Conditions: Adult Acute Myeloid Leukemia in Remission Recurrent Adult Acute Myeloid Leukemia
Keywords: Myeloid leukemia in remission Recurrent myeloid leukemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 31
Healthy volunteers: no

Brief summary:
This phase II trial will test whether the Hedgehog signaling pathway inhibitor PF-04449913 can decrease disease relapse in high-risk patients with acute myeloid leukemia after donor stem cell transplant.

Detailed description:
Disease relapse is the most common cause of death after allogeneic stem cell transplantation for acute myeloid leukemia. Patients at high risk for relapse may benefit from a novel, biologically rational therapeutic intervention to prevent this outcome. PF-04449913 is a small molecule inhibitor of the hedgehog (Hh) pathway that inhibits the protein Smoothened (SMO). Aberrant Hh signaling may contribute to the survival and expansion of the leukemia stem cell, and inhibiting the Hh pathway can eliminate these cells. Therefore, targeting Hh may be a logical intervention in the post-transplantation setting for those with high risk of relapse. The investigators propose a phase 2 study of PF-04449913 in patients with acute myeloid leukemia who have received an allogeneic stem cell transplantation and are at high risk of relapse.

This is an open label, phase 2 study employing PF-04449913 in acute myeloid leukemia patients who received an allogeneic stem cell transplantation and are at high risk of relapse. Patients will receive consecutive 28-day cycles of PF-04449913 at 100 mg/day, beginning on post-transplantation day 80 +/- 10 days, after their routine post-transplant bone marrow biopsy. Treatment will continue for up to one year or until they experience toxicity or disease relapse. 50 patients will be required for a 90% power to detect a 20% difference in one-year relapse-free survival.

Arms:
arm 1: Beginning 80 days after allogeneic stem cell transplant, patients receive PF-04449913 (100mg) orally once daily on days 1-28. Treatment repeats every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: PF-04449913
Intervention descriptions: intervention 1: 100mg given orally

Protocol document:
Prot_SAP_000.pdf: 
A Phase 2 Study of PF-04449913 for the Treatment of Acute Myeloid 
Leukemia Patients with High Risk of Post-Allogeneic Stem Cell 
Transplantation Relapse 
SPONSOR / Coordinating 
Center 
University of Colorado 
Cancer Center 
PARTICIPATING CENTER 
The Ohio State University 
COMIRB # 
12-1558
Version # 
7 / October 15, 2019 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to 
the extent necessary to obtain informed consent, may not be disclosed to another party 
unless law or regulations require such disclosure.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 
NCT#01841333 


 
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COMIRB #12-1558 - Version #7: 15 OCT 2019 
ii
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
Principal Investigator: 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
Printed Name of Investigator 
 
 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB procedures, the Declaration of Helsinki, ICH Good Clinical 
Practices guidelines, and the applicable parts of the United States Code 
of Federal Regulations or local regulations governing the conduct of 
clinical studies. 
 
 
 
 
 
 
 
 
 
 
 


 
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COMIRB #12-1558 - Version #7: 15 OCT 2019 
iii 
STUDY PERSONNEL 
 
Sponsor: 
 
University of Colorado Cancer Center 
1665 Aurora Court 
Aurora, CO 80045 
 
Study Locations: 
 
University of Colorado Cancer Center, 
Aurora, CO 
 
The Ohio State University,  
Columbus, OH 
Investigators: 
 
Daniel A. Pollyea, MD, MS 
University of Colorado Cancer Center 
Mail Stop F754, Room 4328 
1665 Aurora Court 
Aurora, CO 80045 
Phone: 720-848-8084 
 
Jonathan Gutman, MD 
University of Colorado Cancer Center  
1665 Aurora Court 
Aurora, CO 80045 
Phone: 720-848-0220 
 
Sumithira Vasu, MBBS Ohio State University 
Division of Hematology 
B310 Starling Loving Hall 
320 W 10th Avenue 
Phone: 614-293-8197 
Fax: 614-293-7526 
Email: sumithira.vasu@osumc.edu 
 
 
 


 
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COMIRB #12-1558 - Version #7: 15 OCT 2019 
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Contents 
1 PROTOCOL SYNOPSIS .......................................................................................................... 1 
2 SCHEDULE OF STUDY ASSESSMENTS* ............................................................................. 2 
3 INTRODUCTION .................................................................................................................... 4 
3.1 
Background and Rationale ............................................................................................... 4 
3.2 
PF-04449913 .................................................................................................................... 6 
4 STUDY OBJECTIVES ............................................................................................................ 11 
4.1 
Primary Objective .......................................................................................................... 11 
4.2 
Secondary Objectives ..................................................................................................... 11 
5 INVESTIGATIONAL PLAN ................................................................................................... 12 
5.1 
Overall Study Design ..................................................................................................... 12 
5.1.1 
Dosing Schema ...................................................................................................... 12 
5.1.2 
Continuation and Interruptions .............................................................................. 12 
5.2 
Study Endpoints ............................................................................................................. 12 
5.2.1 
Primary Endpoint ................................................................................................... 12 
5.2.2 
Secondary Endpoints ............................................................................................. 13 
5.3 
Selection of Study Population and Enrollment Procedures ........................................... 13 
5.3.1 
Inclusion Criteria ................................................................................................... 13 
5.3.2 
Exclusion Criteria .................................................................................................. 14 
5.3.3 
Lifestyle Guidelines ............................................................................................... 15 
5.4 
Duration of Study ........................................................................................................... 16 
5.5 
Drug Administration ...................................................................................................... 16 
5.5.1 
Premedication ........................................................................................................ 16 
5.5.2 
PF-04449913 .......................................................................................................... 16 
5.6 
Assuring Patient Compliance ......................................................................................... 17 
5.7 
Laboratory Criteria for Initiation of Treatment Cycles .................................................. 17 
5.8 
Study Treatment Schedule ............................................................................................. 17 
5.9 
Concomitant Therapy ..................................................................................................... 18 
5.9.1 
Permitted Concomitant Therapy ............................................................................ 18 
5.9.2 
Prohibited Concomitant Therapy ........................................................................... 18 
5.9.3 
Table 1: Representative prohibited medications based on metabolic isoenzyme 
class. ............................................................................................................... 19 
5.10 
Safety Plan ..................................................................................................................... 20 
5.10.1 
Stopping Rules ....................................................................................................... 20 
5.10.1.1 
Individual Patients’ Stopping Rules............................................................... 20 
5.10.1.2 
Study Stopping Rules..................................................................................... 21 
5.10.2 
Dosing Delays and Modifications .......................................................................... 22 
5.10.2.1 
Missed Doses ................................................................................................. 22 
5.10.2.2 
Dose Delays and De-escalation ..................................................................... 22 
5.10.3 
Data and Safety Monitoring ................................................................................... 25 
5.11 
Study Completion and Termination ............................................................................... 26 
5.12 
Study Activities and Assessments.................................................................................. 27 
5.12.1 
Schedule of Activities ............................................................................................ 27 
5.12.2 
Screening Period .................................................................................................... 27 
5.12.3 
Treatment Schedule ............................................................................................... 27 
5.12.4 
Follow Up .............................................................................................................. 28 
5.12.5 
Study Assessments ................................................................................................. 28 
5.12.5.1 
Vital Signs and ECOG Performance Status ................................................... 28 
5.12.5.2 
Physical Examination .................................................................................... 28 
5.12.5.3 
Adverse Events .............................................................................................. 28 


 
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COMIRB #12-1558 - Version #7: 15 OCT 2019 
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5.12.5.4 
Laboratory Assessments ................................................................................ 29 
5.12.5.5 
EKGs and QTc Calculation ........................................................................... 29 
5.12.5.6 
Minimal Residual Disease (MRD)................................................................. 30 
5.12.5.7 
Disease Assessments and Response Criteria ................................................. 30 
5.12.5.8 
Correlative Assessments ................................................................................ 30 
5.13 
Definitions and Reporting Procedures for Adverse Events ........................................... 31 
5.13.1 
Definitions of Adverse Events ............................................................................... 31 
5.13.1.1 
Adverse Event ................................................................................................ 31 
5.13.1.2 
Serious Adverse Event (SAE) ........................................................................ 32 
5.13.1.3 
Pregnancies .................................................................................................... 32 
5.13.2 
Relationship of the Adverse Event to Treatment ................................................... 33 
5.13.3 
Procedures for Recording Adverse Events ............................................................ 34 
5.13.3.1 
Information to be Collected ........................................................................... 34 
5.13.3.2 
Recording Serious Adverse Events ................................................................ 34 
5.13.4 
Investigator Reporting Responsibilities ................................................................. 34 
5.13.4.1 
Investigational New Drug Annual Reports .................................................... 35 
5.13.4.2 
Format for Adverse Event Reporting ............................................................. 35 
5.13.4.3 
Reporting to the IRB ...................................................................................... 35 
5.13.4.4 
Reporting to Pfizer ......................................................................................... 35 
5.13.4.5 
Non-serious Adverse Event Reporting .......................................................... 35 
5.13.4.6 
SAE Reporting ............................................................................................... 36 
5.14 
Statistical Methods and Sample Size Determination ..................................................... 37 
5.15 
Protocol Deviations ........................................................................................................ 37 
6 ADMINISTRATIVE REQUIREMENTS .................................................................................. 37 
6.1 
Data and Safety Monitoring Plan ................................................................................... 37 
6.2 
Ethics ............................................................................................................................. 37 
6.2.1 
Institutional Review Board .................................................................................... 37 
6.2.2 
Patient Information and Consent............................................................................ 38 
6.3 
Record of Administration .............................................................................................. 39 
6.4 
Confidentiality ............................................................................................................... 39 
6.5 
Study Auditing ............................................................................................................... 40 
7 REFERENCES ....................................................................................................................... 41 
8 APPENDIX A - ECOG Performance Status Scale ................................................................. 44 
9 APPENDIX B - Pfizer Safety Reporting Policy ..................................................................... 45 
 
 


 
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1 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE:  A Phase 2 Study of PF-04449913 For the Treatment of Acute Myeloid Leukemia 
Patients with High Risk of Post-Allogeneic Stem Cell Transplantation Relapse 
 
INDICATION:  Post allogeneic stem cell transplantation for acute myeloid leukemia patients with high 
risk of relapse 
STUDY PHASE: 2 
BACKGROUND AND RATIONALE:  Disease relapse is the most common cause of death after 
allogeneic stem cell transplantation for acute myeloid leukemia.  Patients at high risk for relapse may 
benefit from a novel, biologically rational therapeutic intervention to prevent this outcome.   PF-
04449913 is a small molecule inhibitor of the hedgehog (Hh) pathway that inhibits the protein 
Smoothened (SMO).  Aberrant Hh signaling may contribute to the survival and expansion of the 
leukemia stem cell, and inhibiting the Hh pathway can eliminate these cells.  Therefore, targeting Hh 
may be a logical intervention in the post-transplantation setting for those with high risk of relapse.  We 
propose a phase 2 study of PF-04449913 in patients with acute myeloid leukemia who have received 
an allogeneic stem cell transplantation and are at high risk of relapse.     
STUDY OBJECTIVES: 
Primary:   
• 
Determine whether PF-04449913 can prevent relapse in high risk acute myeloid leukemia 
patients who receive an allogeneic stem cell transplantation  
Secondary:   
• 
Determine the toxicity profile of PF-04449913 in this population 
• 
Determine the impact of this intervention on overall survival (OS) 
STUDY DESIGN: 
This is an open label, phase 2 study employing PF-04449913 in acute myeloid leukemia patients who 
received an allogeneic stem cell transplantation and are at high risk of relapse. Patients will receive 
consecutive 28-day cycles of PF-04449913 at 100 mg/day, beginning on post-transplantation day 28-
50, after their routine post-transplant bone marrow biopsy. Treatment will continue for up to one year or 
until they experience toxicity or disease relapse. 50 patients will be required for a 90% power to detect 
a 20% difference in one-year relapse free survival.  
STUDY ENDPOINTS 
Primary: 
• 
One year relapse-free survival 
Secondary: 
• 
Remission duration 
• 
Incidence and severity of adverse events  
• 
OS (one year) 
STUDY DURATION: 5-7 years 
TOTAL SAMPLE SIZE: 50 


 
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2 
SCHEDULE OF STUDY ASSESSMENTS*  
 
PF-
04449913 
Hx/PE 
Hematology 
Chemistry 
Screening 
Labs & 
Procedures 
12-Lead 
EKG 
MRD 
BM 
Bx 
Screening† 
 
 
X 
X 
X 
X 
X 
 
 
 
Cycle 1 
Days 1-28 
X 
 
 
 
 
 
 
 
Day 1 
 
X¶ 
X¶ 
X¶ 
 
X 
 
 
Day 15 
 
X 
X 
X 
 
X 
 
 
Day 28‡ 
 
X 
X 
X 
 
 
 
 
Cycles 2 - 12 
Days 1-28 
X 
 
 
 
 
 
 
 
Day 1‡ 
 
X 
X 
X 
 
X†* 
 
 
Initiation of New Azole 
Antifungal Medication 
 
 
 
 
 
 
X¶* 
 
 
Post-transplant day 80 
+/- 10 days 
 
 
 
 
 
 
 
X 
X 
Post-transplant day 
175 +/- 15 
 
 
 
 
 
 
 
X 
X 
Post-transplant day 
365 +/- 30 
 
 
 
 
 
 
 
X 
X 
 
DEFINITIONS: 
Hx/PE: Complete or interim medical history, including ECOG performance status, adverse event monitoring and concomitant medications review; 
complete or focused physical examination. Drug compliance assessment will occur with each cycle’s day 1, beginning with cycle 2. 
Hematology: Complete blood count (includes hemoglobin, hematocrit, platelet count and total white blood cell count with differential) 
Chemistry: Complete metabolic profile, including Na, K, calcium, CO2, BUN, creatinine, glucose, magnesium, phosphorous, protein, albumin, AST, ALT, 
alkaline phosphatase and total bilirubin 
Screening labs & procedures: Prothrombin time (PT) and/or international normalized ration (INR), partial thromboplastin time (PTT); serum/urine 
pregnancy test for women of childbearing potential only must be performed within 72 hours of treatment initiation. 
12-lead EKG: To be performed with QTc interval calculated by Fridericia’s correction factor if indicated. 
MRD: Minimal residual disease, as detected by multidimensional flow cytometry (see Section 5.12.5.6)  
BM Bx: Unilateral core and aspirate samples, to be sent for morphological assessment, cytogenetics, flow cytometry and molecular testing 
 


 
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COMIRB #12-1558 - Version #7: 15 OCT 2019 
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FOOTNOTES 
*Variations of ±5 days of scheduled visits are permitted; unscheduled visits can occur at any time during the study.  The date of the unscheduled visit and 
any data generated must be recorded on the appropriate case report form, and source documents for these visits must also be maintained. 
†Includes review of exclusion/inclusion criteria and informed consent.  
¶If screening and day 1 are ≤ 7 days apart, the Hx/PE, CMP and CBC performed at enrollment do not need to be repeated on day 1. 
‡Day 28 visit and labs may be same as day 1 visit and labs of the subsequent cycle 
***Perform 1-4 hours after first dose (at Cmax) 
†* Perform 1-4 hours after first dose (at Cmax) for cycle 2, day 1 only; not necessary to routinely repeat on day 1 of each cycle unless clinically indicated 
¶*Perform 2-5 days after initiation of new azole antifungal medication


 
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COMIRB #12-1558 - Version #7: 15 OCT 2019 
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3 
INTRODUCTION 
Hematopoietic stem cell transplantation (HSCT) is the only therapy with 
curative potential for high risk patients with acute myeloid leukemia (AML) 
2,3 However, disease relapse remains the main cause of treatment failure 
and death after HSCT,4 suggesting that even highly ablative therapies and 
the generation of immunological graft versus leukemia responses are very 
often unable to target the leukemia stem cell population and achieve the 
requisite cure.  At relapse, salvage maneuvers such as secondary 
transplantations or donor lymphocyte infusions are highly toxic and seldom 
effective,5-7 highlighting the need for tolerable therapies in this population. 
 
Predicting imminent relapse in the post-transplant setting is becoming 
increasingly sophisticated.  In post-transplant patients, flow-cytometry 
based minimal residual disease (MRD) detection for AML has been shown 
to be highly predictive of relapse and overall survival (OS).8-10 Molecular 
analyses of leukemia fusion genes can also allow for disease monitoring in 
select patients,11 and persistence of a cytogenetic abnormality at the time 
of transplantation is a poor predictor for relapse and OS after a 
myeloablative HSCT.12  
 
Developing clinical trials for AML post-allogeneic HSCT patients with 
imminent or high-risk of relapse is an area of active interest that warrants 
further exploration using novel therapies. 
3.1 
Background and Rationale 
The Hedgehog (Hh) signaling pathway regulates essential elements 
of embryonic development, homeostasis and tissue regeneration 
and development.15 It is important in a broad range of cancers, 
including basal cell carcinoma, bladder, colorectal, lung, pancreas, 
prostate and stomach.16  Hh signaling is activated by binding of one 
of three Hh ligands, Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), 
or Desert Hedgehog (Dhh) to their receptor, Patched (Ptch).17 
Binding of Hh ligand to Ptch alleviates repression of a second 
transmembrane protein, Smoothened (SMO), allowing SMO to 
transduce the signal to the cytoplasm resulting in activation of Gli 
family zinc finger transcription factors (Gli1, Gli2 and Gli3). Gli 
translocates into the nucleus and activates transcription of target 
genes, causing proliferation. 
 
Activation of the Hh pathway can occur by two mechanisms. First, 
mutations in Ptch or SMO genes result in constitutive activation of 
the pathway and upregulation of Gli. Mutations in Hh signaling 
members 
have 
been 
reported 
in 
basal 
cell 
carcinoma, 


 
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COMIRB #12-1558 - Version #7: 15 OCT 2019 
5 
medulloblastoma, and rhabdomyosarcoma.18,19 A direct link between 
mutation driven aberrant Hh signaling and human tumorgenesis is 
found in Gorlin Syndrome,18 characterized by the development of 
multiple 
basal 
cell 
carcinomas, 
and 
are 
predisposed 
to 
medulloblastoma and rhabdomyosarcoma. These patients have a 
germline inactivating mutation in the repressor Ptch that results in 
constitutively active SMO and upregulation of Hh target genes. The 
link between mutations in Ptch and basal cell carcinoma was also 
reported in a majority of sporadic basal cell carcinoma tumors,18,19 
and a significant number of sporadic medulloblastomas can also be 
attributed to inactivating mutations in Ptch.19 To test these findings, 
a genetically engineered mouse model of medulloblastoma was 
developed by genomic deletion of a Ptch allele;20,21 the heterozygous 
Ptch deletion mutation, coupled with a deletion of p53, resulted in 
posterior fossa tumors with active Hh pathway signaling and 
upregulated expression of Gli target genes.22  
 
The second method of Hh activation is through autocrine or paracrine 
mechanisms of ligand driven Hh pathway activation in adult tissues 
with a normally dormant Hh pathway. In some cancers Hh pathway 
members are expressed in the tumor cells and directly affect the 
growth of the tumor, resulting in an autocrine positive feedback loop. 
In other cases, Hh ligand produced by tumor cells may activate the 
pathway in adjacent stroma, leading to the release of growth factors 
that support tumor growth or angiogenesis as part of the tumor 
microenvironment.23  
 
The Hh pathway is now recognized for its involvement in the 
maintenance, growth and drug resistance of hematological 
malignancies. Hh pathway signaling is preferentially activated in 
MDS-derived cells and CD34+ AML blasts and cell lines, 24-26 
including chemoresistant cell lines,27  and patient derived AML 
samples express Gli-1 in proportion to the number of CD34+ blast 
cells (Jamieson et al, manuscript in preparation), suggesting 
aberrant Hh signaling may contribute to the survival and expansion 
of the leukemia stem cell. Hh signaling is also relevant in B-cell ALL28 
and potentially T-cell ALL,29,30 and can be modulated by pathway 
inhibitors, which were also shown to limit the self-renewal of 
leukemia cells.28  In addition, it was recently shown that inhibiting the 
Hh pathway can selectively eliminate leukemia stem cells (LSCs).31 
Therefore, given the central role that Hh signaling plays in cell 
differentiation, Hh inhibition represents a mechanistically novel 
approach to eliminate the LSC population and thus abrogate tumor 
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COMIRB #12-1558 - Version #7: 15 OCT 2019 
6 
hematopoietic malignancies, making this pathway an attractive 
target for residual, treatment resistant disease. 
 
PF-04449913 (Pfizer) is a novel small molecule inhibitor of the Hh 
pathway that binds and inhibits SMO.  This ultimately results in 
ubiquination of Gli1/2, leading to degradation and clearance of these 
transcription factors.  Early phase clinical trials using this agent has 
shown it to be well tolerated and effective in patients with 
hematological malignancies.32 
 
Hypothesis 
 
PF-04449913 will be well-tolerated and effective therapy for acute 
myeloid leukemia patients who have received HSCT and have high 
risk of disease relapse. We aim to test this hypothesis with this phase 
2 clinical study. 
 
3.2 
PF-04449913 
Cyclopamine, isolated from the corn lily plant, interacts with and 
inhibits SMO.33 PF-04449913 was synthesized to improve the 
hepatic clearance, decrease the lipophilicity and increase the 
solubility of cyclopamine. PF-04449913 is a potent and selective 
inhibitor of Hedgehog (Hh) signaling in vitro and has demonstrated 
significant antitumor efficacy in vivo.  
 
Chemical Structure of PF-04449913 
Molecular weight: 374.439 daltons 
Chemical name: 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1- 
methylpiperidin-4-yl)-3-(4-cyanophenyl)urea 
dihydrochloride monohydrate 
Molecular Formula: C21H26Cl2N6O2 (dihydrochloride 
monohydrate) 
Physical description: White to pale-colored powder 


 
C o nfi d e nti al  
  
 
   
 
   
   
 
C O MI R B # 1 2 -1 5 5 8 - V er si o n # 7 : 1 5 O C T 2 0 1 9  
7  
Bi o a v ail a bilit y: Or al  
Pr e -Cli ni c al D at a  
P h ar m a c o ki n eti c s/ P h ar m a c o d y n a mi c s a n d M et a b oli s m  
Pr e cli ni c al  p h ar m a c o ki n eti c  ( P K)  / p h ar m a c o d y n a mi c s  ( P D)  
m o d eli n g s u g g e st s a t ar g et h u m a n d o s e of 1 5 m g/ d a y i s pr oj e ct e d t o 
yi el d at l e a st 5 0 % of t u m or Gli 1 m R N A i n hi biti o n fr o m b a s eli n e l e v el s. 
A 1 5 m g d o s e i s pr oj e ct e d t o r e s ult i n a C mi n of 6 2 n g/ m L t ot al ( 5. 6 
n g/ m L fr e e) a n d a C a v e of 7 9 n g/ m L t ot al ( 7. 2 n g/ m L fr e e).  
A b s ol ut e  or al  bi o a v ail a bilit y  of  P F -0 4 4 4 9 9 1 3  f oll o wi n g  si n gl e  d o s e 
or al a d mi ni str ati o n w a s 3 3 % i n r at s a n d 6 8 % i n d o g s. Pl a s m a pr ot ei n 
bi n di n g  of  P F -0 4 4 4 9 9 1 3  i n  m o u s e,  r at,  d o g,  a n d  h u m a n  pl a s m a 
r a n g e d fr o m  8 5 %  t o  9 3 %.  A  v ol u m e of di stri b uti o n  at  st e a d y  st at e 
( V s s)  of  4. 7 8  a n d  4. 2 1  L/ k g  w a s  o b s er v e d  i n  r at s  a n d  d o g s, 
r e s p e cti v el y.  
P F -0 4 4 4 9 9 1 3  w a s  e v al u at e d  i n  r at  a n d  d o g  r e p e at -d o s e  t o xi cit y 
st u di e s u p t o 1 m o nt h i n d ur ati o n. P F -0 4 4 4 9 9 1 3 w a s w ell t ol er at e d 
u p t o 5 0 m g/ k g/ d a y  i n t h e r at a n d 5 m g/ k g/ d a y i n t h e d o g. I n b ot h t h e 
r at  a n d  t h e  d o g,  a  gr e at er  t h a n  pr o p orti o n al  i n cr e a s e  i n  e x p o s ur e 
o c c urr e d wit h i n cr e a si n g d o s e. I n t h e r at st u d y, t h e i n cr e a s e i n m e a n 
A U C( 0 -2 4) v al u e s w er e a p pr o xi m at el y 1 7 5 -f ol d a n d 2 3 2-f ol d gr e at er 
t ha n  t h e  d o s e  ( 5 0 -f ol d)  r a n g e  e v al u at e d  f or  D a y  1  a n d  D a y  2 9, 
r e s p e cti v el y. I n t h e 1-m o nt h d o g t o xi cit y st u d y, t h e m e a n A U C( 0 -2 4) 
v al u e s  w er e  a p pr o xi m at el y  1 6 5 -f ol d  ( m al e)  a n d  3 6 0-f ol d  (f e m al e) 
gr e at er t h a n t h e d o s e ( 3 0 -f ol d) r a n g e e v al u at e d o n D a y 1.  
I n  vitr o m et a b oli s m  of  P F -0 4 4 4 9 9 1 3  w a s  c o n si st e nt  a cr o s s 
pr e cli ni c al s p e ci e s a n d h u m a n s. All m et a b olit e s o b s er v e d i n h u m a n 
i n  vitr o i n c u b ati o n s  w er e  pr e s e nt  i n  o n e  or  m or e  of  t h e  e v al u at e d 
pr e cli ni c al  s p e ci e s.  P F -0 4 4 4 9 9 1 3  a p p e ar e d  t o  b e  m et a b oli z e d  t o 
s e v er al 
o xi d ati v e  m et a b olit e s.  Pr eli mi n ar y  a s s e s s m e nt  u si n g 
i n di vi d u al r e c o m bi n a nt P 4 5 0 e n z y m e s s u g g e st s t h at C Y P 3 A 4 pl a y s 
a m aj or r ol e i n m e di ati n g t h e m et a b oli s m of P F -0 4 4 4 9 9 1 3 i n vitr o. 
P F -0 4 4 4 9 9 1 3 w a s e v al u at e d i n vitr o i n h u m a n li v er mi cr o s o m e s f or 
t h e p ot e nti al t o i n hi bit C Y P e n z y m e s. Pr eli mi n ar y r e s ult s s h o w t h at 
P F -0 4 4 4 9 9 1 3  d o e s  n ot  i n hi bit  C Y P 1 A 2,  C Y P 2 C 8,  C Y P 2 C 9, 
C Y P 2 C 1 9, C Y P 2 D 6, or C Y P 3 A 4 at c o n c e ntr ati o n s u p t o 3 0 μ M ( 1 1. 2 
g/ m L).  
I n cr y opr e s er v e d h u m a n h e p at o c yt e s, P F -0 4 4 4 9 9 1 3 d o e s n ot i n d u c e 
C Y P 1 A 2 or C Y P 3 A 4 m R N A l e v el s a n d e n z y m e a cti viti e s at u n b o u n d 
c o n c e ntr ati o n s u p t o 1 0 0 M ( 3 7. 4 g/ m L). C o n si d eri n g t h e h u m a n 
p h ar m a c o ki n eti c s o b s er v e d t o d at e , P F -0 4 4 4 9 9 1 3 i s n ot e x p e ct e d t o 


 
C o nfi d e nti al  
  
 
   
 
   
   
 
C O MI R B # 1 2 -1 5 5 8 - V er si o n # 7 : 1 5 O C T 2 0 1 9  
8  
r e d u c e pl a s m a  c o n c e ntr ati o n s  of  c o -a d mi ni st er e d  C Y P 1 A 2  or 
C Y P 3 A 4 s u b str at e s i n vi v o. 
  
 
T o xi cit y  
D e at h s a n d/ or m ori b u n d e ut h a n a si a o c c urr e d i n t h e 7 -d a y a n d 1 0 -
d a y r at, a n d 1 -m o nt h d o g st u di e s at 2 5 0, 5 0 0 or 3 0/ 1 5 m g/ k g/ d a y, 
r e s p e cti v el y. C a u s e of d e at h/ m or bi dit y i n b ot h s p e ci e s w a s attri b ut e d 
t o ki d n e y t o xi cit y. T h e t ar g et or g a n i n t h e r at 1-m o nt h t o xi cit y st u d y 
i n cl u d e d  ki d n e y  (t u b ul ar  d e g e n er ati o n/ n e cr o si s,  c yt o m e g al y, 
i nfl a m m ati o n,  r e g e n er ati o n)  a n d  b o n e  ( d e cr e a s e d/ di s or g a ni z e d 
c h o n dr o c yt e s  i n  e pi p h y si s);  t h e  n o  o b s er v e d  a d v er s e  eff e ct  l e v el 
( N O A E L) w a s 1 0 m g/ k g/ d a y ( a 5 × s af et y m ar gi n o v er t h e pr oj e ct e d 
h u m a n  C a v e  at  st e a d y  st at e).  T h e  ki d n e y  c h a n g e s  s h o w e d  s o m e 
si g n s  of  r e v er si bilit y  b ut  di d  n ot  e ntir el y  r e v er s e,  w hil e  t h e  b o n e 
c h a n g e s p er si st e d.  
T h e t ar g et org a n i n t h e 1 -m o nt h t o xi cit y st u d y i n t h e d o g w a s li mit e d 
t o  t h e  ki d n e y  (t u b ul ar  n e cr o si s,  gr a n ul ar/ mi n er ali z e d  c a st s,  dil at e d 
t u b ul e s); N O A E L w a s 1 m g/ k g/ d a y w hi c h i s < 1 × t h e pr oj e ct e d h u m a n 
C a v e at st e a d y st at e. Mil d c h a n g e s i n t h e ki d n e y w er e o b s er v e d at  5 
m g/ k g/ d a y w hi c h ar e 1 1 × t h e pr oj e ct e d h u m a n C a v e at st e a d y st at e. 
T h e ki d n e y c h a n g e s i n t h e d o g w er e c o m pl et el y r e v er s e d i n m al e s 
a n d p arti all y r e v er s e d i n f e m al e s aft er a 6 -w e e k r e v er s al p eri o d. I n 
t h e a c ut e c e ntr al n er v o u s s y st e m ( C N S) a n d r e s pir at or y st u di e s i n 
t h e r at, n o eff e ct s w er e o b s er v e d at t h e hi g h d o s e of 5 0 m g/ k g ( 5 5 × 
a b o v e  t h e  pr oj e ct e d  h u m a n  effi c a ci o u s  C mi n  at  st e a d y  st at e). 
I n cr e a s e s i n Q T, Q T c 7 5 w er e n ot e d aft er si n gl e d o s e s of 5 m g/ k g 
t o d o g s w hi c h i s 4 9 ×  a b o v e t h e pr oj e ct e d h u m a n effi c a ci o u s C m a x 
at st e a d y st at e. P F -0 4 4 4 9 9 1 3 w a s n e g ati v e i n t h e d efi niti v e i n vitr o 
b a ct eri al  m ut a g e ni cit y  a s s a y,  h u m a n  l y m p h o c yt e  a s s a y  a n d  t h e i n 
vi v o  r at  mi cr o n u cl e u s.  T h e  m ol ar  e xti n cti o n  c o effi ci e nt  f or  P F-
0 4 4 4 9 9 1 3 at 2 9 0 n m i s 9 6 2 2 L/ m ol/ c m; t h er ef or e, P F -0 4 4 4 9 9 1 3 h a s 
t h e p ot e nti al t o b e p h ot ot o xi c. 
T o e v al u at e  p ot e nti al  eff e ct s  o n  t h e  c e ntr al  n er v o u s  s y st e m,  P F -
0 4 4 4 9 9 1 3 w a s a d mi ni st er e d a s a si n gl e d o s e t o m al e r at s, a n d m ot or 
a cti vit y,  b e h a vi or al  c h a n g e s,  c o or di n ati o n,  s e n s or y/ m ot or  r efl e x 
r e s p o n s e s,  a n d  b o d y  t e m p er at ur e  w er e  e v al u at e d.  T h er e  w er e  n o 
eff e ct s  i n  eit h er  t h e  f u n cti o n al  o b s er v ati o n al  b att er y  or  l o c o m ot or 
a cti vit y a s s e s s m e nt at d o s e s u p t o 5 0 m g/ k g. T h e m a xi m u m pl a s m a 
c o n c e ntr ati o n at 5 0 m g/ k g fr e e gr o u p m e a n C m a x of 6 1 7 n g/ m L fr o m 
t h e 1-m o nt h r at i s 7 2 -f ol d a b o v e t h e pr oj e ct e d h u m a n fr e e effi c a ci o u s 
C m a x c o n c e ntr ati o n of 8. 6 n g/ m L. T o e v al u at e t h e p ot e nti al eff e ct o n 
t h e c ar di o v a s c ul ar s y st e m, P F-0 4 4 4 9 9 1 3 w a s e v al u at e d f or it s eff e ct 
o n  bi n di n g  t o  t h e  h E R G  p ot a s si u m  c h a n n el  st a bl y  e x pr e s s e d  i n 
h u m a n  
e m br y o ni c  
ki d n e y  
( H E K -2 9 3)  
c ell s 


 
C o nfi d e nti al  
  
 
   
 
   
   
 
C O MI R B # 1 2 -1 5 5 8 - V er si o n # 7 : 1 5 O C T 2 0 1 9  
9  
( P F 4 4 4 9 9 1 3/ E S D/ 1 1 0 8/ H E R G).  T h e  h E R G  I C 5 0  f or  P F-0 4 4 4 9 9 1 3 
w a s  3. 1 M  w hi c h  i s  1 6 3 -f ol d  a b o v e  t h e  pr oj e ct e d  fr e e  h u m a n 
effi c a ci o u s ( C a v e) dr u g c o n c e ntr ati o n of 1 9 n M a n d 1 3 5 -f ol d a b o v e 
t h e  pr oj e ct e d  h u m a n  fr e e  effi c a ci o u s  C m a x  ( 2 3  n M).  T o  f urt h er 
i n v e sti g at e Q T pr ol o n g ati o n a n d a n y h e m o d y n a mi c c h a n g e s d u e t o 
i n hi biti o n  of  s e v er al  r e c e pt or s  o utli n e d  i n  t h e  s e c o n d ar y 
p h ar m a c o d y n a mi c s s e cti o n, P F -0 4 4 4 9 9 1 3 w a s a d mi ni st er e d b y or al 
g a v a g e t o c o n s ci o u s t el e m et eri z e d d o g s  at d o s e l e v el s of 1, 5 a n d 
3 0 m g/ k g. At d o s e l e v el s of 5 a n d 3 0 m g/ k g, P F -0 4 4 4 9 9 1 3 pr o d u c e d 
a  st ati sti c all y  si g nifi c a nt  a n d  d o s e  d e p e n d e nt  i n cr e a s e  i n  Q T  a n d 
Q T c 7 5 w hi c h w a s a p p ar e nt u p t o at l e a st 1 4 h o ur s p o st -d o si n g. T h e 
m a xi m u m o b s er v e d Q T c 7 5 pr ol o n g ati o n w a s 6 a n d 2 4 m s e c at 5 a n d 
3 0 m g/ k g, r e s p e cti v el y. I n cr e a s e s i n h e art r at e ( 1 0 b e at s p er mi n ut e) 
o c c urr e d i n t h e 3 0 m g/ k g tr e at e d d o g s w hi c h w er e c oi n ci d e nt wit h 
e pi s o d e s  of  e m e si s a n d  ar e  m o st  li k el y  r el at e d  t o  t h e  l att er eff e ct. 
T h er e w a s al s o a s m all i n cr e a s e ( 3 m s e c) i n t h e Q R S i nt er v al aft er 
t h e 3 0 m g/ k g tr e at m e nt a n d t hi s w a s a p p ar e nt u p t o 1 4 h o ur s p o st-
d o si n g. T hi s l att er eff e ct i s c o n si st e nt wit h t h e w e a k s o di u m c h a n n el 
i n hi biti o n  o b s er v e d  i n  a  f u n cti o n al  p at c h  cl a m p  st u d y  ( s e e  t h e 
s e c o n d ar y p h ar m a c o d y n a mi c s s e cti o n). T h er e w er e n o st ati sti c al or 
r e m ar k a bl e c h a n g e s i n d o g s tr e at e d wit h 1 m g/ k g P F-0 4 4 4 9 9 1 3. At 
5  m g/ k g,  t h e  p e a k  fr e e  pl a s m a  c o n c e ntr ati o n  i n  m al e  a n d  f e m al e 
d o g s w a s 5 1 7 n g/ m L a n d 4 2 0 n g/ m L, r e s p e cti v el y (fr o m t h e 1 -m o nt h 
d o g). T hi s r e pr e s e nt s a 4 9 t o 6 0 -f ol d m ar gi n a b o v e t h e pr oj e ct e d fr e e 
C m a x  ( 8. 6  n g/ m L)  at  a  h u m a n  effi c a ci o u s  d o s e  of  1 5  m g.    P F -
0 4 4 4 9 9 1 3 w a s a d mi ni st er e d a s a si n gl e d o s e t o m al e r at s t o a s s e s s 
p ot e nti al  eff e ct s  o n  t h e  r e s pir at or y  s y st e m.  P F -0 4 4 4 9 9 1 3  h a d  n o 
eff e ct  o n r e s pir at or y r at e, ti d al v ol u m e or mi n ut e v ol u m e at d o s e s u p 
t o 5 0 m g/ k g. T h e m a xi m u m pl a s m a c o n c e ntr ati o n at 5 0 m g/ k g (fr e e 
m e a n C m a x of 6 1 7 n g/ m L fr o m t h e 1 -m o nt h r at i s 8 6 -f ol d a b o v e t h e 
pr oj e ct e d h u m a n ( C a v e) dr u g c o n c e ntr ati o n of 7. 2 n g/ m L a n d 7 2 -fol d 
a b o v e t h e pr oj e ct e d h u m a n fr e e effi c a ci o u s C m a x ( 8. 6 n g/ m L).  
 
Cli ni c al D at a  
S e e c urr e nt  P F -0 4 4 4 9 9 1 3  I n v e sti g at or ’ s Br o c h ur e   – r el e a s e d  b y 
Pfi z er ( m a n uf a ct ur er) . 
 
S e v er al cli ni c al st u di e s h a v e b e e n i niti at e d t o d et er mi n e t h e s af et y, 
effi c a c y, p h ar m a c o d y n a mi c s a n d p h ar m a c o ki n eti c s of P F -0 4 4 4 9 9 1 3 
i n p ati e nt s wit h h e m at ol o gi c m ali g n a n ci e s a n d a d v a n c e d/ m et a st ati c 
s oli d t u m or s. St u d y B 1 3 7 1 0 0 1 w a s a fir st -i n-p ati e nt p h a s e  1 tri al wit h 
a 3 + 3 d o s e e s c al ati o n d e si g n i n p ati e nt s wit h r efr a ct or y, r e si st a nt or 
i nt ol er a nt s el e ct h e m at ol o gi c m ali g n a n ci e s. P ati e nt s r e c ei v e d si n gl e 


 
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agent PF-04449913 orally once daily (QD) continuously in 28 day 
cycles. Eight dose levels were evaluated as of September 2011, 
ranging from 5 mg/d to 270 mg/d. Study B1371002 had a similar 3+3 
dose escalation design in patients with select advanced/metastatic 
solid tumors. The starting dose of PF-04449913 in this study was 80 
mg/d and additional dose levels of 160 mg/d and 320 mg/d have 
been completed to date. Protocol B1371003, a Phase 1b/2 study to 
evaluate the safety and efficacy of PF-04449913 in combination with 
various chemotherapy regimens in patients with AML and high-risk 
MDS, is ongoing.  
 
Pharmacokinetics/Pharmacodynamics and Metabolism  
Preliminary PK data indicate that PF-04449913 is 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 
and were eliminated relatively slowly with a mean terminal half-life 
(estimated from a single dose) ranging from 17.3 to 34.9 hours. 
Following repeated daily dosing, PF-04449913 steady state was 
achieved by Day 8 and showed a drug accumulation of ~ 1.5 fold, 
which is consistent with the estimated half-life. In general, low to 
moderate inter-individual variability were observed in Cmax and AUC 
values following single and multiple dose administration, though 
higher variability was observed at the 180 and 270 mg dose levels.  
 
Hepatic metabolism is predicted to be the major clearance pathway 
for PF-04449913 in humans. In vitro metabolism of PF-04449913 
was consistent across preclinical species and humans. PF-
04449913 appeared to be metabolized to several oxidative 
metabolites. Preliminary assessment using individual recombinant 
P450 enzymes suggests that CYP3A4 plays a major role in 
mediating the metabolism of PF-04449913. All metabolites observed 
in human in vitro incubations were present in one or more of the 
evaluated preclinical species. In vitro, PF-04449913 did not inhibit 
CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at 
concentrations up to 30 μM. Based on in vitro and in vivo evaluations 
of PF-04449913, systemic plasma clearance, volume of distribution 
at steady state, elimination half-life and oral bioavailability in humans 
are projected to be 1.03 mL/min/kg, 2.7 L/kg, 30 hours and 55%, 
respectively.  
 
Preliminary data indicates that renal excretion plays a minor role in 
PF-04449913 elimination, with 4% to 19% (n = 15) of the total 


 
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administered dose excreted unchanged in urine. The renal clearance 
ranged from 0.35 L/hr to 3.4 L/hr. 
 
When 200 mg PF-04449913 was combined with ketoconazole, a 
strong inhibitor of CYP3A4, in healthy volunteers, there was 
evidence for a drug-drug interaction resulting in increased exposure 
(Cmax and AUC) of PF-04449913, potentially to the 400-600 mg 
range observed to result in grade 3 QTc prolongations in study 
B1371001.  
 
Study B1371010, a healthy volunteer study investigating the effects 
of a high fat, high calorie meal on the PK of a single dose of PF-
04449913, indicated that food resulted in a 12.7% decrease in AUC 
and a 34.1% decrease in Cmax for PF-04449913.  
 
Toxicity  
Preliminary results from a phase 1 study in patients with 
hematological malignancies revealed grade 3 toxicities of 
hemorrhagic gastritis, hypoxia and pleural effusions. All other 
adverse events (AEs) were less than grade 3, and included 
dysguesia (16%), alopecia (6%), arthralgia (6%), decreased appetite 
(6%), nausea (6%) and vomiting (6%).32 Roughly 50% of patients 
had at least a grade 1 AE. This study and others are ongoing. 
 
Recommended Dose 
Due to the potential interaction between azoles and PF-04449913, 
100 mg of PF-04449913 has been selected as the recommended 
dose in the ongoing protocol B1371003. 
4 
STUDY OBJECTIVES 
4.1 
Primary Objective 
 Determine whether PF-04449913 can prevent relapse in high 
risk acute myeloid leukemia patients who receive an 
allogeneic stem cell transplantation  
4.2 
Secondary Objectives 
 Determine the toxicity profile of PF-04449913 in this 
population 
 Determine the impact of this intervention on overall survival 
(OS) 


 
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5 
INVESTIGATIONAL PLAN 
5.1 
Overall Study Design 
This is an open-label, phase 2 study of PF-04449913 administered 
to acute myeloid leukemia patients after allogeneic stem cell 
transplantation who have a high risk of disease relapse. 
 
5.1.1 Dosing Schema 
Enrolled patients will receive 100 mg PO daily of PF-
04449913 continuously dosed for 28-day cycles.  Patients will 
begin treatment no sooner than post-transplant day 28 and no 
later than post-transplant day 50, after their routine bone 
marrow biopsy is performed. Treatment cycles can continue 
for one year after initiation of study drug in the absence of the 
parameters listed in Section 5.10.1: Stopping Rules. 
 
5.1.2 Continuation and Interruptions  
Each treatment cycle will be initiated at the full 100 mg dose, 
provided patients have no evidence of disease relapse, 
excessive toxicity, or laboratory values outside of the following 
parameters:  
 
• Either creatinine >1.5 x institutional upper limit of 
normal (ULN) or creatinine clearance <60 mL/min as 
calculated by institution’s standard formula 
• Total bilirubin > 2 x ULN (unless documented Gilbert’s 
syndrome) 
• AST and ALT > 5 x institutional ULN 
• Absolute neutrophil count (ANC) < 1000/mm3  
• Platelet count <25,000/mm3  
 
Patients who experience toxicity may be eligible for dose de-
escalation; please see Section 5.13.1 for Definition of Adverse 
Events and Section 5.10.2.2: Dose Delays and De-Escalation. 
5.2 
Study Endpoints 
5.2.1 Primary Endpoint 
• One year relapse-free survival 


 
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5.2.2 Secondary Endpoints 
• Remission duration 
• Incidence and severity of adverse events 
• Overall survival (one year) 
 
5.3 
Selection of Study Population and Enrollment Procedures 
All subjects will be screened for eligibility; see Section 2: Schedule 
of Study Assessments and Section 5.12:  Study Activities and 
Assessments for screening details. All patients must meet the 
qualifications as outlined below. 
 
5.3.1 Inclusion Criteria 
To be eligible to participate in this study, a patient must meet 
the following criteria: 
• WHO-confirmed AML 
• Age ≥18 years 
• Between days 28 and 50 post transplantation at the time 
of initiation of the study drug  
• ECOG performance status ≤ 2 (See Appendix A: ECOG 
Performance Status Scale) 
• Life expectancy > 2 months 
• Recipient of a myeloablative or non-myeloablative 
allogeneic HSCT 
o Conditioning 
regimen 
to 
be 
prescribed 
at 
investigator’s discretion, but will be prospectively 
defined as myeloablative or non-myeloablative 
• Stable engraftment, as defined by absolute neutrophil 
count (ANC) ≥ 1000/mm3 and platelets ≥ 25,000/mm3 
• In morphologic remission (< 5% marrow blasts) based on 
BM biopsy performed +/- 5 days of day 28 post-
transplantation  
• Without clinical signs of active central nervous system 
disease  
• For non-myeloablative transplants, ≥50% CD3 donor 
chimerism at screening 
• High risk of relapse after HSCT, defined as the presence 
of minimal residual disease as measured by flow 
cytometry in the absence of evidence of morphologic 
disease on a bone marrow biopsy prior to HSCT 


 
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• Adequate organ function as indicated by the following 
laboratory values: 
o Aspartate 
aminotransferase 
(AST), 
alanine 
aminotransferase, (ALT) ≤ 3.0 x institutional upper 
limit of normal (ULN) 
o Total bilirubin ≤ 2.0 x institutional ULN, unless 
documented Gilbert’s syndrome 
o Either creatinine <1.5 x institutional upper limit of 
normal (ULN) or creatinine clearance >60 mL/min 
as calculated by institution’s standard formula 
• Serum/urine pregnancy test (for females of childbearing 
potential) that is negative within 72 hours prior to initiation 
of first dose of treatment (a patient is of childbearing 
potential if, in the opinion of the investigator, she is 
biologically capable of having children and is sexually 
active) 
• Female patients of childbearing potential and sexually 
active males and female partners of childbearing potential 
must agree to use a highly effective method of 
contraception throughout the study and for at least 90 days 
after the last dose of assigned treatment. 
• Subject is able to comply with study procedures and 
follow-up examinations. 
 
5.3.2 Exclusion Criteria 
 
• Concomitant treatment with other anti-neoplastic agents, 
with the exception, when clinically indicated, of prophylaxis 
in the post-transplantation setting with intrathecal 
chemotherapy  
• Use of any other experimental drug or therapy within 28 
days of baseline 
• Inability to swallow or absorb drug 
• Active uncontrolled acute fungal, bacterial, or other 
infection that is unresponsive to therapy at time of study 
drug dosing 
• Unstable angina pectoris 
• New York Heart Association Class III or IV heart failure 
• QTc interval (using Fridericia’s correction formula, QTcF, 
if prolonged) >470 msec 
• Active cardiac arrhythmias with rapid ventricular response 
(defined as heart rate greater than 100 beats/minute) 
• Known HIV infection 
• Grade III/IV acute GVHD 


 
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• Current use or anticipated need for food or drugs that are 
known moderate/strong CYP3A4 inducers (See Table 1 
and section 5.9.2: Prohibited Concomitant Therapy), with 
the exception of azole antifungals, which are permitted. 
• Any medical, psychiatric, addictive or other kind of 
disorder which compromises the ability of the subject to 
give written informed consent and/or to comply with 
procedures. 
• Pregnant or lactating females 
 
5.3.3 Lifestyle 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 a highly effective 
method of contraception consistently and correctly for the 
duration of the active treatment period and for at least 90 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 its consistent and correct use. The investigator, 
at each study visit, will confirm and document consistent and 
correct use. In addition, the investigator will instruct the patient 
to call immediately if the selected birth control method is 
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 (i.e., perfect 
use) and include: 
 
1. Abstinence 
2. Established use of oral, injected or implanted hormonal 
methods of contraception 
3. Correctly placed intrauterine device or intrauterine system  
4. Male condom or female condom used with a spermicide 
(i.e., foam, gel, film, cream, suppository) 
5. Male sterilization with appropriately confirmed absence of 
sperm in the post- vasectomy ejaculate 
6. Bilateral tubal ligation or bilateral salpingectomy 
 
In addition, special precautions will be taken to limit any 
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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, and will be 
advised to report any reaction to sun exposed skin. 
 
5.4 
Duration of Study 
All patients will be followed for 30 days after the last study treatment, 
and with annual phone calls for five years.  It is anticipated that the 
study will be completed within four to five years.   
 
5.5 
Drug Administration 
5.5.1 Premedication 
No premedication is required. 
 
5.5.2 PF-04449913 
 
PF-04449913 will be provided to research subjects for the 
duration of their participation in this trial by Pfizer at no charge 
to them or their insurance providers.  PF-04449913 is 
formulated in tablets containing 10 mg, 25 mg and 100 mg of 
study medication. The tablets are packaged in high-density 
polyethylene 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. PF-04449913 will be administered once 
daily and orally on a continuous basis for all patients. A cycle 
is defined as 28 days, regardless of missed doses or dose 
delays. PF-04449913 will be administered without adjustment 
for body size and irrespective of PO intake. 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 than the prescribed dose at 
any time. If a patient misses a day’s dose entirely, they must 
be instructed not to “make it up” the next day. If a patient 
vomits any time after taking a dose, they must be instructed 
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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 a medication error is accompanied by an AE, 
such as an overdose (accidental or intentional), as 
determined by the investigator, the AE is captured on an AE 
CRF page (see Section 5.13.3: Procedures for Recording 
Adverse Events). 
 
5.6 Assuring Patient Compliance 
Patients will receive all dosages of PF-04449913 by self-
administration in the outpatient setting, and will be instructed to 
continue if admitted to the hospital for reasons other than drug-
related toxicity. Patients will receive a diary to record the specific time 
each dose was taken and to record reasons for any missed doses. 
Patient compliance will be assessed on day 1 of cycles 2 and every 
cycle thereafter.  Patients will be required to bring their diary and any 
remaining pills to clinic during this visit.  Research personnel will 
count and record the number of used and unused drug at each visit 
and reconcile with the patient diary.  Any unused PF-04449913 will 
be returned in compliance with 21 CFR 312.59. 
 
5.7 Laboratory Criteria for Initiation of Treatment Cycles 
 
Before any treatment cycle after cycle 1 may be administered, blood 
samples collected within 72 hours of the first dose of each cycle must 
meet the following criteria: 
 
• Either creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 mL/min 
as calculated by institution’s standard formula 
• Total bilirubin ≤ 2 x institutional ULN (unless documented 
Gilbert’s syndrome) 
• AST and ALT ≤ 5 x institutional ULN 
• ANC > 1000/mm3  
• Platelets >25,000/m3 
 
5.8 
Study Treatment Schedule 
 
Patients will receive study treatment as detailed in Section 5.1: 
Overall Study Design, and assessments will be performed as 
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disease assessments, as dictated by usual standard of care, will 
occur; there are no study-specific disease assessments.  Patients 
will be taken off of the study if they meet criteria listed in Section 
5.10.1: Stopping Rules.  
 
5.9 
Concomitant Therapy 
5.9.1 Permitted Concomitant Therapy 
Transfusion of blood and blood products, antibiotics, 
antiemetics and other standard supportive care medications 
are permitted if necessary.  Azole antifungals (fluconazole, 
voriconazole, posaconazole, itraconazole and ketoconazole) 
may be used. 
 
5.9.2 Prohibited Concomitant Therapy 
Chemotherapy, 
immunotherapy 
and 
radiotherapy 
are 
prohibited.  
 
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: Because inhibition of CYP3A4/5 
isoenzymes were expected to increase PF-04449913 
exposure and the extent of this interaction in humans was 
unknown, the use of moderate/strong CYP3A4/5 inhibitors 
was previously prohibited. 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 co-administration of PF-04449913 in 
combination with moderate/strong CYP3A4/5 inhibitors is not 
recommended. Selection of concomitant medication with no 
or minimal CYP3A4/5 inhibition potential is recommended. 
Moderate CYP3A4/5 inhibitors (Table 1) should be used with 
caution and only if considered medically necessary. If a 
moderate/strong CYP3A4/5 inhibitor is to be initiated in 
addition to PF-04449913, the guidance provided in Section 
5.12.5.5 requiring additional EKG monitoring before, during 
and after starting the medication, electrolyte monitoring 
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modifications for QTcF prolongation per Section 5.10.2.2 
must be followed. Azole antifungals are permitted to be 
administrated concomitantly with PF-04449913. 
 
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 moderate/strong CYP3A4/5 inducers 
(representative medications in Table 1) is not permitted from 
study entry until study treatment discontinuation. 
 
Drugs with known risk of Torsade de Pointes (TdP): PF-
04449913 has been shown to have the potential to prolong 
the QTc interval in pre-clinical studies. In the first-in-patient 
study as single agent, Grade 3 QTcF prolongation was 
observed at the highest doses tested (400 mg and 600 mg). 
While the current clinical dose being 
evaluated in this study is 100 mg, the concomitant 
administration of PF-04449913 and drugs with known risk of 
torsade de pointes 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 5.12.5.5 
requiring additional EKG monitoring before, during and after 
starting the medication, electrolyte monitoring (including 
correction and re-checking values) and dose modifications for 
QTcF prolongation per Section 5.10.2.2 must be followed. QT 
prolonging medications should be avoided whenever 
possible. 
 
Prior or concurrent treatment with a Hedgehog inhibitor or 
concurrent treatment with other investigational agents not 
specified in the protocol is not permitted. 
 
Use of warfarin is strongly discouraged if alternate medication 
(erg, low molecular weight heparin) can be substituted. 
Warfarin is a CYP3A4 substrate and drug interactions causing 
variability in INR are possible. Frequent monitoring of the INR 
is recommended in subjects taking warfarin. Dosage of 
warfarin should be adjusted as needed. 
5.9.3 Table 1: Representative prohibited medications based on 
metabolic isoenzyme class.  
 


 
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Isoenzyme Class 
Representative Drugs 
Strong/moderate 
CYP3A4 inhibitors 
aprepitant, clarithromycin, cimetadine, ciprofloxacin, 
conivaptan, diltiazem, erythromycin, fluconazole, 
grapefruit juice, itraconazole, ketoconazole, mibefradil, 
nefazodone,  posaconazole, telithromycin, tofisopam, 
troleandomycin, verapamil and voriconazole  
(NOTE: antifungal azoles are permitted concomitant 
therapies) 
Strong CYP3A4 
inducers 
carbmezapine, phenobarbital, phenytoin, rifampin, 
rifabutin, rifapentin, St. John’s Wort 
 
However, because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently-
updated list such as:  
http://medicine.iupui.edu/clinpharm/ddis/table.aspx;  
medical reference texts such as the Physicians’ Desk 
Reference may also provide this information.   
 
5.10 Safety Plan 
Patient safety will be assessed by reviewing AEs during planned 
visits and physical and laboratory examinations from the time the 
patient receives the first dose of study drug until 30 days after the 
patient’s last study treatment.  See Section 2: Schedule of Study 
Assessments, and Section 5.13: Definitions and Reporting 
Procedures for Adverse Events.  
 
5.10.1 Stopping Rules 
5.10.1.1 Individual Patients’ Stopping Rules 
Patients may be terminated from the study for the following: 
• Noncompliance with the study protocol 
• Morphological disease relapse, defined as having a bone 
marrow biopsy with > 5% leukemic blasts on the aspirate 
differential, the presence of peripheral blood blasts or 
extramedullary disease  
• Patient decides to withdraw from the study 
• ≥ Grade 3 AE that is possibly related to the study drug and 
does not resolve or improve within 28 days (see Section 
5.10.2.2) 
• Serious AE (SAE) related or possibly related to the study 
drug; 
disabilities, 
hospitalizations, 
prolongation 
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hospitalizations or required interventions that are related 
to the transplant are excepted 
• Development of unrelated illness which compromises 
further participation in the study 
• Investigator determines that continuation on study is no 
longer in the best interest of the patient or a change in the 
patient’s condition renders them ineligible for further 
treatment 
• Subject is lost to follow-up despite reasonable efforts by 
the investigator to locate the subject. 
 
5.10.1.2 Study Stopping Rules 
• 
The study will be suspended pending further review if, at 
any time, there is sufficient evidence to suggest that the 
true probability of hematopoietic toxicity attributable to the 
drug exceeds 25% or the true probability of severe GVHD 
exceeds 25%.  Sufficient evidence will be defined as an 
observed failure rate whose lower one-sided 80% 
confidence limit exceeds the thresholds listed above (25% 
for hematopoietic toxicity and GVHD).  Operationally, the 
study will be suspended if any of the following proportions 
are observed (or exceeded): 3/3-5, 5/6-10, 7/11-15, 9/16-
20, 10/21-25, 11/26-28. The probabilities of early 
termination based on this stopping rule for various rates of 
true toxicity are shown in the table below. The probabilities 
are based on a simulation with 1,000 replications.  
 
  
  
Probability of Early Stopping Due to Toxicity 
  
  
Number of 
Patients 
  
True Toxicity Rate 
  
15% 
25% 
35% 
45% 
28  
0.0016 
0.0693 
0.375 
0.787 
 
• 
If any of the above stopping rules is met upon enrollment 
of the next patient, accrual will be held until it is determined 
that no stopping rules will be met with currently enrolled 
patients. 
 
• 
The study will continue until the last patient is followed 30 
days beyond receiving the last dose of study drug. Annual 


 
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phone calls will be made as appropriate for 5 years after 
discontinuation of the study. 
 
5.10.2 Dosing Delays and Modifications 
5.10.2.1 Missed Doses 
Patients will be encouraged to stay on schedule even if a dose 
is missed. Dosing will be tracked in the patients’ diaries.  Lack 
of compliance with the study protocol may result in removal 
from the study.  This will be decided on an individual basis by 
the investigators. 
5.10.2.2 Dose Delays and De-escalation 
Patients who experience a ≥ grade 3 related or possibly 
related non-hematological AE can have treatment interrupted 
for up to 28 days and restarted at the original dose or reduced 
by 50%, at the discretion of the investigator, if the abnormality 
returns to baseline or ≤ grade 1. An additional 50% dose 
reduction will be permitted for a second episode of a ≥ grade 
3 related or possibly related non-hematological AE. No further 
dose reductions will be permitted. Dose re-escalation by 
100% increments to full dose may be attempted if AEs remain 
resolved. 
 For grade 4 related or possibly related 
hematological toxicities, the dose will be withheld for up to 28 
days, when it returns to ≤ grade 3 it can be resumed at the 
original dose or reduced 50% at the discretion of the 
investigator.  An additional 50% dose reduction will be 
permitted for a second episode of a grade 4 related or possibly 
related non-hematological AE. No further dose reductions will 
be permitted. Dose re-escalation by 100% increments to full 
dose may be attempted if AEs remain resolved. Cycles will 
not be prolonged beyond day 28 to make up for missed doses.  
 
Treatment delays beyond 28 days will result in study 
discontinuation. The dose de-escalation table below is 
provided for guidance. 
 
Myalgias and arthralgias are known to be associated with PF-
04449913, and may be more significant in the post HSCT 
setting. For patients with ≥ grade 3 myalgias or arthralgias, 
dose interruption will occur until the symptoms resolve to ≤ 
grade 1. If this does not occur after an interruption of 28 days 
the patient will come off of the study. If it does occur within 28 
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the 100 mg dose, but after re-introduction the drug will be 
given for 21 days consecutively with 7 days off each cycle. If 
a subsequent ≥ grade 3 myalgia or arthralgia event occurs, 
dose interruption will occur until the symptoms resolve to ≤ 
grade 1. If this does not occur after an interruption of 28 days 
the patient will come off of the study. If it does occur within 28 
days of interruption, resumption of PF-04449913 will occur at 
the 50 mg dose, again administered 21 days on and 7 days 
off. Another ≥ grade 3 myalgia or arthralgia event will result in 
the same interruption and resumption schedule as above, this 
time with a dose reduction to 25 mg, and an additional ≥ grade 
3 myalgia or arthralgia event will result in termination of the 
study. 
 
Other toxicities will be managed as follows: 
 
 
Toxicity 
 
Grade 1 or 2 
Grade 3 
 
Grade 4 
 
Continue at 
current dose 
Withhold until toxicity returns to ≤ 
grade 1 for related or possibly 
related non hematologic toxicities 
then resume the same dose level 
or reduce by 50%, at the 
discretion of the investigator 
(nausea, vomiting or diarrhea 
must persist at grade 3 or 4 
despite maximal medical therapy 
to require a dose reduction).  
One additional 50% dose 
reduction is permitted for a 
second episode. At the discretion 
of the investigator, dose re-
escalation by 100% increments 
to full dose may be attempted if 
AEs remain resolved after dose 
reduction (s). 
Withhold until toxicity returns to 
≤ grade 1 for related or possibly 
related non hematologic 
toxicities and ≤ grade 3 for 
related or possibly related 
hematologic toxicities,  then 
reduce by 50% or discontinue 
treatment, at the discretion of 
the investigator (nausea, 
vomiting or diarrhea must 
persist at grade 3 or 4 despite 
maximal medical therapy to 
require a dose reduction). One 
additional 50% dose reduction 
is permitted for a second 
episode. At the discretion of the 
investigator, dose re-escalation 
by 100% increments to full dose 
may be attempted if AEs 
remain resolved after dose 
reduction (s). 
 
 
 


 
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Recommended Dose Modifications for Treatment-Related QTcF 
Prolongation 
 
 
QTcF Prolongation 
 
Grade 
1 
2 
3 
4 
• No 
change 
• Withhold study treatment 
• Assess for and correct 
electrolyte abnormalities. 
• Withhold any concomitant 
medications that may 
cause QTcF prolongation. 
• Resume study treatment at 
prior dose if QTcF returns 
to ≤470 msec and to within 
20 msec of baseline <7 
days. β 
• Resume study treatment at 
one lower dose level if 
QTcF returns to ≤470 
msec and to within 20 
msec of baseline between 
7-14 days, or if a prior 
dosing interruption for 
QTcF prolongation has 
occurred. β 
 
Discontinue study 
treatment permanently if: 
• The QTcF prolongation 
does not return to ≤470 ms 
within 14 days. 
• ≥ Grade 2 QTcF 
prolongation recurs after 
one dose reduction. 
• If anytime during the 14-
day window, the patient 
has a confirmed mean 
QTcF interval >515 ms or 
becomes symptomatic. 
• Withhold study treatment 
• Assess for and correct 
electrolyte abnormalities. 
• Withhold any concomitant 
medications that may 
cause QTcF prolongation. 
• Resume study treatment at 
prior dose if QTcF returns 
to ≤470 msec and to within 
20 msec of baseline <7 
days. β 
• Resume study treatment at 
one lower dose level if 
QTcF returns to ≤470 
msec and to within 20 
msec of baseline between 
7-14 days, or if a prior 
dosing interruption for 
QTcF prolongation has 
occurred. β 
 
Discontinue study 
treatment permanently if: 
• The QTcF prolongation 
does not return to ≤470 ms 
within 14 days. 
• ≥ Grade 2 QTcF 
prolongation recurs after 
one dose reduction. 
• If anytime during the 14-
day window, the patient 
has a confirmed mean 
QTcF interval >515 ms or 
becomes symptomatic. 
• Discontinue study 
treatment 
permanently 
QTcF = Fridericia’s QT correction, ms = milliseconds 
 
β An ECG should be repeated approximately 7 days after study treatment resumption following 
dose interruption for QTcF prolongation. 
 
 


 
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5.10.3 Data and Safety Monitoring 
AEs and SAEs will be reviewed on an ongoing basis to identify 
safety concerns, and the investigators may discontinue the 
study if excessive toxicity is observed. In addition, the study 
will be monitored by the Cancer Center’s data safety and 
monitoring committee (DSMC) at times designated by the 
committee. 
 
Oversight and Monitoring 
The Principal Investigator will be responsible for monitoring 
the safety and efficacy of the trial, executing the DSM plan, 
and complying with all reporting requirements to local and 
federal authorities. This will be accomplished under the 
oversight of the Data & Safety Monitoring Committee (DSMC) 
of the University of Colorado Cancer Center (UCCC).  The 
DSMC is responsible for monitoring data quality and patient 
safety for all clinical studies at UCCC.   A summary of the 
DSMC activities follows: 
 
• Conduct of internal audits 
• Ongoing review of all reportable adverse events and all 
serious/unanticipated adverse events  
• Supervises internal DSM boards and/or performs as an 
internal DSMB 
• Has the authority to close and/or suspend trials for 
safety or trial conduct issues and may submit 
recommendations for corrective actions to the 
Associate Directors Executive Committee 
• Performs 
routine 
internal 
monitoring 
of 
both 
investigator-initiated and cooperative group clinical 
trials 
 
Data regarding number of subjects, significant toxicities, dose 
modifications, and responses will be discussed at regularly 
scheduled disease-oriented working group meetings.  The 
discussion will be documented in the minutes and summaries 
will be submitted to DSMC quarterly. 
 
The Principal Investigator at the Coordinating Center is 
responsible for the overall conduct of the study at all of the 
participating institutions and for monitoring its progress.  The 
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Center for this study and this site will coordinate patient 
enrollment.  There will be only one version of the protocol, and 
each participating institution will use that document.  The 
protocol must not be rewritten or modified by anyone other 
than the Principal Investigator at the Coordinating Center.  
The Principal Investigator at the Coordinating Center is 
responsible for timely review of Adverse Events (AEs) to 
assure safety of the patients and for the review and timely 
submission of data for study analysis.   
 
Each subject’s treatment outcomes will be monitored at least 
monthly by a conference call with the investigators and CRAs 
from all participating institutions. Data regarding the number 
of patients, significant toxicities, dose modifications, and 
responses will be discussed and documented in meeting 
minutes.   
 
The PI will provide a DSM report to the UCCC DSMC on a six 
month basis. DSM reports will contain data from all 
participating sites. The DSM report will include summaries of 
minutes taken at monthly meetings, the participants’ 
demographic 
characteristics, 
expected 
versus 
actual 
recruitment rates, treatment retention rates, any quality 
assurance or regulatory issues (including a summary of any 
protocol deviations), summary of AEs and SAEs, summary of 
dose modifications, and any actions or changes with respect 
to the protocol. The DSM report to the DSMC will also include, 
if applicable, the results of any efficacy data analysis 
conducted. Results from these reviews will be provided to all 
participating investigators to submit to their IRBs at the time 
of continuing review. 
 
5.11 Study Completion and Termination 
Study patients who have met any of the following endpoints will have 
completed the study: 
• SAE related to the study drug 
• Disease relapse  
• Death 
 
Study patients may be prematurely terminated from the study for the 
following reasons: 


 
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• Physician and/or patient decides to discontinue treatment for 
reasons other than an AE 
• ≥ Grade 3 related or possibly related non-hematologic AE or 
grade 4 related or possibly related hematologic toxicity that does 
not resolve or improve within 28 days  
• Noncompliance with the study protocol 
• Development of unrelated illness which compromises further 
participation in the study 
• The patient is lost to follow up (no further data collection or 
submission will be expected) 
• The patient withdraws consent (no further data collection or 
submission will be expected) 
 
At termination, both concomitant medications and ongoing AEs are 
to be recorded, including any new AEs reported at the end of the 
study.  Any unresolved AE at discontinuation of the study treatment 
should be followed until they have resolved or stabilized. Patients 
may choose to stop study treatment for any reason without 
jeopardizing their relationship with healthcare providers. 
 
5.12 Study Activities and Assessments 
5.12.1 Schedule of Activities 
The time each assessment is performed relative to dosing is 
shown in the Schedule of Study Assessments (Section 2).   
5.12.2 Screening Period 
Written consent must be obtained before performing any 
study-specific screening activities.  The screening activities 
outlined in the Schedule of Study Assessments (Section 2) 
must be completed within 28 days of starting study treatment, 
unless otherwise specified.  
 
The investigators will be responsible for keeping a record of 
all subjects who sign an informed consent form for entry into 
the study. After the patient has signed and dated the informed 
consent form, all screening procedures have been completed 
and clinical eligibility has been confirmed, the patient can be 
officially enrolled in the study.   
5.12.3 Treatment Schedule 
Patients will receive study treatment as detailed in Section 
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Schedule of Study Assessments (Section 2).  Patients will 
continue treatment in the absence of toxicity or disease 
progression.   
5.12.4 Follow Up 
Patients will be followed for 30 days after their final drug 
administration for AEs and SAEs.  Safety data beyond 30 
days may be reported if deemed relevant by the investigator.  
 
Annual phone calls to appropriate patients will be made and 
documented for five years after completion or discontinuation 
of the study. 
 
Study can be terminated prior to the completion of five years, 
per Investigator discretion.  Patients still in follow-up will be 
contacted by study team if study is terminated prematurely. 
 
5.12.5 Study Assessments 
5.12.5.1 Vital Signs and ECOG Performance Status 
All vital signs (blood pressure, pulse, respiratory rate, 
temperature, oxygen saturation) and ECOG performance 
status grade (See Appendix A) will be measured during 
screening and during study visits as specified in the Schedule 
of Study Assessments (See Section 2).   
 
5.12.5.2 Physical Examination 
A complete physical examination, including measurement of 
height during the first visit and weight at each visit, must be 
performed during screening (28 days before beginning study 
treatment) and during study visits as specified in the Schedule 
of Study Assessments (Section 2).   
 
5.12.5.3 Adverse Events 
All AEs will be recorded from the first dose until 30 days after 
the last dose of study treatment.  Patients who experience a 
non-serious AE considered to be possibly or definitely related 
to study treatment will be followed until all significant changes 
have stabilized or returned to baseline, the patient withdraws 
consent, or death.  All SAEs will be followed as described, 
regardless of their relationship to study treatment.  Safety data 


 
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beyond 30 days may be reported if it is deemed relevant by 
the investigators. 
 
5.12.5.4 Laboratory Assessments 
The following laboratory assessments will be performed at 
screening and at study visits throughout the course of the 
patient’s participation in the trial.  See the Schedule of Study 
Assessments (Section 2) for specific timing. 
• Hematology: Hemoglobin, hematocrit, red blood cell 
count, total white blood cell count with differential, platelet 
count 
• Chemistries: Albumin, alkaline phosphatase, ALT, AST, 
bicarbonate, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, glucose, potassium, sodium, total bilirubin, total 
protein 
• Coagulation: 
Prothrombin 
time, 
activated 
partial 
thromboplastin time 
• Pregnancy test (if applicable, 72 hours prior to the first 
dose of PF-0444913) 
 
5.12.5.5 EKGs and QTc Calculation 
A 12-lead EKG will be performed during screening, 1-4 hours 
after the first dose of cycle 1, 1-4 hours after dosing on cycle 
1, day 15, 1-4 hours after the first dose of cycle 2 and 2-5 days 
after the addition of any new azole antifungal medications. 
The QT interval will be calculated and corrected for heart rate 
(QTc) by Fridericia’s formula if QTc is greater than 470 msec. 
(QTcF) is defined as: QTc(F) = QT/ (RR)0.33. The QTcF 
duration will be used to make all decisions based on QT 
criteria. If abnormal, triplicate EKGs should be performed and 
the average value used. Please refer to Section 5.10.2.2: 
Dose Delays and De-Escalation for guidance on dose 
adjustments required by prolonged QTcF intervals. 
 
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: 
o EKGs pre- PF-04449913 dose, 1 and 4 hours 
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o Follow 
dose 
modifications 
for 
QTcF 
prolongation (Section 5.10.2.2) 
• After starting a moderate/strong CYP3A4/5 inhibitor or 
TdP drug: 
o EKGs on Day 2 or 3 and on Day 5, 6, or 7 
o EKGs pre- PF-04449913 dose, 1 and 4 hours 
post- PF-04449913 dose 
o Follow 
dose 
modifications 
for 
QTcF 
prolongation (Section 5.10.2.2). 
• Perform additional EKG 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. 
 
5.12.5.6 Minimal Residual Disease (MRD) 
MRD assessments using multiparameter flow cytometry will 
be performed on all bone marrow biopsy samples.  
 
5.12.5.7 Disease Assessments and Response Criteria 
Disease assessments will be performed on a routine basis 
according to standard of care practices. This involves blood 
tests, and when indicated, bone marrow biopsies. 
 
Relapse definition will be based on the LeukemiaNet 
guidelines:35 >5% blasts in the bone marrow, reappearance of 
blasts 
in 
the 
peripheral 
blood 
or 
development 
of 
extramedullary disease.  
 
5.12.5.8 Correlative Assessments 
Tissue will be banked for future testing and correlative 
studies. Each participating institution will employ their own 
IRB-approved tissue banking protocol for this purpose.  
 
 


 
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5.13 Definitions and Reporting Procedures for Adverse Events 
Subjects will be evaluated for AEs at each visit with the NCI-CTCAE 
version 4.03 used as a guide for the grading of severity.  All adverse 
clinical experiences, whether observed by the investigators or 
reported by the patient, must be recorded, with details about the 
duration and intensity of each episode, the action taken with respect 
to the study, and the patients’ outcomes.  The investigators will 
evaluate each AE for its severity and its relationship to the study. The 
investigators will appraise all abnormal laboratory results for their 
clinical significance.  If any abnormal laboratory result is considered 
clinically significant, the investigators will provide details about the 
action taken with respect to the study and the patients’ outcomes. 
 
5.13.1 Definitions of Adverse Events 
5.13.1.1 Adverse Event 
According to the International Conference on Harmonization 
of 
Technical 
Requirements 
for 
Registration 
of 
Pharmaceuticals for Human Use (ICH) Guidelines (Federal 
Register. 1997;62(90):25691-25709), Title 21 of the US Code 
of Federal Regulation (CFR) 312.32, and Investigational New 
Drug (IND) Safety Reports, an AE is defined as follows:  
 
“Any untoward medical occurrence in a subject or clinical 
investigational subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any untoward 
medical occurrence regardless of relationship to the medicinal 
(investigational) product.” 
 
Abnormal laboratory values for laboratory parameters 
specified in the study should not be recorded as an AE unless 
an intervention is required (repeat testing to confirm the 
abnormality is not considered an intervention), the laboratory 
abnormality results in a SAE, or the AE results in study 
termination or interruption/discontinuation of study treatment.  
Medical conditions present at screening (i.e.: before the study 
treatment is administered) are not SAEs and will not be 
recorded on SAE pages of the case report forms.  These 
medical conditions will be adequately documented in the 
patient chart.  However, medical conditions present at 
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treatment or post-treatment periods will be reported and 
recorded as AEs. 
 
5.13.1.2 Serious Adverse Event (SAE) 
An AE will be classified as an SAE if it meets one of the 
following criteria (Reporting see section 5.13.4 and Appendix 
B): 
 
Fatal: 
AE resulted in death. 
Life threatening: 
The AEs placed the patient at immediate risk of death. 
This classification does not apply to an AE that 
hypothetically might cause death if it were more severe. 
Hospitalization: 
AE that required or prolonged inpatient hospitalization. 
Hospitalizations 
for 
elective 
medical 
or 
surgical 
procedures or treatments planned before enrollment in 
the treatment plan or routine check-ups are not SAEs by 
this criterion. Admission to a palliative unit or hospice 
care facility is not considered to be a hospitalization. 
Disabling/incapacitating: 
AE resulted in substantial and permanent disruption of 
the patient’s ability to carry out normal life functions. 
Congenital anomaly or 
birth defect: 
An adverse outcome in a child or fetus of a patient 
exposed to the treatment regimen before conception or 
during pregnancy. 
Medically significant: 
The AE did not meet any of the above criteria, but could 
have jeopardized the patient and might have required 
medical or surgical intervention to prevent one of the 
outcomes listed above. 
5.13.1.3 Pregnancies 
Pregnancies and suspected pregnancies (including a positive 
pregnancy test regardless of age or disease state) of a female 
subject occurring while the subject is on PF-04449913, or 
within 28 days of the subject’s last dose of, are considered 
immediately reportable events. PF-04449913 is to be 
discontinued immediately, and the patient will discontinue the 
study. 
 
For investigational products and for marketed products, an 
exposure during pregnancy (also referred to as exposure in-
utero) occurs if: 
 


 
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• A female becomes, or is found to be, pregnant either 
while receiving or being exposed (e.g., due to 
treatment or environmental exposure) or after 
discontinuing or having been directly exposed to the 
investigational product 
 
• A male has been exposed (egg, due to treatment or 
environmental exposure) to the investigational product 
prior to or around the time of conception or is exposed 
during his partner’s pregnancy. 
 
If the outcome of the pregnancy meets the criteria for an SAE 
(i.e., 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. 
 
All neonatal deaths that occur within 28 days of birth should 
be reported, without regard to causality, as SAEs. In addition, 
any infant death after 28 days that the Investigator suspects 
is related to the in utero exposure to PF-04449913 should also 
be reported. 
 
5.13.2 Relationship of the Adverse Event to Treatment 
The investigator will evaluate the relationship of each AE to 
study treatment using the following criteria: 
Fatal: 
AE resulted in death. 
Unrelated: 
Another cause of the AE is more plausible, a temporal sequence 
cannot be established with the onset of the AE and 
administration of the treatment, or a causal relationship is 
considered biologically implausible. 
Possibly Related: 
There is a clinically plausible time sequence between onset of 
the AE and administration of treatment, but the AE could also 
be attributed to concurrent or underlying disease, or the use of 
other drugs or procedures. Possibly related should be used 
when treatment is one of several biologically plausible AE 
causes. 
Definitely Related: 
The AE is clearly related to use of the treatment. 


 
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5.13.3 Procedures for Recording Adverse Events 
5.13.3.1 Information to be Collected 
Whether considered related or not, during the reporting 
period, all SAEs and non-serious AEs are to be recorded on 
an AE case report form (CRF).  Patients who terminate the 
study early will be followed for 30 days after the last dose of 
study treatment for AEs and SAEs.  Patients who experience 
a non-serious AE considered to be possibly or definitely 
related to study treatment will be followed until all significant 
changes have returned to baseline or stabilized, the patient 
dies, or the patient withdraws consent.  All SAEs will be 
followed as described, regardless of their relationship to study 
treatment.  During the reporting period, the following 
information should be collected: 
• Description of the AE, including onset and resolution dates 
• Relationship to treatment plan, treatment or other causality 
• Action taken, including use of concomitant medications 
• If the event is serious, note all criteria that apply 
 
5.13.3.2 Recording Serious Adverse Events 
• For SAEs, the primary event will be recorded on both an 
AE CRF and an SAE/Product Complaint Form; events 
occurring as a result of the SAE will be described on the 
SAE/Product Complaint Form in the narrative description 
of the case 
• Death is an outcome of an event. The event that resulted 
in the death will be recorded and reported on both an 
SAE/Product Complaint Form and on an AE CRF. 
• For hospitalizations or surgical or diagnostic procedures, 
the illness leading to the hospitalization or surgical or 
diagnostic procedure will be recorded as the SAE, not the 
procedure itself. The procedure will be captured in the 
narrative as part of the action taken in response to the 
illness. 
5.13.4 Investigator Reporting Responsibilities  
The conduct of the study will comply with all Food and Drug 
Administration (FDA) safety reporting requirements.   


 
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5.13.4.1 Investigational New Drug Annual Reports 
If the FDA determines an IND is necessary, it is a requirement 
of 21 CFR 312.33 that an annual report be provided to the 
FDA within 60 days of the IND anniversary date.  21 CFR 
312.33 provides the data elements that are to be submitted in 
the report.   
 
5.13.4.2 Format for Adverse Event Reporting 
All AE reports will include the patient’s number, age, sex, 
weight, severity of reaction (mild, moderate, severe), 
relationship to the study (fatal relationship, definitely related, 
possibly related, unrelated), date and time of administration of 
test medications and all concomitant medications, and 
subsequent medical treatment provided. An investigator-
initiated research adverse event form will be utilized for 
reporting. 
 
5.13.4.3 Reporting to the IRB 
The Investigators will notify the IRB of an AE or SAE 
according to institutional policy.   
 
The serious adverse event reports will be reviewed by PI. If 
the adverse event meets the coordinating center’s criteria for 
reporting then an official signed report will be submitted to the 
coordinating center’s IRB. 
 
5.13.4.4 Reporting to Pfizer 
Within 24 hours of first awareness of the event (immediately 
if the event is fatal or life-threatening), the PI will report to 
Pfizer any SAE that occurs within the SAE reporting period 
(see Section 5.13.4.6 and Appendix B).  
 
5.13.4.5 Non-serious Adverse Event Reporting 
All non-serious AEs that occur before study drug 
administration but after informed consent is obtained and are 
associated with protocol-specific procedures (eg: AEs 
associated with blood draws performed only for protocol 
purposes) will be reported according to local and coordinating 
center IRB guidlines.  
 


 
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Events that occur before informed consent is obtained should 
be documented as medical history.  All non-serious AEs that 
occur between the first study treatment and the safety follow-
up 
 visit will be reported according to local and coordinating 
center IRB guidlines.   
 
All non-serious AEs that occur subsequent to the safety 
follow-up visit and are considered to be pertinent in the 
opinion of the investigators may be reported according to local 
and coordinating center IRB guidlines. 
 
5.13.4.6 SAE Reporting 
SAEs will be reported within 24 hours of first awareness of the 
event (immediately if the event is fatal or life-threatening). 
 
All sites will report SAEs directly to Pfizer Drug Safety 
and Surveillance.  A copy of each SAE will also be sent to 
the University of Colorado (coordinating center) via email 
within 24 hours of the event. 
 
The PI will then review and submit to the University of 
Colorado regulatory authorities and the FDA, if applicable, in 
accordance with 21 CFR 312.32. 
 
All SAEs will be reported using the FDA 3500A Mandatory 
MedWatch report form. SAE form can be found at:  
 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsFo
rms/Forms/UCM048334.pdf 
 
Periods: 
• All SAEs that occur after informed consent is obtained 
will be reported up to 30 days after administration of 
the last study treatment, regardless of relationship to 
study treatment.  
 
• All SAEs that occur beyond 30 days after the 
administration of the last study treatment and are 
considered 
pertinent, 
in 
the 
opinion 
of 
the 
investigators, may be reported. 
 
 


 
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5.14 Statistical Methods and Sample Size Determination 
The one-year probability of relapse-free survival for high-risk patients 
is roughly 30%.12,36-38 Using this as a null hypothesis, and 
speculating that the use of PF-04449913 will increase the one-year 
probability of relapse-free survival to 50%, we will require 50 patients 
to allow for a 90% power to detect this 20% difference, with a 
significance level of 0.05.39 We predict the need to screen roughly 60 
patients to enroll 50 with high risk of relapse.   
 
Kaplan-Meier estimates using SAS software will be utilized for 
statistical analysis.  
 
5.15 Protocol Deviations 
Data from patients who do not receive at least one full cycle of 
treatment due to early termination, death or non-compliance will be 
described.  Protocol violations during treatment and follow-up will be 
listed.  Additional analyses will include summaries of patient 
demographics, baseline characteristics, compliance and concurrent 
treatments.  When an emergency occurs that requires a deviation 
from the protocol, a deviation will be made only for that subject.  A 
decision will be made as soon as possible to determine whether or 
not the subject for whom deviation from the protocol occurred is to 
continue on the study.  The subject’s medical records will completely 
describe the deviation from the protocol and state the reasons for 
such deviation.  In addition, the investigators will notify the IRB, per 
IRB guidelines, in writing of such deviation from protocol. Non-
emergency minor deviations from the protocol will be permitted with 
approval of the investigators.  
 
6 
ADMINISTRATIVE REQUIREMENTS 
6.1 
Data and Safety Monitoring Plan 
Please refer to section 5.10.3: Data and Safety Monitoring. 
6.2 
Ethics 
6.2.1 Institutional Review Board 
The protocol for this study has been designed in accordance 
with the general ethical principles outlined in the Declaration 
of Helsinki.  The review of this protocol by the IRB and the 
performance of all aspects of the study, including the methods 


 
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used for obtaining informed consent, are in accordance with 
principles enunciated in the Declaration, as well as ICH 
Guidelines, Title 21 of the CFR, Part 50 (Protection of Human 
Subjects) and Part 56 (Institutional Review Boards).  The 
investigators will be responsible for preparing documents for 
submission to the IRB and obtaining written approval for this 
study.  The approval will be obtained prior to the initiation of 
the study.  The approval for both the protocol and informed 
consent must specify the date of approval, protocol number 
and version, or amendment number.  Any amendments to the 
protocol after receipt of IRB approval must be submitted by 
the investigators to the IRB for approval.  The investigators 
are also responsible for notifying the IRB of any serious 
deviations from the protocol, or anything else that may involve 
added risk to subjects.  Any advertisements used to recruit 
subjects for the study must be reviewed and approved by the 
IRB prior to use.  The IRB will be informed regarding the 
progress of the study and any changes made to the protocol, 
and will be updated at least once a year.  For collaborating 
institutions, consents will be reviewed and approved by the 
local IRB. 
 
6.2.2 Patient Information and Consent 
The investigators must obtain informed consent of a subject 
or his/her designee prior to any study-related procedures as 
set forth in the CFR and ICH Guidelines for Good Clinical 
Practice.  Documentation that informed consent occurred 
prior to the subject’s entry into the study and the informed 
consent process should be recorded in the subject’s source 
documents.  The original consent form signed and dated by 
the subject and by the person consenting the subject prior to 
the subject’s entry into the study must be maintained in the 
investigators’ study files.  No substantial deviations from the 
informed consent form will be made.  The informed consent 
form will be submitted to and approved by the IRB prior to 
distribution to patients.  Before initiating protocol-specific 
procedures that would not otherwise be done, written and 
signed informed consent must be obtained.  This form must 
be signed and dated by the patient or by the patient’s legally 
authorized representative if the patient is unable to sign.  The 
case history for each patient will document that informed 
consent was obtained before the patient’s participation.  A 
copy of the informed consent must be provided to the patient 
or the patient’s legally authorized representative, and if 


 
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applicable, it will be provided in a certified translation into a 
foreign language.  Signed informed consents will remain in 
each patient’s chart and will be available for verification at any 
time. 
6.3 
Record of Administration 
Accurate records will be kept in the source documents of all drug 
administration, including prescribing and dosing.  The investigators 
must ensure that the records and documents pertaining to the 
conduct of the study and the distribution of the protocol therapy 
(includes copies of CRF's and source documents such as: hospital 
records; clinical and office charts; laboratory notes; memoranda; 
subjects’ diaries or evaluation checklists; SAE reports; pharmacy 
dispensing records; recorded data from automated instruments; 
copies or transcriptions certified after verification as being accurate 
copies; microfiches, photographic negatives, microfilm, or magnetic 
media; x-rays; subject files; records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the 
clinical study; documents regarding subject treatment and drug 
accountability; original signed informed consents) be retained for as 
long as needed to comply with national and international regulations.  
By signing the protocol, the investigators agree to adhere to the 
document/records retention procedures. CRFs for this study will be 
collected at standard intervals by the local PI or the study coordinator 
and transferred to the coordinating center.  The local principal 
investigator will ensure that data collected for this study conform to 
all established guidelines for coding, collection, key entry and 
verification.   
6.4 
Confidentiality 
The patient’s medical information obtained in this study is 
confidential, and disclosure to third parties is prohibited, unless the 
patient allows information to be shared with his or her personal 
physician or other appropriate medical personnel responsible for his 
or her welfare.  In compliance with United States federal regulations, 
data generated by this study will be available for inspection upon 
request by representatives of Pfizer, the FDA, national and local 
health authorities, and the IRB, who may review and/or copy relevant 
medical records in accordance with the law.  Should direct access to 
medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the 
investigators to obtain such permission in writing from the 
appropriate individual. 


 
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6.5 
Study Auditing 
Investigator responsibilities are set out in the ICH guideline for Good 
Clinical Practice and in the US CFR.  Investigators must enter study 
data onto CRF’s or another data collection system.  The investigators 
will permit study-related audits by Pfizer or its representatives, IRB 
review, and regulatory inspection(s) (e.g., FDA, EMEA, TPP), 
providing direct access to the facilities where the study took place, to 
source documents, to CRF's, and to all other study documents.  The 
investigators, or a designated member of the investigators’ staff, 
must be available at some time during audits to review data, resolve 
any queries and to allow direct access to the subjects’ records (e.g., 
medical records, office charts, hospital charts, and study-related 
charts) for source data verification.  In addition, the Data Safety 
Monitoring Committee at the University of Colorado will audit the 
study according to institutional policy. 
 
 
 


 
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7 
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Maurillo L, Buccisano F, Del Principe MI, et al. Toward optimization of 
postremission therapy for residual disease-positive patients with acute myeloid 
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Stelljes M, Beelen DW, Braess J, et al. Allogeneic transplantation as post-
remission therapy for cytogenetically high-risk acute myeloid leukemia: landmark 
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 APPENDIX A - ECOG Performance Status Scale 
 
SCORE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to 
carry out any work activities.  Up and about more than 
50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead 
 
 


 
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9 
APPENDIX B - Pfizer Safety Reporting Policy 
Pfizer Serious Adverse Event Reporting Policy 
For Investigator-Initiated Research Studies 
Reporting of Serious Adverse Events. Within 24 hours of first awareness of the event (immediately 
if the event is fatal or life-threatening), Principal Investigator will report to Pfizer by facsimile any 
Serious Adverse Event (“SAE,” as defined below) that occurs during the SAE reporting period (as 
defined below) in a Study subject assigned to receive the Pfizer product that is the focus of the 
Study (“Pfizer Product”). Principal Investigator will report such SAEs using an FDA 
MEDWATCH form, CIOMS form, Investigator-Initiated Research Serious Adverse Event (IIR 
SAE) form, or other Pfizer agreed upon form for SAE reporting. The Reportable Event Fax Cover 
Sheet provided by Pfizer should also be included. Principal Investigator should report SAEs as soon 
as they are determined to meet the definition, even if complete information is not yet available.  
a. SAE Definition. An SAE is any adverse event, without regard to causality, that is life-threatening 
or that results in any of the following outcomes: death; in-patient hospitalization or prolongation 
of existing hospitalization; persistent or significant disability or incapacity; or a congenital anomaly 
or birth defect. Any other medical event that, in the medical judgment of the Principal Investigator, 
may jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above is also considered an SAE. A planned medical or surgical procedure is not, 
in itself, an SAE.  
b. Exposure During Pregnancy, Exposure During Lactation, and Lack Of Effect. Even though there 
may not be an associated SAE, exposure to the Pfizer Product during pregnancy and exposure to 
the Pfizer Product during lactation are reportable, and lack of effect of the Pfizer Product may also 
be reportable. This requirement is further explained in the training material provided by Pfizer (see 
Section f, below). In this Agreement, the term SAE will be understood to include exposure during 
pregnancy, exposure during lactation, and reportable instances of lack of effect.  
c. SAE Reporting Period. The SAEs that are subject to this reporting provision are those that occur 
from after the first dose of the Pfizer Product through 28 calendar days after the last administration 
of the Pfizer Product or longer if so specified in the Protocol. In addition, investigators should 
submit SAEs to Pfizer any time after the administration of the last dose of the Pfizer Product, if the 
Principal Investigator suspects a causal relationship between the Pfizer Product and the SAE.  
d. Follow-Up Information. Institution will assist Pfizer in investigating any SAE and will provide 
any follow-up information reasonably requested by Pfizer.  
e. Regulatory Reporting. Reporting an SAE to Pfizer does not relieve Institution of responsibility 
for reporting it to FDA and/or other appropriate Regulatory Authorities, as required.  
 
f. Pfizer-Provided Training. Pfizer will make available training material that provides information 
about the SAE reporting requirements for IIR studies. Principal Investigator will review this 
material and share it with any Study staff engaged in the reporting of SAEs.”