baseline as well as the maximum post-baseline value will be calculated across time points 
using the correction method(s) deemed appropriate.  Outlier analysis of the QTc (using the 
most appropriate correction method) data will be conducted and summarized as follows:

The number of patients with maximum increase from baseline in QTc 
(<30, 30-60, and 60 msec);

The number of patients with maximum post-dose (post-baseline) QTc 
(<450, 450-480, 481-500, and 501 msec);

PR changes from baseline 25% and absolute values over >200 msec;

QRS changes from baseline 25% and absolute values over >110 msec;

Number and percentage of individuals with abnormal ECG findings.
Shift tables will be provided for baseline vs. worst on study QTc (one or more correction 
methods may be used) using maximum CTCAE Grade, as well as tables of ECG abnormality 


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at baseline (yes, no, not done: (n, %)).  Patients experiencing clinically relevant 
morphological ECG changes will be summarized (including frequency and percentage).
The ECG analyses described above for the safety population may be repeated separately for 
the QTc-evaluable population.
9.6. Data Safety Monitoring Committee 
An external Data Safety Monitoring Committee will not be established for the study.  For the 
purpose of this protocol, Pfizer procedures for periodic safety review will be applied by an 
internal safety review team with medical and statistical capabilities to review individual and 
summary data collected in the safety and clinical databases.  
Procedures include:

Surveillance for serious adverse events (SAEs) according to regulatory guidelines;

Discussions between the Investigators and the Sponsor of AEs and laboratory tests 
alterations seen at each cohort in an on-going manner at regular teleconferences 
and/or meetings to determine the safety profile and risk/benefit ratio and decide if 
further enrollment is appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.
The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Pfizer, or 
companies working with or on behalf of Pfizer, and/or to inspection by appropriate 
regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 


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third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true.  Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.  
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.


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12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.
Patient names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Pfizer in order to de-identify the trial 
patient.
In case of data transfer, Pfizer will maintain high standards of confidentiality and protection 
of patient personal data.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent document(s) used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/IEC before use, and available for inspection.
The investigator must ensure that each study patient, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.  


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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legal representative before any study-specific 
activity is performed.  The investigator will retain the original of each patient's signed 
consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
End of Trial is defined as date upon which enrollment is completed according to protocol 
planned sample size and the assessments and requirements are completed according to 
protocol (including the follow-up period).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of PF-04449913 at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within a reasonable time period.  As directed by Pfizer, 
all study materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 


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Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date for 
studies in adult populations or within 6 months of the primary completion date for studies in 
pediatric populations.
Primary completion date is defined as the date that the final patient was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies  at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer has no objection to publication by an Investigator of any information collected or 
generated by the Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, the Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
The Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc) to Pfizer at 
least 30 days before they are submitted for publication or otherwise disclosed.  If any patent 
action is required to protect intellectual property rights, Investigator agrees to delay the 
disclosure for a period not to exceed an additional 60 days.
The Investigator will, on request, remove any previously undisclosed Confidential 
Information (other than the study results themselves) before disclosure.
If the study is part of a multi-centre study, the Investigator agrees that the first publication is 
to be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, the Investigator is free to publish separately, subject to the other 
requirements of this Section.


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For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.


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leukaemia. Leuk Lymphoma 1992: 7 (5-6): 425-9.
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immunophenotyping in adults with acute myelocytic leukaemia: the significance of the 
stem-cell glycoprotein CD34 (My10). Br J Haematol 1990;76 (3): 340-7.
29. Campos L, Guyotat D, Archimbaud E, et al.: Clinical significance of multidrug resistance 
P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood 
1992; 79 (2): 473-6. 
30. Kantarjian H, O'brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients 
age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic 
syndrome: predictive prognostic models for outcome. Cancer 2006; 106:1090.
31. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 
2006; 107(9):3481-3485. 
32. Rowe JM, Neuberg D, Friedenberg W, et al. A phase 3 study of three induction regimens 
and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the 
Eastern Cooperative Oncology Group. Blood. 2004;103(2):479-485.
33. Anderson JE, Kopecky KJ, Willman CL, et al.Outcome after induction chemotherapy for 
older patients with acute myeloid leukemia is not improved with mitoxantrone and 
etoposide compared to cytarabine and daunorubicin: a Southwest. Oncology Group 
study. Blood. 2002; 100(12):3869-3876.
34. Arlin Z, Case DC Jr, Moore J, et al. Randomized multicenter trial of cytosine arabinoside 
with mitoxantrone or daunorubicin in previously untreated adult patients with acute 
nonlymphocytic leukemia (ANLL). Lederle Cooperative Group. Leukemia 1990; 4:177. 
35. MacCallum PK, Davis CL, Rohatiner AZ, et al. Mitoxantrone and cytosine arabinoside 
as treatment for acute myelogenous leukemia (AML) at first recurrence. Leukemia 1993; 
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36. Büchner T, Hiddemann W, Wörmann B, et al. Double induction strategy for acute 
myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of 
standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the 
German AML Cooperative Group. Blood 1999; 93:4116. 
37. Ho AD, Lipp T, Ehninger G, et al. Combination of mitoxantrone and etoposide in 
refractory acute myelogenous leukemia--an active and well-tolerated regimen. J Clin 
Oncol 1998; 6:213. 
38. Feldman EJ, Alberts DS, Arlin Z, et al. Phase I clinical and pharmacokinetic evaluation 
of high-dose mitoxantrone in combination with cytarabine in patients with acute 
leukemia. J Clin Oncol 1993; 11:2002. 


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39. Estey EH, Thall PF, Cortes JE, et al. Comparison of idarubicin + Ara-C-, fludarabine + 
Ara-C-, and topotecan + Ara-C-based regimens in treatment of newly diagnosed acute 
myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory 
anemia with excess blasts. Blood 2001; 98:3575. 
40. Russo D, Malagola M, de Vivo A, et al. Multicentre phase III trial on fludarabine, 
cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction 
treatment of younger, newly diagnosed acute myeloid leukaemia patients. Br J Haematol 
2005; 131:172. 
41. Bishop JF, Lowenthal RM, Joshua D, et al. Etoposide in acute nonlymphocytic leukemia. 
Australian Leukemia Study Group. Blood 1990; 75:27. 
42. Hann IM, Stevens RF, Goldstone AH, et al. Randomized comparison of DAT versus 
ADE as induction chemotherapy in children and younger adults with acute myeloid 
leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). 
Adult and Childhood Leukaemia Working Parties of the Medical Research Council. 
Blood 1997; 89:2311. 
43. Kolitz JE. Current therapeutic strategies for acute myeloid leukaemia. Br J Haematol 
2006; 134:555.
44. Atallah E, Cortes J, O'Brien S, et al. Establishment of baseline toxicity expectations with 
standard frontline chemotherapy in acute myelogenous leukemia. Blood 2007; 110:3547. 
45. Mandelli F, Vignetti M, Suciu S, et al. Daunorubicin versus mitoxantrone versus 
idarubicin as induction and consolidation chemotherapy for adults with acute myeloid 
leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol 2009; 
27:5397. 
46. Larson R, Lowenberg R and Connor R.Induction therapy for acute myeloid leukiemia in 
younger adults. Up To Date 2011.
47. Burnett AK, Milligan D, Goldstone A, et al. The impact of dose escalation and resistance 
modulation in older patients with acute myeloid leukaemia and high-risk myelodysplastic 
syndrome: the results of the LRF AML14 trial. Br J Haematol 2009; 145:318.
48. Fierro FA et al, Combining SDF-1/CXCR4 antagonism and chemotherapy in relapsed 
acute myeloid leukemia Leukemia. 2009 Feb;23(2):393-6.
49. Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid 
leukemia in adults: recommendations from an international expert panel, on behalf of the 
European LeukemiaNet. Blood 2010; 115:453.
50. Burnett AK, Milligan D, Prentice AG, et al. A comparison with or without all-trans 
retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in 
patients not considered fit for intensive treatment. Cancer. 2007; 109(6):1114-1124.


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51. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs 
conventional care regimens in older patients with newly diagnosed AML with >30% 
blasts. Blood 2015; 126(3):291-9.
52. EU Summary of Product Characteristics (SPC) for Vidaza®, Celgene UK Ltd; 2013.
53. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in 
Oncology.
54. Nippon Shinyaku Co. Usage results surveillance, 4th interium analysis report of Vidaza
for injection 100 mg. January 2017.
55. Kimura H, Ng JMY, Curren T. Transient inhibition of the Hedgehog pathway in young 
mice causes permanent defects in bone structure. Cancer Cell 2008; (13):249-60.
56. Amando K, Ichida F, Sugita A, et al. Msx2 stimulates chondrocyte maturation by 
controlling Ihh expression. J Biol Chem 2008; (283):29513-21.
57. 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An 
Evidence-Based Clinical Practice Guideline. JCO Jul 1, 2006:3187-3205.
58. Faderl S, Talpaz M, Estrov Z, Kantarjian HM: Chronic myelogenous leukemia: biology 
and therapy. Ann Intern Med. 1999 Aug 3;131(3):207-19.
59. Cohen, Johnson, Pazdur: U.S. Food and Drug Administration Drug Approval Summary: 
Conversion of Imatinib Mesylate (STI571; Gleevec) Tablets from Accelerated Approval 
to Full Approval. Clinical Cancer Research 2005;(11):12-19.
60. Vardiman JW, Harris NL, Brunning RD: TheWorld Health Organization (WHO) 
classification of the myeloid neoplasms. Blood. 2002;(100):2292-2302.
61. Cheson BD, Greenberg PL, Bennett JM et al.  Clinical application and proposal for 
modification of the international working group (IWG) response criteria in 
myelodysplasia.  Blood 2006; 108(2) 419-25.
62. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the 
International Working group for diagnosis, standardization of response criteria, treatment 
on outcomes and reporting standards for therapeutic trials in acute myeloid leukemia. J 
Clin Oncol 2003; 21(24)4642-4649.
63. Lowenberg B, Ossenkoppele GJ, Putten W, et al. High-dose daunorubicin in older 
patients with acute myeloid leukemia. N Engl J Med 2009;361(13):1235-48.
64. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid 
leukemia. N Engl J Med 2009;361(13):1249-59.


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65. Rowe JM, Neuberg D, Friedenberg W, et al. A phase 3 study of three induction regimens 
and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the 
Eastern Cooperative Oncology Group. Blood 2004;103:479-85.
66. Cortes JE, O’Connell A, Shaik MN, et al. Phase IB Study of PF-04449913, a Hedgehog 
(Hh) Inhibitor, in Combination with Low-Dose Cytarabine or Intensive Chemotherapy, in 
Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS).Poster 
Presented at the 19th Congress of the European Hematology Association, June 12-15, 
2014, Milan, Italy.
67. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: 
The 2008 World Health Organization criteria and point of care diagnostic algorithms. 
Leukemia 2008; (22) 14.
68. Tefferi A, Barosi G, Mesa RA, et al.  International working group (IWG) consensus 
criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for 
myelofibrosis research and treatment (IWG-MRT).  Blood 2006; 108(5):1497-1503.


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Appendix 1. ECOG Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease activities without 
restriction.
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, eg, light house work or 
office work.
2
Ambulatory and capable of all selfcare but unable to carry out any 
work activities.  Up and about more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 
50% of waking hours.
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined 
to bed or chair.
5
Dead.


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Appendix 2. Table of French-American-British (FAB) classification of Acute Myeloid 
Leukemia
Acute Myeloid Leukemia (AML) Diagnosis
FAB Classification
Myeloblastic leukemia minimally differentiated
M0
Myeloblastic leukemia without maturation
M1
Myeloblastic leukemia with maturation
M2
Hypergranular promyelocytic leukemia
Variant, microgranular promyelocytic leukemia
M3
M3V
Microgranular variant Myelomonocytic leukemia
With bone marrow eosinophilia
M4
M4Eo
Monocytic Leukemia
Poorly differentiated
Differentiated
M5
M5a
M5b
Erythroleukemia
M6
Megakaryoblastic Leukemia
M7


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Appendix 3. WHO Classification of Myelodysplastic Syndromes (MDS)
Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) 
classification of the myeloid neoplasms. Blood 2002;(100):2292-2302.60


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Appendix 4. Diagnostic Criteria for Chronic Myelomonocytic Leukemia (CMML)*

Persistent peripheral blood monocytosis greater than 1x109/L;

No Philadelphia chromosome or BCR/ABL fusion gene;

Fewer than 20% blasts* in the blood or bone marrow;

Dysplasia in one or more myeloid lineages.  If myelodysplasia is absent or minimal, 
the diagnosis of CMML may still be made if the other requirements are present and: 
an acquired, clonal cytogenetic abnormality is present in the marrow cells, or the 
monocytosis has been persistent for at least 3 months and all other causes of 
monocytosis have been excluded;

Diagnose CMML-1 when blasts fewer than 5% in blood and fewer than 10% in bone 
marrow;

Diagnose CMML-2 when blasts are 5% to 19% in blood, or 10% to 19% in marrow, 
or if Auer rods are present and blasts are fewer than 20% in blood or marrow;

Diagnose CMML-1 or CMML-2 with eosinophilia when the criteria above are 
present and when the eosinophil count in the peripheral blood is greater than 
1.5 x109/L.
*In this classification of CMML, blasts include myeloblasts, monoblasts, and promonocytes.
Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) 
classification of the myeloid neoplasms. Blood 2002;(100);2292. 60


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Appendix 5. Response Criteria and Progression Definitions for Myelodysplasia and CMML
Response Criteria
Peripheral Blood
Bone Marrow Blasts 
(BMB) (%)
Other
Hgb 
(g/dL)
Neutrophils 
(L)
Platelets
(L)
Blasts (%)
Complete Remission
≥11
≥1 x 109 
≥100 x 109
0
≤5
Normal maturation of all cell lines, note if has 
persistent dysplasia
Partial Remission
Decreased by 50% 
but still >5%
All CR criteria if abnormal before treatment except 
BMB
Marrow CR
If hematologic improvement (HI) response, note in addition to 
Marrow CR
5% & decreased by 
50%
Stable Disease
Failure to achieve PR & no evidence of progression*
Failure
Death, or disease progression:  worsening cytopenia, 
increase in % BM blasts, progression to a more 
advanced MDS FAB subtype
Relapse after CR or PR
At least one of the following:
Return to pre-treatment BMB %
Decrement of ≥50% from maximum 
remission/response levels in granulocytes or platelets
Reduction in Hb ≥1.5g/dL or transfusion dependence
Cheson BD, Greenberg PL, Bennett JM et al. Clinical application and proposal for modification of the international working group (IWG) response criteria in 
myelodysplasia.  Blood 2006; 108(2) 419-25.61
*SD must last > 8 weeks but response is documented regardless of duration.


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Additional Response Criteria for Myelodysplasia and CMML
Cytogenetic Response
Complete
Partial
Disappearance of chromosomal abnormality with no appearance of new ones
≥50% reduction of chromosomal abnormality
Disease Progression
For patients with % blasts at screening:
<5% bone marrow blasts
5-10% bone marrow blasts
10-20% bone marrow blasts
20-30% bone marrow blasts
For all categories, any of:
≥50% increase to >5% bone marrow blasts
≥50% increase to >10% bone marrow blasts
≥50% increase to >20% bone marrow blasts
≥50% increase to >30% bone marrow blasts
At least 50% decrease from maximum remission/response in granulocytes or platelets
Reduction in Hgb by ı2 g/dL
Transfusion dependence
Proposed modified IWG Myelodysplasia and CMML Response Criteria for Hematologic Improvement (HI)**
Erythroid response (pre-treatment <11g/dl)*
Hb increase by ≥1.5 g/dl
Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 weeks as 
compared to the pretreatment transfusion number in the previous 8 weeks (only RBC transfusions given for 
Hb≤9/dL pretreatment will count in the RBC transfusion evaluation).
Platelet Response (pretreatment <100 x109)*
Absolute increase of ≥30 x109 /L if starting with >20 x 109/L platelets
Increase from <20 x 109/L to >20 x109/L and by at least 100%
Neutrophil Response (pretreatment <1x109/L)*
At least a 100% increase and an absolute increase >0.5 x109/L
Progression or relapse after HI in the absence of another 
explanation
At least one of the following:
At least 50% decrease from maximum response levels in granulocytes or platelets;
Reduction in Hgb by ≥1.5g/dL;
Transfusion dependence
*Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) ≥1 week apart.
** Hematologic Improvement must last ≥8 weeks and is derived based on lab data entered in the database.
.


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Appendix 6. 2008 WHO Diagnostic Criteria for Primary Myleofibrosis*
Abbreviations: CML, chronic myeloid leukemia; LDH, lactate dehydrogenase; MDS, myelodysplastic 
syndrome; PMF, primary myelofibrosis; PV, polycythemia vera; WHO, World Health Organization.
*Diagnosis requires meeting all three major criteria and two minor criteria.
†Small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly 
folded nuclei and dense clustering.
Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health 
Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008; (22) 14.67


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Appendix 7. Response Criteria and Progession Definitions for Myleofibrosis
Response Criteria
Peripheral Blood
BM Blasts (%)
Other
Hgb 
(g/L)
Neutrophil
s 
(L)
Platelets
(L)
Other
Complete 
Remission (CR)
110
1 x 109 
100 x 
109
All 
ULN
5%
Complete resolution of 
disease-related symptoms & 
signs including 
hepatosplenomegaly.
Normal leukocyte differential.
Bone marrow histologic 
remission including 
osteomyelofibrosis Grade ≤1
Major Cytogenetic 
Response
This is a failure to detect a 
cytogenetic abnormality if pre-
existing
Minor Cytogenetic 
Response
≥ 50% reduction in abnormal 
metaphases
Partial Remission 
(PR)
≥110
≥1 x 109 
≥100 x 
109
All 
≤ULN
All CR criteria except for bone 
marrow histologic remission.  
A repeat bone marrow biopsy 
is required.
Clinical 
Improvement (CI)
In the absence of both PD & 
CR/PR requires one of the 
following for ≥8 weeks (over 
any 8-week period):
-≥20g/L increase in Hgb, or 
becoming transfusion 
independent (baseline 
<100 g/L).
- either ≥50% reduction in 
splenomegaly of >10 cm or 
palpable at >5 cm at baseline 
and becomes not palpable.
-Minimum 100% increase in 
ANC and ANC ≥ 0.5 x 109/L if 
baseline neutrophil <1x 109/L
-Minimum 100% increase 
platelet count and absolute 
platelet count of 50,000x109/L 
if baseline <50x109/L
Progressive 
Disease (PD)
One of the following:
- progressive splenomegaly*
- leukemic transformation 
confirmed by bone marrow 
blasts >20%
- >20% increase peripheral 
blood blast lasting >8 wks
Stable Disease 
(SD)
None of the above
Relapse
Loss of CR, PR or CI
* Progressive splenomegaly that is defined by the appearance of a previously absent splenomegaly that is palpable at greater 
than 5 cm below the left costal margin or a minimum 100% increase in palpable distance for baseline splenomegaly of 5-10 
cm or a minimum 50% increase in palpable distance for baseline splenomegaly of greater than 10 cm.


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Tefferi A, Barosi G, Mesa RA et al. International working group (IWG) consensus criteria for treatment response in 
myelofibrosis with myeloid metaplasia, for the IWG for myelofibrosis research and treatment (IWG-MRT).  Blood 2006; 
108(5):1497-1503. 68
Appendix 8. Response Criteria and Progression Definitions for Acute Myeloid 
Leukemia
Hematologic Responses to Treatment
Response Criteria
Neutrophils 
(L)
Platelets
(L)
Bone Marrow Blasts 
(%)
Other
Morphologic Complete 
Response (CR)
This is morphologic 
leukemia-free
plus neutrophil & 
platelet response
>1,000
100,000
<5 with spicules 
present, no Auer rods 
Transfusion independent, no EMD
Morphologic CR with 
incomplete blood count 
recovery (CRi)
<1,000 
-or-
<100,000
<5
Either neutrophils or platelets not 
recovered, no EMD.
Elderly AML (>60 years) may be in 
a clinical CR with persistence of a 
cytopenia  (usually neutropenia or 
thrombocytopenia)
Morphologic leukemia-
free state
<1,000 
-and-
<100,000
<5 blasts in BM with 
spicules and no blasts 
with Auer rods
Neutrophils and platelets not 
recovered, Flow cytometry negative, 
No EMD
Partial remission (PR)
>1,000
>100,000
decrease to 5-25 & 
50% decrease from 
start
Blasts 5% if Auer rod positive
Partial remission with 
incomplete blood count 
recovery (PRi)
<1,000 
-or-
<100,000
decrease to 5-25 & 
50% decrease from 
start
Minor Response
NA
NA
25% decrease from 
start
Stable Disease
NA
NA
Blasts stable 25%
There is no minimum requirement for bone marrow cellularity or hemoglobin concentration for response 
criteria 
Cytogenetic Responses to Treatment
Response Criteria
Neutrophils 
(L)
Platelets
(L)
Bone Marrow 
Blasts (%)
Other
Cytogenetic CR (CRc)
>1,000
>100,000
<5
Cytogenetics - normal, no EMD
Molecular CR (CRm)
>1,000
>100,000
<5
Molecular-negative, no EMD


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Criteria for Treatment Failure
Definition
Criteria
TF due to resistant disease
Pt survives 7 days post chemo; persistent AML >25% blasts in 
blood or BM
TF due to aplasia
Pt survives 7 days post chemo; death while cytopenic with 
aplastic bone marrow
TF indeterminate cause
Pt dies <7 days post therapy; Pt dies >7 days post
therapy with no PB blasts, but no bone marrow exam; Pt does not 
complete 1st course of therapy
TF due to morphologic 
relapse
Reappearance of blasts post CR in PB or 5% blasts in bone 
marrow not attributed to another cause
TF due to molecular or 
cytogenetic relapse
Reappearance of molecular or cytogenetic abnormality
Modified from Cheson BD, Bennett JM, Kopecky KJ et al. Revised recommendations of the International 
Working group for diagnosis, standardization of response criteria, treatment on outcomes and reporting 
standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003; 21(24) 4642-4649.62


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Appendix 9. Response Criteria and Progression Definitions for Chronic Myeloid 
Leukemia
Hematologic Responses to Treatment; maintained for at least 4-weeks
Subjects with Accelerated or Blast Phase CML
Hematologic Responses
Definition
Return to Chronic Phase
Disappearance of features defining accelerated & blast phases, 
but still in chronic phase 
(May have platelets <100 x109/L, if related to therapy)
Persistence of clonal evolution, if present at the time of therapy, 
is acceptable for return to chronic phase
Minor Response
<15% blasts in marrow and blood
< 30% blasts + promyelocytes in marrow and same in blood
< 20% basophils in peripheral blood
No extramedullary disease other than spleen and liver
No Evidence of Leukemia (NEL)
Blast ≤ 5% in bone marrow
0.5  x109 ≤ ANC <1.0 x109/L 
20x109 ≤ Platelets < 100 x109/L
No blood blasts or promyelocytes
<20% basophils in blood
Myelocytes + metamyelocytes <5% in blood
No extramedullary involvement (incl. hepato- or splenomegaly)
Complete Hematologic Response
Blast ≤5% in bone marrow
No peripheral blasts or promyelocytes
Myelocytes + metamyelocytes <5% in blood
ANC ≥ 1.0 x109/L
WBC ≤ institutional ULN
Platelets ≥ 100 but <450 x109/L, unless related to therapy
<20% basophils in blood
No extramedullary involvement (incl. hepato- or splenomegaly)
Subjects with Chronic Phase CML
No Evidence of Leukemia (NEL)
0.5  x109 ≤ ANC <1.0 x109/L 
20x109 ≤ Platelets <100 x109/L
No blood blasts or promyelocytes
<20% basophils in blood
Myelocytes + metamyelocytes <5% in blood
No extramedullary involvement (incl. hepato- or splenomegaly)
Complete Hematologic Response
No Peripheral blasts or promyelocytes
Myelocytes + metamyelocytes <5% in blood
ANC ≥ 1.0 x109/L
WBC ≤ institutional ULN
Platelets ≥ 100 but <450 x109/L, unless related to therapy
<20% basophils in blood
No extramedullary involvement (incl. hepato- or splenomegaly)


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Cytogenetic Responses to Treatment (Any Phase of CML)
Cytogenetic Responses*
% Philadelphia chromosome positive cells
None
> 95% 
Minimal
66-95%
Minor
36-65%
Partial
1-35%
Complete
0%
Major
Complete + Partial Rates
* 
Based on analysis of 20 metaphases.  Or For post-baseline disease assessments, FISH analysis may 
be used if the bone marrow sample is inadequate for cytogenetic analysis in order to confirm the 
presence of BCR-Abl fusion product and its percentage in marrow.
Molecular Responses (MR) to Treatment (Any Phase of CML)
Molecular Responses
PCR for BCR-ABL
None
No Change
Partial
< 3 log reduction from standardized baseline
Major
≥ 3 log reduction from standardized baseline
Complete
Undetectable BCR-Abl
Definitions of Treatment Failure and Disease Progression
DEFINITIONS OF TREATMENT FAILURE

OCCURRENCE OF AT LEAST ONE OF THE CRITERIA FOR DISEASE PROGRESSION 
SHOWN BELOW

DEATH (ANY CAUSE)

WITHDRAWAL FROM TREATMENT OWING TO AN ADVERSE EVENT, SUBJECT
REFUSAL, OR LOSS TO FOLLOW-UP
DEFINITIONS OF PROGRESSION
Definition 
Criteria
Early Progressor from CP
For Chronic Phase: If subject enters study in chronic phase clearly 
progresses to advanced phase during the first 4 weeks of therapy (to 
be considered a progressor to accelerated phase, a subject must have 
an absolute increase of at least 10% in their count(s) qualifyinf the 
subject for accelerated phase )
Progressor to Accelerated Phase or 
Blast Crisis from Chronic Phase or 
Return to Chronic Phase
Subject evolving from chronic phase or return to chronic phase to 
accelerated phase or blast crisis (on two consecutive assessments at 
least a week apart).


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Progressor to Accelerated Phase to 
Blast Crisis
A subject evolving from accelerated phase to blast crisis (on two 
consecutive assessments at least a week apart).
Loss of Confirmed CHR
Loss of confirmed CHR that is confirmed by a subsequent 
hematologic assessment ≥at least 2 weeks after the initial finding of 
loss
Loss of MCyR
Loss of MCyR-Ph+ rate increased by 30%


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Appendix 10. Doxorubicin Equivalent
Doxorubicin equivalent
Doxorubicin
×1
Daunorubicin
×3/4
Epirubicin
×1/2
Pirarubicin
×1/2
Mitoxantron
×3


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Appendix 11. 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 PF-04449913 is not recommended. If 
any of these drugs are considered to be medically necessary, then they should be used with 
caution in combination with PF-04449913.
Generic Name
Drug Class
Therapeutic Use
Route
Aclarubicin
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
Antihistamine
Allergic rhinitis
oral
Azithromycin
Antibiotic
Bacterial infection
oral,injection
Bepridil
Anti-anginal
Heart pain
oral
Cesium Chloride
Toxin
Alternative therapy 
cancer
oral,injection
Chloroquine
Anti-malarial
Malaria infection
oral
Chlorpromazine
Anti-psychotic / Anti-
emetic
Schizophrenia/ nausea
oral,injection,suppository
Chlorprothixene
Anti-psychotic
Schizophrenia
oral,injection
Cilostazol
Phosphodiesterase 3 
inhibitor
Intermittent 
claudication
oral
Ciprofloxacin
Antibiotic
Bacterial Infection
oral, injection
Cisapride
GI stimulant
Heartburn
oral
Citalopram
Anti-depressant, SSRI
Depression
oral
Clarithromycin
Antibiotic
Bacterial infection
oral
Cocaine
Local anesthetic
Topical anesthesia
oral, topical
Disopyramide
Anti-arrhythmic
Abnormal heart rhythm
oral
Dofetilide
Anti-arrhythmic
Abnormal heart rhythm
oral
Domperidone
Anti-nausea
Nausea
oral,injection,suppository
Donepezil
Cholinesterase inhibitor
Dementia
oral
Dronedarone
Anti-arrhythmic
Atrial Fibrillation
oral
Droperidol
Anti-psychotic / Anti-
emetic
Anesthesia adjunct, 
nausea
injection
Erythromycin
Antibiotic
Bacterial infection; 
increase GI motility
oral,injection
Escitalopram
Anti-depressant, SSRI
Major depression/ 
Anxiety disorders
oral
Flecainide
Anti-arrhythmic
Abnormal heart rhythm
oral
Fluconazole
Anti-fungal 
Fungal infection
oral, injection
Gatifloxacin
(Off market worldwide)
Antibiotic
Bacterial infection
oral, injection
Grepafloxacin (Off 
market worldwide)
Antibiotic
Bacterial infection
oral
Halofantrine
Anti-malarial
Malaria infection
oral
Haloperidol
Anti-psychotic
Schizophrenia, 
agitation
oral,injection


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B1371005
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Generic Name
Drug Class
Therapeutic Use
Route
Hydroquinidine
Anti-arrhythmic
Arrhythmia
oral
Hydroxychloroquine
Anti-malarial, anti-
inflammatory
Malaria infection, 
systemic lupus 
erythematosus, 
rheumatoid arthritis
oral
Ibogaine
Psychedelic
Narcotic addiction, 
unproven
oral
Ibutilide
Anti-arrhythmic
Abnormal heart rhythm
injection
Levofloxacin
Antibiotic
Bacterial infection
oral, injection
Levomepromazine
Anti-psychotic
Schizophrenia
oral, injection
Levomethadyl
Opiate
Pain control, narcotic 
dependence
oral
Levosulpiride
Anti-psychotic
Schizophrenia
oral, injection
Meglumine antimoniate
Antiparasitic
Leishmaniasis
injection
Mesoridazine
Anti-psychotic
Schizophrenia
oral
Methadone
Opiate
Pain control, narcotic 
dependence
oral,injection
Moxifloxacin
Antibiotic
Bacterial infection
oral,injection
Nifekalant
Anti-arrhythmic
Arrhythmia
injection
Ondansetron
Anti-emetic
Nausea, vomiting
oral,injection
Oxaliplatin
Anti-neoplastic
Cancer
injection
Papaverine HCl
Vasodilator, Coronary
Diagnostic adjunct
injection
Pentamidine
Antibiotic
Pneumocystis 
pneumonia
injection,inhaled
Pimozide
Anti-psychotic
Tourette's tics
oral
Probucol
Antilipemic
Hypercholesterolemia
oral
Procainamide
Anti-arrhythmic
Abnormal heart rhythm
oral, injection
Propofol
Anesthetic
Anesthesia
injection
Quinidine
Anti-arrhythmic
Abnormal heart rhythm
oral,injection
Roxithromycin
Antibiotic
Bacterial infection
oral
Sertindole
Anti-psychotic, atypical
Schizophrenia, anxiety
oral
Sevoflurane
Anesthetic, general
Anesthesia
inhaled
Sotalol
Anti-arrhythmic
Abnormal heart rhythm
oral
Sparfloxacin
Antibiotic
Bacterial infection
oral
Sulpiride
Anti-psychotic, atypical
Schizophrenia
oral
Sultopride
Anti-psychotic, atypical
Schizophrenia
oral, injection
Terfenadine
Antihistamine
Allergic rhinitis
oral
Terlipressin
Vasoconstrictor
Septic shock
injection
Terodiline
Muscle relaxant
Bladder spasm
oral
Thioridazine
Anti-psychotic
Schizophrenia
oral
Vandetanib
Anti-cancer
Thyroid cancer
oral
Source: Credible Meds.org (http://crediblemeds.org/healthcare-providers/drug-list/?rf=All). TdP risk category 
filtered on “Drugs with known TdP risk”. Revision date: December 17, 2020.


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SAP_001.pdf: 
Protocol B1371005 Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol B1371005
A PHASE 1 STUDY TO EVALUATE THE SAFETY, TOLERABILITY, EFFICACY,
PHARMACOKINETICS, AND PHARMACODYNAMICS OF PF-04449913
(GLASDEGIB), AN ORAL HEDGEHOG INHIBITOR, ADMINISTERED AS A 
SINGLE AGENT IN JAPANESE PATIENTS WITH SELECT HEMATOLOGIC 
MALIGNANCIES AND IN COMBINATION WITH INTENSIVE CHEMOTHERAPY,
LOW-DOSE ARA-C, OR AZACITIDINE IN PATIENTS WITH ACUTE MYELOID 
LEUKEMIA OR HIGH-RISK MYELODYSPLASTIC SYNDROME
Statistical Analysis Plan 
(SAP)
Version:
4.0
Author:
 Clinical Statistics Group 1, Pfizer R&D Japan G.K.
Date:
16-DEC-2019
PPD


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PFIZER CONFIDENTIAL
Page 2
TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
APPENDICES ...........................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................7
2.1. Study Design .............................................................................................................7
2.2. Study Objectives .....................................................................................................10
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING................................12
4. HYPOTHESES AND DECISION RULES.........................................................................13
4.1. Statistical Hypotheses .............................................................................................13
4.2. Statistical Decision Rules........................................................................................13
5. ANALYSIS SETS ...............................................................................................................14
5.1. Full Analysis Set .....................................................................................................15
5.2. DLT-evaluable Analysis Set (‘Per Protocol’ Analysis Set)....................................15
5.3. Safety Analysis Set..................................................................................................15
5.4. Other Analysis Set...................................................................................................15
5.4.1. PK Analysis Set ..........................................................................................15
5.4.2. PD Analysis Set ..........................................................................................15
5.4.3. QTc-evaluable Analysis Set .......................................................................15
5.5. Treatment Misallocations........................................................................................15
5.6. Protocol Deviations.................................................................................................15
6. ENDPOINTS AND COVARIATES ...................................................................................16
6.1. Efficacy Endpoints (excluding the Continuation Cohort).......................................16
6.2. Safety Endpoints .....................................................................................................17
6.2.1. Dose Limiting Toxicities [excluding the Expansion Cohort of LDAC 
Combination for Efficacy (Unfit Patient) and the Continuation Cohort] ........17
6.2.2. Adverse Events...........................................................................................18
6.2.3. Laboratory Safety Tests..............................................................................18
6.3. Other Endpoints.......................................................................................................18
6.3.1. PK Endpoints (excluding the Continuation Cohort)...................................18
6.3.2. Drug-Drug Interaction Endpoints (Combination Cohorts Only)................19
6.3.3. ECG ............................................................................................................19


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6.3.4. PD Biomarker Endpoints (excluding the Continuation Cohort).................20
6.3.5. Extramedullary Disease Endpoint (excluding the Continuation 
Cohort).............................................................................................................20
6.4. Covariates................................................................................................................20
7. HANDLING OF MISSING VALUES ................................................................................20
7.1. Missing Dates..........................................................................................................20
7.2. Efficacy Analysis ....................................................................................................20
7.3. PK............................................................................................................................21
7.4. QTc..........................................................................................................................21
7.5. PD Parameters.........................................................................................................22
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................22
8.1. Statistical Methods ..................................................................................................22
8.1.1. Analyses of Time-to-Event Endpoints........................................................22
8.1.2. Analyses of Binary Endpoints ....................................................................22
8.1.3. Analyses of Continuous Data .....................................................................22
8.2. Statistical Analyses .................................................................................................22
8.2.1. Analysis of Primary Endpoints...................................................................22
8.2.2. Analysis of Efficacy Endpoints ..................................................................23
8.2.3. Subset Analysis...........................................................................................28
8.2.4. Analysis of Safety Data ..............................................................................28
8.2.5. Analyses of Vital Signs ..............................................................................32
8.2.6. Analysis of PK Data (excluding the Continuation Cohort)........................32
8.2.7. Analysis of Drug-Drug Interaction (Combination Cohorts 1, 2, 3
Only) ................................................................................................................33
8.2.8. Analysis of PD Biomarker Data (excluding the Continuation Cohort)......34
8.2.9. Population PK Analysis or PK/PD Modeling (excluding the 
Continuation Cohort) .......................................................................................35
8.2.10. Other Analyses..........................................................................................35
9. REFERENCES ....................................................................................................................44
10. APPENDICES ...................................................................................................................45


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PFIZER CONFIDENTIAL
Page 4
APPENDICES
Appendix 1. Categorical Classes for ECG and Vital Signs.....................................................45
Appendix 2. Response Criteria for Myelodysplasia and CMML ............................................46
Appendix 3. Response Criteria for Myelofibrosis...................................................................47
Appendix 4. Response Criteria for Acute Myeloid Leukemia ................................................48
Appendix 5. Response Criteria for Chronic Myeloid Leukemia.............................................49


Protocol B1371005 Statistical Analysis Plan
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Page 5
1. AMENDMENTS FROM PREVIOUS VERSION(S)  
This Statistical Analysis Plan (SAP) v4 for study B1371005 is based on the protocol dated 
21JAN2019 (protocol amendment 7) and the addition of the interim analysis.  The analysis 
planned in SAP v4 will supersede the previous versions of the SAP and the statistical 
sections of the protocol.
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
1
Not Applicable
Not Applicable
2
- Added the analysis plan of the 25 
mg QD dose level in Monotherapy
Cohort and amended the sample 
size of Monotherapy Cohort.
- Added the analysis plan of the 
Combination Cohort 3.
- Added the analysis plan of the 
Continuation Cohort.
- Section 3 – Stated the timings of 
the primary and final analysis.
- Section 6.1 – Added the 
definitions of the dates for the 
disease response.
- Section 6.3.1 – Modified 
according to protocol amendment.
- Section 7.4 – Conformed to 
Section 8.2.3.4 about analysis 
population.
- Section 7.5 – Deleted the 
explanations of handlings of 
concentrations below/upper the 
limit of quantification.
- Section 8.2.9.1.4 – Changed the 
definitions of the actual dose 
intensity and the relative dose
intensities with reference to 
B1371003
- Section 8.2.9.1.4 – Added the 
listing of the actual dose intensity 
and the relative dose intensities 
with reference to B1371003
- Section 8.2.9.5 – Added the 
analysis plan of cytogenetics by 
European Leukemia Net.
- Protocol amendment 3.
- Protocol amendment 4.
- Protocol amendment 5.
- To clarify the timing of each
analysis.
- To include the dates related 
the efficacy as endpoints.
- Protocol amendment 4.
- Refer to Section 8.2.3.4.
- Further amendment of SAP
will be planned after 
investigation of handling of PD 
endpoints.
- To unify the definition of 
these endpoints in Glasdegib 
program.
- To unify the definition of 
these endpoints in Glasdegib 
program.
- This characteristic is the 
prognostic factor for AML and 
will also be corrected in Phase 3 
study for AML patients 


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PFIZER CONFIDENTIAL
Page 6
- Section 8.2.9.11 – Added the 
analysis plan of cardiac function 
evaluation
- Section of Investigators 
Comments – This section was 
deleted 
B1371019.
- The analysis plan of this item
was simply omitted.
- This item is not included in 
analysis dataset.
3
- Survival follow-up was added to 
Combination Cohort 1 (Unfit 
Patients) [Section 2.1].
- Expansion Cohort of LDAC 
combination for efficacy (Unfit 
Patients) was added to this study
[Section 2.1, 2.2].  In this cohort, 
statistical test is planned [Section
4].  Other plans related to addition 
of this cohort were described
[Section 5, 6, 7, 8].
- Timing of primary analysis was 
changed according to the statistical 
test [Section 3].
- Efficacy endpoints were added; 
DMR and transfusion 
independence [Section 6].
- Event definition of duration of 
response was changed [Section 6].
The definition was different with 
one described in Protocol.
- Transfusion independence was 
added [Section 6.1].
- Handlings of missing values for 
OS and disease response were 
described [Section 7].
- Statistical methods for time-to-
event endpoints and binary 
endpoints were added
[Section 8.1]. 
- Analysis methods of DMR, 
disease response, duration of 
response, time to response, OS and 
transfusions were added 
[Section 8.2.2].
- Subset analysis by DMR was 
planned for OS and transfusions 
[Section 8.2.3].
- Worst on-study abnormality of 
- Protocol Amendment 6.
- Protocol Amendment 7.
- Protocol Amendment 7.
- Protocol Amendment 7.
- To unify the definition 
described in Prorocol.
- This endpoint was added as 
exploratory efficacy endpoint.
- Protocol Amendment 7.
- Protocol Amendment 7.
- Protocol Amendment 7.
- Protocol Amendment 7.
- To conduct same analysis with 


Protocol B1371005 Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 7
laboratory test was added
[Section 8.2.4.2].
- Details of ECG analyses were 
updated [Section 8.2.4.4].
- Analyses of risk category were 
added [Section 8.2.10.2]. 
- Physical examination were added 
[Section 8.2.10.10]
- Description adjustment.
B1371003.
- To conduct same analysis with 
B1371003.
- To summarize and grasp the 
distributions of prognostic 
factors of AML and MDS.
4
- Possibility of interim analysis 
was added [Section 3].
- In Expansion Cohort of LDAC
combination for efficacy (Unfit 
Patients), the study would be 
considered positive if at least
4 DMR responders in 
15 patients are observed.  This 
amendment describes the
possibility to conduct interim 
analyses prior to the primary 
completion provided that this
criterion is met. No analysis of
the primary endpoint will be 
conducted at the interim 
analysis.
2. INTRODUCTION
This document describes the planned statistical analysis for Protocol B1371005. This 
statistical analysis plan (SAP) is meant to supplement the study protocol.  This document 
may modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition or its analysis will also be reflected in a protocol amendment.  
Any deviations from this SAP will be described in the Clinical Study Report (CSR).
Note: in this document any text taken directly from the protocol is italicised.
2.1. Study Design
This is an open-label, multi-center, Phase 1 study of PF-04449913 in Japanese patients. 
PF-04449913 will be administered orally as a single agent in up to 15 patients with select 
advanced hematologic malignancies (Monotherapy Cohort), or in combination with
Low-dose Ara-C (LDAC) (Combination Cohort 1, unfit patients) or cytarabine and 
daunorubicin (7:3) (Combination Cohort 2, fit patients) in up to 12 previously untreated 
patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).  
PF-04449913 will be administered in combination with LDAC in a total of 15 patients with 
previously untreated AML or high-risk MDS (Expansion Cohort of LDAC combination for 
efficacy, unfit patients).  PF-04449913 will be also administered in combination with 
azacitidine in a total of 6 patients with previously untreated AML who are eligible for 
non-intensive chemotherapy (Combination Cohort 3, Azacitidine Combination).
PF-04449913 will be administered as a single agent in 1 Japanese MF patient who has been 


Protocol B1371005 Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 8
treated in Study B1371013 and on the study treatment at the time of the study discontinuation 
(Continuation Cohort).
Monotherapy Cohort:
The monotherapy cohort will evaluate the safety and tolerability of PF-04449913 
administered as a single agent once daily continuously. Cycle 1 will be preceded by a single 
lead-in dose of PF-04449913 administered on Day -5 (lead-in period) in order to 
characterize the single-dose PK of PF-04449913 prior to initiation of continuous dosing in 
the first cycle of treatment. From Cycle 1/Day 1 onwards, PF-04449913 will be 
administered continuously once daily, in 28-day cycles.
A standard 3+3 dose escalation design will be used to evaluate the tolerability of 
PF-04449913 with 3-6 patients per dose level. Two dose levels of PF-04449913 (Dose 
Level 1: 50 mg QD and Dose Level 2: 100 mg QD) will, in the first instance, be investigated 
in sequential cohorts of patients. Intermediate (such as 80 mg QD) or lower dose levels 
(such as 25 mg) may be explored at any time during the study if this is clinically and 
scientifically warranted.  Study centers will receive a notification if additional dose levels are 
explored.
As of 7 August 2014, it was decided by the study team that a lower dose level (25 mg QD) 
will be explored in the study, since evaluation of PD data at the 25 mg QD dose is 
scientifically warranted.  Up to 3 patients will be enrolled at the 25 mg dose level.  DLT 
evaluation will be performed on this dose level, however, it will not be used for the dose 
escalation decision, or for the determination of whether or not to proceed with the 
combination cohort.  The Sponsor will discuss with the Investigator to confirm that there is 
no safety issue for patients enrolled at this dose level.
Treatment with PF-04449913 may continue for up to 12 cycles or until disease progression
or relapse, patient withdrawal, or unacceptable toxicity occurs (whichever is first). Patients 
who complete 12 cycles of treatment will be deemed to have completed the study. However, 
patients who complete 12 cycles of study treatment who demonstrate clinical benefit with 
manageable toxicity, and are willing to continue receiving the study treatment, may be given 
the opportunity to do so following agreement between the Investigator and Sponsor, and 
pending study drug availability. If treatment continues beyond 12 cycles, study procedures 
should continue to be performed as per Protocol Table 1 (See Protocol Schedule of Activities).
The study may at any time evaluate additional dose levels of single-agent PF-04449913 
based upon the emerging data from the ongoing pre-clinical and clinical studies, following 
discussion between the Investigators and the Sponsor.
Combination Cohorts:
The combination cohorts will evaluate the safety and tolerability of PF-04449913 at the 
starting dose of 100 mg once daily continuously administered in combination with 3 different 
chemotherapy regimens.


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PFIZER CONFIDENTIAL
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Combination Cohort 1 (Unfit Patients):
In this cohort, patients who are “unfit for intensive chemotherapy” based on predefined 
criteria (See Protocol Inclusion Criteria) will receive PF-04449913 once daily continuously 
in combination with LDAC over 28 day cycles.
Treatment with PF-04449913 in combination with LDAC may continue for up to 12 cycles or 
until disease progression or relapse, patient refusal, or unacceptable toxicity occurs 
(whichever is first). Unfit patients who complete 12 cycles of study treatment will be deemed 
to have completed the study. However, patients who complete the 12 cycles of study 
treatment and demonstrate clinical benefit with manageable toxicity, and are willing to 
continue receiving the study treatment (monotherapy of PF-04449913 or combination 
therapy), may be given the opportunity to do so following agreement between the 
Investigator and Sponsor, and pending study drug availability. If treatment continues 
beyond 12 cycles, study procedures should continue to be performed as listed in Protocol
Table 2 (Schedule of Activities). This cohort includes survival follow-up.
Expansion Cohort of LDAC Combination for Efficacy (Unfit Patients):
In this cohort, patients who are “unfit for intensive chemotherapy” based on predefined 
criteria (See Protocol Inclusion Criteria) will receive PF-04449913 once daily continuously 
in combination with LDAC over 28-day cycles. 
A total of 15 patients will be treated and Disease Modifying Response (DMR) rate will be 
evaluated. Treatment with PF-04449913 in combination with LDAC may continue until 
disease progression or relapse, patient refusal, or unacceptable toxicity occurs (whichever is 
first). All patients will be followed for survival every 8 weeks up to 2 years from the first 
dose of the last patient enrolled in the study, or until death, end of the study, or patient 
withdrawal of consent, whichever comes first, regardless of initiation of new cancer therapy.
Combination Cohort 2 (Fit Patients):
In this cohort, patients defined as “fit for intensive chemotherapy” based on pre-defined 
criteria (See Protocol Inclusion Criteria) will receive PF-04449913 once daily continuously 
in combination with daunorubicin and cytarabine during induction and consolidation. For 
the first induction cycle only, PF-04449913 will commence on Day -3 and will then be given 
once daily continuously for the duration of treatment. Following completion of induction 
and consolidation, single-agent PF-04449913 may be given to eligible patients as 
maintenance therapy for a maximum of 6 cycles.
Treatment will continue until disease progression or relapse, patient refusal, or unacceptable
toxicity (whichever is first). Fit patients who complete induction, consolidation and 6 cycles 
of maintenance with PF-04449913 will be deemed to have completed the study treatment. 
However, patients who complete the 6 cycles of maintenance and demonstrate clinical 
benefit with manageable toxicity, and are willing to continue receiving single-agent 
PF-04449913, may be given the opportunity to do so following agreement between the 
Investigator and Sponsor, and pending study drug availability. If treatment continues 
beyond 6 cycles of maintenance, study procedures should continue to be performed as listed 
in Protocol Table 3 (Schedule of Activities).


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Combination Cohort 3 (Azacitidine Combination):
In this cohort, patients with previously untreated AML and eligible for non-intensive 
chemotherapy will receive PF-04449913 once daily continuously at the starting dose of 
100 mg in combination with azacitidine over 28 day cycles.
Since responses to azacitidine may require 4-6 cycles of administration to emerge, treatment 
with the study drug combination should be continued for at least 6 cycles, or until death, 
unacceptable toxicity, or patient refusal (whichever is first).  If documentation of disease 
progression occurs within the first 6 cycles of study treatment, the patient SHOULD NOT be 
withdrawn from study treatment following agreement between the Investigator and Sponsor
if, in the Investigator’s judgment, the patient is still likely to receive clinical benefit.
Treatment with the study drug combination should be continued beyond 6 cycles of treatment 
until objective disease progression or relapse (unless according to the Investigator there is 
reasonable evidence of clinical benefit, eg, HI [hematologic improvement], to justify 
continuation on treatment following agreement between the Investigator and Sponsor), 
death, unacceptable toxicity, or patient refusal (whichever is first).  All patients will be
followed for survival up to 3 years from the first dose of the last patient enrolled in the study,
or until death, end of the study, or patient withdrawal of consent, whichever comes first, 
regardless of initiation of new cancer therapy.
Continuation Cohort:
PF-04449913 at the same dose as the patient was taking in Study B1371013 will be orally 
administered once daily continuously as a single agent over 28 day cycles in 1 Japanese MF 
patient who has been treated in Study B1371013 and without documented objective 
progression of disease and with continuous clinical benefit at the time the patient 
discontinued from Study B1371013. 
In this cohort, the patient receiving PF-04449913 will continue to receive study treatment 
until the time of disease progression, unacceptable toxicity, death, withdrawal of consent or 
termination of the study by Sponsor, whichever comes first. The patient may continue 
PF-04449913 treatment after objective progression of disease has been determined if the 
patient continues to experience clinical benefit, in the opinion of the investigator, and 
following discussion with the Sponsor.
2.2. Study Objectives
Monotherapy Cohort:
Primary Objective
To determine the safety and tolerability of PF-04449913 administered as monotherapy in 
Japanese patients with select advanced hematologic malignancies.


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Secondary Objectives

To evaluate the pharmacokinetics (PK) of PF-04449913 as monotherapy in Japanese 
patients with select advanced hematologic malignancies;

To evaluate the pharmacodynamics (PD) of PF-04449913 as monotherapy in 
Japanese patients with select advanced hematologic malignancies;

To assess preliminary evidence of clinical efficacy of PF-04449913 administered as 
monotherapy in Japanese patients with select advanced hematologic malignancies.
Combination Cohorts 1 and 2 (Unfit and Fit Patients):
Primary Objective
To determine the safety and tolerability of PF-04449913 administered in combination with 
LDAC (Combination Cohort 1, unfit patients), or cytarabine/daunorubicin (7:3) 
(Combination Cohort 2, fit patients) to Japanese patients with previously untreated AML, or 
high-risk MDS.
Secondary Objectives

To evaluate the PK of PF-04449913 and potential drug-drug interaction (DDI) 
between PF-04449913 and LDAC (Combination Cohort 1, unfit patients) or
cytarabine/daunorubicin (7:3) (Combination Cohort 2, fit patients) administered to 
Japanese patients with previously untreated AML or high-risk MDS;

To evaluate the PD of PF-04449913 administered in combination with LDAC 
(Combination Cohort 1, unfit patients) or cytarabine/daunorubicin (7:3) 
(Combination Cohort 2, fit patients) to Japanese patients with previously untreated 
AML or high-risk MDS;

To assess any preliminary evidence of clinical efficacy (including disease-specific 
measures) of PF-04449913 administered in combination with LDAC (Combination 
Cohort 1, unfit patients) or cytarabine/daunorubicin (7:3) (Combination Cohort 2, fit 
patients) to Japanese patients with previously untreated AML or high-risk MDS.
Expansion Cohort of LDAC Combination for Efficacy (Unfit Patients):
Primary Objective

To evaluate the efficacy (DMR rate) of PF-04449913 administered in combination 
with LDAC to Japanese patients with previously untreated AML or high-risk MDS.
Secondary Objectives

To evaluate the safety of PF-04449913 administered in combination with LDAC to 
Japanese patients with previously untreated AML or high-risk MDS;


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
To evaluate the efficacy [including overall survival (OS)] of PF-04449913 
administered in combination with LDAC to Japanese patients with previously 
untreated AML or high-risk MDS;

To evaluate the PK and PD of PF-04449913 administered in combination with LDAC 
to Japanese patients with previously untreated AML or high-risk MDS.
Combination Cohort 3 (Azacitidine Combination):
Primary Objective
To determine the safety and tolerability of PF-04449913 administered in combination with 
azacitidine in Japanese patients with previously untreated AML who are eligible for 
non-intensive chemotherapy.
Secodary Objectives

To evaluate the PK of PF-04449913 and azacitidine when administered to Japanese 
patients with previously untreated AML who are eligible for non-intensive
chemotherapy;

To evaluate the PD of PF-04449913 administered in combination with azacitidine to 
Japanese patients with previously untreated AML who are eligible for non-intensive 
chemotherapy;

To assess any preliminary evidence of clinical efficacy including OS of PF-04449913 
administered in combination with azacitidine to Japanese patients with previously 
untreated AML who are eligible for non-intensive chemotherapy.
Continuation Cohort:

To assess the safety of PF-04449913 administered as monotherapy in the Japanese 
MF patient who has been treated with PF-04449913 in Study B1371013 and without 
documented objective progression of disease and with continuous clinical benefit at 
the time the patient discontinued from Study B1371013.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
The interim analyses could be performed after the enrollment of 15 patients is completed and 
4 or more DMR responders are observed in the Expansion Cohort of LDAC combination for 
efficacy (Unfit Patients).  In this interim analysis, the statistical test for the primary endpoint 
of this cohort will not be conducted and the achievement of at least 4 DMR responders in
15 patients of this cohort will be confirmed.  The other analyses required at the interim 
analysis will be conducted according to this SAP.


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The primary analysis will be performed after disease assessment on Cycle 9/Day 1 for the 
last (15th) patient treated in Expansion Cohort of LDAC combination for efficacy (Unfit 
Patients). The timing of the primary analysis is estimated to be after approximately 
19 months after the first dose for the first patient in Expansion Cohort of LDAC combination 
for efficacy (Unfit Patients), assuming the enroll speed as 15 patients per year. The final 
analysis will be performed after all patients have died or 2 years after the first dose for the 
last patient treated, whichever occurs first. Further analyses could be performed, if 
necessary.
Unblinding is not applicable, as this is an open-label study.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
For the Expansion Cohort of LDAC combination for efficacy (Unfit Patients), a total of
15 patients will provide 80.8% power to reject the null hypothesis DMR rate=6.8% when the 
true DMR rate=34.1% for the alternative hypothesis.  The DMR rates for the hypotheses are 
based on the result of the analysis based on the derived response for B1371003 CSR 
(P2 Unfit, data cut off: 3 Jan 2017).
For other cohorts, there are no formal statistical hypotheses. The emphasis of the primary 
analysis will be on estimation of key summary statistics.
4.2. Statistical Decision Rules
For cohorts excluding the Expansion Cohort of LDAC combination for efficacy (Unfit 
Patients), no statistical sample size determination was performed. The number of patients to 
be enrolled in the study depends on the observed safety profile within the cohorts. The total 
expected number of patients is estimated to be 34 patients. For Expansion Cohort of LDAC 
combination for efficacy (Unfit Patients), the statistical decision rule is described as follows.
Monotherapy Cohort:
The DLT evaluation period includes the PK lead-in period, and the first cycle of treatment. 
Dose escalation to the 100 mg QD dose level will occur if <1/3 or <2/6 patients at the 
50 mg QD dose level experience DLT during the first cycle of treatment. If ≤1 patient 
experiences a DLT event in the first 3 patients, an additional 3 patients will be enrolled to
give a total of 6 patients in the 100 mg QD cohort. If ≤1 of the 6 patients experiences a DLT 
by the end of Cycle 1, the tolerability of the 100 mg QD dose level in the monotherapy cohort 
will be deemed confirmed, and the study will proceed to the combination cohort. If 2 or 
more of the 6 patients treated at 100 mg QD in the monotherapy cohort experience a DLT by 
the end of Cycle 1, an intermediate dose level (80 mg QD) may be explored in the 
monotherapy cohort prior to proceeding with the combination cohort. If two or more of the 
3 or 6 patients treated at 50 mg QD in the monotherapy cohort experiences a DLT by the end 
of Cycle 1, the dose escalation will be terminated, and a lower dose may be explored.


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Combination Cohorts:
Combination Cohort 1 (Unfit Patients):
A total of 6 patients will be treated in this cohort and followed up for DLT evaluation. The 
DLT evaluation period includes the first cycle of treatment.  If 1 of the 6 patients 
experiences a DLT by the end of Cycle 1, the tolerability of the combination will be deemed 
confirmed. If more than 2 of the 6 patients experience a DLT by the end of Cycle 1, 
additional lower dose levels may be tested, applying identical criteria to those outlined above 
with respect to DLT events.
Expansion Cohort of LDAC Combination for Efficacy (Unfit Patients):
The combination of PF-04449913 and LDAC will be considered superior to the historical
data of LDAC as single-agent with respect to DMR if the DMR rate is statistically significant 
at the 1-sided 0.05 level using exact test for a single proportion.  An observed DMR rate of 
26.7% or above (eg, 4 or more responders out of 15 patients) will reject the null hypothesis.
Combination Cohort 2 (Fit Patients):
A total of 6 patients will be treated in this cohort and followed up for DLT evaluation. If 
1 of the 6 patients experiences a DLT event by the end of Induction Cycle 1, the tolerability 
of the combination will be confirmed. If more than 2 of the 6 patients experience a DLT by 
the end of Induction Cycle 1, additional lower dose levels may be tested using identical
criteria to those outlined above with respect to DLT events.
Combination Cohort 3 (Azacitidine Combination):
A total of 6 patients will be treated in this cohort and followed up for DLT evaluation.  The 
DLT evaluation period includes the first cycle of treatment. If 1 of the 6 patients 
experiences a DLT by the end of Cycle 1, the tolerability of the combination will be deemed 
confirmed.  If more than 2 of the 6 patients experience a DLT by the end of Cycle 1, the 
investigator and the sponsor will review all available safety data and discuss the next steps.
Continuation Cohort:
No decision rule for this cohort.
5. ANALYSIS SETS
Analysis sets are defined as below although the patients enrolled in the Expansion Cohort of 
LDAC combination for efficacy (Unfit Patients) are excluded from DLT-evaluable analysis 
set and the patient enrolled in the Continuation Cohort is excluded from all of these analysis 
sets except the safety analysis set.  The patient enrolled in the Continuation Cohort is 
included in the safety analysis set if the patient receives at least one dose of study medication.


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5.1. Full Analysis Set
The full analysis set includes all enrolled patients who receive at least one dose of study 
medication on or after Cycle 1/Day 1 (Induction Cycle/Day 1 for fit patients in the 
Combination Cohort 2).
5.2. DLT-evaluable Analysis Set (‘Per Protocol’ Analysis Set)
The per protocol analysis set includes all enrolled patients who receive at least one dose of 
study medication and who do not have major treatment deviations during first cycle (DLT 
observation period).  Patients with major treatment deviations during the DLT observation 
period are not evaluable for the DLT assessment and will be replaced as needed. Major 
deviations include, but are not limited to, administration of less than 80% of the planned 
dose during the DLT observation period of PF-04449913 or any component of the 
combination therapy [LDAC for Combination Cohort 1 (Unfit Patients),
cytarabine/daunorubicin for Combination Cohort 2 (Fit Patients), and azacitidine for 
Combination Cohort 3 (Azacitidine Combination)] for reasons other than drug related 
toxicity.
5.3. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least one dose of study 
medication.
5.4. Other Analysis Set
5.4.1. PK Analysis Set
The PK analysis set is defined as all treated patients who have at least 1 concentration of any 
of the study drugs.  The PK parameter analysis population is defined as all treated patients 
who have at least one of the PK parameters of interest of any of the study drugs.
5.4.2. PD Analysis Set
The PD analysis set is defined as all enrolled subjects who receive at least 1 dose of 
PF-04449913 and have at least 1 pharmacodynamic parameter in active treatment period.
5.4.3. QTc-evaluable Analysis Set
The QTc-evaluable analysis set is defined as all patients who have baseline and at least one 
triplicate ECG assessment after having at least one PF-04449913 dose on study.
5.5. Treatment Misallocations 
Not applicable.
5.6. Protocol Deviations
All deviations will be described in the CSR. Major deviations include, but are not limited to, 
administration of less than 80% of the planned dose during the DLT observation period of 
PF-04449913 or any component of the combination therapy [LDAC for Combination 
Cohort 1 (unfit patients), cytarabine/daunorubicin for Combination Cohort 2 (fit patients), 


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and azacitidine for Combination Cohort 3 (Azacitidine Combination)] for reasons other than 
drug related toxicity.
6. ENDPOINTS AND COVARIATES
The assessments on the day of the lead-in dose of PF-04449913 for Monotherapy Cohort and 
Combination Cohort 2 (Fit Patients) are considered baseline whenever they are available. 
The assessments on Cycle 1 Day 1 for Combination Cohort 1 (Unfit Patients), Expansion 
Cohort of LDAC combination for efficacy (Unfit Patients), Combination Cohort 3 
(Azacitidine Combination) and Continuation Cohort are considered baseline whenever they 
are available. If not available, the assessment closest and prior to the lead-in dose (for 
Monotherapy Cohort and Combination Cohort 2) or Cycle 1 Day 1 [for Combination 
Cohort 1, Expansion Cohort of LDAC combination for efficacy (Unfit Patients),
Combination Cohort 3 and Continuation Cohort)] is considered baseline for patients in any
arm, respectively.
6.1. Efficacy Endpoints (excluding the Continuation Cohort)
The efficacy endpoints of the disease response per investigator evaluation based on the 
Response Criteria CRF pages (see Protocol Appendix 5 through Appendix 9) is the primary 
method of documentation of disease. The response criteria differ for each hematologic 
malignancy (see Appendix 2 through Appendix 5 for details). Objective Response (OR) 
needs to be established before any subsequent documentation of progression.
The following dates are identified.

The first objective response date: the assessment date of first documented objective 
response. However, these responses for MDS, CMML and CML need to be 
confirmed as described above. 

The first progression date: the assessment date of first documented (objective) disease 
progression. 

The first relapse date (except for CML): the assessment date of first documented 
relapse.

The last disease assessment date: the date of last disease assessment date.
Combination Cohort 1 (Unfit Patients) and Expansion Cohort of LDAC combination 
for efficacy (Unfit Patients):
The following efficacy endpoints are defined.
DMR and its rate includes complete remission (CR), CR with incomplete blood count 
recovery (CRi), morphologic leukemia-free state (MLFS), marrow CR (mCR) and partial 
remission (PR) (see Protocol Appendix 5 and Appendix 8).


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OS is defined as the time from the date of first dose of study drug to the date of death due to 
any cause. Patients last known to be alive will be censored at the date of last contact. The
primary interest is the survival probability at 6 months and at 12 months.
Duration of response is only defined for patients who have ever achieved CR/CRi on study as
the time from the date of first documentation of a CR/CRi (Protocol Appendix 5 and 
Appendix 8) to the date of loss of response after CR/CRi or death due to any cause.  Duration 
of response data will be censored on the date of the last adequate response assessment for 
patients who do not have an event (loss of response or death).  Duration of DMR for patients 
who have ever achieved DMR on study is also defined.
Time to response is only defined for patients who have ever achieved CR/CRi on study as the 
time from the date of first dose of study drug to the date of first documentation of a CR/CRi.  
Time to DMR for patients who have ever achieved DMR on study is also defined.
Transfusion independence is defined as follows taking into consideration of the schedule of 
activity described in Protocol.  Transfusion history includes the transfusions prior to first 
dose of study treatment including Cycle 1 Day 1.  Transfusion status on study includes the 
transfusions after first dose of study treatment.

Independence of transfusion history for AML patients in Combination Cohort 1 
(Unfit Patients) and Expansion Cohort of LDAC combination for efficacy (Unfit 
Patients) is defined as a lack of requirement for transfusion for at least 4 weeks;

Independence of transfusion history for MDS patients is defined as a lack of 
requirement for transfusion for at least 8 weeks; 

Independence of transfusion status on study for AML and MDS patients is defined as
a lack of requirement for transfusion for at least 8 weeks and ever met this definition
after first dose of study treatment.  Patients not followed by end of treatment for 8 
weeks are not categorized as independent and dependent.
Combination Cohort 3 (Azacitidine Combination):
Same efficacy endpoints described in Combination Cohort 1 (Unfit Patients) will be defined.  
Note that only AML patients will be enrolled in this cohort.  
The definition of transfusion independence of transfusion history is as follows:

Independence of transfusion history in Combination Cohort 3 (Azacitidine 
Combination) is defined as a lack of requirement for transfusion for at least 8 weeks.  
6.2. Safety Endpoints
6.2.1. Dose Limiting Toxicities [excluding the Expansion Cohort of LDAC Combination 
for Efficacy (Unfit Patient) and the Continuation Cohort]
The DLT evaluation of PF-04449913 is based on the definition in Protocol Section 3.2. 


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6.2.2. Adverse Events
Assessment of adverse events (AEs) will include the type, incidence, severity (graded by the 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]
version 4.0) timing, seriousness, and relatedness.  AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA).  AEs will be assigned to the appropriate 
cycle based on Day 1 of each cycle.  Specifically, treatment emergent and treatment related 
AEs are defined as follows.
Treatment Emergent Adverse Events 

All deaths from start of treatment until 28 days after the final dose.

All treatment related SAEs.

All unrelated SAEs from treatment start until 28 days after final dose of treatment.

All non-fatal AEs occurring after treatment start until 28 days after final dose of 
treatment.

Disease progression is not considered a treatment emergent AE unless the subject dies 
of disease prior to 28 days after discontinuation of treatment.

Events that are continuations of baseline abnormalities are considered treatment 
emergent AEs only if the grade increases from baseline.
Treatment Related Adverse Events
Treatment Related Adverse Events are AEs with cause categorized by the investigator as 
related to study treatment.  Events that are continuations of baseline abnormalities (signs and 
symptoms) are not considered treatment emergent, and therefore not considered treatment 
related, unless there is an increase in grade over baseline. 
6.2.3. Laboratory Safety Tests
Laboratory tests will be graded referring to CTCAE grade definitions.  For laboratory tests 
without CTCAE grade definitions, results will be categorized as above, below, within or not 
done if the site has institutional ULN/LLN.
6.3. Other Endpoints
6.3.1. PK Endpoints (excluding the Continuation Cohort)
Monotherapy Cohort
Plasma PK parameters of PF-04449913.
The following single and multiple dose PK parameters will be calculated for PF-04449913
from the plasma concentration/time data obtained after PK Lead-In dose, on Day -5 (single 
dose) and Cycle 1 Day 21 (multiple dose), using non-compartmental method. Descriptive 


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statistics will be provided for these PK parameters in tabular form (n, mean, SD, CV, median, 
minimum, maximum, geometric mean and its associated CV) by dose, cycle and day.

Single Dose - Cmax, Tmax, AUClast, AUC, CL/F, and Vz/F, t1/2, AUCinf as data permit.

Multiple Dose (assuming steady-state is achieved) - Cmax, Tmax, AUC, Cmin, Cav, 
Ctrough, CL/F, Rac (AUCss,/AUCsd,) and Rss (AUCss,/AUCsd,inf) as data permit.
Combination Cohort 1 (Unfit Patients), Expansion Cohort of LDAC Combination for 
Efficacy (Unfit Patients), Cohort 2 (Fit Patients) and Cohort 3 (Azacitidine 
Combination)
Plasma PK parameters of PF-04449913, cytarabine, daunorubicin, and azacitidine.
Standard plasma PK parameters include Cmax, Tmax, and AUC for each drug (and metabolite 
if relevant) will be estimated using non-compartmental method. If data permit or if 
considered appropriate, Cmin, Cave, Ctrough, AUCinf, and t1/2 may be estimated. Descriptive 
statistics will be provided for these PK parameters in tabular form (n, mean, SD, CV, median, 
minimum, maximum, geometric mean and its associated CV) by analyte, dose, 
administration route, cycle and day.
For Expansion Cohort of LDAC combination for efficacy (Unfit Patients), descriptive 
summary of PF-04449913 concentration will be provided but PK parameters will not be 
calculated.
6.3.2. Drug-Drug Interaction Endpoints (Combination Cohorts Only)
6.3.2.1. Combination Cohort 1 (Unfit Patients): PF-04449913 and LDAC
The primary PK parameters, AUC and Cmax, will be utilized to estimate the effect of 
coadministration of PF-04449913 and LDAC on the PK of either PF-04449913 or LDAC.
6.3.2.2. Combination Cohort 2 (Fit Patients): PF-04449913 and
Cytarabine/Daunorubicin
The primary PK parameters, AUC and Cmax, will be utilized to estimate the effect of 
coadministration of PF-04449913 and daunorubicin/cytarabine on the PK of PF-04449913.
6.3.2.3. Combination Cohort 3 (Azacitidine Combination): PF-04449913 and
Azaciditine
The primary PK parameters, AUC and Cmax, will be utilized to estimate the effect of 
co administration of PF-04449913 and azacitidine on the PK of either PF-04449913 or 
azacitidine.
6.3.3. ECG
Triplicate, 12 lead ECGs for PF-04449913 is described in the relevant Schedule of Activities 
(see Protocol Table 1 through Table 6).


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The baseline evaluations for ECGs are the average of the triplicate pre-dose values. The 
baseline ECG for Monotherapy Cohort and Combination Cohort 2 (Fit Patients) is defined as 
the last ECG(s) prior to the lead-in dose of PF-04449913. The baseline ECG for 
Combination Cohort 1 (Unfit Patients), Expansion Cohort of LDAC combination for efficacy 
(Unfit Patients), Combination Cohort 3 (Azacitidine Combination) is defined as the last 
ECG(s) prior to the dose of PF-04449913. If this was not collected, the baseline will be 
calculated from the ECG closest to the first dose of study drug during the screening period.
If the last ECGs are triplicate ECGs (or only 2), they will be averaged.  If the last ECG is a 
single, that will be used as baseline. 
6.3.4. PD Biomarker Endpoints (excluding the Continuation Cohort)
PD Biomarker assessments may include the following; (i) evaluation of Hh pathway genes 
and proteins, (ii) circulating cytokine levels, and (iii) molecular analysis of somatic 
mutations and translocations with a known frequency of occurrence in the AML and MDS 
populations.  Additional PD biomarkers may also be included, based on emerging data on 
Hh pathway biology.
The baseline PD biomarker measurements are defined to follow Section 6.
6.3.5. Extramedullary Disease Endpoint (excluding the Continuation Cohort)
The baseline extramedullary disease assessments are defined to follow Section 6.
6.4. Covariates
Not applicable.
7. HANDLING OF MISSING VALUES
7.1. Missing Dates
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used (unless for OS a later contact date in the month
is established and then the day after will be used as the date of death for the patients with
partial death date) to replace the missing date unless the calculation results in a negative time 
duration (eg, date of onset cannot be prior to day one date).  In this case, the date resulting in 
duration of 1 day will be used.  Pfizer standards are also used if both month and day are 
missing (Jan 1 unless negative time duration or for OS the day after the latest contact date in
that year will be used as the date of death for the patients with partial death date).
7.2. Efficacy Analysis
For efficacy analyses, no values will be imputed for missing data.  Censoring for 
time-to-event endpoints is defined in Section 6.1.
In the assessment of CR/CRi or DMR rate, patients who are not known to have achieved the 
endpoint of interest (CR/CRi or DMR) will be counted as non-responders.


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7.3. PK
Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification).
Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated with 
concentrations set to missing if one of the following cases is true:
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
PK Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie, not calculated).  (Note that NC values will not be generated beyond the 
day that a subject discontinues).
For evaluation of changes in pharmacokinetics of a compound when administered alone vs. 
in combination, only subjects with matching pair of pharmacokinetic assessments under both 
conditions will be included in the pharmacokinetic summary (ie, alone and in combination).
In summary tables, statistics will not be presented for a particular treatment group if more 
than 50% of the data are NC.  For statistical analyses (ie, analysis of variance), PK 
parameters coded as NC will also be set to missing.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the drug is absorbed in the body), this will 
be footnoted in summary tables and will not be included in the calculation of summary 
statistics or statistical analyses.
7.4. QTc
For analyses using the QTc-evaluable analysis set and safety analysis set, no values will be 
imputed for missing data except for averaging of triplicate measurements.  If one or two of 
the triplicate measurements for an ECG parameter are missing, the average of the remaining 
two measurements or the single measurement can be used in the analyses.  If all triplicate 
measurements are missing at a time point for an ECG parameter, no values will be imputed 
for this time point and this subject will be excluded from the analyses related to this time 
point.  Unplanned ECGs will be in triplicate and averaged.


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7.5. PD Parameters
Missing data for the pharmacodynamic parameters will be treated as such and no imputed 
values will be derived.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods 
Hypothesis testing will be performed as discussed in Section 4.
8.1.1. Analyses of Time-to-Event Endpoints
Unless otherwise stated, time-to-event endpoints will be summarized using the Kaplan-Meier
method and displayed graphically (with number of patients still at risk noted on the
horizontal axis) when appropriate.
Median event times and two-sided 90% and 95% confidence intervals (CIs) for each 
time-to-event endpoint will be provided. Point estimate of selected survival probabilities and 
two-sided 90% and 95% CIs will also be provided, where the log-log transformation and
back-transformation will be used in the calculation.
8.1.2. Analyses of Binary Endpoints
The rates of binary endpoints will be provided along with the corresponding two-sided 
90% and 95% CIs using exact method.
8.1.3. Analyses of Continuous Data
The descriptive statistics, such as the mean, standard deviation, coefficient of variation, 
median, minimum, and maximum values, will be provided for continuous endpoints.
8.2. Statistical Analyses 
For the Continuation Cohort, only the listings will be produced and the tables and figures will 
not be produced.
8.2.1. Analysis of Primary Endpoints
Monotherapy Cohort:
Analysis set: DLT-evaluable Analysis Set.
Table produced by: dose level.
Analysis:
The safety and tolerability is determined by quantification of patients experiencing 
DLTs at each dose level during the PK lead-in period and the first cycle of treatment.
Table: Number of patients who experienced DLT will be tabulated by dose level.
Listing: All records on DLT CRF page will be listed.


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Combination Cohorts Other Than Expansion Cohort of LDAC combination for 
efficacy (Unfit Patients):
Analysis set: DLT-evaluable Analysis Set.
Table produced by: cohort (Combination Cohort 1, 2 and 3).
Analysis:
The safety and tolerability is determined by quantification of patients experiencing 
DLTs at each dose level during the PK lead-in period and the first cycle of treatment.
Table: Number of patients who experienced DLT will be tabulated by cohort.
Listing: All records on DLT CRF page will be listed.
Expansion Cohort of LDAC combination for efficacy (Unfit Patients):
Analysis set: Full Analysis Set.
Table produced by: Not applicable.
Analysis: 
The DMR is defined in Section 6.1.  The number and percentage of patients who 
have ever achieved DMR will be summarized for irrespective of AML and MDS
patients.  An exact test for a single proportion (1-sided significance level: 0.05) will 
be used.  The null hypothesis is that DMR rate=6.8%, and the alternative hypothesis 
is that DMR rate=34.1%.  The two-sided 90% and 95% CIs will be also presented.  
Table: Table will include the number and percentage of DMR responders, p-value and CI.
Listing: Not applicable.  The listing of DMR will be included in the listing of disease
response (see Section 8.2.2.1).
8.2.2. Analysis of Efficacy Endpoints
All efficacy analyses are secondary excluding the primary endpoint for Expansion Cohort of 
LDAC combination for efficacy (Unfit Patients) in the section above.
For Combination Cohort 1 (Unfit Patients), Expansion Cohort of LDAC combination for 
efficacy (Unfit Patients), and Combination Cohort 3 (Azacitidine Combination), the 
statistical analysis methods are described in the following sections.  
For other cohorts, listings of subject’s disease status on study will be provided by dose level,
cohort and malignancy using the Full Analysis Set. 
8.2.2.1. Disease Response
Combination Cohort 1 (Unfit Patients) and Expansion Cohort of LDAC combination 
for efficacy (Unfit Patients):
Analysis set: Full Analysis Set.


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Table produced by: Table will be produced by cohort. See the following.
Analysis: 
For AML patients, the best overall response will be summarized in frequency tables.  
The further endpoints of interest including CR/CRi and DMR will also be 
summarized with 90% and 95% exact CIs.  
For MDS patients, the best overall response will be summarized in frequency tables.  
The further endpoints of interest including CR and DMR will also be summarized 
with 90% and 95% exact CIs.
For irrespective of AML and MDS patients, CR/CRi rate and DMR rate will be 
summarized in frequency tables with 90% and 95% exact CIs.
Table:

Best overall response, CR/CRi and DMR for AML patients;

Best overall response, CR and DMR for MDS patients;

CR/CRi rate and DMR rate for irrespective of AML and MDS patients.
Listing: The disease responses will be listed by malignancy.
Combination Cohort 3 (Azacitidine Combination):
Same analyses described in Combination Cohort 1 (Unfit Patients) and Expansion Cohort of 
LDAC combination for efficacy (Unfit Patients) will be conducted.  Note that only AML 
patients will be enrolled in this cohort.
8.2.2.2. Duration of Response
Combination Cohort 1 (Unfit Patients) and Expansion Cohort of LDAC combination 
for efficacy (Unfit Patients):
Analysis set: Full Analysis Set.
Table produced by: AML, MDS and irrespective of AML and MDS.
Analysis: 
Kaplan-Meier estimates (productlimit estimates) will be presented together with a 
summary of associated statistics including the median duration of CR/CRi or DMR
with two-sided 90% and 95% CIs.
Table:

Summary of duration of response.


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Figure:

Kaplan-Meier curve of duration of response.
Listing:

Listings include, but are not limited to, event/censor date, event/censor day from first 
dose, event type, reason for censoring, European Leukemia Net (ELN) cytogenetic 
risk and age (≤60 vs >60 years).
Combination Cohort 3 (Azacitidine Combination):
Same analyses described in Combination Cohort 1 (Unfit Patients) and Expansion Cohort of 
LDAC combination for efficacy (Unfit Patients) will be conducted.  Note that only AML 
patients will be enrolled in this cohort.
8.2.2.3. Time to Response
Combination Cohort 1 (Unfit Patients) and Expansion Cohort of LDAC combination 
for efficacy (Unfit Patients):
Analysis set: Full Analysis Set.
Table produced by: AML, MDS and irrespective of AML and MDS.
Analysis: 
Kaplan-Meier estimates (productlimit estimates) will be presented together with a 
summary of associated statistics including the time to CR/CRi or DMR with two-
sided 90% and 95% CIs.
Table:

Summary of time to response.
Figure:

Kaplan-Meier curve of time to response.
Listing:

Listings include, but are not limited to, event/censor date, event/censor day from first 
dose, event type, reason for censoring, ELN cytogenetic risk and age 
(≤60 vs >60 years).
Combination Cohort 3 (Azacitidine Combination):
Same analyses described in Combination Cohort 1 (Unfit Patients) and Expansion Cohort of 
LDAC combination for efficacy (Unfit Patients) will be conducted.  Note that only AML 
patients will be enrolled in this cohort.


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8.2.2.4. Overall Survival
Combination Cohort 1 (Unfit Patients) and Expansion Cohort of LDAC combination 
for efficacy (Unfit Patients):
Analysis set: Full Analysis Set.
Table produced by: AML, MDS and irrespective of AML and MDS.
Analysis: 
OS time will be summarized using the Kaplan-Meier method (product-limit 
estimates) and displayed graphically where appropriate. CIs for the 25th, 50th, and 
75th percentiles will be reported. In addition, the median OS and its two-sided
90% and 95% CIs using the Brookmeyer and Crowley method1 will be provided.
The OS rate at 6, 12, and 18 months will be estimated with corresponding two-sided 
90% and 95% CIs. The CIs for the median will be calculated according to 
Brookmeyer and Crowley and the CIs for the survival function estimates at the 
timepoints defined above will be derived using the log(-log) method according to 
Kalbfleisch and Prentice2 (conftype=loglog default option in SAS Proc LIFETEST). 
The estimate of the standard error will be computed using Greenwood’s formula.
Frequency (number and percentage) of patients with an event (death) and censoring 
reasons will be presented.
Table:

Summary of OS.
Figure:

Kaplan-Meier curve of OS.
Listing:

Listings include, but are not limited to, event/censor date, event/censor day from first 
dose, event type, reason for censoring, ELN cytogenetic risk and age 
(60 vs >60 years).
Combination Cohort 3 (Azacitidine Combination):
Same analyses described in Combination Cohort 1 (Unfit Patients) and Expansion Cohort of 
LDAC combination for efficacy (Unfit Patients) will be conducted.  Note that only AML 
patients will be enrolled in this cohort.


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8.2.2.5. Transfusions
Analysis set: Full Analysis Set. 
Table produced by: AML, MDS, irrespective of AML and MDS for Combination Cohort 1 
(Unfit Patients), Expansion Cohort of LDAC combination for efficacy (Unfit Patients), and 
Combination Cohort 3 (Azacitidine Combination), respectively.
Tables: 
For the transfusion independence, the transfusion history and transfusion status on 
study will be summarized in frequency tables as following.  
Mock Table:
Number (%) of Subjects
n++
Transfusion Status on Study
Independent
n+1 (n+1/n++)
Dependent
n+2 (n+2/n++)
Not Followed for 8 Weeks
n+3 (n+3/n++)
Transfusion History
Independent
n1+ (n1+/n++)
Transfusion Status on Study
Independent
n11 (n11/n1+)
Dependent
n12 (n12/n1+)
Not Followed for 8 
Weeks
n13 (n13/n1+)
Dependent
n2+ (n2+/n++)
Transfusion Status on Study
Independent
n21 (n21/n2+)
Dependent
n22 (n22/n2+)
Not Followed for 8 
Weeks
n23 (n23/n2+)
Notation:
Transfusion
History
Transfusion Status on Study
Independent
Dependent
Not Followed for 8 
Weeks
Total
Independent 
n11
n12
n13
n1+
Dependent
n21
n22
n23
n2+
Total
n+1
n+2
n+3
n++
(Full Analysis Set)
Listings: 

Transfusion records including transfusion type, date of transfusion and number of 
units (Listing by dose level, cohort);


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
Transfusion independence: transfusion history and transfusion status on study.
8.2.3. Subset Analysis
Subset analyses will be performed for OS (Section 8.2.2.4) and transfusion independence
(Section 8.2.2.5) based on the FAS for the subgroups defined below. 
The following subgroups will be defined and used for analyses:

DMR

DMR responder vs non-responder
Subset analyses for OS will use the primary censoring rules described in Section 6.1. All the 
subgroup analyses are exploratory. 
8.2.4. Analysis of Safety Data
Patients in Monotherapy Cohort will be analyzed by dose level and regardless of them. 
Patients in Combination Cohort will be analyzed separately as Combination Cohort 1 (Unfit 
Patients), Combination Cohort 2 (Fit Patients) and Combination Cohort 3 (Azacitidine 
Combination).
8.2.4.1. Adverse Events
Analysis set: Safety Analysis Set. 
Table produced by: dose level and cohort.  For the Continuation Cohort, only the listings will 
be produced.
Analysis:
The focus of AE summaries will be on Treatment Emergent Adverse Events, those 
with initial onset or increasing in severity after the first dose of study medication. 
See Section 6.2.2 for the definition of treatment emergent adverse event. The
number and percentage of patients who experienced any AE, serious AE (SAE), 
treatment related AE, and treatment related SAE will be summarized according to 
worst toxicity grades.  The summaries will present AEs both on the entire study 
period and by cycle (Cycle 1 and Cycles beyond 1).  For the summaries of AEs 
occurring at Cycles beyond 1, only the patients who start the study treatment of 
Cycle 2 will be analyzed.
Table:
Every table as described below will be created for any AE and treatment related AE.

Discontinuations due to AEs;

Temporary discontinuations or dose reductions due to AEs;

Overall summary of AEs;


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
Number of patients observed with AEs and corresponding percentages by MedDRA 
system organ class and preferred term;

Number of patients observed with AEs and corresponding percentages by MedDRA 
preferred term sorted by frequency;

Summary of death (Frequency of subject who died on-treatment, subject who died 
during follow-up, and cause of death).
Listings: 

AEs (all grade, and grade 3 and greater);

Death;

SAE.
8.2.4.2. Laboratory Tests
Analysis set: Safety Analysis Set.
Table produced by: dose level and cohort.  For the Continuation Cohort, only the listings will 
be produced.
Analysis: 
The number and percentage of patients who experienced laboratory test 
abnormalities will be summarized according to worst toxicity grade observed for 
each laboratory assay.  The summary and shift summary of baseline grade by 
maximum post-baseline CTCAE grade will be presented. For laboratory tests 
without CTCAE grade definitions, results will be categorized as normal, abnormal 
or not done.
Tables: 

Summary results by maximum CTCAE grade;

Shift summary results of baseline grade by maximum post-baseline CTCAE grade;

Worst on-study abnormality.
Figure: 
Individual values will be plotted over time for each continuous laboratory parameters by 
dose level and cohort as data allow.
Listings: 

Measured data;

NCI-CTCAE grades;


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
Measured data with NCI-CTCAE grades 3 and 4;

Abnormality records (by subject, by test).
8.2.4.3. Hy’s Law
Analysis set: Safety Analysis Set.
Table produced by: Not applicable.
Analysis: The subjects will be identified as potential Hy’s Law cases based on 
Protocol Section 8.6.2.
Tables: Not applicable.
Figure: Not applicable.
Listings: Listing includes baseline values, actual value, ULN, and ratio of actual value to
ULN with flag indicates the result meets the Hy’s law criteria for each laboratory test
(bilirubin, AST, ALT, and alkaline phosphatase) by study day measured laboratory test.
Listing will be produced by dose level, cohort and malignancy.
8.2.4.4. Analysis of ECG
Analysis set: 
(1) QTc-evaluable Analysis Set; (2) Safety Analysis Set
Table produced by: dose level, cohort.  For the Continuation Cohort, only the listings will be 
produced.
Analysis: 
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis (duplicate ECGs will also be averaged and single ECGs used if 
necessary).  Any data obtained from ECGs repeated for safety reasons after the 
nominal time-points will not be averaged along with the preceding triplicates.  
Interval measurements from repeated ECGs will be included in the outlier analysis 
as individual values obtained at unscheduled time points. The average of triplicate 
or duplicate measurements will be rounded off and handle as integer in the analyses 
of ECG.
Descriptive statistics (n, mean, median, standard deviation, minimum, and 
maximum) will be used to summarize the absolute QTc, QT, HR, PR, QRS values
and changes from baseline in QTc, QT, HR, PR, QRS by treatment arm, cohort and 
time point.  For each patient and by treatment, the maximum increase from baseline 
as well as the maximum post-baseline value will be calculated across time points 
using the correction method(s) deemed appropriate.  Categorical summarization of 
the QTc (using the most appropriate correction method), QT, HR, PR, QRS data 
will be conducted and summarized as follows:


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
The number of patients with maximum increase from baseline in QTc 
(<30, ≥30-<60, and ≥60 msec);

The number of patients with maximum post-dose (post-baseline) QTc 
(<450, ≥450-≤480, ≥481-≤500, and ≥501 msec);

PR changes from baseline ≥25% and baseline absolute values over >200 msec, or PR 
changes from baseline ≥50% and baseline absolute values over ≤200 msec;

PR ≥300 msec;

QRS changes from baseline ≥25% and baseline absolute values over >110 msec, or
QRS changes from baseline ≥50% and baseline absolute values over 110 msec;

QRS 200 msec.
Shift tables will be provided for baseline vs. worst on study QTc (one or more correction 
methods may be used) using the categories described above.
Tables: 

Descriptive statistics of absolute values by time point [analysis set (1) and (2)];

Descriptive statistics of change from baseline values by time point [analysis set (1)];

Descriptive statistics of maximum post-baseline values [analysis set (1)];

Descriptive statistics of maximum increase from baseline values [analysis set (1)];

Categorical summary of post-baseline maximum absolute values [analysis set (1) 
and (2)];

Categorical summary of maximum increase from baseline values [analysis set (1)];

Shift summary of QTcF results [analysis set (1)].
Listings: 

Measured data (QT, HR, PR, QRS and QTcF);

Change from baseline (QT, HR, PR, QRS and QTcF);

Qualitative results;

Maximum values (QT, HR, PR, QRS and QTcF);

Maximum change from baseline (QT, HR, PR, QRS and QTcF).


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8.2.5. Analyses of Vital Signs
Analysis set: Safety Analysis Set. 
Table produced by: dose level and cohort.  For the Continuation Cohort, only the listings will 
be produced.
Table: Not applicable.
Figure:
For actual measures and changes from baseline, individual plot will be created for 
each vital sign as data allow. Actual time from Cycle 1 Day 1 will be used as 
X-axis in unit of day.
Listing:
Listing will be prepared for each vital sign, and will include actual measures, change 
from baseline and both met the specific categories (see Appendix 1).
8.2.6. Analysis of PK Data (excluding the Continuation Cohort)
8.2.6.1. Pharmacokinetic Parameters [excluding the Expansion Cohort of LDAC 
combination for efficacy (Unfit Patients)]
Analysis set: PK Parameter Analysis set
Each PK parameter will be summarized wherever applicable.  The set of summary statistics 
as specified in the table below will be included: 
Parameter
Summary statistics
AUC, Cmax, Cmin, 
Cavg, Ctrough*, CL
(CL/F), Vz (Vz/F)
N, geometric c mean, median, geometric 
CV%, standard deviation, minimum, 
maximum, arithmetic mean
Tmax, Rac, Rss
N, median, minimum, maximum
t½
N, arithmetic mean, median, CV%, 
standard deviation, minimum, maximum.
* Ctrough is defined as the observed concentration prior to dose administration.
These summary tables will be generated by analyte for the PK analysis set.  The PK 
parameters generated will be summarized by cohort, analyte, dose, cycle and day. 
Ctrough will be summarized separately for each cohort.  Additionally, summaries will be 
generated for ONLY patients that received PF-04449913 daily without interruptions or dose 
reductions 6 days prior to the day of sample collection.


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
Box and whisker plots for individual subject parameters by analyte (AUC, Cmax and 
Ctrough, CL/F, Vz/F) and overlaid with geometric means will be presented for the PK 
analysis set and for ONLY patients that received PF-04449913 daily without 
interruptions or dose reductions 6 days prior the day of sample collection.

A listing of PK parameters by cohort, analyte, dose cycle, and day.
8.2.6.2. Pharmacokinetic Concentrations
Analysis set: PK Concentration Analysis set

A listing of daily dosing including dose modification status and day as appropriate for 
each cohort by analyte. 

A listing of all plasma concentrations sorted by cohort, analyte, dose, cycle, day and 
nominal time post dose.  The listing of plasma concentrations will include the actual 
times.  Deviations from the nominal time will be given in a separate listing.

A summary of plasma concentrations by cohort, analyte, dose, cycle, day and nominal 
time post-dose, where the set of statistics will include n, mean, median, standard 
deviation, coefficient of variation (% CV), minimum, maximum and the number of 
concentrations above the lower limit of quantification for the PK analysis set.  Plasma 
concentrations by cohort, analyte, dose, cycle, day and nominal time post-dose, will 
be reported also for ONLY patients that are considered dose compliant (steady state 
with respect to that analyte).

Median plasma concentrations time plots (on both linear and semi-log scales) against 
nominal time post-dose by analyte and dose for the PK analysis set and for ONLY 
patients that are considered dose compliant (steady state with respect to that analyte).

Individual plasma concentration time plots by analyte and dose (on both linear and 
semi-log scales) against actual time post-dose.

Individual Ctrough plasma concentration time plots for PF-04449913 (on linear scales) 
against Cycle/Day.
8.2.7. Analysis of Drug-Drug Interaction (Combination Cohorts 1, 2, 3 Only)
8.2.7.1. Unfit Cohort: PF-04449913 and LDAC
The primary pharmacokinetic parameters, AUC and Cmax, will be utilized to estimate the 
effect of co-administration of PF-04449913 and LDAC on the pharmacokinetics of either 
PF-04449913 or LDAC. The geometric mean ratios and its 90% confidence intervals (if 
data permit) for the PK parameters will be used for assessment of the extent of interaction
for PF-04449913 in presence of LDAC and PF-04449913 alone.
PF-04449913 AUC and Cmax when administered alone (Cycle 1/Day 21) will be compared to 
Cycle 1/Day 10 AUC and Cmax, when administered in combination with LDAC.  A similar 
assessment will be performed to determine the effect of PF-04449913 on LDAC.  The AUC 
and Cmax on Cycle 1 Day 2 when LDAC is administered alone will be compared to 
Cycle 1/Day 10 AUC and Cmax when administered in combination with PF-04449913. 


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8.2.7.2. Fit Cohort: PF-04449913 and Daunorubicin/Cytarabine 
The primary pharmacokinetic parameters, AUC and Cmax, will be utilized to estimate the 
effect of co-administration of PF-04449913 and daunorubicin/cytarabine on the 
pharmacokinetics of PF-04449913. The geometric mean ratios and its 90% confidence 
intervals (if data permit) for the PK parameters will be used for assessment of the extent of 
interaction for PF-04449913 in presence of daunorubicin/cytarabine and 
PF-04449913 alone.
PF-04449913 AUC and Cmax when administered alone (Induction Cycle Day 10) will be 
compared to Induction Cycle/Day 3 AUC and Cmax, when administered in combination with 
daunorubicin/cytarabine.  The effect of PF-04449913 on daunorubicin/cytarabine will not be 
conducted within the study due to the inability to dose daunorubicin/cytarabine alone.
8.2.7.3. Azacitidine Combination Cohort: PF-04449913 and Azacitidine
The primary PK parameters, AUC and Cmax, will be utilized to estimate the effect of 
co-administration of PF-04449913 and azacitidine on the PK of either PF-04449913 or 
azacitidine.  The geometric mean ratios and its 90% confidence intervals (if data permit) for 
the PK parameters will be used for assessment of the extent of interaction for 
PF-04449913+ azacitidine vs. PF-04449913 alone.  A similar assessment will be conducted 
for azacitidine + PF-04449913 vs. azacitidine alone.
PF-04449913 AUC and Cmax when administered alone (Cycle 1/Day 21) will be compared to 
Cycle 1/Day 7 AUC and Cmax, when administered in combination with azacitidine.  A similar 
assessment will be performed to determine the effect of PF-04449913 on azacitidine.  The 
AUC and Cmax on Cycle 1 Day 1 when azacitidine is administered alone will be compared to 
Cycle 1/Day 7 AUC and Cmax when azacitidine is administered in combination with 
PF-04449913.
8.2.8. Analysis of PD Biomarker Data (excluding the Continuation Cohort)
PD biomarkers will be assessed separately for blood, serum, normal skin biopsies, bone 
marrow aspirate and bone marrow biopsies. In each case, summaries of baseline levels,
changes from baseline (where appropriate), and mutation status will be reported. Summary 
statistics may include the mean and standard deviation, median, %CV and 
minimum/maximum levels of biomarker measures or frequency statistics, as appropriate.
Data from biomarker assays will be analyzed using graphical methods. 
If data permit, data from biomarker assays will be analyzed using graphical methods and 
descriptive statistics such as linear regression, Wilcoxon and ranked sum. Moreover, the 
statistical approach may examine correlations of biomarker results with pharmacokinetic 
parameters and measures of anti tumor efficacy.
Analysis set: PD Analysis Set. 
Table produced by: dose level, cohort and biomarker type (plasma and cells).


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Analysis:
Summaries of baseline and change from baseline (screening) to post-treatment as 
measured using ratio to baseline will be provided by time point. Graphical displays 
will be provided, as appropriate.  All data will be listed.
For Combination Cohort 2 (Fit patients), summaries will be done separately for the 
induction, consolidation and maintenance periods, as well as together across periods.
When summaries will be done separately for perieds, the baseline in each period will 
be defined as the pharmacodynamic biomarker assessments on the first dosing day of 
study treatment in each period.
Tables: 

Summaries of actual value from baseline to post-treatment;

Summaries of change from baseline (screening) to post-treatment by ratio to baseline.
Figure: 
Individual plot will be plotted over time for each biomarker by dose level and cohort
as data allow.
Listings: Each PD biomarker data will be listed. 
8.2.9. Population PK Analysis or PK/PD Modeling (excluding the Continuation Cohort)
PK and PD data from this study may be analyzed using compartmental or mixed-effect 
modeling approaches and may also be pooled with other study results.  PK/PD modeling 
may be attempted to investigate any causal relationship between PF-04449913 exposure and 
biomarkers or significant safety endpoints. The results of these analyses, if performed, may 
be reported separately.
8.2.10. Other Analyses
8.2.10.1. Standard Analyses
8.2.10.1.1. Study Conduct and Subject Disposition
An accounting of the study subjects will be tabulated. Subjects not completing the 
treatment/study (completing the treatment means the subject completes treatment for 
12 cycles; completing the study means the subject completes the post-treatment follow-up 
period) will be listed along with the reason for discontinuation.
Analysis set: Screened patients. 
Table produced by: dose level and cohort.


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Table: 
Subject disposition and evaluability will be summarized. Summary table will include 
following number of subjects:

Assigned to study treatment (treated, completed, discontinued);

Analyzed for DLT;

Analyzed for safety (AEs, laboratory data);

Analyzed for PK (PK parameter, PK concentration);

Analyzed for PD;

Analyzed for QTc.
Listings: Subject disposition and evaluability will be listed.
8.2.10.1.2. Subject Discontinuation
Analysis set: Safety Analysis Set.  
Table produced by: dose level and cohort.  For the Continuation Cohort, only the listings will 
be produced.
Table: Subject discontinuation will be summarized. 
Listing: Information of subject discontinuation will be listed.
8.2.10.1.3. Baseline Characteristics
Analysis set: Safety Analysis Set. 
Table produced by: dose level and cohort.  For the Continuation Cohort, only the listings will 
be produced.
Tables:

Demography (sex, age, race, weight, height);

Subject accrural (site No.);

Primary diagnosis (diagnosis, duration);

Medical history (past, present);

ECOG performance status at Screening.


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The duration of primary diagnosis is obtained by the time from the date of 
histopathological diagnosis to one of enrollment.
Listings: 
All the above characteristics will be listed. In addition, following information will be 
also provided.

Prognostic scores (Sokal Score for CML, IPSS for MDS, Dupriez Score for MF);

Childbearing potential (childbearing potential, contraceptive method);

Primary diagnosis as AML (AML-Fab subtype, AML disease history).
8.2.10.1.4. Treatment Administration
Analysis set: Safety Analysis Set. 
Table produced by: dose level, cohort and regimen. (Regimen is for Combination Cohort 2, 
fit patients; induction, consolidation and maintenance)  For the Continuation Cohort, only the 
listings will be produced.
Analysis: Initial planned dose is defined as prescribed dose at the start day defined below. 
The units of the prescribed daily dose of cytarabine and daunorubicin (Combination 
Cohort 2, fit patients), and azacitidine (Combination Cohort 3) are transformed mg/m2 to mg 
based on body surface area (BSA) on Cycle 1 Day 1.
Definition of the start day for initial planned dose

PF-04449913 in Combination Cohort 1: Cycle 1 Day 3;

PF-04449913 on induction cycle in Combination Cohort 2: Cycle 1 Day -3;

PF-04449913 in Combination Cohort 3: Cycle 1 Day 2;

PF-04449913 for others, LDAC, daunorubicin, cytarabine and azacitidine: Cycle 1 
Day 1.
Tables: 
Dose administration will be summarized as follows:

Treatment duration (day) by regimen. (Number (%) of subjects with duration 
category, median, range) [Duration category (day): 1, 2-7, 8-14, 15-28, 29-56, 57-84, 
85-112, 113];

Total number of cycle started (median, range);

Number (%) of subjects started each cycle;


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
Number (%) of subjects with at least one cycle delay, where cycle delay is defined as 
any delay of the cycle start date, based on the previous cycle’s start date;

Number (%) of subjects with at least one dose reduction, where dose reduction is 
defined as a day when the actual dose taken is less than the initial planned dose for 
any reason with the exception that a day with total dose administered of 0 mg is not 
considered a dose reduction [by study treatment]. In the event that the prescribed 
dose varies across cycles as a result of body weight change of >10% per protocol, the 
adjusted prescribed dose is considered the initial planned dose for the relevant cycles;

Number (%) of subjects with at least one dose interruption/missed dose, where dose 
interruptions/missed dose is defined as a planned dosing day with 0 mg total dose 
administered only PF-04449913.
Relative dose intensity will be summarized using mean, standard deviation, median, and 
range as follows:

Actual dose intensity [mg/week] = total dose received / (cycle length / 7), where

Total dose received [mg/cycle] is an actual total dose in the cycle,

Cycle length [day/cycle] = date of end of treatment in the cycle − date of start 
of treatment in the cycle + 1, that is the cycle length includes the delay until
the next cycle.

Relative dose intensity by cycle = {total dose received / (dose duration / 7)} / planned 
dose intensity, where 

Dose duration [day/cycle] = sum of dose duration from each dosing record,

Planned dose intensity [mg/week] = (prescribed dose at start of cycle * 
planned dose duration per protocol) / (planned dose duration per protocol / 7).

Overall relative dose intensity = {sum of “total dose received” / (sum of “dose 
duration” / 7)} / {sum of “prescribed dose at start of cycle * planned dose duration 
per protocol” / (sum of “planned dose duration per protocol” / 7)}.
Listings:

Listings by subject: study drug, start date and stop date of each dosing period within 
each cycle (including records with 0 mg), prescribed dose and actual received dose 
for each period, any missed doses with unknown dates (Y/N), number of missed 
doses with unknown dates, reason for any dosing changes.

Listings by study treatment, subject and each cycle: cycle start/stop date and study 
day, planned total dose (based on prescribed dose at Day 1 of each cycle), prescribed
total dose, total dose received, percentage of starting dose (compared to Day 1 
prescribed dose for that cycle), percent of prescribed dose (ie, compliance derived by 


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the following equation, total dose received/planned total dose), dose delay (yes/no), 
dose reduction (yes/no), dose interruption (yes/no).

Listings of dose intensity by study treatment, prescribed dose at start of cycle, 
planned dose duration per protocol, total dose received, cycle length, dose duration, 
planned dose intensity, actual dose intensity, relative dose intensity by cycle.
8.2.10.1.5. Prior, concomitant, post-treatment drug and non-drug treatments
Analysis set: Safety Analysis Set. 
Table produced by: dose level and cohort.  For the Continuation Cohort, only the listings will 
be produced.
Tables: 

Prior treatments (prior surgery, Y/N; prior radiation, Y/N; previous drug therapy for 
primary diagnosis, number of regimen [0/1/2/3/4+]);

Previous drug therapy for primary diagnosis [Frequency of drug;

Prior nondrug treatments/procedures (radiation therapies, surgeries, non-drug 
treatment/procedures);

Concomitant drug treatments;

Concomitant nondrug treatments/procedures (radiation therapies, surgeries, non-drug 
treatment/procedures).
Listings: 
All the above information will be listed. In addition, following information will be also 
provided.

Previous drug therapies for primary diagnosis (excluding the Continuation Cohort);

Previous drug therapies;

Prior radiation therapies (excluding the Continuation Cohort);

Prior surgeries for primary diagnosis (excluding the Continuation Cohort);

Concomitant drug therapies;

Concomitant radiation therapies;

Concomitant surgeries for primary diagnosis;

Non-drug treatment/procedure.


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8.2.10.2. Risk Category (excluding Combination Cohort 3 and the Continuation 
Cohort)
Analysis set: Not applicable. 
Table produced by: Table will be produced by cohort.
Tables: 

AML risk category;

MDS risk category.
Listings: The listing will be presented based on AML Risk Category and MDS Risk Category
CRF pages.
8.2.10.3. Prior Therapy Response (excluding the Continuation Cohort)
Analysis set: Not applicable. 
Table produced by: Not applicable.
Tables: Not applicable.
Listings: 
Listing will be produced by dose level, cohort and malignancy.

Prior therapy response (MDS);

Prior therapy response (CMML);

Prior therapy response (MF);

Prior therapy response (AML);

Prior therapy response (CML-AP/BP);

Prior therapy response (CML-CP).
8.2.10.4. Bone Marrow Biopsy or Aspirate (excluding the Continuation Cohort)
Analysis set: Not applicable. 
Table produced by: Not applicable.
Tables: Not applicable.
Listings: Listing will be prepared for each sample site by dose and cohort.


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8.2.10.5. Cytogenetics and Immunophenotyping (excluding the Continuation Cohort)
Cytogenetics data will be referred to the Cytogenetic Blood CRF page and the Cytogenetic 
Bone Marrow CRF page.
Analysis set: Not applicable. 
Table produced by: Not applicable.
Tables: Not applicable.
Listings: 
Listing will be produced by dose level, cohort and malignancy.

Cytogenetics (blood, bone marrow);

Immunophenotyping.
8.2.10.6. Cytogenetics (excluding the Continuation Cohort)
Cytogenetics data will be referred to the Genetic Record CRF page.
Analysis set: Safety Analysis Set. 
Table produced by: Table will be produced by cohort. 
Tables: 
Cytogenetics data will be summarized. Summary table will include following 
number of subjects:

Adequate sample (Yes); 

Done cytogenetics (Yes).
Denominator for the followings is a numbers of patients done cytogenetics;

Karyotype (normal, abnormal); 

Abnormality (favorable, intermediate, adverse) [AML Patients in Expansion Cohort 
of LDAC combination for efficacy (Unfit patient) and Combination Cohort 3 only];

Abnormality detail: the number of patients and its percentage with each cytogenetics 
will be summarized.
Listings: The listing will be presented based on Genetic Record CRF pages.


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8.2.10.7. Extramedullary Disease (excluding the Continuation Cohort)
Analysis set: Not applicable. 
Table produced by: Not applicable.
Tables: Not applicable.
Listings: 
A listing of extramedullary disease will be produced (ie, involvement of liver (Y/N), 
spleen (Y/N), and other organs (Y/N, if other organs are involved, also provide the 
organ names)) by dose level, cohort and malignancy.  Spleen and liver size (in cm) 
will be listed for all subjects at each assessment (including baseline, which is 
defined below).  The absolute change from baseline, as well as change from the 
most extreme value (maximum or minimum), in liver and spleen size will be also 
listed.  Note that an extramedullary disease of “not palpable” is considered 0 cm, 
and “Indeterminate” is considered null and the absolute change from baseline will 
not be calculated in the reporting.

Extramedullary disease (liver);

Extramedullary disease (spleen);

Extramedullary disease (other extramedullary disease).
8.2.10.8. Molecular Studies for CML
Analysis set: Not applicable. 
Table produced by: Not applicable.
Tables: Not applicable.
Listings: 
The listing will include the molecular biology records based on the Molecular 
Biology of Disease CRF page, and also include the change from baseline of the 
number of abnormal transcripts (Listing by dose level, cohort and malignancy).
8.2.10.9. Molecular Studies for CMML, AML, MDS and MF (excluding the 
Continuation Cohort)
Analysis set: Not applicable. 
Table produced by: Not applicable.
Tables: Not applicable.


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Listings: The listing will include sample source and mutation for each assessment (Listing by 
dose level, cohort and malignancy).
8.2.10.10. Physical Examination
Analysis set: Not applicable. 
Table produced by: Not applicable.
Tables: Not applicable.
Listings: The listing will be presented based on “Physical Examination – Screening” and 
“Physical Examinstion - Brief” CRF pages, respectively.
8.2.10.11. Medication Error
Analysis set: Not applicable. 
Table produced by: Not applicable.
Tables: Not applicable.
Listings: The listing will be presented based on Medication Error CRF pages.
8.2.10.12. Cardiac Function Evaluation [Combination Cohorts 2 (Fit Patients) Only]
Analysis set: Not applicable. 
Table produced by: Not applicable.
Tables: Not applicable.
Listings: The listing will be presented based on Cardiac Function Evaluation CRF pages.


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9. REFERENCES
1.
Brookmeyer R and Crowley J. A confidence interval for the median survival time.
Biometrics 38:29-41, 1982.
2.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd
Edition.Hoboken, Wiley Interscience.


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10. APPENDICES 
Appendix 1. Categorical Classes for ECG and Vital Signs
Categories for QTcF
QTcF (ms)
max. < 450
450 ≤max. ≤480
481 ≤max. ≤500
501 ≤max.
QTcF (ms) 
increase from 
baseline
max. < 30
30 ≤ max. <60
60 ≤max.
Categories for PR and QRS
PR (ms)
max 300
PR (ms) increase 
from baseline
Baseline 
>200 and max. 
25% increase
Baseline 200 and 
max. 50% 
increase
QRS (ms)
max 200
QRS (ms) 
increase from 
baseline
Baseline 
>110 and max. 
25% increase
Baseline 110 and 
max. 50% 
increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from baseline
max. decrease 30
max. increase 30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease 20
max. increase 20
Heart rate (bpm)
min. <40
max. >120


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Appendix 2. Response Criteria for Myelodysplasia and CMML
Objective response and Disease Progression
The objective status at each evaluation is determined per investigator evaluation (Protocol 
Appendix 5).  However, the status will be verified per clinical judgment by the Sponsor.  
More specifically, the following categories on the CRF page will be considered objective 
response and disease progression for the purpose of this study.  
Objective Response (OR)
Disease status assessments (if available)

Complete remission (CR);

Partial remission (PR);

Marrow complete remission (mCR).
Cytogenetic response (if available)

Complete cytogenetic response;

Partial cytogenetic response.
Hematologic improvement (if available)

Erythroid response;

Platelet response;

Neutrophil response.
Objective Disease Progression
Disease status assessments (if available)

Disease progression;

Failure;

Relapse after CR or PR.
Cytogenetic response (if available)

Loss of cytogenetic response.
Hematologic improvement (if available)

Progression or relapse after HI.
Relapse
Disease status assessments (if available)

Relapse after CR or PR.
Cytogenetic response (if available)

Loss of cytogenetic response.
Hematologic improvement (if available)

Progression or relapse after HI.


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Appendix 3. Response Criteria for Myelofibrosis
Objective response and Disease Progression
The objective status at each visit is determined per investigator evaluation (Protocol 
Appendix 7).  However, the status will be verified per clinical judgment by the Sponsor.  
More specifically, the following categories on the CRF page will be considered objective 
response and disease progression for the purpose of this study.
Objective Response
Disease status assessments (if available)

Complete remission (CR);

Partial remission (PR);

Clinical improvement (CI).
Cytogenetic response (if available)

Major cytogenetic response;

Minor cytogenetic response.
Objective Disease Progression
Disease status assessments (if available)

Progressive disease (PD);

Relapse.
Cytogenetic response (if available)

Loss of cytogenetic response.
Relapse
Disease status assessments (if available)

Relapse.
Cytogenetic response (if available)

Loss of cytogenetic response.


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Appendix 4. Response Criteria for Acute Myeloid Leukemia
Objective response and Disease Progression
The objective status at each visit is determined per investigator evaluation (Protocol 
Appendix 8).  However, the status will be verified per clinical judgment by the Sponsor.  
More specifically, the following categories on the CRF page will be considered objective
response and disease progression for the purpose of this study. 
Objective Response
Disease assessments

Morphologic complete remission (CR);

Cytogenetic CR (CRC);

Molecular CR (CRM);

Morphologic complete remission with incomplete blood count recovery (CRi);

Morphologic leukemia-free state (MLFS);

Partial remission (PR);

Partial remission with incomplete blood count recovery (PRi);

Minor response (MR).
Disease Progression
Disease assessments

Treatment failure 

Resistant disease;

Aplasia;

Indeterminate cause.

Relapse

Morphologic relapse;

Molecular relapse;

Cytogenetic relapse.
Relapse
Disease assessments

Relapse

Morphologic relapse;

Molecular relapse;

Cytogenetic relapse.


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Appendix 5. Response Criteria for Chronic Myeloid Leukemia
Objective response and Disease Progression
The objective status at each visit is determined per investigator evaluation (see Protocol 
Appendix 9).  However, the status will be verified per clinical judgment by the Sponsor.  
Reporting will be done for subjects in chronic phase and accelerated phase/blast crisis at 
baseline separately. The following categories on the CRF page will be considered objective 
response and disease progression respectively for the purpose of this study.  A response 
needs to be confirmed by a subsequent investigator assessment a minimum of 4 weeks later.  
Subjects whose response is not confirmed will be deemed as un-confirmed responders.
Accelerated Phase/Blast Crisis (AP/BC)
Objective Response (hematologic)
Disease assessments

Complete hematologic response (CHR);

No evidence of leukemia (NEL);

Return to chronic phase;

Minor response.
Disease Progression

Progressor to Accelerated Phase or Blast Crisis from Chronic Phase or Return 
to Chronic Phase;

Progressor from Accelerated Phase to Blast Crisis;

Loss of confirmed CHR;

Loss of major cytogenetic response.
Chronic Phase
Objective Response
Disease status assessments

Complete hematologic response (CHR);

No Evidence of Leukemia (NEL).
Disease Progression

Early progressor from Chronic Phase;

Progressor to Accelerated Phase or Blast Crisis from Chronic Phase or Return 
to Chronic Phase;

Loss of confirmed CHR;

Loss of major cytogenetic response.