Clinical trial NCT04051996
Conditions: ACUTE MYELOID LEUKEMIA
Sponsor: Yale University
Start date: 2019-12-06; Completion date: 2020-06-09
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multi-center, randomized phase 2 study is designed to evaluate the complete remission (including complete remission with incomplete count recovery) rates of glasdegib in combination with either decitabine on a 5-day or 10-day schedule in patients with newly-diagnosed poor-risk AML who either refuse or are ineligible for intensive therapy.

Detailed description:
The primary objective of this multi-center, randomized phase 2 study is to determine the response rates, complete remission (CR) and complete remission with incomplete count recovery (CRi), of glasdegib/DAC5 and glasdegib/DAC10 in patients with newly-diagnosed PrAML.

There are two secondary objectives for this study. The first secondary objective is to evaluate the toxicity and safety profiles of glasdegib/DAC5 and glasdegib/DAC10 in patients with newly-diagnosed PrAML. The other secondary objective is to determine the event-free survival (EFS), relapse-free survival (RFS), overall survival (OS), duration of response, bone marrow mutational clearance, and remission clonality of glasdegib/DAC5 and glasdegib/DAC10 in patients with newly-diagnosed PrAML.

Arms: arm 1: Glasdegib will be administered at the starting dose of 100 mg orally once daily and continuously in combination with either DAC5 (decitabine 20 mg/m2 IV on a 5-day schedule) or DAC10 (decitabine 20 mg/m2 IV on a 10-day schedule) as per randomization. Treatment will be administered in 28-day cycles. arm 2: Glasdegib will be administered at the starting dose of 100 mg orally once daily and continuously in combination with either DAC5 (decitabine 20 mg/m2 IV on a 5-day schedule) or DAC10 (decitabine 20 mg/m2 IV on a 10-day schedule) as per randomization. Treatment will be administered in 28-day cycles.
Interventions: intervention 1: Glasdegib intervention 2: Decitabine
Intervention descriptions: intervention 1: Glasdegib will be administered at the starting dose of 100 mg orally once daily. intervention 2: Decitabine will be administered per local label and will be administered by IV infusion at a dose of 20 mg/m2/day for either 5 days or 10 days as determined by randomization. Each cycle will be every 28 days.

Protocol documents:
Prot_SAP_000.pdf: 
NCT #: NCT04051996    
Yale IRB HIC #: 2000024738 
PI: Dr. Amer Zeidan  
Title: GLAD-AML - Glasdegib (Pf-04449913) With Two Standard Decitabine Regimens for Older Patients 
With Poor-risk Acute Myeloid Leukemia 
Date of Document : July 17th 2020 
 
 


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Protocol Draft- RPh2 glasdegib + DAC5/DAC10 in PrAML 
v.4.1 May 31, 2019 
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A RANDOMIZED, PARALLEL-ARM, PHASE 2 CLINICAL TRIAL OF THE COMBINATION 
OF GLASDEGIB (PF-04449913) WITH TWO STANDARD DECITABINE REGIMENS FOR 
PATIENTS WITH POOR-RISK ACUTE MYELOID LEUKEMIA WHO ARE UNFIT FOR OR 
REFUSE INTENSIVE CHEMOTHERAPY (GLAD-AML STUDY) 
 
 
Sponsor: 
Amer Zeidan, MBBS, MHS 
 
 
Assistant Professor of Medicine 
 
 
Yale University 
333 Cedar Street, PO Box 208028, New Haven, CT 06520-8028 
 
IND Number: 143356 
 
NCT Number: TBD 
 
 
Version: 
v4.1 
Date:  
May 31, 2019 
 
Supersedes: 
v4, May 30, 2019 
v3, April 26, 2019 
v2, March 29, 2019 
Original v1, January 23, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. ABBREVIATIONS 
 
Abbreviation 
Term 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
alloSCT 
allogeneic hematopoietic stem cell transplant 
ALT, SGPT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST, SGOT 
aspartate aminotransferase 
AUC 
area under the curve 
BID, b.i.d 
twice daily 
BSC 
best supportive care 
CNS 
central nervous system 
CBC 
complete blood count 
CTCAE v5.0 
Common Terminology Criteria for Adverse Events Version 5 
CR 
complete remission 
CRc 
cytogenetic complete remission 
CRh 
complete remission with partial hematologic recovery 
CRi 
complete remission with incomplete hematologic recovery 
CRm 
molecular complete remission 
CRMRD 
complete remission with minimal residual disease 
CRp  
complete remission with incomplete platelet recovery 
CRF 
case report form 
DAC 
decitabine 
DAC5 
decitabine 20 mg/m2 intravenous daily for five days on 28-day cycles 
DAC10 
decitabine 20 mg/m2 intravenous daily for ten days on 28-day cycles 
DLT 
drug-limiting toxicity 
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DL 
dose level 
DNMTi 
deoxyribonucleic acid methyltransferase inhibitor 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
EC 
ethics committee 
ECG, EKG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event free survival 
EOS 
end of study 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FLT3 
FMS-like tyrosine kinase 3 
G-CSF 
granulocyte colony stimulating factor  
GCP 
good clinical practice 
GLI 
glioma 
Hh 
Hedgehog 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
HMA 
hypomethylating agent(s) 
IB 
investigators brochure 
IC 
intensive chemotherapy 
ID 
identification   
ICH 
International Council for Harmonization 
IHH 
Indian hedgehog 
IRB 
institutional review board 
IRT 
Interactive Response Technology System 
IVR 
Interactive Voice Response 
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IWR 
Interactive Web Response 
IV 
intravenous  
IWG 
International Working Group 
LFS 
leukemia-free survival 
LFT 
liver function test 
MDS 
myelodysplastic syndrome 
MLF 
morphologic leukemia-free [state] 
MPN 
myeloproliferative neoplasm 
MRD 
measurable residual disease 
MTD 
maximally tolerated dose 
NCI 
National Cancer Institute 
OR 
overall response 
ORR 
overall response rate 
OS 
overall survival 
PE 
physical exam 
PI 
package insert 
PK 
pharmacokinetics 
PR 
partial response 
PrAML 
poor-risk AML 
PS 
performance status 
PT 
prothrombin time 
PTCH 
patched 
QTcF 
QT interval with Fridericia’s correction 
RBC 
Red blood cell 
RFS 
relapse-free survival 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SMO 
smoothened 
SOC 
standard of care 
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TTR 
time to response  
ULN 
upper limit of normal 
US 
United States 
VAF 
variant allele frequency 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 
 
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2. PROTOCOL SUMMARY  
 
2.1. Introduction 
The small molecule glasdegib (PF-04449913/PF-913) is an oral, selective SMO receptor antagonist which 
has recently been studied as a therapy in acute myeloid leukemia (AML); glasdegib, however, has not 
been extensively studied either as monotherapy or in combination with other chemotherapeutic agents for 
patients with cytogenetically or molecularly-defined poor-risk AML (PrAML).  
 
This multi-center, randomized phase 2 study is designed to evaluate the complete remission (including 
complete remission with incomplete count recovery) rates of glasdegib in combination with either 
decitabine on a 5-day or 10-day schedule in patients with newly-diagnosed poor-risk AML who either 
refuse or are ineligible for intensive therapy. 
 
2.2. Indication  
Previously-untreated adult patients with cytogenetically or molecularly-defined PrAML who either 
decline or are not candidates for intensive chemotherapy 
 
2.3. Background and rationale 
2.3.1. Disease overview 
Approximately 30% of newly-diagnosed AML is characterized as being poor-risk AML (PrAML) and is 
specifically-defined by specific myeloblast karyotypic aberrations including del(5q)/-5, del(7q)/-7, inv(3), 
t(3;3), t(6;9), -17, abn 17p, monosomal karyotype, complex karyotype (defined as three or more 
abnormalities) as well as those molecularly-defined by the presence of mutated TP53.1, 2 Complete 
response (CR) rates to standard induction chemotherapy in PrAML are no higher than 55% in patients 
aged 55 years and only 32% in older patients.3, 4 The presence of monosomal karyotype predicts CR as 
low as 18%.5 Concordant with CR rates, survival also remains inferior in PrAML, with 4-year overall 
survival (OS) ranging from 4-10% and even as low as 1% based on the degree of poor-risk cytogenetic 
abnormality on the myeloblast karyotype.3-6 TP53-mutated AML provides another informative example: 
only 41% of patients achieve CR and fewer than 10% remain alive three years following allogeneic stem 
cell transplantation (alloSCT) performed while in CR.7, 8 PrAML patients have few if any curative 
therapeutic options. 
 
Hedgehog (Hh) pathway proteins are a collection of small molecules which participate in intercellular 
signaling pathways responsible for embryogenesis and maintenance of adult stem cells. The primitive 
differentiation into definitive cell types is a result of cellular response to heterogeneous concentrations 
and gradients of Hh ligand which induces eventual expression of varying target genes responsible for 
such.9 This cellular response is predicated upon Hh-induced activation of patched-1 and patched-2 
(PTCH-1/2), the 12-pass transmembrane proteins which act as Hh ligand receptor.9, 10 PTCH-1/2 acts 
upon smoothened (SMO), a 7-pass transmembrane Hh-related, constitutively-active signal transducer 
protein whose activation culminates in the downstream phosphorylation of the glioma (GLI) family zinc 
ﬁnger activating transcription factors GLI1 and GLI2 (oncogene homologues of the cubitus interruptus 
transcription factor), and the ultimate expression of target genes responsible for inciting cell cycling, anti-
apoptotic mechanisms, and cellular differentiation.9, 10 Conversely, the absence of Hh, its receptor or 
signaling transduction, Hh-related transcription factors are alternatively-cleaved, assume the role of 
transcriptional repressors, and halt differentiation that was not predestined.9, 10 Indian Hh (IHH) is a 
tissue-specific Hh isoform which has been shown to have a crucial role in primitive hematopoiesis, the 
early stage at which embryogenesis commits cells to hematopoietic precursors and the development of 
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early hematopoietic tissue, which is also shown to express PTCH1/2, SMO and the GLI family 
transcription factors.11, 12 Subsequent to its pivotal role in early tissue development, Hh additionally 
maintains an active role in adult multipotent hematopoietic stem cells (HSC) expansion, self-renewal in 
response to biological insults, and thus lifelong hematopoiesis.11, 12  
 
AML pathology is likely founded in the presence of leukemic stem cells (LSC), which yield leukemic 
progenitor cells, downstream CD34+ leukemic effector cells, and the ultimate hematopoietic dysfunction 
with which AML manifests.13 Ex vivo AML data has shown that CD34+ leukemic cells are characterized 
by high expression of IHH, GLI1, GLI2, and Hh-related downstream pro-survival gene expression, all 
indicative of Hh pathway activation.13-16 Overexpression of downstream GLI2 mRNA has been shown to 
have a negative impact on overall survival.17  
 
The Hh pathway has furthermore been implicated in the leukemic cell chemoresistance. Direct SMO 
antagonists and anti-IHH monoclonal antibodies to cytarabine-resistant CD34+ human myeloid 
leukemic cell lines are shown to specifically inhibit the Hh pathway, induce Hh-specific apoptosis, 
and more strikingly, restore chemosensitivity.13 It is reasonable to posit that chemosensitivity to other 
standard AML therapies may be restored with leukemic cell exposure to Hh-pathway inhibitors. 
 
2.3.2. Glasdegib 
The small molecule glasdegib (PF-04449913/PF-913) is an oral, selective SMO receptor antagonist which 
has recently been studied as a therapy in AML. Initial in vitro and ex vivo studies of AML cell lines 
demonstrated that glasdegib reduced SMO-targeting gene transcripts, c-Myc expression, cell cycle 
progression and ultimately the fraction of CD34+CD38- cells, which infers a reduced leukemia-initiation 
potential of AML LCS.15  
 
A phase 1 study of glasdegib monotherapy in 47 patients with myeloid malignancies including 28 with 
AML established a maximum tolerated dose (MTD) of 400 mg daily with 60% of patients experiencing a 
treatment-related adverse event (three of which were grade 4), which included dysgeusia (28%), anorexia 
(19%), and alopecia (15%). A recommended phase 2 dose of 200 mg daily or lower was established; 
clinical activity was suggested in 49% of all patients.18 
 
2.3.3. Decitabine in Patients with Poor-risk Acute Myeloid Leukemia 
An initial phase II study of the DNA methyltransferase inhibitor (DNMTi) decitabine 20 mg/m2 on a 5-
day schedule in patients aged 60 years and older (median age 74) showed a 24% CR rate in the PrAML 
subset.19 A subsequent phase II trial of decitabine 20 mg/m2 given on a 10-day schedule in a comparable 
population induced a CR of 47%. Interestingly, half of these study patients had PrAML; a CR rate of 
nearly 50% was noted in this subset.20 A recent study by Welch, et al claimed overall response rates 
(ORR, defined as CR/CRi plus morphologic remission) of 67% in PrAML using the 10-day schedule, 
with most strikingly a 100% ORR in TP53-mutated AML in addition to robust mutation clearance and 
survival rates that seemed to remit to those observed in intermediate-risk AML populations.21 However, 
the largest randomized trial testing decitabine (the randomized DACO-16 trial) in older unfit adults 
showed a CR rate of 20%.22 
 
2.3.4. Rationale for the Combination of Glasdegib with Decitabine in Poor-risk Acute Myeloid 
Leukemia 
The use of targeted therapy in AML is made difficult by the heterogeneous nature of the disease with 
respect to the multitude of molecular and chromosomal abnormalities which initiate leukemogenesis. 
However, targeting and disrupting the Hh-pathway, the primary mechanism by which diseased and often 
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chemoresistant LSC maintain their self-renewal and leukemia-initiating potential offers the potential of 
more robust leukemic cell kill and clinical outcomes of standard AML therapies, which to date have 
yielded unacceptable results for the PrAML population.  
 
Glasdegib has previously combined with decitabine in only very few AML patients. A recent, three-arm 
phase 1b study included an arm in which patients aged 65 years or older with newly-diagnosed AML (5 
patients [71%]) or high-risk myelodysplastic syndrome and no prior DNMTi exposure received glasdegib 
100 or 200 mg daily in combination with decitabine 20 mg/m2 on a 5-day schedule; two patients (29%) 
were characterized by poor-risk cytogenetics.23 Two patients (29%) were characterized by poor-risk 
cytogenetics and three patients (43%) were treated at the 200 mg daily dose. The MTD was not reached, 
no dose-limiting toxicities were observed, and the most common treatment-related effects (not 
surprisingly given the role of the Hh pathway in normal hematopoiesis) were hematologic toxicities: 
neutropenia (57%), thrombocytopenia (43%), anemia (43%).23 Of the AML patient subset, 40% achieved 
CR/CRi with a median of 3 cycles administered, and median duration of response of 2.6 months.23 Given 
the absence of a MTD, its well-tolerated nature and convincing efficacy signal, glasdegib 100 mg daily 
was selected as the randomized, phase 2 dose for use with other standard AML therapies including 
decitabine. Given the striking report of robust response to decitabine on the 10-day schedule in AML 
patients with TP53-mutated disease (an inherently large proportion of patients with PrAML), it stands to 
reason that glasdegib 100 mg daily in combination with decitabine on the 10-day schedule might induce 
more robust responses in comparison to that observed in combination with the decitabine on the 5-day 
schedule. 
 
2.4. Study Objectives And Endpoints  
 
2.4.1. Objectives 
Primary objective 
To determine the response rates, complete remission (CR) and complete remission with 
incomplete count recovery (CRi), of glasdegib/DAC5 and glasdegib/DAC10 in patients with 
newly-diagnosed PrAML 
 
Secondary objectives 
To evaluate the toxicity and safety profiles of glasdegib/DAC5 and glasdegib/DAC10 in 
patients with newly-diagnosed PrAML  
To determine the event-free survival (EFS), relapse-free survival (RFS), overall survival (OS), 
duration of response, bone marrow mutational clearance, and remission clonality of 
glasdegib/DAC5 and glasdegib/DAC10 in patients with newly-diagnosed PrAML 
 
2.4.2. Endpoints 
Primary endpoint 
CR/CRi rate as defined by the 2017 European LeukemiaNet response criteria (Appendix 1) 
 
Secondary endpoints 
Adverse events (AE)  
Serious Adverse Events (SAE) 
CR 
CRi 
CRh 
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RBC transfusion independence (per the International Working Group [IWG] response criteria 
for MDS) for patients who are transfusion dependent 
OS 
EFS 
RFS 
Time to CR/CRi 
Duration of CR/CRi 
Bone marrow mutational clearance of frequently-mutated genes in AML (e.g. NPM1, CEBPA, 
DNMT3A, RUNX1, TET2, IDH1/2) via next-generation DNA sequencing 
Remission clonality 
 
2.5. Study Design 
This multi-center, randomized phase 2 study is designed to evaluate the complete remission (including 
complete remission with incomplete count recovery) rates of glasdegib in combination with either 
decitabine on a 5-day or 10-day schedule in patients with newly-diagnosed poor-risk AML who either 
refuse or are ineligible for intensive therapy.  Induction cycles are cycles 1-6 (or until CR or CRi is 
achieved, if earlier).  Consolidation cycles are cycles 7 (or earlier if CR or CRi is achieved)-24.  Patients 
who have achieved CR or CRi will remain on study beyond cycle 6 for up to 24 cycles.  
 
Figure 1. Schematic of Study Design 
 
Key Eligibility:
•
Previously-untreated 
poor-risk AML
•
Refusal of/ineligible 
for intensive therapy
•
ECOG 0 - 2
Primary Endpoint:
Complete remission + complete remission with 
incomplete count recovery rates 
Secondary Endpoints:
OS, EFS, RFS, time to CR/CRi, duration of CR/CRi, 
bone marrow mutational clearance
R
A
N
D
O
M
I
Z
E
(1:1)
Glasdegib (PF-04449913) 100 mg PO 
daily on a 28 day cycle
+
Decitabine 20 mg/m2 IV daily x 10 days 
on a 28 day cycle 
Glasdegib (PF-04449913) 100 mg PO 
daily on a 28 day cycle
+
Decitabine 20 mg/m2 IV daily x 5 days 
on a 28 day cycle 
Stage 1 safety 
assessment
 
2.6. Study Assessments 
Patients will be followed for efficacy throughout the study by means of bone marrow aspirates.  
Following study entry, bone marrow biopsies will only be required if adequate bone marrow aspirates are 
not obtained. A CR/CRi needs to be confirmed at least 4 weeks after the bone marrow (BM) evaluation 
by assessing the stability of improved counts on peripheral blood (PB) according to the 2017 European 
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v.4.1 May 31, 2019 
Page 10 of 79 
 
LeukemiaNet response criteria (Appendix 1); an additional marrow confirmatory specimen is not 
required. Transfusional support (packed red blood cells and platelets) will also be recorded. Timely and 
complete disease assessments (BM evaluation and peripheral blood (PB) counts) at screening and during 
the study, whenever clinically indicated, are essential. Failure to perform any of the required disease 
assessments will result in the inability to determine disease status for that time point and may weaken the 
study conclusions. Safety assessments (laboratory, instrumental and clinical) will be performed regularly 
during the active treatment period. Please refer to the Schedule of Activities for a complete list of 
assessments to be performed on patients in the study.  
 
2.7. Study Treatments  
Treatment will be administered in 28-day cycles. All patients will receive glasdegib 100 mg oral daily and 
will be subsequently randomized 1:1 to receive glasdegib in combination with either decitabine 20 mg/m2 
IV on a 10-day schedule (DAC10) or decitabine 20 mg/m2 IV on a 5-day schedule (DAC5).  
 
Since responses to decitabine may require 4-6 cycles of administration to emerge, treatment with the 
study drug combination should be continued for at least 6 cycles in patients with a response of stable 
disease (SD) or greater, or until progressive disease (PD), unacceptable toxicity, patient refusal, or death, 
whichever occurs first. 
 
If glasdegib is permanently discontinued for reasons other than objective disease progression, patient 
refusal, or consent withdrawal, single-agent treatment with decitabine may be continued if the patient has 
experienced at least a CRi to study therapy. In cases of unacceptable toxicity or pregnancy, the patient 
must be withdrawn from both study drugs and entered into the follow-up phase of the study. When study 
treatment with both drugs (decitabine and glasdegib) is permanently discontinued, patients will enter into 
the follow-up phase as detailed below. 
 
2.8. Statistical Methods  
The study will proceed as a pair of two-arm, randomized phase 2 study. Each arm will be compared to the 
historical record with its own early stopping rule for futility. Patients will be randomized to one of two 
arms (glasdegib/DAC10 or glasdegib/DAC5). For each arm separately, CR/CRi will be evaluated. 
Assuming a historical CR rate of 17% for decitabine 20 mg/m2 on the standard of care five-day schedule 
(the null hypothesis, based on the largest, phase 3, multicenter, randomized study of decitabine in older 
patients with AML [DACO-16]), a minimum acceptable CR rate of 25% (given the addition of glasdegib 
and additional potential toxicity) and ultimately a predicted minimum CR rate of 47% (the alternative 
hypothesis) for patients accrued to either arm of the proposed randomized phase 2 study, a minimum of 
23 evaluable patients per arm will be accrued to test for a statistically-significant difference with an 80% 
power and a 90% confidence interval (which is equivalent to a type 1 error rate, alpha one-sided of 0.05). 
Stage one of the Simon two-stage minimax decision rule will be assessed after 10 patients are treated in 
each arm. We will stop enrollment in either arm if 2 or fewer patients in that arm achieve CR. The 
probability of early termination is 0.53 in each arm, under the null hypothesis. The same null hypothesis 
will be applied to both treatment arms, separately, without correction for multiplicity. Randomization 
tables in blocks of four will be created before the trial begins.  
 
If we achieve 3 or more responses among the first 10 patients in an arm, then we will move to stage 2 of 
enrollment to 23 patients per arm.  If 8 or fewer responses are observed in an arm by the end of the second 
stage of the study then no future investigation of the drug combination is warranted. Accrual will be 
increased by 10% (a minimum total of 51 patients) to account for those patients that are anticipated to be 
unevaluable and maintain the integrity of the statistical design. The final analysis of CR/CRi will be 
performed when the full information of CR/CRi is reached.  All eligible and treated patients will be included 
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into the analysis. For each arm separately, 80% and 95% confidence intervals of CR/CRi rates based on 
exact binomial distribution and will be compared to the historic CR/CRi (approximately 25%).  
 
All toxicities will be graded according to NCI CTCAE v5.0. Incidence tables will be generated to 
summarize incidence of patients reporting at least one episode of each specific adverse event, incidence of 
adverse events causing withdrawals and incidence of serious adverse events. Listing of adverse events by 
patients will include the time to onset, the duration of each event, the severity of each event, and the 
relationship of the event to study therapy, whether it was a serious event, and whether it caused withdrawal. 
The adverse events rate will be estimated accompanied by an exact 95% confidence interval. 
 
Descriptive statistics will be used to summarize all patient data.  When applicable, t-tests or Wilcoxon 
rank-sum tests will be used to make comparisons between patient subgroups of interest for continuous 
variables for parametric and non-parametric outcomes respectively.  Categorical data will be summarized 
using frequencies and percentages.  Chi-square tests or Fisher’s exact tests will be used to make 
comparisons between patient subgroups of interest for categorical variables.  
 
2.9. Schedule Of Activities  
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the 
Study Procedures and Assessments sections of the protocol for detailed information on each procedure 
and assessment required for compliance with the protocol.  
 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of 
activities, in order to conduct evaluations or assessments required to protect the well-being of the patient.  
 
 
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Table 1.   Schedule of Activities for Study Participants 
 
 
Screening 
Cycle 1 
(28-day cycle) 
Cycles 2-6 
(28-day cycle) 
Cycles 7-24        
(28-day cycle)* 
End of Treatment 
Visit19 
Long Term  
Follow-up 
Protocol activity 
(<28 days 
from study 
entry) 
Day 1 
(+/- 3) 
Day 15 
(+/- 1) 
Day 1  
(+/- 3)   
Day 1    
(+/- 3) 
Within 14 days of 
last dose 
(+/- 1) 
Every 3 
months20 
(+/- 7 days) 
Informed consent1 
X 
 
 
 
 
 
 
Medical History2 
X 
 
 
 
 
 
 
ECOG Performance Status3 
X 
X 
X 
X 
X 
X 
 
Disease classification4 
X 
X 
 
X 
X 
X 
 
Physical Examination5 
X 
X 
X 
X 
X 
X 
 
Laboratory studies 
Hematology6 
X 
X 
X 
X 
X 
X 
 
Blood Chemistry7 
X 
X 
X 
X 
X 
X 
 
Urinalysis8 
X 
 
 
 
 
 
 
Coagulation9 
X 
 
 
 
 
 
 
Pregnancy Test/Contraception Reminders10 
X 
X 
 
X 
X 
X 
X 
Triplicate 12-lead ECG 
X 
X 
 
X 
X 
X 
 
Registration and Treatment 
Glasdegib11 
 
Oral Once Daily Continuous Dosing 
 
 
Decitabine12 
 
IV infusion Days 1-10 per local label or per the 
Investigational Product Manual  
 
 


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*Inclusive only of patients with response (CR/CRi) by cycle 6 of respective therapy; patients without response by cycle 6 will be taken off of study 
 
Footnote for Schedule of Activities 
1. Informed Consent: Must be obtained prior to undergoing any study procedure. Informed consent document may be signed up to 60 days prior to C1D1 as long ass all screening 
procedures take place within the 28 days immediately preceding C1D1.  
2. Medical History: Includes cancer history as well as prior and concomitant illnesses.  
3. ECOG Performance Status: See TBD Appendix  
4. Disease Classification: AML by WHO 2016 classification (Appendix 9). Prognostic system using 2017 European Leukemia Net (ELN) criteria (Appendix 1). A disease 
classification does not need ot be repeated on C1D1 if the screening disease classification was done within 14 days prior to C1D1. 
5. Physical Examination: Examination of major body systems (includes general appearance, head, neck, lungs, heart, abdomen, musculoskeletal, extremities, skin, lymph nodes, 
neurological), body weight, height, and vital signs (blood pressure and heart rate to be recorded in sitting position). Weight must be recorded at Screening, Day 1of each cycle, and 
End of Treatment. Height need not be recorded after the first measurement at screening. Date of last period should be assessed and documented.  
6. Hematology: No need to repeat on C1D1 if screening assessment performed within 3 days prior to that date. The list of required laboratory tests is in Appendix 6. 
Drug Compliance13 
 
 
 
X 
X 
X 
 
Disease Assessments 
Bone Marrow Biopsy14 
X 
 
 
X15 
X,15 
X 
 
Bone Marrow Aspirate14,15 
X 
 
 
X15 
X15 
X 
 
Bone Marrow Immunophenotyping, Flow 
Cytometry and Cytogenetics14,15 
X 
 
 
X15 
X,15 
X 
 
Myeloid Gene Next Generation Sequencing15 
X 
 
 
X15 
X15 
X 
 
Other Clinical Assessments 
Adverse Event/Serious Adverse Event 
Monitoring16 
X 
X 
X 
X20 
Survival Follow-up 
 
 
 
X20 
Review Prior/Concomitant Treatments17 
X 
X 
 
 
Recording of RBC and Platelet Transfusions18 
X 
X 
 
 


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7. Blood Chemistry: No need to repeat on C1D1if screening assessment performed within 3 days prior to that date.  The list of required laboratory tests is in Appendix 6. 
8. Urinalysis: Should be performed after Screening if clinically indicated. The list of required laboratory tests is in Appendix 6. 
9. Coagulation: Should be performed after Screening if clinically indicated. The list of required laboratory tests is in Appendix 6.  
10. Pregnancy Tests/Contraception Reminders: Pregnancy tests (serum/urine) for patients of child-bearing potential only must be performed on two occasions prior to starting 
study therapy (once at the start of screening and once prior to treatment), on C1D1 every cycle during the active treatment period and at the End of Treatment. Following a 
negative pregnancy result at screening, appropriate contraception for males and females (Refer to Table 2) must be commenced and a further negative pregnancy result will then 
be required at the baseline visit before the patient may receive the investigational product. It may also be repeated as per request of IRB/ECs (or if required by local regulations), if 
one menstrual cycle is missed or when potential pregnancy is otherwise suspected during the active treatment period or as clinically indicated.  
11. Glasdegib Dosing: Treatment will be administered in 28-day cycles (cycle duration may be extended to allow for toxicity resolution). Glasdegib will be administered once 
daily, continuously, in the morning at approximately the same time each day.  
12. Decitabine Dosing: Decitabine will be administered per local label. Treatment can be administered as an IV infusion on Days 1-10. Day 1 of each cycle is determined by the 
first day of decitabine. Visit time window added to accommodate varying decitabine dosing schedules to accommodate patient and treatment center availability. The start of 
subsequent cycles can be delayed to allow for toxicity resolution.  
13. Drug Compliance: All glasdegib bottles including any unused tablets and patient dosing diaries will be returned to the clinic for compliance assessment and drug 
accountability.  
14. Bone Marrow Assessments for Disease Evaluation. 
• 
Type of Bone Marrow Sample: For all patients, a bone marrow aspirate sample is required at the timepoints of bone marrow sampling described below. Bone marrow 
biopsies are optional unless required for clinical staging in cases that the aspirate is not sufficient (e.g. dry tap). Samples taken prior to consent but within the 28-day 
window maybe used for disease evaluation and need not be repeated.  Bone marrow samples required for other study assessments (e.g. MRD assessment) must be 
collected after consent is signed.  
  
• 
Timepoints for Bone Marrow Sampling: Bone marrow assessment must be completed at screening (within 28 days prior to first dose), after completion of cycles 2, 4 and 
6 and within 7 days prior to the start of cycles 3, 5 and 7, respectively. After cycle 6, bone marrow assessments will be required every six cycles until the completion of 
cycle 24/EOT, progression of disease or at any time as per investigators discretion if CR is suspected. Bone marrow assessment is necessary if non-response or 
progressive disease can be diagnosed from peripheral blood evaluation or radiological/clinical assessment.  
15. Bone Marrow Genetics: Genetics analysis (local), including molecular profiling, myeloid gene panel next generation sequencing and karyotyping will be conducted on all 
patients using any scheduled or unscheduled bone marrow samples collected during study participation. Genetics to be analyzed are specified in Appendix 8. Baseline genetics 
classification must be completed on a sample collected within 28 days prior to first dose.  
16. Adverse Event (AE)/Serious Adverse Event (SAE) Monitoring: Adverse events should be documented and recorded at each visit using the NCI CTCAE version 5.0.  . 
Patients must be followed for AEs for 30 days after the last treatment administration or until all drug related toxicities have resolved, whichever is later; or earlier than 30 days 
should the patient commence another anticancer therapy in the meantime.  For serious adverse events (SAEs), the active reporting period begins from the time that the patient 
provides informed consent, through and including 30 calendar days after the last administration of the investigational product, even if another anticancer therapy has been started.  
Serious adverse events occurring to a patient after the active reporting period has ended should be reported to the project manager if the investigator becomes aware of them; at a 
minimum, all serious adverse events that the investigator believes have at least a reasonable possibility of being related to study drug are to be reported, 


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17. Concomitant Medications and Treatments: All concomitant medications and treatments should be recorded in the eCRF.  
18. Red Blood Cells and Platelets Transfusion Recording: Transfusion history up to 8 weeks prior to screening should be recorded.  All red blood cell and platelet transfusions, 
including date of each transfusion and number of red blood cell and platelet units transfused will be recorded while on treatment.  Note that number of units not number of bags 
must be recorded. 
19. End of Treatment: Bone Marrow Samples collected at the following time point should be shipped according to the lab manual at the end of participation; screening, after 
cycle 2 and after cycle 6 (unless the patient is coming off study treatment for disease progression).  
20. Long Term Follow-up: The first follow-up contact should occur at least 28 days, and no more than 35 days after the last dose of study drug to capture any potential adverse 
events and to confirm appropriate contraception usage (refer Table 2). Follow-up may be made via telephone call, but must be performed every 3 months (+/- 7 days) for a total 
duration of 2 years. Patients continuing to experience toxicity following discontinuation of treatment will be followed by the Investigator at least every 4 weeks until resolution or 
determination, in the clinical judgment of the investigator, that no further improvement is expected.  


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3. SIGNATURE OF PRINCIPAL INVESTIGATOR  
  
The signatory agrees to the content of the final clinical study protocol as presented and in 
compliance with all applicable regulations including those outlined in Good Clinical Practice 
and the Code of Federal Regulations. 
  
Name:  
  
Affiliation:    
Date:  
  
  
Signature:   
 
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file.  
 
 
 
 
 
 
 
 
 
 
 
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Table of Contents 
1. 
ABBREVIATIONS ................................................................................................................................... 2 
2. 
PROTOCOL SUMMARY ......................................................................................................................... 6 
2.1. 
Introduction .................................................................................................................................. 6 
2.2. 
Indication ...................................................................................................................................... 6 
2.3. 
Background and rationale ............................................................................................................ 6 
2.3.1. 
Disease overview .................................................................................................................. 6 
2.3.2. 
Glasdegib .............................................................................................................................. 7 
2.3.3. 
Decitabine in Patients with Poor-risk Acute Myeloid Leukemia ......................................... 7 
2.3.4. 
Rationale for the Combination of Glasdegib with Decitabine in Poor-risk Acute Myeloid 
Leukemia 7 
2.4. 
Study Objectives And Endpoints .................................................................................................. 8 
2.4.1. 
Objectives ............................................................................................................................. 8 
2.4.2. 
Endpoints .............................................................................................................................. 8 
2.5. 
Study Design ................................................................................................................................. 9 
2.6. 
Study Assessments ....................................................................................................................... 9 
2.7. 
Study Treatments ....................................................................................................................... 10 
2.8. 
Statistical Methods..................................................................................................................... 10 
2.9. 
Schedule Of Activities ................................................................................................................ 11 
3. 
SIGNATURE OF PRINCIPAL INVESTIGATOR ........................................................................................ 16 
4. 
INTRODUCTION .................................................................................................................................. 22 
4.1. 
Indication .................................................................................................................................... 22 
4.2. 
Background and Rationale ......................................................................................................... 22 
4.2.1. 
Disease Overview ............................................................................................................... 22 
4.2.2. 
Hedgehog Signaling and Hematopoiesis ........................................................................... 22 
4.2.3. 
Acute Myeloid Leukemia and the Hedgehog Pathway ..................................................... 23 
4.2.4. 
Glasdegib (PF-04449913) ................................................................................................... 23 
4.2.5. 
Decitabine in Poor-risk Acute Myeloid Leukemia.............................................................. 24 
4.2.6. 
Rationale for the Combination of Glasdegib with Decitabine in Poor-risk Acute Myeloid 
Leukemia 24 
4.2.7. 
Glasdegib Clinical Toxicity Data in Patients with Myeloid Malignancies ........................ 25 
4.2.8. 
Decitabine Clinical Toxicity Data ....................................................................................... 26 
4.2.9. 
Rationale for the Glasdegib Dose Used in Combination with Decitabine ........................ 27 
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4.2.10. 
Assessment of the Drug-Drug Interaction (DDI) Potential between Glasdegib and 
Decitabine ........................................................................................................................................... 28 
4.2.11. 
Summary of Benefit-Risk Assessment ................................................................................ 28 
5. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................................ 29 
5.1. 
Objectives ................................................................................................................................... 29 
5.1.1. 
Primary objective................................................................................................................ 29 
5.1.2. 
Secondary objectives .......................................................................................................... 29 
5.1.3. 
Exploratory objectives ........................................................................................................ 29 
5.2. 
Endpoints .................................................................................................................................... 30 
5.2.1. 
Primary endpoint ................................................................................................................ 30 
5.2.2. 
Secondary endpoints .......................................................................................................... 30 
6. 
STUDY DESIGN .................................................................................................................................... 30 
6.1. 
Study Overview .......................................................................................................................... 30 
6.2. 
Study Treatments ....................................................................................................................... 31 
6.3. 
Study Assessments Summary .................................................................................................... 32 
7. 
PATIENT SELECTION............................................................................................................................ 32 
7.1. 
Inclusion Criteria ........................................................................................................................ 33 
7.2. 
Exclusion Criteria ........................................................................................................................ 34 
7.3. 
Lifestyle Guidelines .................................................................................................................... 35 
7.4. 
Sunlight Exposure ....................................................................................................................... 36 
8. 
STUDY TREATMENTS .......................................................................................................................... 36 
8.1. 
Allocation to Treatment ............................................................................................................. 36 
8.2. 
Patient Compliance .................................................................................................................... 36 
8.3. 
Formulation and Packaging ........................................................................................................ 36 
8.3.1. 
Glasdegib ............................................................................................................................ 36 
8.3.2. 
Decitabine ........................................................................................................................... 37 
8.4. 
Administration ............................................................................................................................ 37 
8.4.1. 
General Guidelines ............................................................................................................. 37 
8.4.2. 
Treatment Duration ........................................................................................................... 37 
8.4.3. 
Dose Modifications ............................................................................................................. 38 
8.5. 
Drug Storage ............................................................................................................................... 44 
8.6. 
Drug Accountability .................................................................................................................... 44 
8.7. 
Concomitant Treatment(s) ......................................................................................................... 44 
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8.7.1. 
Restricted or Prohibited Concomitant Medications .......................................................... 45 
8.7.2. 
Permitted Concomitant Medications ................................................................................. 46 
8.7.3. 
Surgery ................................................................................................................................ 46 
9. 
STUDY PROCEDURES .......................................................................................................................... 47 
9.1. 
Screening .................................................................................................................................... 47 
9.2. 
Study Period ................................................................................................................................ 47 
9.3. 
End of Treatment Visit................................................................................................................ 47 
9.4. 
Long Term Follow-up .................................................................................................................. 47 
10. 
ASSESSMENTS ................................................................................................................................. 49 
10.1. 
Pregnancy Testing .................................................................................................................. 49 
10.2. 
Adverse Events........................................................................................................................ 49 
10.3. 
Laboratory Safety Assessments ............................................................................................. 49 
10.4. 
Transfusions ............................................................................................................................ 50 
10.5. 
Vital Signs and Physical Examination .................................................................................... 50 
10.6. 
Triplicate (12-Lead) ECGs........................................................................................................ 50 
10.7. 
Efficacy Assessments .............................................................................................................. 50 
10.7.1. 
Response Criteria ................................................................................................................ 50 
10.7.2. 
Bone Marrow Biopsies and Aspirates ................................................................................ 51 
10.7.3. 
Banked Biospecimens ......................................................................................................... 51 
10.7.4. 
Collection, Processing and Storage .................................................................................... 51 
11. 
ADVERSE EVENT REPORTING ......................................................................................................... 52 
11.1. 
Definitions .............................................................................................................................. 52 
11.1.1. 
Adverse Event (AE) ............................................................................................................. 52 
11.1.2. 
Serious Adverse Event (SAE) ............................................................................................... 52 
11.1.3. 
Expected Serious Adverse Event (SAE-E) ............................................................................ 53 
11.1.4. 
Unexpected Serious Adverse Event (SAE-U) ...................................................................... 53 
11.2. 
What to Do in Case of a Serious Adverse Event .................................................................... 53 
11.3. 
Protocol-Specified Serious Adverse Events ........................................................................... 54 
11.4. 
Potential Cases of Drug-Induced Liver Injury ........................................................................ 54 
11.5. 
Hospitalization ........................................................................................................................ 55 
11.6. 
Severity Assessment ............................................................................................................... 56 
11.7. 
Causality Assessment ............................................................................................................. 56 
11.8. 
Exposure During Pregnancy ................................................................................................... 57 
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11.9. 
Occupational Exposure ........................................................................................................... 58 
11.10. 
Withdrawal Due to Adverse Events ....................................................................................... 58 
11.11. 
Eliciting Adverse Event Information ...................................................................................... 58 
11.12. 
Reporting Requirements ........................................................................................................ 58 
11.12.1. 
Routine Reporting of Adverse Events ............................................................................ 58 
11.12.2. 
Reporting of Serious Adverse Events, including Death ................................................. 59 
11.12.3. 
Reporting to the IRB ....................................................................................................... 60 
11.12.4. 
Reporting to External Regulatory Bodies ...................................................................... 60 
12. 
DATA ANALYSIS/STATISTICAL METHODS ...................................................................................... 61 
12.1. 
Sample Size Determination .................................................................................................... 61 
12.2. 
Futility Analysis....................................................................................................................... 61 
12.3. 
Analysis Populations .............................................................................................................. 61 
12.3.1. 
Full Analysis Set (FAS) ......................................................................................................... 61 
12.3.2. 
Safety Analysis Set ............................................................................................................. 62 
12.4. 
Efficacy Analysis ..................................................................................................................... 62 
12.4.1. 
Complete Response ............................................................................................................ 62 
12.4.2. 
Response Rate .................................................................................................................... 62 
12.4.3. 
Overall Survival................................................................................................................... 62 
12.4.4. 
Duration of Response ......................................................................................................... 62 
12.4.5. 
Time to Response................................................................................................................ 63 
12.4.6. 
Other Efficacy Measures .................................................................................................... 63 
12.4.7. 
Analysis of Exploratory Endpoints ..................................................................................... 63 
12.5. 
Safety Analysis ........................................................................................................................ 63 
12.5.1. 
Stopping Rules for Unacceptable Toxicity ......................................................................... 63 
12.6. 
Monitoring .............................................................................................................................. 64 
13. 
DATA HANDLING AND RECORD KEEPING ...................................................................................... 64 
13.1. 
Case Report Forms/Electronic Data Record .......................................................................... 64 
13.2. 
Record Retention .................................................................................................................... 65 
14. 
ETHICS ............................................................................................................................................. 65 
14.1. 
Ethical Principles ..................................................................................................................... 65 
14.2. 
Institutional Review Board (IRB)/Ethics Committee (EC) ..................................................... 65 
14.3. 
Financial Disclosure ................................................................................................................ 65 
15. 
REFERENCES .................................................................................................................................... 67 
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4. INTRODUCTION 
Glasdegib (PF-04449913/PF-913) is an oral, selective SMO receptor antagonist and thus inhibitor of the 
Hedgehog (Hh) pathway which has recently been studied as a monotherapy and in combination therapy in 
patients with acute myeloid leukemia (AML). Decitabine, a DNA methyltransferase inhibitor (DNMTi), 
has likewise been studied as monotherapy and in combination therapies for AML, and is reported to have 
promising activity in patients with molecularly or cytogenetically-defined poor-risk AML (PrAML). 
 
This multi-center, randomized phase 2 study is designed to evaluate the efficacy (as defined by complete 
remission [including complete remission with incomplete count recovery] rates) of glasdegib in 
combination with either decitabine on a 5-day or 10-day schedule in patients with newly-diagnosed, 
PrAML who either refuse or are ineligible for intensive therapy. 
 
4.1. Indication  
Previously-untreated, older adult patients with cytogenetically or molecularly-defined PrAML who either 
decline or are not candidates for intensive chemotherapy (according to WHO 2016 classification) 
 
4.2. Background and Rationale  
4.2.1. Disease Overview 
Acute myeloid leukemia (AML) comprises a variety of malignant diseases characterized by the clonal 
expansion of myeloid precursors. Of the estimated 21,380 new cases of AML in the United States during 
2017, more than half will occur in patients aged 65 or older. Though older patients are traditionally 
burdened by both comorbidities precluding intensive induction therapy and a higher risk of treatment-
related mortality, responses to induction therapy and the observed outcomes have been found to be 
critically and independently predicted by cytogenetically-determined and biologically-diverse subsets of 
risk. Poor-risk AML (PrAML) comprises approximately 30% of all newly-diagnosed AML and is defined 
by specific myeloblast karyotypic aberrations which include del(5q)/-5, del(7q)/-7, inv(3), t(3;3), t(6;9), -
17, abn 17p, monosomal karyotype, complex karyotype (defined as three or more abnormalities) as well 
as those molecularly-defined by the presence of mutated TP53. These genotypes define the WHO-system 
category of AML with myelodysplasia-related changes (AML-MRC), regardless of whether the histology 
contains sufficient morphologic dysplasia to be included in that category in the absence of cytogenetic 
abnormalities. 
 
Complete response (CR) rates to standard induction in PrAML remain inferior with no higher than 55% 
in patients aged 55 years or younger, but only 32% in older patients. The presence of monosomal 
karyotype predicts CR as low 18%. Concordant with CR rates, survival also remains inferior in PrAML, 
with a 4-year overall survival (OS) specifically ranging from 4-10% and even as low as 1% based on the 
degree of poor-risk cytogenetic burden on the myeloblast karyotype. TP53-mutated AML provides 
another informative example: only 41% of patients achieve CR and fewer than 10% remain alive three 
years following allogeneic stem cell transplantation (alloSCT) performed while in CR. In fact, event-free 
survival in TP53-mutated AML approximates one month. PrAML patients have few if any curative 
therapeutic options. 
 
4.2.2. Hedgehog Signaling and Hematopoiesis 
Hedgehog (Hh) proteins of a collection of small molecules which participate in intercellular signaling 
pathways responsible for embryogenesisand maintenance of adult stem cells.The primitive differentiation 
into definitive cell types is a result of cellular response to heterogeneous concentrations and gradients of 
Hh ligand which induces eventual expression of varying target genes responsible for such. This cellular 
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response is predicated upon Hh-induced activation of patched-1 and patched-2 (PTCH-1/2), the 12-pass 
transmembrane proteins which act as Hh ligand receptor. PTCH-1/2 acts upon smoothened (SMO), a 7-
pass transmembrane Hh-related, constitutively-active signal transducer protein whose activation 
culminates in the downstream phosphorylation of the glioma (GLI) family zinc ﬁnger activating 
transcription factors GLI1 and GLI2 (oncogene homologues of the cubitus interruptus transcription 
factor), and the ultimate expression of target genes responsible for inciting cell cycling, anti-apoptotic 
mechanisms, and cellular differentiation. Conversely, the absence of Hh, its receptor or signaling 
transduction, Hh-related transcription factors are alternatively-cleaved, assume the role of transcriptional 
repressors, and halt differentiation that was not predestined. Indian Hh (IHH) is a tissue-specific Hh 
isoform which has been shown to have a crucial role in primitive hematopoiesis, the early stage at which 
embryogenesis commits cells to hematopoietic precursors and the development of early hematopoietic 
tissue, which is also shown to express PTCH1/2, SMO and the GLI family transcription factors. 
Subsequent to its pivotal role in early tissue development, Hh additionally maintains an active role in 
multipotent hematopoietic stem cells (HSC) expansion, self-renewal in response to biological insults, and 
thus lifelong hematopoiesis.  
 
4.2.3. Acute Myeloid Leukemia and the Hedgehog Pathway 
AML pathology is likely founded in the presence of leukemic stem cells (LSC), which yield leukemic 
progenitor cells, downstream CD34+ leukemic effector cells, and the ultimate hematopoietic dysfunction 
with which AML manifests. Ex vivo AML data has shown that CD34+ leukemic cells are characterized 
by high expression of IHH, GLI1, GLI2, and Hh-related downstream pro-survival gene expression, all 
indicative of Hh pathway activation. Overexpression of downstream GLI2 mRNA has been shown to 
have a negative impact on overall survival.  
 
The Hh pathway has furthermore been implicated in the leukemic cell chemoresistance. Direct SMO 
antagonists and anti-IHH monoclonal antibodies to cytarabine-resistant CD34+ human myeloid 
leukemic cell lines are shown to specifically inhibit the Hh pathway, induce Hh-specific apoptosis, 
and more strikingly, restore chemosensitivity. It is reasonable to posit that chemosensitivity to other 
standard AML therapies may be restored with leukemic cell exposure to Hh-pathway inhibitors. 
 
4.2.4. Glasdegib (PF-04449913) 
The small molecule glasdegib (PF-04449913/PF-913) is an oral, selective SMO receptor antagonist which 
has recently been studied as a therapy in AML. Initial in vitro and ex vivo studies of AML cell lines 
demonstrated that glasdegib reduced SMO-targeting gene transcripts, c-Myc expression, cell cycle 
progression and ultimately the fraction of CD34+CD38- cells, which infers a reduced leukemia-initiation 
potential of AML LCS.  
 
A phase 1 study of glasdegib monotherapy in 47 patients with myeloid malignancies including 28 with 
AML studied doses of glasdegib ranging from 5 to 600 mg daily.18 Of evaluable patients, 60% 
experienced a treatment-related adverse event (three of which were grade 4), which included dysgeusia 
(28%), anorexia (19%), and alopecia (15%). Hematologic grade 3 events included lymphopenia (n=16), 
anemia (n=10), thrombocytopenia (n=8), and neutropenia (n=8); grade 4 hematologic adverse events 
included thrombocytopenia (n=33), neutropenia (n=26), leukopenia (n=15), lymphopenia (n=6), and 
anemia (n=4). Other grade 3 laboratory adverse events included elevations in aminotransferases or 
bilirubin, hypokalemia, hyponatremia, hyperglycemia, hypocalcemia and hypophosphatemia, but these 
events occurred in only 4 patients or less. Increases in corrected QT interval (QTc) to greater than 500 
milliseconds (msec) occurred in 5 patients receiving the glasdegib 600 mg daily dose. A dose-dependent 
increase in QTc was noted with increasing doses of glasdegib, but no ECG changes were found to be 
clinically-significant or symptomatic. This phase 1b study established a maximum tolerated dose (MTD) 
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of 400 mg daily and a phase 2 dose of 200 mg daily or lower was recommended. Clinical activity was 
suggested in 49% of patients.18 
 
Glasdegib is now FDA approved in combination with low-dose cytarabine for the treatment of newly-
diagnosed AML in adult patients aged 75 years or greater or who have comorbidities that preclude the use 
of intensive induction therapy. Of note, glasdegib has not been studied in patients with severe renal or 
moderate-to-severe hepatic impairment. 
 
4.2.5. Decitabine in Poor-risk Acute Myeloid Leukemia 
An initial phase 2 study of the DNMTi decitabine 20 mg/m2 on a 5-day schedule in patients aged 60 years 
and older (median age 74) reported a 25% CR/CRi in all patients with a 20% CR/CRi rate in the PrAML 
subset. All patients who achieved CR/CRi had a median relapse-free survival (RFS) of 16.3 months and a 
median OS of 14 months.19 A subsequent phase II trial of decitabine 20 mg/m2 given on a 10-day 
schedule in a comparable population induced a CR of 47%. Interestingly, half of these study patients had 
PrAML; a CR rate of nearly 50% was noted in this subset. A recent study by Welch, et al claimed overall 
response rates (ORR, defined as CR/CRi plus morphologic remission) of 67% in PrAML using the 10-
day schedule, with most strikingly a 100% ORR in TP53-mutated AML in addition to robust mutation 
clearance and survival rates that seemed to remit to those observed in intermediate-risk AML populations. 
However, a recent retrospective review of TP53-mutated patients treated at MD Anderson included 13 
patients treated with DAC10, 5 of whom achieved CR or CRp.24 In addition, a small phase 2 study of 
DAC5 and DAC10 in AML patients (43% and 35% of whom with therapy-related or secondary AML and 
TP53-mutated disease, respectively) aged 60 years or older noted similar response rates and survival 
between the two dosing schedules including when stratified by TP53 status.25 However, the largest 
randomized trial testing decitabine (the randomized DACO-16 trial) in older unfit adults showed a CR 
rate of 20%.22 
 
4.2.6. Rationale for the Combination of Glasdegib with Decitabine in Poor-risk Acute Myeloid 
Leukemia 
The use of targeted therapy in AML is made difficult by the heterogeneous nature of the disease with 
respect to the multitude of molecular and chromosomal abnormalities which initiate leukemogenesis. 
However, targeting and disrupting the Hh-pathway, the primary mechanism by which diseased and often 
chemoresistant LSC maintain their self-renewal and leukemia-initiating potential offers the potential of 
more robust leukemic cell kill and clinical outcomes of standard AML therapies, which to date have 
yielded unacceptable results for the PrAML population.  
 
Glasdegib has been previously combined with decitabine in only very few AML patients. A recent, three-
arm phase 1b study included an arm in which patients aged 65 years or older with newly-diagnosed AML 
(5 patients [71%]) or high-risk myelodysplastic syndrome and no prior DNMTi exposure received 
glasdegib 100 or 200 mg daily in combination with decitabine 20 mg/m2 on a 5-day schedule; two patients 
(29%) were characterized by poor-risk cytogenetics. Two patients (29%) were characterized by poor-risk 
cytogenetics and three patients (43%) were treated at the 200 mg daily dose. The maximum tolerated dose 
(MTD) was not reached, no dose-limiting toxicities were observed, and the most common treatment-
related effects (not surprisingly given the role of the Hh pathway in normal hematopoiesis) were 
hematologic toxicities: neutropenia (57%), thrombocytopenia (43%), anemia (43%). Of the AML patient 
subset, 40% achieved CR/CRi with a median of 3 cycles administered, and median duration of response 
of 2.6 months. Given the absence of a MTD, its well-tolerated nature and convincing efficacy signal, 
glasdegib 100 mg daily was selected as the randomized, phase 2 dose for use with other standard AML 
therapies including decitabine. 
 
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4.2.7. Glasdegib Clinical Toxicity Data in Patients with Myeloid Malignancies 
4.2.7.1. Glasdegib as Monotherapy 
A phase 1 dose escalation study of glasdegib monotherapy in 47 patients with myeloid malignancies 
including 28 (59.6%) with AML tested doses ranging from 5 mg to 600 mg oral daily. The median age of 
all patients was 69 years (range [R], 25-89 years) with the majority of patients being male (59.6%). Of 41 
evaluable patients, only 2 patients experienced a dose-limiting toxicity with cycle 1. A maximum tolerated 
dose (MTD) of 400 mg daily was established with 60% of all patients experiencing a treatment-related 
adverse event (three of which were grade 4), which included dysgeusia (27.7%), anorexia (19.1%), and 
alopecia (14.9%). With regards to hematologic adverse events, grade 3 events included lymphopenia 
(n=16), anemia (n=10), thrombocytopenia (n=8), and neutropenia (n=8); other grade 3 laboratory adverse 
events included elevations in aminotransferases or bilirubin, hypokalemia, hyponatremia, hyperglycemia, 
hypocalcemia and hypophosphatemia, but these events occurred in only 4 patients or less. Grade 4 adverse 
events were most hematologic and included thrombocytopenia (n=33), neutropenia (n=26), leukopenia 
(n=15), lymphopenia (n=6), and anemia (n=4). Electrocardiogram (ECG) changes were also noted, 
specifically 3 patients (2 patients receiving glasdegib 600 mg daily and a single patient receiving glasdegib 
400 mg daily) had an increased corrected QT interval (QTc) to greater than 500 milliseconds (msec) with 
5 patients from the glasdegib 600 mg daily subset experiencing an increase in QTc greater than 60 msec 
from baseline; an increased incidence and severity of QTc change from baseline was noted in patients 
receiving higher doses of glasdegib, however, all ECG changes were asymptomatic and had no effect on 
other clinical parameters.18  
 
A recommended phase 2 dose of 200 mg daily or lower was established given the observation of lower 
incidence of treatment-related adverse events observed at such doses. Although not a primary objective of 
the phase 1 study, clinical activity was suggested in 49% of all patients. Of the 28 patients with AML, one 
patient (3.6%) had morphologic CRi, 4 patients (14.3%) had partial remission with incomplete blood count 
recovery (PRi), and 4 patients (14.3%) had minor response (MR). The sum of these responses (CR + CRi 
+ PR + PRi + SD + MR) yielded clinical benefit in 16 AML patients (57.1%). Treatment-resistant disease 
was reported in 7 patients (25%). The median duration of treatment of 64.5 days (R, 5- 261 days) for AML 
patients.18 Based on the results of this phase 1 study, glasdegib appeared to be well tolerated with an efficacy 
signal noted in the AML subset of patients and advocated for further consideration of glasdegib in 
combination with other agents with known efficacy in hematologic disease including AML. 
 
4.2.7.2. Glasdegib in Combination with Other Therapies 
Given the favorable toxicity profile and preliminary efficacy signal noted in the first phase 1 study of 
glasdegib as monotherapy in hematologic malignancy, further studies evaluated glasdegib in combination 
with other therapies in similar populations. In a phase 2 study (NCT01546038) patients with previously-
untreated AML or high-risk MDS and ineligible for intensive therapy were randomized 2:1 to receive either 
low-dose cytarabine (LDAC) 20 mg subcutaneously twice a day for 10 days on a 28-day cycle with oral 
glasdegib 100 mg daily versus glasdegib alone.26 A total of 132 patients were enrolled (including 116 of 
such having a diagnosis of AML) and 88 were randomized to the LDAC plus glasdegib arm. Median 
treatment duration was 83 days in the combination arm. All-grade treatment-related adverse events were 
noted in 95.5% of patients in the combination arm with the most common being anemia (41.7%), febrile 
neutropenia (36.9%), nausea (35.7%), anorexia (31.0%), and fatigue (31.0%). Glasdegib-related adverse 
events included dysgeusia (23.8%), muscle spasms (20.2%) and alopecia (10.7%). Interestingly, grade 2-4 
QTc prolongation was noted more frequently in the LDAC monotherapy arm. CR rates were higher in the 
combination arm in comparison to the LDAC monotherapy arm (n = 17, 15% vs. n = 1, 2.3%; p=0.0142). 
Based on intention to treat analysis, median OS was longer in the LDAC plus glasdegib arm in comparison 
to LDAC alone stratified by cytogenetic risk (8.3 months vs. 4.9 months; HR 0.511, 80% CI 0.386-0.675; 
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one-sided log rank p=0.0020). For the poor-risk cytogenetic group specifically, median OS for the LDAC 
plus glasdegib arm was 4.4 vs 2.3 months (HR 0.575, p=0.0422). When evaluating AML patients only, the 
median OS for the LDAC + glasdegib was 8.3 months was significantly-improved compared to 4.3 months 
for the LDAC monotherapy arm (HR 0.462, p=0.0004).26 
 
A phase 1b/2 study evaluated the combination of glasdegib 100 mg or 200 mg daily not only with LDAC 
20 mg administered subcutaneously twice daily on days 1 to 10 of each 28-day cycle (n=23), but also 
decitabine 20 mg/m2 IV for the ﬁrst 5 days of each 28-day cycle (n=7), or standard “7+3” induction 
chemotherapy (cytarabine/daunorubicin; n=22) in 52 patients with AML or higher-risk MDS.23 The phase 
1b portion of the study enrolled 23 patients onto the LDAC plus glasdegib arm with 17 (73.9%) of such 
receiving glasdegib 100 mg daily and the remaining patients receiving 200 mg daily. No dose-limiting 
toxicities were noted in this arm, but the most frequently noted treatment-related adverse events were 
nausea (35.3%), diarrhea (29.4%), neutropenia (29.4%), muscle spasms (23.5%), and dysgeusia (23.5%). 
Of the 7 patients randomized to the decitabine plus glasdegib arm, 4 received glasdegib 100 mg daily with 
3 receiving glasdegib 200 mg daily. No dose-limiting toxicities were observed in this arm, and the most 
frequently observed treatment-related adverse events of any grade were nausea (75.0%), diarrhea (50.0%), 
thrombocytopenia (50.0%), and neutropenia (50.0%). Of the 22 patients receiving both 7+3 and glasdegib, 
16 patients received glasdegib 100 mg daily and 6 received glasdegib 200 mg daily. The most common 
treatment-related adverse events were nausea (68.2%), diarrhea (50.0%), muscle spasms (45.5%), febrile 
neutropenia (36.4%), and dysgeusia (31.8%). Grade 3 pyrexia occurred in 2 patients in the 7+3 plus 
glasdegib arm.23 The recommended phase 2 dose of glasdegib was established as 100 mg daily.23 
 
In the phase 2 portion of the study, 2 patients (8.7%; 80% CI, 2.3%– 21.5%) in the LDAC plus glasdegib 
arm, 2 patients (28.6%; 80% CI, 7.9%–59.6%) in the decitabine plus glasdegib arm, and 12 patients (54.5%; 
80% CI, 38.9%–69.5%) in the 7+3 plus glasdegib arm achieved CR/CRi. When evaluating only the AML 
patients in each arm, a clinically-beneficial response defined as CR/CRi, morphologic leukemia-free state, 
partial response (PR), or PR with incomplete blood count recovery (PRi) was noted in 10%, 60% and 60% 
of patients in the LDAC plus glasdegib, decitabine plus glasdegib and 7+3 plus glasdegib arms, 
respectively. AML patients in the decitabine plus glasdegib arm achieved were found to have a 40% 
CR/CRi rate. Median overall survival (OS) in the combined AML and MDS patient cohort was 4.4 months 
(80% CI: 2.5, 6.6) in the LDAC plus glasdegib arm, 11.5 months (80% CI: 4.5-17.4 months) in the 
decitabine plus glasdegib arm, and 34.7 months (80% CI: 14.5, not reached) in the 7+3 plus glasdegib arm.23  
 
Another ongoing, multicenter, open-label, phase 2 study (NCT01546038) recently investigated the 
combination of glasdegib 100 mg daily with 7+3 (with daunorubicin 60 mg/m2) in patients with previously-
untreated AML or high-risk MDS.27 Median age was 64 years (R, 27-75) and the majority of patients were 
males (60.0%) and Caucasian (84.5%). Of 69 evaluable patients, CR was reached in 46.4% (80% CI: 38.7-
54.1%) including a 40% CR rate in patients aged 55 years or older (n=60; 80% CI: 31.9-48.1%). The most 
common treatment-related adverse events were nausea and diarrhea which each occurred in 50% or greater 
of patients. Consolidation therapy with 2-4 cycles of cytarabine 1 g/m2 twice daily on days 1, 3, 5 of each 
cycle followed by maintenance glasdegib 100 mg daily for a maximum of 6 cycles was given to patients in 
CR. For 69 evaluable patients, the median OS was 14.9 months (80% CI 13.4-19.3 months). Of note, 
mutational status (as judged by the status of 12 myeloid related genes) had no effect on clinical response.27 
Given this favorable risk-benefit profile, a randomized phase 3 trial of glasdegib 100 mg daily in 
combination with 7+3 is ongoing. 
 
4.2.8. Decitabine Clinical Toxicity Data 
4.2.8.1. Decitabine Dosing Schedule  
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An initial phase 1 study of decitabine initially planned to treat patients with AML, acute lymphoblastic 
leukemia (ALL), MDS, or myeloproliferative neoplasm at 5, 10, 15, or 20 mg/m2 IV daily on a 5-day 
schedule every for 2 weeks.28 An additional two cohorts of 3 patients were treated with decitabine 15 
mg/m2 for either 15 or 20 days; a final cohort of 11 patients was ultimately treated at 15 mg/m2 daily for 
10 days as a means of confirming drug activity. Of the 48 total evaluable patients treated, 35 carried a 
diagnosis of AML (and a majority with relapsed/refractory disease; 67% with poor-risk cytogenetics). 
Cytopenias were noted in the vast majority of patients and the most commonly-observed treatment-related 
adverse event was febrile neutropenia (n=26, 56%). Grade 2 non-hematologic adverse events across all 
cohorts included bilirubin elevation (n=7, 14%), creatinine elevation (n=5, 10%), transaminase elevation 
(n=3, 6%), and nausea (n=2, 4%); the only grade 3-4 treatment-related adverse events were bilirubin 
elevation (n=4, 8%), transaminase elevation (n=4, 8%), and nausea (n=1, 2%).28 
 
A phase 2 study of decitabine 20 mg/m2 on a 5-day schedule in patients aged 60 years and older was the 
first to evaluate such a dosing schedule only in patients with AML.19 The median age was 74 years (R, 
61-87) with equal numbers of males and females. The majority (62%) of patients were older than 70 
years. All patients on study experienced myelosuppression. A total of 26 patients (47.3%) experienced a 
decitabine-related serious adverse event. The most frequent grade 3-4 treatment-related adverse events 
were febrile neutropenia (29%), thrombocytopenia (22%), neutropenia (20%), anemia (18%), dyspnea 
(15%), bacteremia (13%), and pneumonia (n=6, 1%). Treatment-related adverse events caused dosing 
delays or reductions in 13 patients (24%) and 1 patient (2%), respectively. An adverse event led to 
discontinuation of treatment in 7 patients (13%) and 3 patients (6%) died as a result of an adverse 
events.19 
 
A subsequent phase 2 trial investigated the use decitabine 20 mg/m2, but given on a schedule extended to 
10 days in 53 patients with previously-untreated AML (49% were defined as PrAML).20 The median age 
was 74 years (R, 60–85) with 8 patients (15%) aged 80 years or older. The investigators also calculated 
the hematopoietic stem cell transplantation index to provide descriptive data on the risk of toxic death 
with treatment and noted that 26 patients (49%) had a comorbidity scores of 3 or greater. Febrile 
neutropenia was a common adverse event and occurred in 68% of patients. The most common grade 3-4 
non-hematologic toxicities included infection (n=31), hypoxia (n=8), pain (n=7), febrile neutropenia 
(n=5), and hemorrhage/hematoma (n=5). One patients died within 30 days of starting therapy and 8 
patients (15%) died during the first 2 cycles of therapy with cause of death felt to be related to 
documented infection, though 7 of these patients had active leukemia at time of death. Infectious 
complications after the achievement of CR was rare.20 Another prospective study of 84 patients with 
AML or MDS treated with DAC10 reported a similar toxicity profile.21 Untreated AML and relapsed 
AML comprised 47% and 31% of patients, respectively. The median age of all patients was 74 years (R, 
29-88 years) and 59% were male. Similar to previous studies, the most common adverse events were 
related to myelosuppression, namely neutropenia and thrombocytopenia. During the first two cycles, 
grade 3-5 febrile neutropenia occurred in 56 patients and bleeding or transfusion reactions occurred in 8 
patients. Death due to infection, acute kidney injury or cardiac arrest was noted in 6 patients, 1 patient and 
1 patient, respectively.21 
 
  
 
4.2.9. Rationale for the Glasdegib Dose Used in Combination with Decitabine 
The MTD for glasdegib monotherapy in patients with a hematologic malignancy was previously-
identified as 400 mg daily with a recommended phase 2 dose of 200 mg daily or lower. A dose of 100 mg 
daily is the FDA approved dose when used in combination with low-dose cytarabine and is suggested as 
the optimal starting dose of glasdegib when used in combination with other therapies (including DAC5) for 
patients with myeloid malignancies including AML. This conclusion is supported by the following data: 
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• In the phase 1b portion of the study conducted by Savona et al, treatment arms included the 
combination of glasdegib 100 mg or 200 mg daily with decitabine 20 mg/m2 IV on a 5-day schedule and 
28-day cycles (n=7), or glasdegib 100 mg or 200 mg daily with standard “7+3” induction chemotherapy 
(cytarabine/daunorubicin; n=22). Of the 7 patients randomized to the decitabine plus glasdegib arm, 4 
received glasdegib 100 mg daily with 3 receiving glasdegib 200 mg daily. No dose-limiting toxicities were 
observed in this arm, and the most frequently observed treatment-related adverse events of any grade were 
nausea (75.0%), diarrhea (50.0%), thrombocytopenia (50.0%), and neutropenia (50.0%). In the absence of 
an estimated MTD for glasdegib plus DAC5 combination therapy, the recommended phase 2 dose of 
glasdegib was established as 100 mg daily.23 
 
• Glasdegib 100 mg daily is found to have favorable and dose-proportional plasma pharmacokinetics 
congruent with expected plasma exposures (AUC and maximum plasma concentration). The median time 
to maximum concentration of glasdegib when administered at 100 mg daily in combination with DAC5 is 
found to range from 1.03 to 2.00 hour; in addition, exposures for glasdegib appear to be similar irrespective 
of co-administration with DAC5.23 
 
• Glasdegib is markedly metabolized by CYP3A4 (99.8%). Co-administration with strong CYP3A4 
inhibitors such as the -azole class of antifungals, which remain a mainstay of supportive care and often 
dedicated treatment of infectious complications of disease and therapy, influence the plasma exposures, 
AUC and peak plasma concentrations of glasdegib. Such advocates for the lower recommended phase 2 
dose and optimal starting dose of glasdegib 100 mg daily.29 
 
• In the phase 2 portion of the Savona et al study, 2 patients (28.6%; 80% CI, 7.9%–59.6%) in the 
decitabine plus glasdegib arm achieved CR/CRi. When evaluating only the AML patients, a clinically-
beneficial response defined as CR/CRi, morphologic leukemia-free state, partial response (PR), or PR with 
incomplete blood count recovery (PRi) was noted in 60% of patients in the decitabine plus glasdegib arm. 
AML patients in the decitabine plus glasdegib arm achieved were found to have a 40% CR/CRi rate. Median 
overall survival (OS) in the combined AML and MDS patient cohort was 11.5 months (80% CI: 4.5-17.4 
months) in the decitabine plus glasdegib arm and 34.7 months (80% CI: 14.5, not reached).23  
 
These data provide strong rationale for the 100 mg daily dose of glasdegib being a safe and potentially 
clinically effective dose in combination with decitabine. 
 
4.2.10. Assessment of the Drug-Drug Interaction (DDI) Potential between Glasdegib and Decitabine  
Both in vitro and ex vivo data have demonstrated that glasdegib is primarily metabolized by CYP3A4.30 
The exact mode of metabolism and elimination of decitabine remains unknown in humans, but is postulated 
to occur via deamination by cytidine deaminase, which is extensively located in the liver, but is also present 
in the intestinal epithelium and granulocytes. Given the lack of related mechanisms of metabolism, the 
drug-drug interaction potential between glasdegib and decitabine is considered to be low.  
 
4.2.11. Summary of Benefit-Risk Assessment  
The available clinical data concerning glasdegib not only used as monotherapy but in combination with 
other chemotherapeutic agents including decitabine supports the conclusion of a predictable and safe 
toxicity profile, characterized by manageable, not unexpected and ultimately often-reversible mild to 
moderate toxicities. The primary toxicities observed to date are mostly related to anticipated 
myelosuppression with the major non-hematologic treatment-related toxicities being muscle spasms, 
dysgeusia, decreased appetite, and alopecia.  
 
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Prolongation of QTc intervals have been observed, though small and overwhelmingly not clinically 
significant or symptomatic. Dose modification recommendations for QTc changes can be found in Table 
5. Given the established mechanism of glasdegib metabolism via CYP3A4, the concurrent use of moderate 
to strong CYP3A4 inhibitors (Appendices 3 and 4) is not recommended given the possibility of DDI and 
augmented effect of potential QTc prolongation. Concurrent administration of drugs known to increase the 
risk of Torsade de Pointes (Appendix 5) are similarly not recommended.  
 
The data reported to date supports the use of Hh pathway antagonists such as glasdegib in hematologic 
malignancies and more recently increasing data supports its use in patients with AML. The combination of 
glasdegib with chemotherapeutic agents such as LDAC, decitabine and even standard 7+3 induction therapy 
for patients with AML has demonstrated attractive response rates as well as improvements in survival 
compared to historical controls. The efficacy of glasdegib in combination with low-dose cytarabine was 
evaluated in a multicenter, open-label, randomized study (Study BRIGHT AML 1003, NCT01546038) that 
included 115 patients age 55 years or older with newly-diagnosed AML who met at least one of the 
following criteria: a) age > 75 years, b) severe cardiac disease, c) baseline Eastern Cooperative Oncology 
Group (ECOG) performance status of 2, or d) baseline serum creatinine >1.3 mg/dL. Patients were 
randomized 2:1 to receive glasdegib at a 100 mg daily dose with low-dose cytarabine 20 mg subcutaneously 
twice daily on days 1 to 10 of a 28-day cycle (N=77) or low-dose cytarabine alone (N=38) in 28-day cycles 
until disease progression or unacceptable toxicity. Patients were stratified by cytogenetic risk 
(good/intermediate or poor). Overall survival and CR were both improved with the addition of glasdegib to 
low-dose cytarabine compared to low-dose cytarabine alone. 
 
Decitabine has recently been reported to induce robust responses and clinically meaningful survival 
improvement in PrAML patients with one study by Welch et al demonstrating a 100% response rate in 
TP53-mutated AML. In sum, given the increasingly-understood role of the Hh pathway as it related to 
leukemic stem cell survival and the impressive clinical improvements induced by decitabine in PrAML 
patients, the data support investigation into the efficacy of the combination of glasdegib with decitabine on 
both a standard of care 5-day schedule as well as the recently-promising 10-day schedule.  
 
5. STUDY OBJECTIVES AND ENDPOINTS  
5.1. Objectives 
 
5.1.1. Primary objective 
• 
To determine the response rates, complete remission (CR) and complete remission with 
incomplete count recovery (CRi) rates of glasdegib/DAC5 and glasdegib/DAC10 in 
patients with newly-diagnosed PrAML 
 
5.1.2. Secondary objectives 
• 
To evaluate the toxicity and safety profiles of glasdegib/DAC5 and glasdegib/DAC10 in 
patients with newly-diagnosed PrAML  
• 
To determine the event-free survival (EFS), relapse-free survival (RFS), overall survival 
(OS), duration of response, bone marrow mutational clearance, and remission clonality of 
glasdegib/DAC5 and glasdegib/DAC10 in patients with newly-diagnosed PrAML 
 
5.1.3. Exploratory objectives 
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• 
To evaluate for specific cytogenetic and molecular markers which may predict efficacy of 
glasdegib/DAC5 and glasdegib/DAC10 in patients with newly-diagnosed PrAML 
• 
To evaluate for any differences in the quantity and activity of Hh pathway-related effector 
proteins downstream to the effect of the SMO-antagonist glasdegib (GLI-1 and GLI-2) 
and if any such difference correlates with and predicts response to such 
 
5.2. Endpoints 
 
5.2.1. Primary endpoint 
• 
CR/CRi rate as defined by the 2017 European LeukemiaNet (ELN) AML response criteria 
(Appendix 1) 
 
5.2.2. Secondary endpoints 
• 
AE 
• 
SAE 
• 
CR 
• 
CRi 
• 
CRh 
• 
RBC transfusion independence (per the International Working Group [IWG] response 
criteria for MDS) for patients who are transfusion dependent 
• 
OS 
• 
EFS 
• 
RFS 
• 
Time to CR/CRi 
• 
Duration of CR/CRi 
• 
Bone marrow mutational clearance of frequently-mutated genes in AML (e.g. NPM1, 
CEBPA, DNMT3A, RUNX1, TET2, IDH1/2) via next-generation DNA sequencing 
• 
Remission clonality 
 
6. STUDY DESIGN 
6.1. Study Overview 
This multi-center, parallel-arm, randomized phase 2 study is designed to evaluate the complete remission 
(including complete remission with incomplete count recovery) rates of glasdegib 100 mg daily in 
combination with either decitabine 20 mg/m2 IV daily on a 5-day or 10-day schedule every 28 days per 
local label in patients with newly-diagnosed poor-risk AML who either refuse or are ineligible for 
intensive therapy. 
 
The assignment of lack of candidacy for intensive induction therapy will be determined based on each 
patient’s comorbidity, performance status, baseline level of fitness, and any other clinical variable as 
deemed clinically-relevant by the Investigator. Patients will be randomized 1:1 to receive glasdegib 100 mg 
orally once daily and continuously either in combination with decitabine 20 mg/m2 IV on a 10-day schedule 
(DAC10) or decitabine 20 mg/m2 IV on a 5-day schedule (DAC5). 
 
The primary objective of this randomized phase 2 study is to demonstrate that the CR/CRi rate of the 
combination of glasdegib treatment in each patient population (DAC5 and DAC10) outperforms the 
historical CR/CRi rate for DAC5 alone using decision criteria allowing early stopping for futility.  
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Using the historical CR rate of 17% for decitabine 20 mg/m2 on the standard of care five-day schedule 
(based on the largest randomized study of decitabine in older patients with AML [DACO-16]), a minimum 
acceptable CR rate of 25% (given the addition of glasdegib and additional potential toxicity) and ultimately 
a predicted minimum CR rate of 47% (the alternative hypothesis) for patients accrued to either arm of the 
proposed randomized phase 2 study, a minimum of 23 patients per arm will be accrued to test for a 
statistically-significant difference with an 80% power and a 90% confidence interval (which is equivalent 
to a type 1 error rate, alpha one-sided of 0.05). 
 
The separate, Simon two-stage minimax decision rule is to stop enrollment in either arm if 2 or fewer 
patients in that arm achieve CR of the first 10 patients required to be accrued during the stage 1 portion of 
the study. After the first 10 patients are enrolled and futility analysis of each arm allowed continued 
enrollment, the second stage of the study will be conducted. 
 
Additionally, analysis of safety data will be performed to stop enrollment in an arm when there is at least 
70% probability that the unacceptable toxicity rate in that arm is above 25%. The safety stopping criteria 
will be applied starting when at least 10 patients have completed 24 weeks (stage 1) or experienced a DLT, 
and applied continuously thereafter. 
 
All AEs will be classified according to CTCAE version 5.0.  
 
Figure 1. Schematic of Study Design 
Key Eligibility:
•
Previously-untreated 
poor-risk AML
•
Refusal of/ineligible 
for intensive therapy
•
ECOG 0 - 2
Primary Endpoint:
Complete remission + complete remission with 
incomplete count recovery rates 
Secondary Endpoints:
OS, EFS, RFS, time to CR/CRi, duration of CR/CRi, 
bone marrow mutational clearance
R
A
N
D
O
M
I
Z
E
(1:1)
Glasdegib (PF-04449913) 100 mg PO 
daily on a 28 day cycle
+
Decitabine 20 mg/m2 IV daily x 10 days 
on a 28 day cycle 
Glasdegib (PF-04449913) 100 mg PO 
daily on a 28 day cycle
+
Decitabine 20 mg/m2 IV daily x 5 days 
on a 28 day cycle 
Stage 1 safety 
assessment
 
6.2. Study Treatments  
Glasdegib will be administered at the starting dose of 100 mg orally once daily and continuously in 
combination with either DAC5 (decitabine 20 mg/m2 IV on a 5-day schedule) or DAC10 (decitabine 20 
mg/m2 IV on a 10-day schedule)  as per randomization. Treatment will be administered in 28-day cycles.  
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• All patients will be administered glasdegib 100mg orally once daily and continuously 
 
• Decitabine will be administered per local label and will be administered by IV infusion at a dose 
of 20 mg/m2/day for either 5 days or 10 days as determined by randomization. Each cycle will be 
every 28 days.  
 
Induction cycles are cycles 1-6 (or until CR or CRi is achieved, if earlier).  Consolidation cycles are 
cycles 7 (or earlier if CR or CRi is achieved)-24.  Patients who have achieved CR or CRi will remain on 
study beyond cycle 6 for up to 24 cycles. 
 
Since responses to decitabine may require 4-6 cycles of administration to emerge, treatment with the study 
drug combination should be continued for at least 6 cycles in patients with a response of SD or greater, or 
until progressive disease PD, death, unacceptable toxicity, or patient refusal, whichever occurs first.  If 
documentation of disease progression occurs beyond cycle 1, the patient should be withdrawn from study 
treatment. Treatment with the study drug combination should be continued beyond cycle 6, for cycles 7-24 
of treatment, only for patients who achieve CR or CRi or until objective disease progression or relapse, 
unacceptable toxicity, patient refusal or death, whichever occurs first. Patients who do not achieve at least 
a CRi after 6 cycles should be taken off study treatment.  
 
If glasdegib is permanently discontinued for reasons other than objective disease progression, patient 
refusal, or consent withdrawal, single-agent treatment with decitabine may be continued if the patient has 
experienced at least a CRi to study therapy. In cases of unacceptable toxicity or pregnancy, the patient must 
be withdrawn from study drug combination and entered into the follow-up phase.  
 
When study treatment with both drugs (glasdegib and decitabine) is permanently discontinued, patients will 
enter into the follow-up phase. Patients receiving at least one dose of study treatment will be followed up 
for survival for up to 2 years from the first visit of the last patient enrolled or until death, lost to follow-up, 
or consent withdrawal. 
 
6.3. Study Assessments Summary  
Patients will be followed for efficacy throughout the study by means of bone marrow aspirates.  Following 
study entry, bone marrow biopsies will only be required if adequate bone marrow aspirates are not obtained.  
A CR or PR response needs to be confirmed at least 4 weeks following the BM evaluation by assessing the 
stability of improved counts on PB, an additional bone marrow confirmatory specimen is not required. 
 
Blood counts will be monitored and transfusional support (red blood cells and platelets) will also be 
recorded.  Timely and complete (bone marrow AND peripheral blood counts) disease assessments at 
screening and during the study essential.  Failure to perform any of the required disease assessments will 
result in the inability to determine disease status for that time point and may weaken the conclusions of the 
study.  
 
Safety assessments (laboratory, instrumental and clinical) will be performed regularly during the active 
treatment period.  
 
7. PATIENT SELECTION  
This study can fulfill its objectives only if appropriate patients are enrolled.  The following eligibility 
criteria are designed to select patients for whom protocol treatment is considered appropriate.  All relevant 
medical and non-medical conditions should be taken into consideration when deciding whether this protocol 
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is suitable for a particular patient. These criteria must also be met prior to dosing on Cycle 1 Day 1. No 
exceptions will be granted. 
 
Prior to obtaining signed consent from a patient, the site principal investigator or coordinator must email 
the project manager to inquire about study space availability. If a slot is available, the potential study 
participant will complete the consent process. The informed consent process must be completed before any 
study screening procedures may begin. The site principal investigator or other approved investigator must 
document that the patient has met all inclusion criteria and has none of the exclusion criteria. Following 
completion of eligibility testing, eligibility documents will be sent to the YCCI project manager. 
 
7.1. Inclusion Criteria  
Patient eligibility must be reviewed and documented by an appropriate member of the investigator’s study 
team before patients are included in the study. Patients must meet all the following inclusion criteria to be 
eligible for enrollment into the study: 
 
1. Patients must be ≥ 18 years of age 
 
2. Patients must have a morphologically-confirmed diagnosis of AML according to WHO 2016 
classification (Appendix 9) with poor-risk disease as defined by the cytogenetic or molecular 
abnormalities in Appendix 8 (excluding FLT3-mutated AML). 
 
 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2. See Appendix 7 
 
4. Adequate Renal Function: 
 
a. Calculated creatinine clearance (determined by MDRD) ≥50mL/min/1.73m2, or serum creatinine 
<1.5x upper limit of normal (ULN);  
 
5. Adequate Liver Function: 
 
a. Total serum bilirubin ≤ 2.0 x ULN (unless the bilirubin is principally unconjugated and there is strong 
suspicion of sub-clinical hemolysis or the patient has documented Gilbert's disease); 
  
b.  Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 3.0 x ULN; 
 
c. Alkaline phosphatase ≤ 3.0 x ULN.  
 
6. Serum or urine pregnancy test (for female patients of childbearing potential) with a minimum 
sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin (HCG) negative at 
screening. 
 
7. Males and female patients both of childbearing potential and at risk for pregnancy must agree to use 
two highly effective method(s) of contraception throughout the study and for 180 days after the last 
dose of decitabine and the last dose of glasdegib, whichever occurs later. 
 
8. Female patients who are not of childbearing potential (i.e. meet at least 1 of the following criteria):  
 
a. Have undergone a documented hysterectomy and/or bilateral oophorectomy;  
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b. Have medically confirmed ovarian failure; 
 
c. Have achieved postmenopausal status, defined as follows: cessation of regular menses for at least 
12 consecutive months with no alternative pathological or physiological cause; status may be 
confirmed by having a serum follicle stimulating hormone (FSH) level within the laboratory’s 
reference range for postmenopausal women. 
 
7.2. Exclusion Criteria 
Patients with any of the following may not be included in the study:  
 
1. Patients who are candidates for and willing to receive intensive induction chemotherapy. 
2.  
3. Prior use of a hypomethylating agent. 
 
4. Prior use of cytotoxic chemotherapy for any myeloid malignancy (prior immunosuppressive 
therapy is permitted provided that treatment is stopped within 8 weeks from study entry; 
hydroxyurea is allowed through the end of cycle 1 on study). 
 
5. Previous hematopoietic stem cell transplant. 
 
6. Prior treatment with a licensed or experimental smoothened inhibitor (SMOi) and/or 
hypomethylating agent (HMA). 
 
7. Participation in a clinical study involving an investigational drug(s) (Phases 1-4) within 4 weeks 
prior to study entry or within 5 half-lives of the investigational agent, whichever is greater. 
 
8. Major surgery or radiation within 12 weeks prior to study entry. 
 
9. Patients known to be refractory to platelet or packed red cell transfusions as per institutional 
guidelines, or who are known to refuse or who are likely to refuse blood product support. 
 
10. Treatment with hematopoietic growth factors including: erythropoietin, granulocyte colony 
stimulating factor (G-CSF), and granulocyte macrophage colony stimulating factor (GM-CSF), or 
thrombopoietin receptor agonists within 3 weeks prior to study entry. 
 
11. Any ongoing medical condition requiring chronic use of moderate to high dose steroids (defined 
as ≥10 mg/day of prednisone or equipotent dose of another corticosteroid). 
 
12. Any anti-cancer treatment within 2 weeks prior to study entry (including hydroxyurea as above). 
 
13. Current use or anticipated requirement for drugs that are known moderate to strong CYP3A4 
inducers (Appendix 2). 
 
14. Presence of concurrent active malignancy requiring active systemic therapy  
 
15. Patients with known active, uncontrolled bacterial, fungal or viral infection, including hepatitis B 
(HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV), or acquired 
immunodeficiency syndrome (AIDS) related illness. 
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16. Known uncontrolled central nervous system (CNS) involvement. 
 
17. Poorly-controlled active medical conditions that as per investigator judgement would interfere with 
the conduct of the study. 
 
18. Active cardiac dysrhythmias of NCI CTCAE Grade ≥2 (e.g. atrial fibrillation) or QTcF interval 
>470 msec. 
 
19. Pregnant or breastfeeding female patients. 
 
7.3. Lifestyle Guidelines  
In this study, male patients who are able to father children and female patients who are of childbearing 
potential will receive decitabine, a compound that in preclinical studies in mice and rats has been shown to 
be teratogenic, fetotoxic, and embryotoxic, though no high-level studies of decitabine use in pregnant 
women exist or are published. Patients will also receive glasdegib, a compound which can cause embryo-
fetal death or severe birth defects when administered to a pregnant woman. Glasdegib is embryotoxic, 
fetotoxic, and teratogenic in animals. Patients who are, in the opinion of the investigator, sexually active 
and at risk for pregnancy with their partner(s) must agree to pregnancy testing in females of reproductive 
potential prior to initiation of glasdegib treatment and use at least 1 highly effective form of contraception 
throughout the study and for at least 180 days after the last dose of investigational product. The investigator 
must advise males of the potential risk of exposure through semen and to use condoms with a pregnant 
partner or a female partner of reproductive potential during treatment with glasdegib and for at least 180 
days after the last dose to avoid potential drug exposure. 
 
The investigator or his or her designee, in consultation with the patient, will confirm that the patient has 
selected at least 1 appropriate method of contraception for the individual patient and his/her partner(s) from 
the list of permitted contraception methods (see below) and will confirm that the patient has been instructed 
in their consistent and correct use.  At time points indicated in the Table 1 Schedule of Activities, the 
investigator or designee will inform the patient of the need to use at least 1 highly effective method of 
contraception consistently and correctly and document the conversation, and the patient’s affirmation, in 
the patient’s chart.  In addition, the investigator or designee will instruct the patient to call immediately if 
the selected contraception method is discontinued or if pregnancy is known or suspected in the patient or 
partner(s).  
 
Highly effective methods of contraception are those that, alone or in combination, result in a failure rate of 
less than 1% per year when used consistently and correctly (i.e. perfect use) and include the methods 
described in Table 2. 
 
Table 2. Methods of Birth Control  
 
Highly effective low user dependency 
Highly effective  high user dependency 
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• 
Progestogen only contraceptive implant; 
 
• 
Intrauterine hormone releasing system (IUS); 
 
• 
Intrauterine device (IUD); 
 
• 
Bilateral tubal occlusion. 
 
Combined hormonal contraception (estrogen and 
progestogen)  
• 
Oral; 
 
• 
Intravaginal; 
 
• 
Transdermal; 
• 
 
Vasectomized partner: 
 
A vasectomized partner is a highly effective form of 
contraception provided they are the sole male partner 
of the women of child bearing potential and the 
absence of sperm has been confirmed. If not an 
additional highly effective method of contraception 
should be used. 
 
Progestogen only hormonal contraception  
• 
Oral; 
 
• 
Injectable. 
 
 
7.4. Sunlight Exposure  
Patients will be advised to report any reaction to sun exposed skin.  In addition, special precautions will be 
taken to limit any potential photo irritation effect, by instructing patients to minimize exposure to light 
including high intensity ultraviolet b (UVb) sources such as tanning beds, tanning booths and sunlamps.  
Patients should be advised to apply sunscreen/sunblock daily.  
 
8. STUDY TREATMENTS  
8.1. Allocation to Treatment 
Allocation of patients to treatment groups will proceed through the use of the OnCore System.  The 
randomization and patient registration process is outlined in the eCRF guidelines.  
 
8.2. Patient Compliance  
For glasdegib, all patients will maintain patient dosing diaries throughout the study which will record the 
date of administration and all regular, missed, changed, or delayed doses.  
 
Patients are required to return all bottles, unused study drug and the patient dosing diary, at each cycle and 
at End of Treatment visit for compliance assessment and drug accountability. The number of tablets 
returned by the patient at the end of the cycle will be counted, documented and recorded.  
 
8.3. Formulation and Packaging  
8.3.1. Glasdegib  
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Glasdegib will be supplied by Pfizer Worldwide Research and Development as 25 mg and 100 mg tablets 
for oral administration. Supplies will be labeled according to local regulatory requirements.  
 
Glasdegib will be packaged in high-density polyethylene (HDPE) bottles and should be handled with care.  
Each bottle will contain enough medication for a 28-day cycle of daily dosing, plus an additional amount 
to cover the time between site visits.  Patients should be instructed to keep their medication in the bottles 
provided and not transfer it to any other containers and return the bottles to the site at the next study visit.  
Site personnel must ensure that patients clearly understand the directions for self-medication.  
 
8.3.2. Decitabine  
Decitabine will be prepared and administered according to local institutional practice. Only qualified 
personnel who are familiar with procedures that minimize undue exposure to them and to the environment 
should undertake the preparation, handling, and safe disposal of chemotherapeutic agents. 
 
8.4. Administration  
8.4.1. General Guidelines  
Both study drugs are administered in 28-day cycles. Cycle duration maybe extended beyond 28 days to 
allow resolution of toxicities related to study treatments. All patients will receive glasdegib 100 mg oral 
daily. Patients will subsequently be randomized 1:1 to receive decitabine either 20 mg/m2 IV on a 10-day 
schedule (DAC10) or 20 mg/m2 IV on a 5-day schedule (DAC5). 
 
Glasdegib will be self-administered by the patient at home. Glasdegib will be administered orally with 
approximately 8 ounces (240mL) of water and should be taken in the morning, at the same time each day.  
Tablets must not be crushed or cut; they must be swallowed whole, not manipulated or chewed prior to 
swallowing.  Patients should be instructed to self-administer their medication in the morning at 
approximately the same time each day and to not take more than the prescribed dose at any time.  If a patient 
forgets to take their dose at the regularly scheduled time, and if less than 12 hours have passed since the 
scheduled dosing time, that dose should be taken as soon as possible; two doses of glasdegib should not be 
taken within 12 hours. If more than 12 hours have passed since the scheduled dosing time, the dose should 
be skipped and the patient should continue on their normal dosing schedule. If a patient misses a day’s dose 
entirely, they must be instructed not to “make it up” the next day.  If a patient vomits any time after taking 
a dose, they must be instructed not to “make it up,” but to resume the next dose at the regular time. If a 
patient inadvertently takes 1 extra dose during a day, the patient should not take the next dose of glasdegib. 
The patient will be reminded NOT to take their dose at home on clinic days but to bring their bottle(s) and 
patient dosing diary into clinic so that glasdegib may be administered there.  
 
Patients requiring glasdegib dose reduction(s) will be administered multiples of 25mg tablets and should 
continue taking the glasdegib at the same time each morning at the dose prescribed by the Investigator (i.e. 
75 mg daily and 50 mg daily in the form of three or two 25 mg tablets, respectively). Dose modifications 
are discussed in Tables 4, 5&6.  
 
8.4.2. Treatment Duration  
Since responses to decitabine may require 4-6 cycles of administration to emerge, treatment with the study 
drug combination should be continued for at least 6 cycles in patients with a response of SD or greater, or 
until PD, death, unacceptable toxicity, or patient refusal whichever occurs first. If documentation of disease 
progression occurs beyond cycle 1, the patient should be taken off study treatment.  
 
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Treatment with the study drug combination should be continued beyond 6 cycles of treatment only for 
patients who achieve CR or CRi, until objective disease progression or relapse, death, unacceptable toxicity, 
or patient refusal whichever occurs first. Patients who do not achieve at least a CRi after 6 cycles should be 
taken off study treatment. 
 
If glasdegib is permanently discontinued for reasons other than objective disease progression, patient 
refusal, or consent withdrawal, single-agent treatment with decitabine may be continued if the patient has 
experienced at least a CRi to study therapy.  
 
In cases of a significant toxicity that does not resolve with a dose interruption or a dose reduction as outlined 
below or pregnancy, the patient must be withdrawn from study drug combination and entered into the 
follow-up phase of the study.  
 
When study treatment with both drugs (glasdegib and decitabine) is permanently discontinued, patients will 
enter into the follow-up phase. 
 
8.4.3. Dose Modifications  
Every effort should be made to administer the study drug treatment according to the planned dose and 
schedule.  
 
In the event of significant toxicity, dosing must be interrupted, delayed and/or reduced as outlined below. 
In the event of multiple toxicities, dose modification should be based on the worst toxicity observed. 
Patients must be instructed to notify investigators at the first occurrence of any adverse symptom/s.  
 
Dose modifications may occur in three ways: 
 
• Within a cycle: Dosing interruption until adequate recovery followed by dose reduction (if 
required) of glasdegib during a given treatment cycle. 
 
• Between cycles: The next treatment cycle may be delayed if toxicity from the preceding cycle 
persists. 
 
• In the next cycle: Dose reduction may be required based on toxicities experienced in the previous 
cycle. 
 
A cycle is determined by the decitabine administration schedule. A cycle is 28 days, but will be extended 
if there are dose delays or modifications for decitabine. Decitabine administration should not be interrupted 
if glasdegib dosing is interrupted for toxicity.  
 
If start of glasdegib administration in the next cycle is delayed due to toxicities potentially attributable to 
glasdegib, decitabine administration should not be delayed, and the day when decitabine administration 
occurs will be counted as Day 1 of the next cycle for both study drugs. 
 
8.4.3.1. Decitabine  
Following the first cycle of decitabine, if any of the following non-hematologic toxicities are present, 
decitabine treatment should not be restarted until the toxicity is resolved:  
• serum creatinine ≥2 mg/dL;  
• ALT, SGPT ≥2 times ULN;  
• total bilirubin ≥2 times ULN 
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• active or uncontrolled infection 
 
Treatment should be permanently discontinued if any of the following hematologic toxicities occur in 
patients who do not have active disease in the absence of bone marrow hypocellularity, and the toxicity is 
possibly, probably or definitely related to study drug as determined by the investigator,   
• 
Grade 4 neutropenia that does not resolve to ≤Grade 3 within 42 days of the start of each 
cycle 
• 
Grade 4 thrombocytopenia that does not resolve to ≤Grade 3 within 42 days of the start of 
each cycle 
 
8.4.3.2. Glasdegib 
Glasdegib does not need to be delayed or dose reduced for hematologic toxicity deemed unrelated or 
unlikely related to study drug by the Investigator. However, as with decitabine, treatment should be 
permanently discontinued for the following hematologic toxicities in patients who do not have active 
disease in the absence of bone marrow hypocellularity and the toxicity is possibly, probably, or definitely 
related to study drug as determined by the investigator: 
• 
Grade 4 neutropenia that does not resolve to ≤Grade 3 within 42 days of the start of each 
cycle 
• 
Grade 4 thrombocytopenia that does not resolve to ≤Grade 3 within 42 days of the start of 
each cycle 
 
 
Patients experiencing Grade 3 non-hematological toxicities potentially attributable to glasdegib should have 
their glasdegib treatment interrupted regardless of when it occurs in the cycle until the toxicity resolves or 
returns to baseline or remits to Grade 1 or less (as described in Table 4). If these parameters have not been 
met following >28 consecutive days of dose interruption, glasdegib should be permanently discontinued. 
Glasdegib should be permanently discontinued in patients experiencing a Grade 4 non-hematologic toxicity. 
If glasdegib treatment is permanently discontinued, patients may continue single agent treatment with 
decitabine, if the patient has experienced at least a CRi to study therapy.  
 
Appropriate follow-up assessments should be implemented until adequate recovery (toxicity resolves or 
returns to baseline) occurs. Depending on when the adverse event resolved, treatment interruption may lead 
to the patient missing all subsequent planned doses of glasdegib within the cycle.  If the AE leading to 
treatment interruption recovers within the same cycle, re-commencement of dosing in that cycle is allowed. 
The need for a dose reduction at the time of treatment resumption should be based on the criteria outlined 
in Table 5, unless specifically agreed otherwise following discussion between the Investigator and the 
Sponsor. If a dose reduction for glasdegib is applied in the same cycle, the patient must return to the clinic 
to receive a new supply of drug.  Glasdegib doses omitted for toxicity will not be replaced within that cycle 
(e.g. cycles will not be prolonged beyond the 28 days in order to make up for any missed glasdegib doses 
during that cycle).  
 
Glasdegib may be interrupted or permanently discontinued for any reason as per Good Clinical Practice. In 
the event of glasdegib treatment interruption for reasons other than treatment-related toxicity (e.g. elective 
surgery) for a duration >28 days, the details of treatment resumption will be determined in consultation 
with the Sponsor PI.  
 
Dose reduction of glasdegib by 1 or, if necessary, 2 dose levels (Table 3) will be allowed depending on the 
type and severity of toxicity encountered. All dose modifications/adjustments must be clearly documented 
in the patient's notes and electronic case report form (eCRF).  
 
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Once the glasdegib dose has been reduced, all subsequent cycles should be administered at that dose level, 
unless further dose reduction is required. Dose re-escalation is not allowed. Deviations from any of the dose 
modifications must be discussed and agreed with the Sponsor PI. 
 
Table 3. Available Dose Levels  
Glasdegib (mg daily) 
100 
75 
50 
   
 
Dose modifications for treatment-related non-hematologic toxicities (excluding QTc prolongation, muscle 
spasms, and myalgia) are outlined in Table 4. 
 
Table 4. Dose Modifications for Non-Hematologic Toxicities Considered Possibly, Probably or 
Definitely Related to Study Therapy)  
 
 
Toxicity 
(NCI CTCAE version 5.0) 
Glasdegib 
Grade 4 toxicity (any) 
Permanently discontinue 
Grade 3 toxicity  
(Nausea, vomiting, and/or diarrhea must persist 
for 7 days at Grade 3 (despite maximal 
appropriate medical therapy) or necessitate / 
prolong hospitalization or TPN or NGT feeding 
to require dose modification) 
 
Hold glasdegib until toxicity has recovered to 
baseline or <  Grade 1.  
First episode: Decrease by 1 dose level  
 
Second episode: Permanently discontinue 
Potential drug induced liver injury/Hy’s Law 
(see below this table) 
Investigate alternative causes of liver injury and 
interrupt glasdegib dosing until drug injury 
remits to grade 1 or less. If an alternative cause 
is found, restarting of glasdegib at the same dose 
may be considered. Discussion with the Sponsor 
PI is required.  
 
Confirmed drug induced liver injury/Hy’s Law 
(see below this table) 
 
Permanently discontinue glasdegib. 
 
 
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Patients who present with the following laboratory abnormalities should be evaluated further to definitively 
determine the etiology of the abnormal laboratory values:  
 
• 
Patients with AST or ALT and total bilirubin baseline values within the normal range who subsequently 
present with AST or ALT values 3 times the upper limit of normal (X ULN) concurrent with a total 
bilirubin value 2X ULN with no evidence of hemolysis and an alkaline phosphatase value 2X ULN or 
not available.  
 
• 
For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, the following 
threshold values should be used in the definition mentioned above: 
 
o 
For patients with preexisting AST or ALT baseline values above the normal range: AST or 
ALT values >2 times the baseline values and >3X ULN, or >8X ULN (whichever is 
smaller).  
 
Concurrent with  
 
o 
For patients with preexisting values of total bilirubin above the normal range: Total bilirubin 
level increased from baseline by an amount of at least 1X ULN or if the value reaches ≥ 3X 
ULN (whichever is smaller). 
 
Patients should be closely monitored for potential cardiovascular symptoms. Appropriate monitoring 
should include clinical examinations, vital signs, routine ECGs, and AE monitoring at the times specified 
in the calendar of events or more often if clinically indicated. In case of QTc prolongation, concomitant 
conditions such as electrolyte imbalances, hypoxia, or use of medications affecting the QT interval should 
be ruled out and/or corrected. In case of clinically significant toxicities, glasdegib administration should be 
interrupted and the dose reduced as indicated in Table 4.  
 
Concomitant administration of glasdegib with moderate to strong CYP3A4 inhibitors (Appendices 3 and 
4) and drugs with known risk of Torsade de Pointes (TdP) (Appendix 5) is not recommended due to the 
potential for drug-drug interaction to prolong the QTc interval. All protocol specified QTcF prolongation-
related exclusion criteria must be followed. Investigators must be aware of the QTcF-prolonging potential 
of all medications that patients on study are taking and should take appropriate action when clinically 
indicated. Given the potential for QTcF prolongation, the measurement and immediate correction of 
electrolyte abnormalities such as potassium and magnesium, and of other reversible causes of QTcF 
prolongation such as hypoxia, are especially important. In the event that the QTcF interval is prolonged 
beyond 480 msec (CTCAE v.5.0 >Grade 2), Table 5 must be referenced and actioned. Additional ECG and 
cardiac consultation should be obtained if clinically indicated. 
 
Table 5. Glasdegib Dose Modifications for mean QTcF (mQTcF) Prolongation 
CTCAE v 5.0 
 
Electrocardiogram 
QT corrected (QTc) 
interval prolonged* 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
450-480 msec 
481-500 msec 
≥501 msec at 
least two 
separate ECGs 
QTc > 501 or >60 
msec change from 
baseline and 
Torsade de pointes 
or polymorphic 
ventricular 
tachycardia or 
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signs/symptoms of 
serious arrhythmia 
*The severity of QTc prolongation assessment is to be done by calculating a mean QT of 3 
consecutive ECGs performed approximately 2 minutes (but no longer than 5 minutes) apart by using 
the Fridericia correction method (mQTcF).  
 
Category 
 
Action 
 
Grade 
      1              2                3                4 
ECG monitoring 
Monitor ECGs at least weekly for 2 
weeks following resolution of 
mQTcF prolongation to < 480 msec 
 
 
X 
 
X 
 
X 
Initial glasdegib 
action 
Discontinue and do not re-
challenge 
 
 
 
X 
Interrupt treatment 
 
X 
 
Continue treatment at same dose 
X 
X 
 
 
General 
management 
Assess electrolyte levels and 
supplement as clinically indicated 
 
X 
X 
X 
Review and adjust concomitant 
medications with known QTc 
interval-prolonging effects 
 
X 
X 
X 
Resume glasdegib 
dosing 
at a reduced dose of 50 mg once 
daily when QTc interval returns to 
within 30 ms of baseline or less 
than or equal to 480 ms.  
 
 
X 
 
Consider re-escalating the dose of 
glasdegib to 100 mg daily if an 
alternative etiology for the QTc 
prolongation can be identified. 
 
 
X 
 
Discontinue 
glasdegib 
permanently 
If two prior glasdegib dose 
interruptions related to QTcF 
prolongation have occurred  
 
 
X 
 
 
Dose modifications for glasdegib in case of drug class related AEs are outlined in Table 6. 
 
Table 6. Dose Modifications for Glasdegib in Case of Drug Class Related AEs 
Muscle Spasms or 
Myalgia 
Grade 1 
Grade 2 
Grade 3 
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Glasdegib 
Continue at same dose 
level. 
 
Administer oral 
rehydration solutions 
containing 
electrolytes.a 
 
Consider other 
appropriate 
interventions (e.g. 
anti-spasmodics) as 
per institutional 
guidelines. 
 
Evaluate levels of: 
CK, Vit B6, Vit D, 
ferritin, transferrin and 
electrolytes (Na, K, 
Mg, Ca and P).b 
 
If CK is elevated, 
evaluate urine and 
serum myoglobin, CK 
isoenzymes, and serum 
creatinine. 
Continue at same dose 
level. 
 
Administer oral re-
hydration salts 
containing 
electrolytes.a 
 
Consider other 
appropriate 
interventions (e.g. 
anti-spasmodics) as 
per institutional 
guidelines. 
 
Evaluate levels of: 
CK, Vit B6, Vit D, 
ferritin, transferrin and 
electrolytes (Na, K, 
Mg, Ca and P).b 
 
If CK is elevated, 
evaluate urine and 
serum myoglobin, CK 
isoenzymes, and serum 
creatinine. 
 
If event persists for 7 
days, hold dose until 
resolution to Grade ≤1. 
 
Upon resolution, 
restart at prior dose, or 
for prolonged muscle 
spasms, consider 
reducing dose by one 
dose level. 
Hold dose. 
 
 
Administer oral re-
hydration salts 
containing 
electrolytes.a 
 
Consider other 
appropriate 
interventions (e.g. 
anti-spasmodics) as 
per institutional 
guidelines. 
 
Evaluate levels of: 
CK, Vit B6, Vit D, 
ferritin, transferrin and 
electrolytes (Na, K, 
Mg, Ca and P).b 
 
If CK is elevated, 
evaluate urine and 
serum myoglobin, CK 
isoenzymes, and serum 
creatinine. 
 
Upon resolution to 
Grade ≤1, restart study 
treatment at next lower 
dose level. 
 
If the event does not 
resolve within 3 weeks 
to Grade ≤1, glasdegib 
should be permanently 
discontinued.  
Abbreviations: CK creatinine kinase; Vit vitamin; Na sodium; K potassium; Mg magnesium; Ca calcium; P phosphorous. 
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a. Electrolyte replacement drinks should include Na, K, Mg, Ca and P.  Consideration should be given to ensuring adequate 
hydration prior to bedtime, and whenever fluid intake is decreased for a prolonged duration.  
b. Labs may be drawn as unscheduled assessments between protocol visits. In the event of alopecia or dysgeusia, 
investigator discretion should be applied with respect to dose interruption and/or dose reduction of glasdegib as preliminary 
analysis of available clinical data suggests that these events are not dose dependent. 
 
 
8.5. Drug Storage  
The investigator, or an approved representative, e.g. pharmacist will ensure that all investigational products, 
including any comparative agents and/or marketed products are stored in a secured area with controlled 
access under recommended storage conditions and in accordance with applicable site and regulatory 
requirements.  
 
Storage conditions stated in the SRSD (IB for glasdegib and PI for decitabine) will be superseded by the 
storage conditions stated in the labeling.  
 
Glasdegib should be stored as described on the drug label. Note that the storage conditions in any study 
documentation will be superseded by the storage conditions stated on the product label. Patients should be 
instructed to keep their medication in its original container. Returned medication should be stored at the 
clinical site separately from medication that needs to be dispensed.  
 
Decitabine will be stored according to the labeled storage conditions.  
 
Investigators and site staff are reminded to check temperatures daily (i.e., manually or by using alarm 
systems to alert of any excursions) and ensure that thermometers are working correctly as required for 
proper storage of investigational products.  These include thermometers for both the room storage and 
refrigerator storage.  Any temperature excursions should be reported to the Project Manager.  
 
The investigational product(s) must be stored as indicated. Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the Project Manager. Once a deviation 
is identified, the investigational product must be quarantined and not used until the Project Manager 
provides documentation of permission to use the investigational product. 
8.6. Drug Accountability  
The Investigator’s site must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the drug supplies. At each dispensing visit (Cycle 2 Day 1, Cycle 3 Day 1, etc. or when there 
is a dose reduction), all unused or partially used bottles must be returned by patients to the Investigator.  
The number of tablets returned by the patient at the end of the cycle will be counted, documented and 
recorded. The Sponsor PI or designee will provide guidance on the destruction of unused investigational 
product (e.g. at the site).  If destruction is authorized to take place at the study site, the local investigator 
must ensure that the materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by drug manufacturer or designee and all 
destruction must be adequately documented. 
 
8.7. Concomitant Treatment(s)  
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All concomitant medications and treatments must be recorded in the eCRF. Any prior treatment received 
within 28 days prior to study entry (including hematopoietic growth factor receptor agonists: erythropoietin, 
granulocyte colony stimulating factor (G-CSF), romiplostim, eltrombopag) will be recorded in the eCRF.  
 
In addition, any transfusion (red blood cells or platelets) within 8 weeks prior to screening should be 
recorded in the eCRF.  
 
All prior immunosuppressive therapy (e.g., cyclosporine) used to treat MDS, or all prior cytoreductive 
therapy (e.g. hydroxyurea) used to treat AML or other myeloid malignancy, will be recorded regardless of 
when they were received by the patient. Information collected will include dates of use, best treatment 
response and the reasons for stopping therapy.  
 
Every concomitant treatment, blood products, growth factors, as well as interventions, required by the 
patients during the active study treatment (and up to 28 days following last study drug administration or 
until initiation of another anti-cancer treatment) and the reason for its administration must be recorded on 
the eCRF.  
 
All concomitant medications the patient is currently receiving must be reviewed by the Sponsor prior to 
enrollment in the study. 
 
8.7.1. Restricted or Prohibited Concomitant Medications 
The following medications are not allowed during the active study treatment period:  
 
• 
Investigational agents; 
 
• 
CYP3A4 Inducers: A drug-drug interaction study in health patients with the strong CYP3A4 
inducer, rifampin, resulted in a 70% decrease in plasma exposures (AUCinf) and a 35% decrease in 
peak plasma concentration (Cmax) of a single 100 mg oral dose of glasdegib. Therefore, co-
administration of glasdegib and moderate to strong CYP3A4 inducers is not permitted. A 
comprehensive list of moderate to strong CYP3A4 inducers is provided in Appendix 2. However, 
if you are uncertain whether a concomitant medication is contraindicated, you should contact the 
Project Manger study team. 
 
The following medications have use restrictions during the active study treatment period:  
 
• 
CYP3A4 Inhibitors: In vitro studies with human liver microsomes and recombinant CYP 
enzymes indicated that glasdegib metabolism is primarily mediated by the drug-metabolizing 
enzyme CYP3A4. Clinically, there is likelihood that glasdegib plasma concentrations may be 
increased in the presence of co-administered inhibitors of the CYP3A4 enzyme. In a healthy 
volunteer study, ketoconazole, a potent CYP3A4 inhibitor, produced a 2.4-fold increase in plasma 
exposure and a 1.4-fold increase in peak plasma concentration of glasdegib. Therefore, a potential 
exists for drug-drug interactions with CYP3A4 inhibitors, and co-administration of glasdegib in 
combination with moderate to strong CYP3A4 inhibitors is not recommended.  Selection of 
concomitant medication with no or minimal CYP3A4/5inhibition potential is recommended. 
Moderate to strong CYP3A4 inhibitors (Appendices 3 and 4) should be used with caution and 
only if considered medically necessary. If a moderate to strong CYP3A4 inhibitor is to be 
initiated in addition to glasdegib, the guidance provided below. and dose modifications for QT 
prolongation per Table 5 must be followed. 
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• 
Drugs with a known risk of Torsade de pointes (TdP): Glasdegib has been shown to have the 
potential to prolong the QTc interval in pre-clinical studies and at doses >200 mg.  While the 
glasdegib dose being evaluated in this study is 100 mg, the concomitant administration of glasdegib 
and drugs with a known risk of Torsade de pointes should be avoided whenever possible. A list of 
such drugs is provided in Appendix 5. Use of these drugs is not recommended unless there are no 
alternatives. If a drug listed in Appendix 5 is to be initiated in addition to glasdegib, the guidance 
provided in the dose modifications for QT prolongation per Table 5 must be followed.  
 
• 
QT prolonging medications (without a risk of TdP) should be avoided whenever possible.  
 
• 
Concomitant administration of multiple moderate to strong CYP3A4 inhibitors, TdP-associated 
drugs, and/or QT prolonging medications (without a risk of TdP) is not recommended and must be 
discussed with the Sponsor PIr. 
 
8.7.2. Permitted Concomitant Medications  
8.7.2.1. Best Supportive Therapy  
Best Supportive Therapy (BST) administration is permitted according to Institutional guidelines for all 
patients on study. BST will be provided by the site and may vary depending on the patient’s signs and 
symptoms, site current practice.  It includes medications and supportive measures that may palliate 
disease-related symptoms, improve quality of life and treat bacterial, fungal or viral infections.  BST 
may include:  
 
• 
Blood transfusions;  
 
• 
Platelet transfusions;  
 
• 
Antibiotics;  
 
• 
Anti-fungal agents;  
 
• 
Anti-viral agents. 
 
8.7.2.2. Hematopoietic Growth Factors  
Hematopoietic growth factors (e.g. G-CSF, GM-CSF) may be used according to local practice and 
guidelines during active study treatment.  They cannot be used for 3 weeks prior to study inclusion. 
 
8.7.2.3. Anti-Emetic and Anti-Diarrheal Therapy  
Patients should be pre-medicated with anti-emetics for nausea and vomiting before each dose of decitabine 
in all cycles according to local practice and guidelines. Primary prophylaxis of diarrhea is permitted at the 
Investigator’s discretion. The choice of the prophylactic drug is up to the investigator assuming the drug is 
not contraindicated.  
 
8.7.3. Surgery  
Caution is advised on theoretical grounds for any surgical procedures during the study. The appropriate 
interval of time between surgery and glasdegib required to minimize the risk of impaired wound healing 
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and bleeding has not been determined. Stopping glasdegib is recommended at least 7 days prior to surgery. 
Post-operatively, the decision to reinitiate glasdegib treatment is up to the local investigator with Sponsor 
PI approval and should be based on a clinical assessment of satisfactory wound healing and recovery from 
surgery. 
 
9. STUDY PROCEDURES  
9.1. Screening  
Screening can be accomplished over one or multiple visits over a 4-week period (28 days), unless 
specifically noted otherwise. Protocol specific tests or procedures not considered standard of care can only 
be done after the patient has signed the Informed Consent document. The Informed Consent document may 
be signed up to 60 days prior to study entry.  
 
See the Schedule of Activities for a complete list of assessments and procedures to be collected during the 
screening visit.  
 
9.2. Study Period  
See the Schedule of Activities for a detailed list of the assessments and procedures to be collected.  
 
All assessments on Cycle 1 Day 1 should be collected and reviewed pre-dose, unless documented otherwise. 
 
9.3. End of Treatment Visit  
The End of Treatment Visit should be scheduled as soon as possible once a patient has been withdrawn 
from study drug. For a detailed list of assessments and procedures to be completed please refer to the 
Schedule of Activities. 
 
9.4. Long Term Follow-up  
The first follow up contact should occur at least 28 days, and no more than 35 days after the last dose of 
study drug to capture any potential adverse events and to confirm appropriate contraception usage. 
Follow-up may be made via telephone call, but must be performed every 3 months for a total duration of 
two years, unless a safety event has occurred at which point this event must be followed until resolution. 
For a detailed list of assessments and procedures to be completed please refer to the Schedule of 
Activities. 
In cases of unacceptable toxicity or pregnancy, the patient must be withdrawn from study drug combination 
and entered into the follow-up phase of the study.  
 
Patients who permanently discontinue both study drugs (decitabine and glasdegib) for any reason (except 
death, or withdrawal of patient consent) will enter into the follow-up phase.  
 
Patients continuing to experience toxicity following discontinuation of treatment will continue to be 
followed minimally every 4 weeks until resolution or determination, in the clinical judgment of the 
Investigator, that no further improvement is expected.  
 
Patients will be contacted every 3 months to confirm survival status, and to collect information on any new 
anti-cancer therapy initiated. Telephone calls are acceptable and patients will be followed up to the time of 
death or consent withdrawal.  
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Patients receiving at least one dose of study treatment will be followed for survival for up to 2 years from 
the first visit of the last patient enrolled or until death, lost to follow-up, or consent withdrawal.  
 
Patients may withdraw from the study at any time at their own request, or they may be withdrawn at any 
time at the discretion of the local investigator or Sponsor PI for safety or behavioral reasons or the inability 
of the patient to comply with the protocol required schedule of study visits or procedures at a given study 
site. 
 
Reasons for permanent discontinuation of study drug combination treatment may include: 
• 
Objective disease progression or relapse;  
 
• 
Global deterioration of health status; 
 
• 
Unacceptable toxicity;  
 
• 
Need for cycle start delay >28 days due to persistent drug combination related toxicity; 
 
• 
Lost to follow-up;  
 
• 
Patient refused further treatment (follow-up permitted by the patient);  
 
• 
Withdrawal of patient consent (cessation of follow-up);  
 
• 
Pregnancy;  
 
• 
Start of another anti-cancer treatment; 
 
• 
Study terminated by Sponsor- PI or drug manufacturer; 
 
• 
Death.  
 
Reasons for withdrawal from study may include:  
 
• 
Study terminated by Sponsor - PI or drug manufacturer;;  
 
• 
Lost to follow-up;  
 
• 
Withdrawal of patient consent for any further contact;  
 
• 
Death. 
 
If a patient does not return for a scheduled visit, every effort should be made to contact the patient. All 
attempts to contact the patient and information received during contact attempts must be documented in the 
patient’s medical record. In any circumstance, every effort should be made to document patient outcome, 
if possible. The Investigator should inquire about the reason for withdrawal, request that the patient return 
all unused investigational product(s), request that the patient return for a final visit, if applicable, and follow 
up with the patient regarding any unresolved AEs.  
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If the patient withdraws from the study and also withdraws consent for disclosure of future information, no 
further study specific evaluations should be performed, and no additional data should be collected. The 
Sponsor- PI may retain and continue to use any data collected before such withdrawal of consent. 
 
10. ASSESSMENTS  
Every effort should be made to ensure that the protocol-required tests and procedures are completed as 
described.  However, it is anticipated that from time to time there may be circumstances, outside of the 
control of the investigator, which may make it unfeasible to perform the test.  In these cases, the investigator 
will take all steps necessary to ensure the safety and well-being of the patient. When a protocol-required 
test cannot be performed, the investigator will document the reason for this and any corrective and 
preventive actions that they have taken to ensure that normal processes are adhered to as soon as possible. 
The study team must be informed of these incidents in a timely manner 
 
10.1. 
Pregnancy Testing  
For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 
25 mIU/mL, will be performed on two occasions prior to starting study therapy -once at the start of 
screening and once at the C1D1, immediately before investigational product administration.  Following a 
negative pregnancy result at screening, appropriate contraception must be commenced and a further 
negative pregnancy result will then be required at the C1D1 visit before the patient may receive the 
investigational product.  Pregnancy tests will also be routinely repeated at every cycle during the active 
treatment period, at the end of study treatment, and additionally whenever one menstrual cycle is missed 
or when potential pregnancy is otherwise suspected.  In the case of a positive confirmed pregnancy, the 
patient will be withdrawn from administration of study drug combination and enter into the Follow-up 
phase. Additional pregnancy tests may also be undertaken if requested by Institutional Review Boards 
(IRBs)/Ethic Committees (ECs) or if required by local regulations. 
10.2. 
Adverse Events  
Assessment of AEs will include the type, incidence, severity (graded by the NCI CTCAE version 5.0) 
timing, seriousness, and relatedness.  Additional information regarding AE and Serious AE (SAE) reporting 
is provided below.  
 
10.3. 
Laboratory Safety Assessments  
Hematology, blood chemistry, coagulation and urinalysis assessments will be drawn at the time points 
described in the Schedule of Activities and will be analyzed by the site/Investigator at local laboratories. 
Laboratory certifications and normal ranges with units must be provided to the Project Manager. 
 
If a complete blood count (CBC) with differential is obtained within 3 days of scheduled blood draw, the 
collection need not be repeated. For those patients achieving a CR or PR, a CBC should be done at least 4 
weeks after the BM assessment in order to confirm response. Hematology tests may be repeated also as 
clinically indicated.  
 
If blood chemistry or coagulations are obtained within 3 days of scheduled blood draw, the collection need 
not be repeated. 
 
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If a urinalysis was obtained within 3 days of the scheduled collection, it should not be repeated. For 
urinalysis, dipstick is acceptable. Microscopic analyses should be done if abnormal results (i.e. the presence 
of protein or blood).  
 
See Appendix 6 for list of required tests. 
 
10.4. 
Transfusions  
All red blood cell and platelet transfusions, including the date of each transfusion and number of red blood 
cell or platelet units transfused must be recorded while the patient is on treatment. Transfusion histories for 
the 8 weeks prior to screening must also be recorded in the CRF. Note that the number of units (not the 
number of bags) must be recorded.  
 
10.5. 
Vital Signs and Physical Examination  
Vital signs will include blood pressure and heart rate (to be recorded in sitting position). Patients will have 
a physical exam (PE) including an examination of major body systems (includes general appearance, head, 
neck, lungs, heart, abdomen, musculoskeletal, extremities, skin, lymph nodes, neurological), measurement 
by palpation of spleen and liver, weight, height and assessment of ECOG status. If PE obtained within 48 
hours of previous assessments, the evaluation need not be repeated. Height need not be recorded after the 
first measurement at screening. Weight must be recorded at Screening, Day 1 of each cycle, and End of 
Treatment.  
 
10.6. 
Triplicate (12-Lead) ECGs  
See Table 1 for the specific time points of ECG collection, and Table 5 for dose modification related to 
management of QTcF prolongation.  
 
Triplicate 12-lead (with a 10-second rhythm strip) tracing will be performed for ECGs at every timepoint. 
It is preferable that the machine used has a capacity to calculate the standard intervals automatically. The 
acceptable mean on treatment upper limit of QTc interval will be using the Fridericia (QTcF) correction 
method. At each time point 3 consecutive supine ECGs will be performed approximately 2 minutes (but 
no longer than 5 minutes) apart, to determine the mean QTcF interval. 
If Grade 3 mean QTcF (mQTcF) prolongation occurs (mQTcF ≥ 501 msec), continuous ECG monitoring 
and cardiology specialist evaluation and guidance are required.  
 
The acceptable mean on-treatment upper limit of QTcF interval is 480 msec. If any patient has a mean pre-
or post-dose QTcF value >480 msec, please refer to Table 5 of the protocol for detailed instructions on 
management of QTcF prolongation and handling dose delays and dose modifications for glasdegib. A 15-
min window for each ECG collection is allowed around the nominal ECG time point. 
 
10.7. 
Efficacy Assessments  
10.7.1. Response Criteria  
Disease response, will be evaluated using the 2017 European LeukemiaNet (ELN) Response Criteria 
(Appendix 1).  
 
Genetics                                                                                                                                                                                      
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For all patients, genetics analysis, including karyotyping, must be performed locally using any scheduled 
or unscheduled bone marrow samples collected during study participation as described in the Schedule of 
Activities. Genetics to be analyzed are specified in Appendix 8. 
 
Baseline genetics classification must be completed on a sample collected within 28 days prior to first dose.  
 
10.7.2. Bone Marrow Biopsies and Aspirates  
Please see the Schedule of Activities for specific assessment timepoints for BM biopsy and aspirate 
collection.  A CR or PR needs to be confirmed at least 4 weeks after the BM evaluation by assessing the 
stability of improved counts on PB according to the 2017 ELN response criteria (Appendix 1); the need 
for an additional marrow confirmatory specimen is not required. Minimal residual disease (MRD) 
assessment will be performed centrally on enrolled patients enrolled in this study using multi-parametric 
flow cytometry. In addition to epitopes traditionally used to define AML leukemic blasts such as CD34, 
additional antigens such as CD99 (potential myeloid leukemia stem cell marker) may be profiled to gain a 
broader standing of baseline patient immunophenotype and relationship to response, and potential changes 
in immunophenotype with study treatment. Full details regarding the collection, processing, storage and 
shipping of samples will be provided in the central laboratory manuals. 
 
The importance of timely and complete disease assessments (including BM and PB assessments) at 
screening and during the study, whenever clinically indicated, cannot be understated.  Failure to perform 
any of the required disease assessments will result in the inability to determine disease status for that time 
point and have the potential to weaken the conclusions of this study.  
 
10.7.3. Banked Biospecimens  
10.7.3.1. 
Purpose 
Banked biospecimens will be collected from all patients for possible future biomarker studies and other 
exploratory research relating to the drug response, potential mechanisms underlying resistance and other 
aspects of AML biology. Such results may assist the future development of glasdegib as a single agent 
and/or in combination with other approved agents in AML. For example, putative safety biomarkers, drug-
metabolizing enzyme genes, drug-transport protein genes, or genes thought to be related to the mechanism 
of drug action may be examined. The primary purpose is to examine DNA; however, the biospecimen may 
also be used to study other molecules (e.g. RNA, proteins, and metabolites).  
 
Unless prohibited by local regulations or IRB/EC decision, all patients will be asked to indicate on the 
consent form whether they will allow banked biospecimens to also be used to design and conduct research 
in order to gain a further understanding of other diseases and to advance science, including development of 
other medicines for patients.  
 
Patients need not provide additional biospecimens for the uses described in this section; the biospecimens 
collected as part of scheduled study activities will be used. Patients may still participate in the study if they 
elect not to allow their banked biospecimens to be used for the additional purposes described in this section. 
 
It is possible that the use of these biospecimens may result in commercially viable products. Patients will 
be advised in the informed consent document that they will not be compensated in this event. 
 
10.7.4. Collection, Processing and Storage 
Unless prohibited by local regulations or ethics committee decision, a 4-mL blood genomic banked 
biospecimen Prep D1 (dipotassium edetic acid [ethylenediaminetetraacetic acid] [K2EDTA] whole-blood 
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collection optimized for DNA analysis) will be collected on Cycle 1 Day 1 prior to first dose of study 
treatment to be retained for potential pharmacogenomic/genomic/biomarker analyses related to drug 
response and disease/condition under study.  
 
These collections are not typically associated with a planned assessment described in the protocol. They 
will be handled in a manner that protects each patient’s privacy and confidentiality. Banked biospecimens 
will be assigned the patient’s study identification code (ID) at the site. The data generated from these banked 
biospecimens will also be indexed by this ID. Biospecimens will be kept until destruction in facilities with 
access limited to authorized personnel, and biospecimen-derived data will be stored on password-protected 
computer systems. The key between the patient’s ID and the patient’s direct personally identifying 
information (e.g. name, address) will be held at the study site. Biospecimens will be used only for the 
purposes described in the protocol and informed consent document; any other uses require additional ethical 
approval. Unless a time limitation is required by local regulations or ethical requirements, biospecimens 
will be stored for many years (no time limit) to allow for research in the future, including research conducted 
during the lengthy drug-development process and also post-marketing research. Patients may withdraw 
their consent for the use of their banked biospecimens at any time by making a request to the investigator; 
in this case, any remaining biospecimens will be destroyed, but data already generated from the 
biospecimens will continue to be available to protect the integrity of existing analyses. 
 
11. ADVERSE EVENT REPORTING  
11.1. 
Definitions 
11.1.1. Adverse Event (AE) 
Broadly, an AE (also referred to as an adverse experience) is any expected or unexpected harmful and 
unintended occurrence or exacerbation in a clinical trial patient, whether or not related to the trial or the 
study drug.  
 
An AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, 
exacerbation of a concomitant disease, an accident, or any other deterioration in the patient’s health. It can 
be an intercurrent disease temporally associated with the use of a drug, without and implication of causality. 
An AE can arise with any use of the drug (e.g., off-label use, use in combination with another drug) and 
with any route of administration, formulation, or dose, including an overdose. 
 
Any medical condition that existed before the start of the study treatment and that remains unchanged or 
improves must not be recorded as an AE. If a medical condition worsens, it must be recorded as an AE. 
The diagnosis or syndrome rather than the individual signs or symptoms must be recorded on the AE pages 
of the case report form. 
 
11.1.2. Serious Adverse Event (SAE) 
An SAE is defined as an AE or suspected adverse reaction if it: 
• 
results death (death due to disease progression is excluded); 
• 
is life-threatening; 
• 
requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
causes a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
• 
cases a congenital anomaly, birth defect, or abortion; 
• 
is a new cancer;  
• 
is associated with overdose;  
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• 
is another medically significant event. 
 
Important medically significant event is any clinical event or laboratory finding considered by the 
investigator to be serious that does not meet the seriousness criteria defined above but based upon 
appropriate medical judgment, may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. 
 
The following are not considered as serious adverse events:  
• 
death due to disease progression; 
• 
hospitalization for < 24 hours; 
• 
hospitalization scheduled before the start of the trial and/or stipulated in the protocol (e.g. for 
biopsy or chemotherapy).  
 
11.1.3. Expected Serious Adverse Event (SAE-E) 
An expected SAE is an event already mentioned in the most recent version of the Investigator Brochure, or 
in the Summary of Product Characteristics (SmPC) for medicinal products that have already been granted 
marketing authorization (MA). This definition also applies to the study drug when it is administered for the 
same population but for an unlicensed indication. 
 
11.1.4. Unexpected Serious Adverse Event (SAE-U) 
Any adverse drug experience, the specificity or severity of which is not consistent with the current 
investigator brochure; or, if an investigator brochure is not required or available, the specificity or severity 
of which is not consistent with the risk information described in the general investigational plan. 
“Unexpected” as used in this definition, refers to an adverse drug experience that has not been previously 
observed (e.g., included in the investigator brochure) rather than from the perspective of such experience 
not being anticipated from the pharmacological properties of the pharmaceutical product. 
 
 
11.2. 
What to Do in Case of a Serious Adverse Event 
The investigator must report any expected Serious Adverse Event (SAE-E) or unexpected Serious Adverse 
Event (SAE-U) that occurs during the treatment period starting at the time the consent is signed, or within 
30 days after the last administration of the study drug, regardless of whether it is attributable to the study. 
Events must be reported to the Yale Project Manager and Sponsor PI within 24 hours of becoming aware 
of such events. Yale Project Manager and/or Sponsor PI will have up to 7 calendar days to report events to 
Pfizer either via a fax or email.  
 
Sites are responsible for reporting to their IRB per local policy. All events will be forwarded by the Yale 
Project Manager who will submit to Pfizer and FDA as required following the method and timeline outlined 
below.  
 
All SAEs should be entered into OnCore within 24 hours of the site becoming aware of the event. 
 
Any delayed serious adverse event (occurring after the 30-day period) that may reasonably be considered 
related to the treatment(s) described in the protocol or to the study must be reported, and no time limit 
applies to such adverse events. For each event, the investigator shall complete the SAE reporting form. 
 
SAEs will be followed until resolution or until clinically relevant improvement or stabilization. 
  
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11.3. 
Protocol-Specified Serious Adverse Events  
All cases of Grade >2 mQTcF prolongation regardless of causality and treatment arm must be reported as 
an SAE for up to 30 calendar days after the last dose of study drug administered. All SAEs will be reported 
by the investigator as described in previous sections and will be handled as SAEs in the safety database.  
 
11.4. 
Potential Cases of Drug-Induced Liver Injury  
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels 
concurrent with abnormal elevations in total bilirubin level that meet the criteria outlined below in the 
absence of other causes of liver injury are considered potential cases of drug-induced liver injury (potential 
Hy’s law cases) and should always be considered important medical events.  
 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury depends on the 
patient’s individual baseline values and underlying conditions. Patients who present with the following 
laboratory abnormalities should be evaluated further to definitively determine the etiology of the abnormal 
laboratory values:  
 
• 
Patients with AST or ALT and total bilirubin baseline values within the normal range who 
subsequently present with AST or ALT values 3 times the upper limit of normal (X ULN) 
concurrent with a total bilirubin value 2X ULN with no evidence of hemolysis and an 
alkaline phosphatase value 2X ULN or not available.  
 
• 
For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, the 
following threshold values should be used in the definition mentioned above: 
 
o For patients with preexisting AST or ALT baseline values above the normal range: 
AST or ALT values >2 times the baseline values and >3X ULN, or >8X ULN 
(whichever is smaller).  
 
Concurrent with  
 
o For patients with preexisting values of total bilirubin above the normal range: Total 
bilirubin level increased from baseline by an amount of at least 1X ULN or if the 
value reaches ≥ 3X ULN (whichever is smaller). 
 
 
The patient should return to the investigational site and be evaluated as soon as possible, preferably within 
48 hours from awareness of the abnormal results.  This evaluation should include laboratory tests, detailed 
history, and physical assessment. The possibility of hepatic neoplasia (primary or secondary) should be 
considered.  
 
In addition to repeating measurements of AST and ALT, laboratory tests should include albumin, creatine 
kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time 
(PT)/international normalized ratio (INR), and alkaline phosphatase. A detailed history, including relevant 
information, such as review of ethanol, acetaminophen, recreational drug and supplement consumption, 
family history, occupational exposure, sexual history, travel history, history of contact with a jaundiced 
person, surgery, blood transfusion, history of liver or allergic disease, and work exposure, should be 
collected. Further testing for acute hepatitis A, B, or C infection and liver imaging (e.g. biliary tract) may 
be warranted. All cases confirmed on repeat testing as meeting the laboratory criteria defined above, with 
no other cause for liver function test (LFT) abnormalities identified at the time, should be considered 
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potential Hy’s law cases irrespective of availability of all the results of the investigations performed to 
determine etiology of the abnormal LFTs.   
 
Such potential Hy’s law cases should be reported as SAEs. A potential Hy’s law case becomes a confirmed 
case only after all results of reasonable investigations have excluded an alternative etiology. 
 
11.5. 
Hospitalization  
Admission also includes transfer within the hospital to an acute/intensive care unit (e.g. from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a tuberculosis unit). 
An emergency room visit does not necessarily constitute a hospitalization; however, the event leading to 
the emergency room visit should be assessed for medical importance.  
 
Hospitalization does not include the following: 
 
• 
Rehabilitation facilities; 
 
• 
Hospice facilities;  
 
• 
Respite care (e.g., caregiver relief);  
 
• 
Skilled nursing facilities; 
 
• 
Nursing homes;  
 
• 
Same-day surgeries (as outpatient/same-day/ambulatory procedures). 
 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is not in 
itself an SAE.  Examples include: 
 
• 
Admission for treatment of a preexisting condition not associated with the development of a new 
AE or with a worsening of the preexisting condition (e.g. for workup of persistent pre-treatment 
laboratory abnormality);  
 
• 
Social admission (e.g. patient has no place to sleep);  
 
• 
Administrative admission (e.g. for yearly physical examination);  
 
• 
Protocol-specified admission during a study (e.g. for a procedure required by the study protocol);  
 
• 
Optional admission not associated with a precipitating clinical AE (e.g. for elective cosmetic 
surgery);  
 
• 
Hospitalization for observation without a medical AE;  
 
• 
Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;  
 
• 
Admission exclusively for the administration of blood products. 
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Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be reported 
as AEs.  However, the medical condition for which the procedure was performed should be reported if it 
meets the definition of an AE. For example, an acute appendicitis that begins during the AE reporting period 
should be reported as the AE and the resulting appendectomy should be recorded as treatment of the AE. 
 
11.6. 
Severity Assessment  
AEs will be reported using concise medical terminology (verbatim) as well as the Common Terminology 
Criteria (CTC) term for Adverse Events (Version 5.0, Publish Date: November 27, 2017, 
https://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm)) listed in the Cancer Therapy 
Evaluation Program.  
 
The investigator may use the following definitions of Severity in accordance with CTCAE Version 5.0 to 
describe the maximum intensity of the adverse event. 
 
GRADE Clinical Description of Severity 
1 
MILD adverse events 
2 
MODERATE adverse event 
3 
SEVERE adverse event 
4 
LIFE-THREATENING consequences; urgent intervention indicated 
5 
DEATH RELATED TO adverse event 
 
Note the distinction between the severity and the seriousness of an AE. A severe event is not necessarily 
an SAE.  For example, a headache may be severe (interferes significantly with the patient's usual 
function) but would not be classified as serious unless it met one of the criteria for SAEs, listed above.  
 
11.7. 
Causality Assessment  
All AEs must be attributed to study drugs unless there is a reasonably acceptable alternate cause for AEs. 
Assessment of attribution is made by consideration of all clinically relevant data prior to, during, and after 
occurrence of the event, including diagnostic tests to assess the cause of the event. Clinically relevant data 
include, but are not limited to underlying disease, past and present medical history (all concurrent non-
malignant disease), concurrent medications, and timing between event and drug administration. The 
mechanism of action and prior toxicology of the study drug should be considered. An adverse event is 
associated with the use of the drug when there is a reasonable possibility that the experience may have been 
caused by the drug. Attribution standards are described as follows: 
 
• unrelated: the adverse event is clearly not related to the study drug(s); the event has no temporal 
relationship to study drug(s) administration (too early or late or study drug not taken), or there is a 
reasonable causal relationship between the AE and another drug, concurrent disease or a circumstance; 
 
• unlikely: the adverse event is doubtfully related to the study drug(s); the event with a temporal 
relationship to study drug(s) administration which makes a causal relationship improbable, and in 
which other drugs, chemicals or underlying disease provide plausible explanations; 
 
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• possible: the adverse event may be related to the study drug(s); the event follows a reasonable 
temporal sequence from the administration of the study drug(s), and the event follows a known 
response pattern to the study drug BUT the event could have been produced by an intercurrent medical 
condition which, based on the pathophysiology of the condition, and the pharmacology of the study 
drug, would be unlikely related to the use of the study drug, or the event could be the effect of a 
concomitant medication; 
 
• probable: the adverse event is likely related to the study drug(s); the event follows a reasonable 
temporal sequence from administration of the study drug(s), and the event follows a known 
response pattern to the study drug AND the event cannot have been reasonably explained by an 
intercurrent medical condition or the event cannot be the effect of a concomitant medication; 
 
• definitely: the adverse event is clearly related to study drug(s); the event follows a reasonable 
temporal sequence from administration of the study drug(s), and the event follows a known 
response pattern to the study drug and based on the known pharmacology of the study drug, the event 
is clearly related to the effect of the study drug. 
 
11.8. 
Exposure During Pregnancy  
For both unapproved/unlicensed products and for marketed products, an exposure during pregnancy 
occurs if: 
 
1. A female becomes, or is found to be, pregnant either while receiving or having been exposed (e.g. 
because of treatment or environmental exposure) to the investigational product; or the female 
becomes, or is found to be pregnant after discontinuing and/or being exposed to the investigational 
product;  
 
An example of environmental exposure would be a case involving direct contact with a Pfizer 
product in a pregnant woman (e.g. a nurse reports that she is pregnant and has been exposed to 
chemotherapeutic products).  
 
2. A male has been exposed (e.g. because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed during his 
partner’s pregnancy. 
 
If a study patient or study patient’s partner becomes or is found to be pregnant during the study patient’s 
treatment with the investigational product, the YCCI Project Manager must submit this information to the 
Pfizer drug safety unit on a Serious Adverse Event (SAE) regardless of whether an SAE has occurred. 
This must be done irrespective of whether an AE has occurred and within 24hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).  
The pregnancy of a study participant or their partner will be followed during long term follow up. 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 baby, a terminated fetus, 
an intrauterine fetal demise, or a neonatal death]), the investigator should follow the procedures for 
reporting SAEs. 
 
Additional information about pregnancy outcomes that are reported as SAEs follows:  
 
• 
Spontaneous abortion includes miscarriage and missed abortion;  
 
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• 
Neonatal deaths that occur within 1month of birth should be reported, without regard to 
causality, as SAEs.  In addition, infant deaths after 1month should be reported as SAEs when 
the investigator assesses the infant death as related or possibly related to exposure to the 
investigational product.  
 
Additional information regarding the exposure during pregnancy may be requested by the investigator.  
Further follow-up of birth outcomes will be handled on a case-by-case basis (e.g. follow-up on preterm 
infants to identify developmental delays). In the case of paternal exposure, the investigator will request to 
follow the pregnancy.  
 
11.9. 
Occupational Exposure  
An occupational exposure occurs when during the performance of job duties, a person (whether a 
healthcare professional or otherwise) gets in unplanned direct contact with the product, which may or may 
not lead to the occurrence of an adverse event.  
 
An occupational exposure is reported to the drug safety unit within 24hours of the investigator’s 
awareness, using the SAE Report form, regardless of whether there is an associated AE/SAE. Since the 
information does not pertain to a patient enrolled in the study, the information is not reported on a Case 
Report Form e(CRF), however a copy of the completed SAE Report form is maintained in the 
investigator site file.  
 
11.10. Withdrawal Due to Adverse Events  
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, according to the 
definition of AE noted earlier, and recorded on the appropriate AE CRF page. When a patient withdraws 
because of an SAE, the SAE must be reported in accordance with the reporting requirements defined 
below.  
 
11.11. Eliciting Adverse Event Information  
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the study 
patient/legally acceptable representative. In addition, each study patient/legally acceptable representative 
will be questioned about AEs.  
 
11.12. Reporting Requirements  
11.12.1. 
Routine Reporting of Adverse Events 
AEs, whether or not associated with study drug administration, will be recorded on the AE eCRF The 
information to be entered in the case report form will include: 
 
• 
time of onset of any new AE or worsening of a previously observed AE; in most cases, only date 
of onset will be adequate; however, for days when the patient is evaluated in the clinic and 
receives study drug(s), the time (based on a 24-hour clock) of onset should also be recorded; 
 
• 
specific type of reaction in standard medical terminology; 
 
• 
time of resolution of the event (or confirmation ongoing); in most cases, the date of resolution only 
will be adequate; however, for events that initiate and resolve on days where the patient is in 
the clinic and receives study drug(s), the time (based on a 24-hour clock) of resolution should 
also be recorded; 
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• 
severity/grade of AE; it should be rated according to NCI-CTCAE version 5; 
 
• 
an assessment should be made of the relationship of the AE to the study drug according to the 
definitions outlined above; 
 
• 
description of action taken in treating the AE and/or change in study drug administration or dose. 
 
Follow-up assessments should be repeated to document return of any abnormalities to normal, or to 
document other outcome of the AE. 
 
11.12.2. 
Reporting of Serious Adverse Events, including Death 
Serious adverse events (SAE) including death (except deaths due to disease progression) during this study 
or within 30 days following the last dose of the study drug(s), whether or not related to the administration 
of study drugs, must be reported to the Yale Project Manager and Sponsor PI (Dr. Amer Zeidan) by 
telephone or email within 24 hours of knowledge of the event.  
 
The study site should send the SAE form to the Yale Project Manager and Sponsor PI as soon as possible 
so that the tracking procedure can begin immediately upon receipt of the information. Once the Yale Project 
Manager and Sponsor PI are informed of an SAE with preliminary information obtained, the study site will 
be instructed to update the SAE form with additional information, as per the following guidelines.  
 
If all information is not known at the time of the incident, an initial report should still be made. In the event 
there is a question as to whether the event is serious, the information should be forwarded to the Yale Project 
Manager and Sponsor PI for review. Each Site PI is responsible for following up on completion of the SAE 
form. The Investigator will submit substantiating data in hard copy form, such as diagnostic test reports and 
progress notes, to the Yale Project Manager and Sponsor PI. In the case of fatality, autopsy reports will be 
furnished to the Yale Project Manager and Sponsor PI as soon as available. During the initial 
communication, the Yale Project Manager will require the following information about the patient and the 
reported SAE: 
 
• 
patient identification including patient number, initials, and date of birth; 
• 
date of first dose of study drugs and details of administration, including study drug names 
(including labeled strength and manufacturer), lot number, expiration date, and dose; 
• 
date of last dose of study drugs (i.e., prior to onset of SAE) and details of administration, 
including study drug names (including labeled strength and manufacturer, lot number, 
expiration date, and dose);  
• 
medical diagnosis of the event in standard medical terminology (if a medical diagnosis cannot 
be determined, a description of each sign or symptom characterizing the event); 
• 
date of onset of the AE; 
• 
date of resolution of the AE (or confirmation ongoing); 
• 
severity of the AE; 
• 
assessment of the attribution of the AE to the study drug;  
• 
reason AE is considered serious 
• 
whether the AE is expected  
• 
action taken in treating the AE and/or change in study drug administration or dose (including 
concomitant medications or therapies administered, whether hospitalization or prolongation of 
hospitalization was required, diagnostic procedures performed, and whether the patient was 
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discontinued from the study); all concomitant medications (including doses, routes, regimens, 
and indications); 
• 
pertinent clinical laboratory testing data;  
• 
medical history. 
 
The Yale Project Manager and Sponsor PI will review each SAE report and evaluate the relationship of the 
adverse reaction to the study drug and to the underlying disease. Based on the Investigator’s and Sponsor 
PI assessment of the adverse experience, a decision will be made concerning further actions. The primary 
consideration governing further action is whether new findings affect the safety of patients participating in 
the clinical study. If the discovery of a new adverse experience related to the study drug raises concern over 
the safety of continued administration of study drug, the Sponsor PI will take immediate steps to notify the 
regulatory authorities. 
 
Further action that may be required includes the following: 
• 
modification of the protocol and alteration of existing research plans; 
• 
discontinuation or suspension of the study; 
• 
alteration of the informed consent process by modification of the existing consent form and 
informing current study participants of new findings; 
• 
modification of previously identified expected adverse experiences to include adverse 
experiences newly identified as study medication-related. 
 
11.12.3. 
Reporting to the IRB 
Sites are responsible for reporting to their IRB per local policy.  
 
11.12.4. 
Reporting to External Regulatory Bodies 
 
The Yale Project Manager shall report all SAEs to the drug manufacturer and the FDA, as required.   
 
SAE will be reported to Pfizer based on the following timeline, when required.  
 
• 
within five (5) calendar days upon receipt of initial and follow-up SAEs containing at least one fatal 
or immediately life-threatening event; 
 
• 
within ten (10) calendar days upon receipt of any other initial and follow-up SAEs 
 
Pfizer Inc at 
1-800-438-1985 
 
 
 
SAEs will be reported to the FDA based on the following timeline, when required.   
 
There are two types of expedited safety reports to the FDA: 
1. 7-Calendar-Day FDA Telephone or Fax Report:  The sponsor-investigator will directly notify the 
FDA, within 7 calendar days after his initial receipt of the information, of any adverse event that is 
ALL of the following: 
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Death or immediately life-threatening 
Unexpected 
Associated with the use of study drug 
 
Notification to the FDA will be made directly to the new drug review division in the Center for Drug 
Evaluation and Research or in the product review division for the Center for Biologics Evaluation and 
Research, whichever was responsible for the review of the IND. [21CFR312.32(c)] A written report 
of the event is to follow within 15 calendar days. 
 
2. 
15-Calendar-Day FDA Written Report:  The sponsor-investigator will directly notify the FDA 
within 15 calendar days of any adverse event that is ALL of the following: 
 
Serious(due to non-fatal and non-life threatening criteria 
Unexpected 
Associated with the use of study drug  
 
Note:  Serious Adverse Events which do not meet the criteria for expedited reporting will be reported 
to the FDA in the IND Annual Report. 
 
12. DATA ANALYSIS/STATISTICAL METHODS  
12.1. 
Sample Size Determination  
Using a historical CR rate of 17% for decitabine 20 mg/m2 on the standard of care five-day schedule 
(based on the largest randomized study of decitabine in older patients with AML [DACO-16]), a 
minimum acceptable CR rate of 25% (given the addition of glasdegib and potential additional toxicity) 
and ultimately a predicted minimum CR rate of 47% (the alternative hypothesis) for patients accrued to 
either arm of the proposed randomized phase 2 study, a minimum of 23 evaluable patients per arm will be 
accrued to test for a statistically-significant difference with an 80% power and a 90% confidence interval 
(which is equivalent to a type 1 error rate, alpha one-sided of 0.05).  
 
12.2. 
Futility Analysis 
The separate, Simon two-stage minimax decision rule is to stop enrollment in either arm if 2 or fewer 
patients in that arm achieve CR of the 10 patients required to be accrued during the stage 1 portion of the 
study. The same null hypothesis will be applied to both treatment arms, separately, without correction for 
multiplicity. The probability of early termination is 0.53 in each arm, under the null hypothesis. After the 
first 10 patients are enrolled and futility analysis of each arm allowed continued enrollment, the second 
stage of the study will be conducted. If 8 of fewer responses are observed in an arm by the end of the 
second stage of the study then no further investigation of the drug combination is warranted in that arm. 
Accrual will be increased by 10% (a minimum total of 51 patients) to account for those patients that are 
anticipated to be unevaluable and maintain the integrity of the statistical design. 
 
12.3. 
Analysis Populations  
12.3.1. Full Analysis Set (FAS)  
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The FAS will include all enrolled patients who received at least one dose of any study treatment 
(glasdegib or decitabine). This will be the primary analysis population for evaluating efficacy endpoints 
and patient characteristics.  
 
12.3.2. Safety Analysis Set  
The safety analysis set will include all patients who receive at least one dose of any study treatment 
(glasdegib). It will be the primary analysis population for evaluating treatment administration/compliance 
and safety endpoints.  
 
12.4. 
Efficacy Analysis  
Efficacy analyses will use the FAS. All CI for binary endpoint will use the exact method, unless 
otherwise stated. 
 
12.4.1. Complete Response  
The proportion of patients achieving CR/CRi is the primary endpoint. The final analyses will be performed 
after all patients have been followed for at least 24 weeks.  
 
The proportion and two-sided 95% CI of patients achieving CR/CRi will be provided. 
 
12.4.2. Response Rate  
The proportion of patients achieving response (CR/CRi + PR) is a secondary endpoint. A confirmation of 
response (Peripheral Blood only) is required 4 weeks after the first assessment per ELN 2017.  The final 
analyses will be conducted after all patients have been followed for 24 weeks (to allow for confirmation of 
response per ELN 2017). The proportion and two-sided 95% CI (using exact method) of patients achieving 
response (CR/CRi + PR) will be provided.  
 
12.4.3. Overall Survival 
Overall survival (OS) is defined as the time from date of first study treatment to date of death due to any 
cause.  Patients last known to be alive will be censored at the date of last contact.  
 
OS will be analyzed and displayed graphically for each arm separately using the Kaplan-Meier method. 
The median event time for each arm and corresponding two-sided 95% CI will be provided. The Kaplan-
Meier estimate of survival probabilities at 12, 18, and 24 months and their two-sided 95% CI (using log-
log transformation and back-transformation) will be provided for each arm separately. 
 
First, OS will be analyzed when the primary endpoint of CR is analyzed in each respective arm. A follow-
up analysis of updated OS will be conducted when the study concludes. OS is defined as the date of the 
first dose of any of the study medications to the date of death from any cause.  
 
12.4.4. Duration of Response  
Duration of Response (DoR) is only patients achieving a CR. DoR is defined as the duration from date of 
first achieving CR to the date of disease relapse after CR or death due to any cause. Patients last known to 
be alive who are free from disease progression or relapse after CR are censored at the date of the last 
assessment that verifies their disease status.   
 
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DoR will be analyzed and displayed graphically for each arm separately using the Kaplan-Meier method. 
The median DoR and corresponding two-sided 95% CI will be provided.  
 
12.4.5. Time to Response  
Time to response (TTR) is only defined for patients who have ever achieved response on study as the time 
from date of the first dose of study drug to date of the first documentation of response (CR+PR). TTR will 
be analyzed and displayed graphically for each arm separately using the Kaplan-Meier method. The median 
TTR and corresponding two-sided 95% CI will be provided.  
 
12.4.6. Other Efficacy Measures  
Additional efficacy measures of interest include CR with incomplete hematologic recovery (CRi), complete 
remission with partial hematologic recovery (CRh), morphologic leukemia-free state (MLFS), PR, SD, 
Cytogenetic CR (CRc), and molecular CR (CRm) per Appendix 1. The proportion of patients ever 
achieving each of the endpoints for the respective arm will be estimated with two-sided 95% CI 
respectively. 
 
12.4.7. Analysis of Exploratory Endpoints  
CRMRD 
CRMRD negativity is assessed in CR and CRi patients only by central multiparameter flow cytometry (MFC) 
(Appendix 1). The proportion of patients who achieved CRMRD negativity and its 95% CI will be provided.  
 
12.5. 
Safety Analysis 
Safety will be assessed primarily based on AEs. AEs will be tabulated by system organ class and preferred 
term (per Medical Dictionary for Regulatory Activities [MedDRA]), and will be further categorized by 
decitabine treatment arm (DAC5 and DAC10) and severity. The incidence for each AE will be provided as 
the total number of subjects that experienced the AE, as well as the percentage of the population that this 
represents. Incidence tables will be generated to summarize incidence of patients reporting at least one 
episode of each specific adverse event, incidence of adverse events causing withdrawals and incidence of 
serious adverse events. Listing of adverse events by patients will include the time to onset, the duration of 
each event, the severity of each event, and the relationship of the event to study therapy, whether it was a 
serious event, and whether it caused withdrawal. The adverse events rate will be estimated accompanied by 
an exact 95% confidence interval. 
 
12.5.1. Stopping Rules for Unacceptable Toxicity 
Each of the treatment arms will have a separate stopping rule.  Either arm may be discontinued for safety 
while the other continues to accrue.  Specifically, either treatment arm will be discontinued when there is 
at least a 70% probability that the rate of any of the below pre-defined safety events of interest in that arm  
is above 25% 
 
• 
Treatment-related deaths that occur during study treatment through 28 days following the last 
dose of any study treatment, or the beginning of another anti-cancer therapy, whichever occurs 
first. 
• 
Drug-induced liver injury (Hy’s Law cases), confirmed as detailed in Section 8.6.2, that occurs 
during study treatment through 28 days following the last dose of any study treatment, or the 
beginning of another anti-cancer therapy, whichever occurs first. 
• 
Grade ≥3 non-hematologic treatment-related AEs except for; 
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o Grade 3 electrolyte abnormalities or LFT abnormalities that resolve to baseline or ≤ 
Grade 1 within 7 days 
o Grade 3 nausea or vomiting that does not require/prolong hospitalization or require NGT 
feeding/TPN 
• 
Grade 4 treatment-related neutropenia (ANC<500/mm3) lasting ≥42 days from the start of each 
cycle  without evidence of active AML   
 
The safety stopping criteria will be applied within each arm starting when at least 10 patients have 
completed one cycle or experienced an unacceptable toxicity, and continuously thereafter. Enrollment will 
continue unless the stopping boundary is crossed. Patients who have completed at least one cycle or have 
experienced a pre-defined unacceptable toxicity will be included in the safety decision making. The two 
arms will be analyzed independently. 
 
Table 7: Safety Decision Criteria 
Accrued Sample Size* 
Maximum number of 
unacceptable toxicities to 
continue treatment arm** 
Up to -11 
3 
12-14 
4 
15-18 
5 
19-21 
6 
22-25 (full enrollment) 
7 
* Patients who have completed 24 weeks or who have 
experienced an unacceptable toxicity 
** A weak prior of Beta (0.5,0.5) was used in the calculation. 
 
If the safety stopping rule is met, accrual to the affected arm will be temporarily suspended in order to 
conduct a review of safety data.  If after review, a safety issue is identified and can be corrected, the protocol 
will be amended accordingly and  enrollment will restart to that arm.   
 
12.6. 
Monitoring 
The Sponsor PI or an appointed designee must be allowed to visit all study site locations periodically to 
assess the data quality and study integrity. On-site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, review regulatory and 
essential documents, review the investigational product, and verify that the facilities remain compliant.   
 
In addition, remote monitoring of data may be performed periodically requiring the site to submit data for 
comparison to the OnCore database. The study will also be reviewed by the Yale University DSMC and 
may be reviewed by Yale’s internal auditors.  Yale University DSMC letters will be provided to external 
sites as evidence of continued oversight.  
 
 
13. DATA HANDLING AND RECORD KEEPING  
13.1. 
Case Report Forms/Electronic Data Record 
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As used in this protocol, the term CRF should be understood to refer to either a paper form or an electronic 
data record or both, depending on the data collection method used in this study.  
 
A CRF is required and should be completed for each included patient.   
The investigator has ultimate responsibility for the collection and reporting of all clinical, safety and 
laboratory data entered on the CRFs and any other data collection forms (source documents) and ensuring 
that they are accurate, authentic/original, attributable, complete, consistent, legible, timely 
(contemporaneous), enduring and available when required. Any corrections to entries made in the CRFs or 
source documents must be dated, initialed and explained (if necessary) and should not obscure the original 
entry.  
 
In most cases, the source documents are the hospital's or the physician's patient chart. In these cases, data 
collected on the CRFs must match the data in those charts.  
 
In some cases, the CRF, or part of the CRF, may also serve as source documents.   
 
13.2. 
Record Retention  
To enable evaluations and/or audits from regulatory authorities or Yale, the investigator agrees to keep 
records, including the identity of all participating patients (sufficient information to link records, e.g. CRFs 
and hospital records), all original signed informed consent/assent documents, copies of all CRFs, safety 
reporting forms, source documents, and detailed records of treatment disposition, and adequate 
documentation of relevant correspondence (e.g. letters, meeting minutes, and telephone call reports). The 
records should be retained by the investigator according to International Conference on Harmonization 
(ICH), according to local regulations, or as specified in the clinical study agreement (CSA), whichever is 
longer.  
 
If the investigator becomes unable for any reason to continue to retain study records for the required period 
(e.g. retirement, relocation), Yale should be prospectively notified.   
 
14. ETHICS  
14.1. 
Ethical Principles  
This study will be conducted in accordance with the consensus ethical principles derived from international 
guidelines including the Declaration of Helsinki; applicable Good Clinical Practice (GCP) Guidelines 
published by the International Conference on Harmonisation; and applicable US laws and regulations 
including those found in 21 CFR Parts 50, 54, 56, and 312. 
 
14.2. 
Institutional Review Board (IRB)/Ethics Committee (EC)  
It is the responsibility of the investigator to have prospective approval of the study protocol, protocol 
amendments, informed consent/assent documents, and other relevant documents, e.g. recruitment 
advertisements, if applicable, from the IRB/EC. All correspondence with the IRB/EC should be retained in 
the investigator file. Copies of IRB/EC approvals should be forwarded to the Project Manager. 
 
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is where the 
change is necessary to eliminate apparent immediate hazards to the patients.   
 
14.3. 
Financial Disclosure  
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Investigators and sub-investigators will provide the Sponsor PI with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible for providing 
information on financial interests during the course of the study and for 1 year after completion of the study 
 
 
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15. REFERENCES 
 
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2. Mrozek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD. Clinical relevance of mutations and gene-
expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a 
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3. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, et al. Karyotypic analysis 
predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a 
Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075-83. 
4. Grimwade D, Walker H, Harrison G, Oliver F, Chatters S, Harrison CJ, et al. The predictive value of 
hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 
patients entered into the United Kingdom Medical Research Council AML11 trial. Blood. 2001;98:1312-
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5. Medeiros BC, Othus M, Fang M, Roulston D, Appelbaum FR. Prognostic impact of monosomal karyotype 
in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience. 
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6. Perrot A, Luquet I, Pigneux A, Mugneret F, Delaunay J, Harousseau JL, et al. Dismal prognostic value of 
monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients 
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7. Kadia TM, Jain P, Ravandi F, Garcia-Manero G, Andreef M, Takahashi K, et al. TP53 mutations in newly 
diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. 
Cancer. 2016. 
8. Middeke JM, Herold S, Rucker-Braun E, Berdel WE, Stelljes M, Kaufmann M, et al. TP53 mutation in 
patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell 
transplantation. Br J Haematol. 2016;172:914-22. 
9. Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell. 2008;15:801-12. 
10. Dominguez M, Brunner M, Hafen E, Basler K. Sending and receiving the hedgehog signal: control by 
the Drosophila Gli protein Cubitus interruptus. Science. 1996;272:1621-5. 
11. Lim Y, Matsui W. Hedgehog signaling in hematopoiesis. Crit Rev Eukaryot Gene Expr. 2010;20:129-39. 
12. Trowbridge JJ, Scott MP, Bhatia M. Hedgehog modulates cell cycle regulators in stem cells to control 
hematopoietic regeneration. Proc Natl Acad Sci U S A. 2006;103:14134-9. 
13. Kobune M, Takimoto R, Murase K, Iyama S, Sato T, Kikuchi S, et al. Drug resistance is dramatically 
restored by hedgehog inhibitors in CD34+ leukemic cells. Cancer Sci. 2009;100:948-55. 
14. Fukushima N, Minami Y, Kakiuchi S, Kuwatsuka Y, Hayakawa F, Jamieson C, et al. Small-molecule 
Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer 
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15. Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood. 2012;119:2196-204. 
16. Minami Y, Minami H, Miyamoto T, Yoshimoto G, Kobayashi Y, Munakata W, et al. Phase I study of 
glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic 
malignancies. Cancer Sci. 2017;108:1628-33. 
17. Wellbrock J, Latuske E, Kohler J, Wagner K, Stamm H, Vettorazzi E, et al. Expression of Hedgehog 
Pathway Mediator GLI Represents a Negative Prognostic Marker in Human Acute Myeloid Leukemia and 
Its Inhibition Exerts Antileukemic Effects. Clin Cancer Res. 2015;21:2388-98. 
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18. Martinelli G, Oehler VG, Papayannidis C, Courtney R, Shaik MN, Zhang X, et al. Treatment with PF-
04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and 
pharmacokinetics study. Lancet Haematol. 2015;2:e339-46. 
19. Cashen AF, Schiller GJ, O'Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for the 
first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010;28:556-61. 
20. Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, et al. Clinical response and miR-29b 
predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad 
Sci U S A. 2010;107:7473-8. 
21. Welch JS, Petti AA, Miller CA, Fronick CC, O'Laughlin M, Fulton RS, et al. TP53 and Decitabine in Acute 
Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med. 2016;375:2023-36. 
22. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, et al. Multicenter, 
randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either 
supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute 
myeloid leukemia. J Clin Oncol. 2012;30:2670-7. 
23. Savona MR, Pollyea DA, Stock W, Oehler VG, Schroeder MA, Lancet J, et al. Phase Ib Study of Glasdegib, 
a Hedgehog Pathway Inhibitor, in Combination with Standard Chemotherapy in Patients with AML or High-
Risk MDS. Clin Cancer Res. 2018;24:2294-303. 
24. Boddu P, Kantarjian H, Ravandi F, Garcia-Manero G, Borthakur G, Andreeff M, et al. Outcomes with 
lower intensity therapy in TP53-mutated acute myeloid leukemia. Leuk Lymphoma. 2018:1-4. 
25. Short NJ, Kantarjian HM, Garcia-Manero G, Borthakur G, Kadia T, Huang X, et al. A Randomized Phase 
II Trial of 5-Day Versus 10-Day Schedules of Decitabine for Older Patients with Previously Untreated Acute 
Myeloid Leukemia. Blood. 2017;130:2577-. 
26. Cortes JE, Heidel FH, Heuser M, Fiedler W, Smith BD, Robak T, et al. A Phase 2 Randomized Study of 
Low Dose Ara-C with or without Glasdegib (PF-04449913) in Untreated Patients with Acute Myeloid 
Leukemia or High-Risk Myelodysplastic Syndrome. Blood. 2016;128:99-. 
27. Cortes JE, Douglas Smith B, Wang ES, Merchant A, Oehler VG, Arellano M, et al. Glasdegib in 
combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study 
results. Am J Hematol. 2018;93:1301-10. 
28. Issa JP, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S, et al. Phase 1 study of low-dose 
prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in 
hematopoietic malignancies. Blood. 2004;103:1635-40. 
29. Shaik MN, LaBadie RR, Rudin D, Levin WJ. Evaluation of the effect of food and ketoconazole on the 
pharmacokinetics of the smoothened inhibitor PF-04449913 in healthy volunteers. Cancer Chemother 
Pharmacol. 2014;74:411-8. 
30. Lam JL, Vaz A, Hee B, Liang Y, Yang X, Shaik MN. Metabolism, excretion and pharmacokinetics of 
[(14)C]glasdegib (PF-04449913) in healthy volunteers following oral administration. Xenobiotica. 
2017;47:1064-76. 
 
 
 
 
 
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APPENDICES 
 
Appendix 1. 2017 ELN Response Criteria for Acute Myeloid Leukemia 
 
 


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Appendix 1. 2017 ELN Response Criteria for Acute Myeloid Leukemia (continued) 
 
 
 
Source: Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international 
expert panel. Blood. 2017;129:424–447.  


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Appendix 2. CYP3A4/5 Inducers 
 
Strong CYP3A4/5 Inducers 
Inducer 
Therapeutic Class 
Rifampin 
Antibiotics 
Rifabutin 
Antibiotics 
Avasimibe 
Antilipedimics 
Phenytoin 
Anticonvulsants 
Carbamazepine 
Anticonvulsants 
Phenobarbital 
Anticonvulsants 
Enzalutamide 
Antiandrogens 
St. John’s Wort 
Herbal Medications 
Mitotane 
Antineoplastics 
Moderate CYP3A4/5 Inducers 
Inducer 
Therapeutic Class 
Semagacestat 
Alzheimer’s  
Efavirenz 
Non-nucleoside 
Reverse 
Transcriptase 
Inhibitors (NNRTI) 
Bosentan  
Endothelin Receptor 
Antagonist 
Genistein 
Food Product 
Thioridazine 
Antipsychotics 
Naficillin 
Antibiotics 
Talviraline 
NNRTI 
Lopinavir 
Protease Inhibitor 
Modafinil 
Psychostimulant 
Etravirine 
NNRTI 
Lersivirine 
NNRTI 
 
Source: University of Washington Drug Interaction Database.  “Copyright University of Washington 
1999-2015, UW Metabolism and Transport Drug Interaction Database, accessed: November 2018”. 
 
 
 
 
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Appendix 3. Strong CYP3A4/5 Inhibitors 
 
Inhibitor 
Therapeutic Class 
Ketoconazole 
Antifungal 
Itraconazole 
Antifungal 
Voriconazole 
Antifungal 
Posaconazole 
Antifungal 
Troleandomycin 
Antibiotics 
Clarithromycin 
Antibiotics 
Telithromycin 
Antibiotics 
Mibefradil 
Calcium Channel Blocker 
Conivaptan 
Diuretics 
Nefazodone 
Antidepressants 
Cobicistat  
-- 
Indinavir/Ritonavir 
Protease Inhibitors 
Tipranavir/Ritonavir 
Protease Inhibitors 
Ritonavir 
Protease Inhibitors 
Indinavir 
Protease Inhibitors 
Nelfinavir 
Protease Inhibitors 
Saquinavir 
Protease Inhibitors 
Saquinavir/Ritonavir 
Protease Inhibitors 
Lopinavir/Ritonavir 
Protease Inhibitors 
Telaprevir 
Antivirals 
Boceprevir 
Antivirals 
Danoprevir/Ritonavir 
Antivirals 
Elvitegravir/Ritonavir 
Antivirals 
Idelalisib 
Kinase Inhibitors 
Grapefruit Juice DS 
Food Products 
 
Source: University of Washington Drug Interaction Database.  “Copyright University of Washington 
1999-2015, UW Metabolism and Transport Drug Interaction Database, accessed: November 2018”. 
 
 
 
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Appendix 4. Moderate CYP3A4/5 Inhibitors 
 
 
 
 
Source: University of Washington Drug Interaction Database.  “Copyright University of Washington 
1999-2015, UW Metabolism and Transport Drug Interaction Database, accessed: November 2018”. 
 
 
Inhibitor 
Therapeutic Class 
Fluconazole 
Antifungals 
Erythromycin 
Antibiotics 
Ciprofloxacin 
Antibiotics 
Diltiazem 
Calcium Channel Blockers 
Verapamil 
Calcium Channel Blockers 
Dronedarone 
Antiarrhythmics 
Aprepitant 
Antiemetics 
Casopitant 
Antiemetics 
Netupitant 
Antiemetics 
Tofisopam 
Benzodiazepines 
Cyclosporine 
Immunosuppressant 
Faldaprevir 
Antivirals 
Crizotinib 
Kinase Inhibitor 
Nilotinib 
Kinase Inhibitor 
Atazanivir/Ritonavir 
Protease Inhibitor 
Darunavir 
Protease Inhibitor 
Darunavir/Ritonavir 
Protease Inhibitor 
Atazanavir 
Protease Inhibitor 
Amprenavir 
Protease Inhibitor 
Imatinib 
Antineoplastic 
Grapefruit Juice 
Food Products 
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Appendix 5. List of Drugs with Known Risk of Torsade de Pointes  
 
The following drugs are known to have the risk of Torsade de Pointes due to QTc prolongation and their 
current use in combination with glasdegib is not recommended. If any of these drugs are considered to be 
medically necessary, then they should be used with caution in combination with glasdegib. 
 
Generic Name 
Drug Class 
Therapeutic Use 
Route 
Amiodarone 
Anti-arrhythmic 
Abnormal heart rhythm 
Oral, injection 
Anagrelide 
Phosphodiesterase 
3 inhibitor 
Thrombocythemia 
Oral 
Arsenic trioxide 
Anti-cancer 
Leukemia 
Injection 
Astemizole (Off US mkt) 
Antihistamine 
Allergic rhinitis 
Oral 
Azithromycin 
Antibiotic 
Bacterial infection 
Oral, injection 
Bepridil (Off US mkt) 
Anti-anginal 
Heart pain 
Oral 
Chloroquine 
Anti-malarial 
Malarial infection 
Oral 
Chlorpromazine 
Anti-
psychotic/anti-
emetic 
Schizophrenia/nausea 
Oral, injection, 
suppository 
Cilostazol 
 
Phosphodiesterase 
3 inhibitor 
Intermittent claudication 
Oral 
Ciprofloxacin 
Antibiotic 
Bacterial Infection 
Oral, injection 
Cisapride (Off US mkt) 
GI stimulant 
Heartburn 
Oral 
Citalopram 
Anti-depressant, 
SSRI 
Depression 
 
Clarithromycin 
Antibiotic 
Bacterial infection 
Oral 
Disopyramide 
Anti-arrhythmic 
Abnormal heart rhythm 
Oral 
Dofetilide 
Anti-arrhythmic 
Abnormal heart rhythm 
Oral 
Domperidone (Not on US 
mkt) 
Anti-nausea 
Nausea 
Oral, injection 
Donepezil  
Erythromycin Antibiotic 
Bacterial infection; 
increase GI motility oral, 
injection 
Cholinesterase 
inhibitor 
Dementia 
Oral  
Dronedarone 
Anti-arrhythmic  
Atrial Fibrillation 
Oral 
Droperidol  
Anti-psychotic / 
Anti-emetic 
Anesthesia adjunct, nausea  
Injection 
Escitalopram  
Anti-depressant, 
SSRI 
Major depression/ Anxiety disorders 
 
Oral 
Flecainide  
Anti-arrhythmic 
Abnormal heart rhythm 
Oral 
Fluconazole 
Anti-fungal 
Fungal infection 
Oral, injection 
Gatifloxacin (Off US mkt) 
Antibiotic  
Bacterial infection 
Oral, injection 
Grepafloxacin (Off market 
worldwide) 
 
Antibiotic  
 
Bacterial infection  
Oral 
Halofantrine  
Anti-malarial 
Malaria infection 
Oral 
Haloperidol  
Anti-psychotic  
Schizophrenia, agitation  
Oral, injection 
Ibutilide  
Anti-arrhythmic  
Abnormal heart rhythm 
Injection 
Levofloxacin  
Antibiotic  
Bacterial infection 
oral, injection 
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Levomethadyl (Off US 
mkt) 
 
Opiate  
 
Pain control, narcotic dependence 
Oral 
Mesoridazine (Off US mkt) 
 
Anti-psychotic  
 
Schizophrenia 
Oral 
Methadone  
 
Opiate  
Pain control, narcotic dependence 
oral, injection 
 
Moxifloxacin  
Antibiotic  
Bacterial infection 
oral, injection 
Ondansetron  
Anti-emetic 
Nausea, vomiting  
oral, injection 
Pentamidine  
Antibiotic 
Pneumocystis pneumonia 
injection, inhaled 
Pimozide  
Anti-psychotic 
Tourette's tics 
oral 
Probucol (Off US mkt)  
Antilipemic 
Hypercholesterolemia 
oral 
Procainamide (Oral off US 
mkt)  
Anti-arrhythmic 
Abnormal heart rhythm 
injection 
Propofol  
Anesthetic 
Anesthesia 
injection 
Quinidine  
Anti-arrhythmic 
Abnormal heart rhythm 
oral, injection 
Sevoflurane  
Anesthetic, 
general 
Anesthesia 
inhaled 
Sotalol  
Anti-arrhythmic 
Abnormal heart rhythm 
oral 
Sparfloxacin (Off US mkt)  
Antibiotic 
Bacterial infection 
oral 
Sulpiride (Not on US mkt.)  
Anti-psychotic, 
atypical 
Schizophrenia 
oral 
Terfenadine (Off US mkt)  
Antihistamine 
Allergic rhinitis 
oral 
Thioridazine  
Anti-psychotic 
Schizophrenia 
oral 
Vandetanib  
Anti-cancer 
Thyroid cancer 
oral 
US mkt = United States Market.  
 
Source: Credible Meds.org (http://crediblemeds.org/healthcare-providers/drug-list/?rf=All). TdP risk 
category filtered on Drugs with known TdP risk.  Assessed 12 November 2018. 
 
 
 
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Appendix 6. Laboratory Assessments 
 
Hematology 
Blood Chemistry 
Urinalysis (microscopic 
analysis) 
Coagulation 
Tests 
Hemoglobin 
ALT 
If urine dipstick is positive 
for protein, perform 
urinalysis (U/A) with 
microscopic. If U/A with 
microscopic shows >2+ 
protein, collect 24-hour 
urine for protein. 
aPTT 
Platelets 
AST 
Urine dipstick for urine 
blood: If positive, collect a 
U/A with microscopic 
(unless hematuria can be 
explained by local bleeding 
such as menses). 
INR 
WBC 
Alk Phos 
Specific Gravity 
 
Neutrophils 
Sodium 
PH 
 
Lymphocytes 
Potassium 
Protein 
 
Monocytes 
Magnesium 
Glucose 
 
Eosinophils 
Chloride 
RBC 
 
Basophils 
Calcium 
WBC 
 
Bands 
Bicarbonate 
Ketones 
 
Blast Count 
Total Bilirubin 
Leukocyte Esterase 
 
 
Direct Bilirubin 
Casts 
 
 
BUN or Urea 
Crystals 
 
 
Creatinine 
Nitrate 
 
 
Uric Acid 
 
 
 
Glucose (non-fasting) 
 
 
 
Albumin 
 
 
 
Total Protein 
 
 
 
Phosphorus 
 
 
 
LDH 
 
 
 
CPK 
 
 
 
 
 
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Appendix 7. Eastern Cooperative Oncology Group Performance Status  
 
ECOG PERFORMANCE STATUS 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g. light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 
Source: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
 
By the Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.  
 
 
 
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Appendix 8. 2017 ELN AML Risk Stratification by Genetics 
 
 
 
 
Source: Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN 
recommendations from an international expert panel. Blood. 2017;129:424–447.  
 
 
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Appendix 9. 2016 World Health Organization Classification of Acute Myeloid Leukemia 
 
 
 
Sources:  
1. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN 
recommendations from an international expert panel. Blood. 2017;129:424–447.  
2. Arber DA, Orazi A, Robert, H, et.al. The 2016revision to the World Health Organization classification 
of myeloid neoplasms and acute leukemia. Blood.  2016; 127(20): 2391-2405. 
 
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ICF_001.pdf: 
NCT #: NCT04051996    
Yale IRB HIC #: 2000024738 
PI: Dr. Amer Zeidan  
Title: GLAD-AML - Glasdegib (Pf-04449913) With Two Standard Decitabine Regimens for Older Patients 
With Poor-risk Acute Myeloid Leukemia 
Date of Document : July 17th 2020 
 
 


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 1 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
COMPOUND AUTHORIZATION AND CONSENT FOR PARTICIPATION IN A 
RESEARCH PROJECT
YALE UNIVERSITY SCHOOL OF MEDICINE – YALE-NEW HAVEN HOSPITAL: 
SMILOW CANCER HOSPITAL
Study Title: A randomized, parallel-arm, phase 2 clinical trial of the combination of glasdegib 
(PF-04449913) with two standard decitabine regimens for patients with poor-risk acute myeloid 
leukemia who are unfit for or refuse intensive chemotherapy
Principal Investigator: Amer Zeidan, MBBS, MhS
Principal Investigator’s Phone Number: 203-737-7078
24-Hour Phone Number: 203-200-4363
Principal Investigator’s Mailing Address: 333 Cedar St. P.O. Box 208028, New Haven, CT 
06520
Funding Source:  Yale University
Main Consent Form
INVITATION TO PARTICIPATE AND DESCRIPTION OF PROJECT
You are invited to take part in a research study. The research study is designed to look at the 
effectiveness and safety of a combination of a drug called glasdegib (Daurismo®, Pfizer Inc.) and 
decitabine at different dosing schedules. You have been invited to take part because you have a 
disease called Acute Myeloid Leukemia (AML) and you will not receive intensive chemotherapy.
In order to decide whether or not you wish to be a part of this research study you should know 
enough about its risks and benefits to make an informed decision. This consent form gives you 
detailed information about the study. 
A member of the research team will discuss the study with you. This discussion should go over all 
aspects of this research: the purpose and nature of the research study, the procedures that will be 
performed, the risks of the study drug(s) and procedures, possible benefits, possible alternative 
treatments, your rights as a participant and other information about the research study. You should 
take whatever time you need to discuss the research study with your physician and family. The 
decision to participate or not is yours. Once you understand the study, you will be asked if you 
wish to participate; if so, you will be asked to sign and date where indicated on this form.
If you choose to participate, you will be told of any significant new findings that develop during 
the course of your participation in this study that may affect your willingness to continue to 
participate.
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 2 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
Yale University is providing funding for the study and is responsible for the conduct of the study. 
Pfizer, Inc. is the maker of glasdegib and will be providing it for use in this study.  Yale Cancer 
Center is called the Sponsor
PURPOSE
The purpose of this study is to investigate how well the study drug, glasdegib (Dautismo, Pfizer 
Inc.), in combination with decitabine works in treating patients with AML. The study will evaluate 
two dosing schedules of decitabine.  
The study drug that will be used in this research study is known as glasdegib. Glasdegib is an oral 
medication which works by preventing the growth of cells that are thought to become AML cells. 
This may also help drugs like decitabine work better. Glasdegib is approved by the Food and Drug 
Administration for treatment of adult patients aged 75 years or older newly diagnosed with AML 
who will not receive intensive chemotherapy when used in combination with a low dose of another 
drug cytarabine. In this study the combination of Glasdegib and Decitabine is considered 
experimental.
Decitabine, also known as DacogenTM, is approved by the FDA in the United States for the 
treatment of subjects with myelodysplastic syndrome “MDS” (a disorder that disrupts the 
production of blood cells). Although decitabine is not approved in the United States specifically 
for the treatment of AML, it is sometimes used as an alternative to standard AML chemotherapy 
in some subjects who might not be able to tolerate standard chemotherapy. 
You have been diagnosed with AML that is classified as poor-risk disease. Certain genetic 
abnormalities in your leukemia cells make you “poor-risk”.  This means you are less likely to 
respond to traditional and even intensive chemotherapy. Also, some patients who are not able to 
receive intensive chemotherapy.   Because of these issues, novel ways of approaching patients 
diagnosed with poor-risk AML are needed and are showing promise. Decitabine is being used in 
this study for investigational use in combination with glasdegib to see if it improves outcomes of 
older patients with AML. Decitabine will be administered intravenously (into a vein) daily for the 
first 5 days of a cycle. The length of a cycle will be 21-28 days. Your doctor will decide the length 
of the cycle depending on how well your body tolerates chemotherapy and when you are ready to 
receive another cycle; this will depend on several factors such as your blood counts, electrolytes, 
and how you are feeling. 
Decitabine is a drug that has been reported to induce responses for patients with poor-risk AML 
Decitabine has traditionally administered daily for five consecutive days on a monthly basis. Some 
studies have suggested that longer consecutive dosing (e.g. for ten days every month) is more 
effective without a significant increase in side effects. However, other studies shown no clear 
difference between these two dosing schedules. 
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 3 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
STUDY PROCEDURE
Your study doctor will decide how long you will receive study drug, depending on how well your 
disease responds to study regimen and how well you tolerate the therapy.  The number of visits 
you will need to make to the clinic will depend on how long you continue the study regimen.  
You will either receive glasdegib with decitabine on a five-day schedule or a ten-day schedule. 
You will be randomized to which group you are in.  Randomization means that you are put into a 
group by chance. It is like flipping a coin. You will have an equal chance of being placed in either 
group. Glasdegib will be given daily, every day starting from the day you start the study. 
Decitabine will be given daily for either five days or ten days (depending on to which group you 
are in). Each cycle lasts 28 days.
Prior to starting the study and periodically throughout the study period, you will undergo a bone 
marrow biopsy. During this procedure samples of your bone marrow are collected to look for any 
leukemia cells and to evaluate the status of your disease and determine the initial response to the 
treatment. Should you respond to the therapy, you could remain on the study for up to 24 months. 
If your disease has progressed, you will be taken off the study. Your Study Doctor will review the 
results with you and recommend the course of action at that time. There is always a risk that despite 
the initial response disease can relapse at any time during the study. If this happens, you will be 
taken off the study, and your Study Doctor will review the status of the disease and recommend 
the course of action at that time. 
It is expected that approximately 51 subjects will participate in this study at approximately 4 study 
sites. Up to 26 subjects will participate in each of the groups. It is expected that approximately 20 
subjects will be enrolled at Yale Cancer Center. Considering that the study includes a maximum 
of twenty-four 28-day cycles, this study is estimated to last up to 2 years after enrollment.
Tests and procedures that would be performed for your regular cancer care whether you are on this 
study or not, are called “standard of care.” All of the tests and procedures listed below that will be 
performed at your study visits, should you choose to participate in this study, are standard of care 
unless noted with an asterisk (*).
SCREENING PERIOD (SCREENING AND BASELINE)
If you agree to participate and sign and date this form, you will need to undergo a series of tests 
and procedures to determine if you are eligible to participate in this research study. You will come 
to the study site for screening tests and it is possible that more than one screening visit may be 
needed. 
The following tests or procedures will be performed during the visit(s) within 28 days prior 
to the first dose of the study drug.

Disease history of poor-risk AML;
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 4 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  

Medical history to review conditions and prior medical treatments, including questions on 
your ability to care for yourself, daily activity, and physical ability;

Review and documentation of all medications you currently take;

Physical examination, including height (at screening only), weight and vital signs.

Confirmation of all eligibility criteria;

*Electrocardiogram (ECG), done 3 times in a row; this measures the electrical activity of 
your heart; 

Blood sample collection to evaluate your kidneys, liver, and electrolytes, and blood counts 
(hemoglobin, white blood cell count, and platelets); approximately 2 teaspoons of blood 
are drawn;

Urine sample collection for urinalysis testing;

Pregnancy test within 72 hours prior to the receiving first dose of study drug 

Review and documentation of all medications you currently take;

Bone marrow biopsy and aspiration to measure the status of your leukemia.
At the end of screening, the study doctor will determine if you are eligible to continue into the 
study.  If you are not able to continue in the study, the study doctor will explain why and will 
discuss other treatment options with you.  
STUDY DRUG TREATMENT PERIOD
The following is a list of evaluations that you will undergo during the study drug treatment period 
of this study on day visits:

During the First Cycle
o
Update of interval events and physical examination (on days 1 and 15); 
o
Questions on your ability to care for yourself, daily activity, and physical ability;
o
Review and documentation of all medications you take at that time (on days 1 and 
15);
o
Recording of any side effects from the study drug (on days 1 and 15);
o
*ECG, to measure the electrical activity of the heart; it is done on day 1; each time 
ECG is done 3 times in a row;
o
Pregnancy testing and contraception reminders (days 1 and 15);
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 5 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
o
Blood samples to evaluate your kidneys, liver, and electrolytes and blood counts 
(hemoglobin, white blood cell count, and platelets); approximately 2 teaspoons of 
blood are drawn on days 1 and 15; these may be repeated as required;
o
Drug administration:
•
Decitabine 20 mg/m2 is administered by IV infusion (into a vein) over 
1 hours on days 1-5 or days 1-10 depending on which dosing schedule 
to which you were randomly assigned
•
Glasdegib 100 mg daily is administered orally daily every day 
throughout the study period 

During Cycles 2-6 
o
Update of interval events and physical examination (on day 1); 
o
Questions on your ability to care for yourself, daily activity, and physical ability;
o
Review and documentation of all medications you take at that time (on day 1);
o
Recording of any side effects from the study drug (on day 1);
o
*ECG, to measure the electrical activity of the heart; it is done on day 1; each time 
ECG is done 3 times in a row;
o
Pregnancy testing and contraception reminders (day 1)
o
Blood samples to evaluate your kidneys, liver, and electrolytes and blood counts 
(hemoglobin, white blood cell count, and platelets); approximately 2 teaspoons of 
blood are drawn on day 1; these may be repeated as required;
o
Drug administration:
•
Decitabine 20 mg/m2 is administered by IV infusion (into a vein) over 
1 hours on days 1-5 or days 1-10 depending on which dosing schedule 
to which you were randomly assigned
•
Glasdegib 100 mg daily is administered orally daily every day 
throughout the study period 
o
Review of drug diary
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 6 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
o
Bone marrow biopsy and aspirate to evaluate the status of leukemia and assess the 
amount of disease by measuring a metric called Measurable Residual Disease 
(MRD); the procedure is performed after the completion of cycles 2, 4 and 6 

During Cycles 7-24
o
Update of interval events and physical examination (on day 1); 
o
Questions on your ability to care for yourself, daily activity, and physical ability;
o
Review and documentation of all medications you take at that time (on day 1);
o
Recording of any side effects from the study drug (on day 1);
o
*ECG, to measure the electrical activity of the heart; it is done on day 1; each time 
ECG is done 3 times in a row;
o
Pregnancy testing and contraception reminders (day 1)
o
Blood samples to evaluate your kidneys, liver, and electrolytes and blood counts 
(hemoglobin, white blood cell count, and platelets); approximately 2 teaspoons of 
blood are drawn on day 1; these may be repeated as required;
o
Drug administration:
o
Decitabine 20 mg/m2 is administered by IV infusion (into a vein) over 1 hours on 
days 1-5 or days 1-10 depending on which dosing schedule to which you were 
randomly assigned
o
Glasdegib 100 mg daily is administered orally daily every day throughout the study 
period 
o
Bone marrow biopsy and aspirate to evaluate the status of leukemia and assess the 
amount of disease by measuring a metric called Measurable Residual Disease 
(MRD); the procedure is performed after the completion of cycles 12, 16, and 24 
o
Review of drug diary
Your study doctor may schedule visits (unplanned visits), in addition to those listed on the schedule 
of activities, in order to conduct evaluations or assessments required to protect your wellbeing and 
assess the status of your disease.  You will also be provided with an emergency contact card.  The 
card will contain instructions to ensure access to medical advice in the event that study related 
medical questions or problems arise.  
What Happened If I Stop Taking the Study drug?
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 7 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
If you decide to stop taking the study drug combination, or if the study doctor decides that it is in 
your best interest to stop your study drug treatment period with the study drug combination, you 
will be asked to:

Attend the clinic for an End of Treatment Visit;

Take part in the Long-term Follow-up stage of the study
POST-STUDY DRUG TREATMENT (FOLLOW-UP/END OF STUDY)
Within 14 days after the last dose of the study drug, the following evaluations will be conducted:

Physical examination

Questions on your ability to care for yourself, daily activity, and physical ability;

*ECG, to measure the electrical activity of the heart; it is done on day 1; each time ECG is 
done 3 times in a row;

Pregnancy testing and contraception reminders (day 1)

Blood sample collection to evaluate your kidneys, liver, and electrolytes as well as your 
blood counts (hemoglobin, white blood cell count, and platelets); approximately 2 
teaspoons of blood are drawn;

Recording of any side effects including those from the study drug;

Review and documentation of all medications you currently take.

Review of drug diary
If you have a suspected study drug-related side effect at the last follow-up visit, you will be 
followed until it resolves or until the event is considered irreversible. This may require additional 
clinical assessments and laboratory tests.
After the end of the study period in the clinical trial, your doctor will provide you with appropriate 
and available alternative therapy that will be the best for you. The study doctor or the study staff 
will contact you or your caregiver by phone every 3 months (90 days) for a total period of 2 years. 
They will collect information about your health status, further treatments (including start and stop 
date), and follow-up of any unresolved side effect of the study drug. You are free to refuse these 
contacts and just have to tell the study doctor or study staff. Your decision will not affect your 
future medical care.
How will I receive the study drug? 
Glasdegib will be provided as tablets in childproof packaging. It is important that no one else take 
this study drug.  Glasdegib should be stored at room temperature and handled with care.  You 
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 8 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
should keep your study drug in the bottles provided by the study team and not transfer the tablets 
to any other container since accidental ingestion of this drug may cause serious toxicity, especially 
to children and pregnant women
Always bring your glasdegib bottle to the clinic with you.
You should take your study drug by mouth with approximately 8 ounces (240 mL) of water once 
a day, in the morning, with or without food, approximately at the same time each day.  Tablets 
must be swallowed whole, not crushed, cut or chewed prior to swallowing.  
Do not take more than the prescribed dose of glasdegib at any time.  
If you forget to take your dose at the regularly scheduled time, and if less than 12 hours have 
passed since the scheduled dosing time, take that dose as soon as possible.  If more than 12 hours 
have passed since the scheduled dosing time, do not take your dose that day (skip that dose). 
Continue your normal dosing schedule the next day. 
If you do miss a dose, do not “make it up” the next day.  
If you vomit at any time after taking a dose, do not “make it up,” but resume subsequent doses the 
next day as prescribed.  
If you inadvertently take 1 extra dose during a day, you should not take the next dose of glasdegib.  
You will be issued a dosing diary in which you must ensure all doses (including any missed) are 
documented daily. This diary must be brought to each clinic visit.
On days of scheduled study visits, you will take your dose in the clinic when your nurse tells you 
to take it, so ECGs can be performed after the dose and blood can be drawn before and after this 
dose on some days.  On these days, do not take glasdegib before your clinic visit.  
Subject Responsibilities and Special Instructions 
During this study, it is important that you:

Follow your study doctor’s instructions and come to the clinic for every scheduled visit;

Tell your study doctor about all of the medications and treatments you are receiving within 
28 days before starting the study, while you are being treated with study drug, and during 
the Follow Up.  This includes “over the counter” medications, herbal and natural remedies, 
and vitamins in addition to prescription medications.  Your study doctor will let you know 
if your medications can be taken with glasdegib and decitabine;  
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 9 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  

On the days that you visit the clinic, do not take study drug until asked to by the study 
team; 

Record all of your doses of study drug and the time taken in the dosing diary and return the 
diary to the clinic;

Store the study drug as instructed, and bring all your used and unused study drug and study 
drug containers with you to the study visits;

Certain foods, such as grapefruit juice, and certain other medications will not be allowed 
during your participation in the study.  Your doctor will review these prohibited 
medications with you; 

During study drug treatment with glasdegib, you are advised Not to donate blood or 
blood products for at least 180 days after the last dose.

If you are a Male, you are advised not to donate semen during study drug treatment with 
glasdegib and for at least 180 days after the last dose.

Inform the study doctor or staff if you decide you no longer wish to participate in the 
study. You will be required to complete a close out visit. 

Report any new problems, side effects, illnesses, scheduled surgeries or procedures, or 
changes in medication during the study;

Report if you (or your partner, if you are a man) become pregnant;
POTENTIAL RISKS, SIDE EFFECTS, DISCOMFORTS AND INCONVENIENCES
While receiving study drug and undergoing procedures as a subject enrolled in this study, you 
may experience side effects. This section describes potential side effects of the study drugs and 
procedures based on previous studies. However, there might be additional risks that currently 
remain unknown. If significant new risks develop during the course of the study that could affect 
your willingness to participate, information will be reported to you as soon as possible.
Possible side effects that you may experience during this study will be fully explained to you by 
the study staff. Please ask as many questions as you feel necessary so that you can understand the 
possible adverse effects of specific drugs and procedures you will receive before you decide 
whether you want to be in this study. Please ask the study doctor or the study staff to explain any 
information or words that are not clear to you.
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 10 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
Unforeseen side adverse effects may occur, and you should inform your study doctor of any side 
effects that you experience, even if you do not think they are related to the study drug or are not 
mentioned in this consent form.
Some side effects may be serious and require treatment or additional testing. 
Risks associated with glasdegib
Risks are possible side effects of glasdegib and those related to medical procedures performed in 
the study. Throughout the study your Study Doctor will guide you through assessment and, if 
necessary, treatment of study-drug related adverse effects.
The following are side effects of glasdegib according to how likely they are to occur:
MOST COMMON: (These side effects occurred in 20% or more of patients taking glasdegib 
alone or glasdegib in combination with chemotherapy.)
Dysgeusia (abnormal taste)
Hemorrhage (bleeding)
Decreased appetite
Febrile Neutropenia (fever due to low white blood 
cell counts)
Fatigue (feeling tired)
Thrombocytopenia (decreased platelet count)
Diarrhea 
Edema (swelling)
Nausea
Mucositis (mouth blisters / sores)
Muscle Spasms
Musculoskeletal Pain
Anemia (low red blood cells)
Dyspnea (shortness of breath)
Creatinine Increase (abnormal kidney test) Hyponatremia (low blood levels of sodium)
Hypomagnesemia (low blood levels of 
magnesium)
AST Increased (abnormal liver test)
Blood Bilirubin Increase (abnormal liver 
test)
ALT Increase (abnormal liver test)
Alkaline Phosphatase Increased (abnormal 
liver test)
Constipation
Rash
COMMON: (These side effects occurred in 10-20% of patients taking glasdegib alone or 
glasdegib in combination with chemotherapy.)
Hair loss
Hyperkalemia (high potassium)
Vomiting
CPK Increased (muscle damage)
Decreased weight
Hypokalemia (low blood levels of potassium)
Arthralgia (joint pain)
Pyrexia (fever)
Chest Pain
Abdominal Pain
Cough
Dizziness
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 11 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
Headache
Pneumonia
Leukopenia (decreased white blood cells)
Atrial Arrhythmia (irregular heartbeat)
Renal Insufficiency (decreased kidney 
function)
UNCOMMON: (These side effects occurred in less than 10% of patients taking glasdegib 
alone or glasdegib in combination with chemotherapy.)
QT prolongation (a disorder of the heart’s 
electrical activity, which can lead to death)
Dental Problems
Risks associated with decitabine
The following are side effects of decitabine according to how likely they are to occur:
MOST COMMON: (These side effects occurred in 20% or more of patients taking decitabine 
alone or decitabine in combination with chemotherapy.)
Neutropenia (low white blood cells)
Pneumonia
Thrombocytopenia (low number of 
platelets)
Hyperglycemia (high blood sugar)
Anemia (low number of red blood cells)
Hypoalbuminemia (low level of albumin)
Febrile neutropenia (fever due to low white 
blood cell counts)
Hypomagnesemia (low levels of magnesium in the 
blood)
Leukopenia (low white blood cells)
Hypokalemia (low levels of potassium)
Nausea 
Arthralgia (joint pain)
Constipation
Headache
Diarrhea
Insomnia (difficulty sleeping)
Vomiting
Cough
Pyrexia (fever)
Ecchymosis (bruising)
Edema peripheral (swelling of the arms and 
legs)
Petechiae (tiny dots on the skin)
Rigors (chills)
Pallor (lightening of skin)
Fatigue
COMMON: (These side effects occurred in 10-20% of patients taking decitabine alone or 
decitabine in combination with chemotherapy.)
Lymphadenopathy (lymph node swelling) Ascites (fluid in the abdomen)
Abdominal pain
Edema (swelling)
Oral mucosal petechiae (small red or 
Pain
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 12 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
purple spots in the mouth)
Stomatitis (mouth blisters / sores)
Lethargy (sleepiness)
Dyspepsia (heart burn)
Tenderness
Hyperbilirubinemia (abnormally high 
levels of bilirubin in the blood)
Cellulitis (skin infection)
Candidal infection (infection)
Cardiac murmur (abnormal heart sound)
Blood alkaline phosphatase increased 
(abnormal liver tests)
AST Increase (abnormal liver tests)
Blood urea increased (abnormal kidney 
test)
Hyponatremia (decreased levels of sodium)
Appetite decreased
Pain in limb
Hyperkalemia (high levels of potassium)
Dizziness
Back pain
Confusional state (confusion)
Hypoesthesia (numbness)
Pharyngitis (sore throat)
Anxiety
Breath sounds decreased
Crackles lung
Rash
Hypoxia (low oxygen level)
Skin sores
Erythema (skin redness)
Toothache
Pruritis (itchy skin)
Chills
Asthenia (weakness)
Upper Respiratory Tract Infection
UNCOMMON: (These side effects occurred in less than 10% of patients taking decitabine 
alone or decitabine in combination with chemotherapy.)
Thrombocythemia (high blood platelet 
count)
Pulmonary edema (fluid in the lungs) 
Vision blurred
Gingival bleeding
Hemorrhoids
Loose stools
Tongue ulceration
Dysphagia (difficult swallowing)
Oral soft tissue disorder
Lip ulceration
Abdominal distension
Abdominal pain upper
Gastro-esophageal reflux disease
Glossodynia (tongue pain)
Chest discomfort
Intermittent pyrexia (fever)
Fall
Malaise (lack of energy)
Crepitations (difficulty breathing)
Catheter site redness
Catheter site pain
Injection site swelling
Catheter related infection
Urinary tract infection
Staphylococcal infection (infection)
Oral candidiasis (oral infection)
Sinusitis (sinus infection)
Bacteremia (infection)
Transfusion reaction
Abrasion
Blood lactate dehydrogenase increased 
Blood albumin decreased (abnormal blood test)
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 13 of 24
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(abnormal blood test) 
Blood bicarbonate increased (abnormal 
blood test)
Blood chloride decreased (abnormal blood test)
Protein total decreased (abnormal blood 
test)
Blood bicarbonate decreased (abnormal blood test)
Blood bilirubin decreased (abnormal liver 
test)
Dehydration
Chest wall pain
Musculoskeletal discomfort
Myalgia (muscle pain)
Dysuria (difficult and/or painful urination)
Urinary frequency
Rales (difficulty breathing)
Postnasal drip
Alopecia (hairloss)
Urticaria (hives)
Swelling face
Hypotension (low blood pressure)
Hematoma (a bruise)
Pancytopenia (abnormal blood test)
Cardiac Failure Congestive 
Tachycardia (irregular heart beat)
Ear Pain
Gastro-esophageal Reflux Disease
Dysphagia (difficulty swallowing)
Oral Pain
Oral Inflammation
Pneumonia
Tooth Abscess
Contusion (bruising)
Weight Decrease
Breath Sounds Abnormal
Muscle Spasms Muscle Weakness
Bone Pain
Musculoskeletal Pain
Risks associated with glasdegib in combination with Decitabine:
In studies where patients received low dose chemotherapy in combination with glasdegib the most 
common side effects were anemia (you don't have enough healthy red blood cells to carry adequate 
oxygen), febrile neutropenia (development of fever, often with other signs of infection), nausea 
(precursor to vomiting the contents of the stomach), decreased appetite, fatigue and 
thrombocytopenia (When you have a low blood platelet count).  
OTHER RISKS:
Blood Collection and Intravenous (IV) catheter placement
Some tests done by having blood samples taken. The risks of taking blood may include pain, red-
ness, swelling and/or bruising where the needle enters your body, light-headedness and fainting.
Rarely, these may be a small blood clot or infection at the site of the needle puncture. Blood will 
be taken at each visit for standard medical and study-specific tests. A blood pressure cuff may also 
cause discomfort or bruising to the upper arm.
*Electrocardiogram (ECG)
An ECG is an electrical tracing of your heart’s activity. During the procedure, you will have 
electrodes (small sticky patches with wires attached to them) placed on your chest skin, arms and 
legs. There may be some pulling on your skin or irritation, similar to pulling off an adhesive 
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 14 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
bandage, when the patches are removed. Some amount of adhesive material may remain on your 
skin, and usually is harmless. Mild redness may remain at the sites where a patch or patches were 
attached; usually the redness disappears within a few minutes. In rare instances, the redness may 
persist and/or itchiness at the site(s) where a patch or patches were attached may develop. In this 
case, a Study Doctor may recommend an antihistamine medication such as diphenhydramine 
(Benadryl).
Contraception and Pregnancy
If you are a man and considering to be a participant in the study, you must agree to use a condom 
during intercourse while taking the drug, and not to father a child during the study and for the 
period of 6 months following the last study treatment. In addition, it is advised that your female 
partner uses a highly effective form of birth control method (contraception, see below) if she may 
become pregnant. In case you father a child while in this study, you are asked to report the 
pregnancy to the Study Doctor. A consent from your partner will be needed to allow your 
Study Doctor to medically follow this pregnancy until delivery to monitor the mother’s and 
child’s safety.
Women who are pregnant or nursing a child cannot participate in this trial. Women should not 
nurse for at least 6 months after stopping the study drug. You must confirm, to the best of your 
knowledge, that you are not pregnant at the onset of the study, and that you do not intend to become 
pregnant during the trial.
For the purposes of this study you are considered to be able to become pregnant unless you 
previously had surgery to have your ovaries and/or uterus removed, or it has been more than 12 
months since your last menstrual period. If you are a woman who is able to become pregnant, and 
considering to be a participant in the study, it is important that you use a highly effective form of 
birth control method (contraception, see below) during the trial and 6 months after your study has 
ended. Highly effective methods of birth control have a less than 1% chance of unwanted 
pregnancy during one year, if used appropriately according to the instructions of the manufacturer. 
Please discuss with your Study Doctor the most appropriate birth control method for you that also 
respect your cultural and religious preferences. Examples of highly effective birth control methods 
are:

Total abstinence (no sexual relations), when this is in line with your preferred and usual 
lifestyle. Periodic abstinence like calendar, ovulation, symptothermal, post-ovulation 
methods, and withdrawal are not acceptable methods of contraception;

Female sterilization, when you have been already surgically sterilized prior to the study by 
surgical removal of both ovaries (woman's reproductive system that stores and releases 
eggs for fertilization and produces female sex hormones), total hysterectomy (surgical 
removal of the uterus and cervix) or tubal ligation (getting your “tubes tied”) at least six 
weeks before taking study drug;

Your male partner has already been sterilized with the appropriate documentation. The 
sterilized male partner should be your sole partner;

Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception (in case of oral contraception you 
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 15 of 24
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should have been using the same pill on a stable dose for a minimum of 3 months before 
taking study drug).
It is currently unknown whether glasdegib or decitabine may reduce the effectiveness of hormonal 
contraceptives, and therefore women using hormonal contraceptives should add a barrier method 
of contraception. If you become pregnant or suspect being pregnant during study drug period or 
within 3 months after completing study drug period, you must inform the Study Doctor 
immediately, and you have to stop ongoing study drug treatment immediately. You will not be 
allowed to continue this study if you are pregnant. Your Study Doctor will medically follow your 
pregnancy until delivery to monitor you and your child`s safety.
There are no well-controlled studies in pregnant women. Women of childbearing potential should 
avoid becoming pregnant.
Other Side Effects
Infertility in Male Mice 
Male mice given repeated doses of Glasdigib showed significant decreases in sperm count with 
resultant pregnancy rate reduction and an increase in pre-implantation loss in female mates.  Men 
are advised to seek advice on effective fertility preservation before going on study drug 
(Glasdegib) treatment.
There may also be side effects, other than listed above that we cannot predict. Other drugs will be 
given to make side effects that occur less serious and less uncomfortable. Many side effects go 
away shortly after the drug or procedure is stopped, but in some cases side effects can be serious, 
long lasting, or permanent.
For more information about risks and side effects, ask the researcher or contact their office at 203-
737-7078.
BENEFITS 
If you agree to take part in this research study, we cannot guarantee that you will receive any 
benefits. We hope that the addition of Glasdegib to Decitabine will increase the rate of remission 
observed with the current standard of care. Moreover, we hope the information learned from this 
research study may benefit other patients with acute myeloid leukemia in the future.
ECONOMIC CONSIDERATIONS
You will not be paid for taking part in this study. Tests and procedures that would be performed 
for your regular cancer care whether you are on this study or not are called “standard of care.” All 
of the tests and procedures listed in this consent form that will be performed at your study visits 
are standard of care unless noted with an asterisk (*). There will be no charge to you or your 
insurance provider for the study drug(s), glasdegib and decitabine. The administration of the study 
drug(s), glasdegib and decitabine, will be charged to you or your insurance provider. There will 
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 16 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
be no charge to you or your insurance provider for tests or procedures noted with an asterisk as 
these are performed for study purposes only. All other tests and procedures will be charged to you 
or your insurance provider in the usual way as these are standard of care. This may include other 
tests and procedures not listed in this consent if your doctor feels it is necessary for your care, such 
as additional laboratory tests.
You will still be responsible for any co-pays required by your insurance company for standard 
treatment
Taking part in this research study may lead to added costs for you or your insurance provider.  You 
are encouraged to speak with your insurance provider prior to entering the research study to find 
out your individual coverage. If you have difficulty determining your individual insurance 
coverage, you may call Dr. Amer Zeidan’s office for assistance at 203-737-7078.  
There is a possibility that this research may lead to development of products that will be 
commercialized.  If this happens, there is no plan to share any financial gain with you or your 
family.
You will not be paid for taking part in this study. There are no plans to pay you for such things as 
lost wages, disability, or discomfort as part of this study.
ALTERNATIVE TO TAKING PART IN THIS STUDY
You do not have to participate in this study. There are alternative treatments that may be of benefit 
to you. These would include:

Getting standard of care treatment for your cancer without being enrolled in a study;

Taking part in another study;

Receiving no further treatment.

Comfort Care: This is a type of care that helps reduce pain, tiredness, appetite problems, 
and directed to alleviate symptoms caused by the cancer. Comfort Care does NOT treat 
cancer directly but aims to improve how you feel. Comfort Care tries to keep you as active 
and comfortable as possible.
Some patients may be able to receive treatment with VENCLEXTA® (venetoclax) in 
combination with low dose azacitidine or decitabine or low-dose cytarabine.  This combination is 
approved by the FDA for treatment of newly diagnosed patients with AML who are 75 or older 
or who cannot receive intensive chemotherapy.
These alternatives will be discussed with you by your physician prior to your enrollment into this 
study. You may elect to have no further treatment and to receive supportive care only. You do not 
need to participate in this study to receive treatment for your condition.
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 17 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
Talk to your doctor about your choices before you decide if you will take part in this study.
Confidentiality and Authorization to collect, use and disclose Protected Health Information
For purposes of this study, Yale University, Yale-New Haven Hospital, and Dr. Amer Zeidan will 
use medical information collected or created as part of the study, such as medical records and test 
results, which identifies you by name or in another way. Your consent to participate in the study 
means you agree that Yale University, Yale-New Haven Hospital, and Dr. Amer Zeidan may 
obtain your medical information that they request for study purposes from your physicians and 
your other health care providers from the past or during your participation in the study. 
The protected health information that will be collected in this study includes demographics, 
medical history, physical examinations, routine lab tests, review of adverse events and medications 
you take (past and present), vital signs, ECGs, bone marrow biopsies, pregnancy tests, blood or 
tissue samples for research purposes, information recorded in study questionnaires, survival 
follow-up information and records about any study drug(s) that you received.
Any identifiable information that is obtained in connection with this study will remain confidential 
and will be disclosed only with your permission or as permitted by U.S. or State law.  Examples 
of information that we are legally required to disclose include abuse of a child or elderly person, 
or certain reportable diseases such as HIV or hepatitis. When the results of the research are 
published or discussed in conferences, no information will be included that would reveal your 
identity unless your specific consent for this activity is obtained.  
We understand that information about you obtained in connection with your health is personal, 
and we are committed to protecting the privacy of that information.  If you decide to be in this 
study, the study staff will get information that identifies you and your protected health information.  
This may include information that might directly identify you, such as your name, date of birth, 
and medical record number. This information will be de-identified prior to providing it to the 
sponsor, meaning we will replace your identifying information with a code that does not directly 
identify you. The study doctor will keep a link that identifies you to your coded information, and 
this link will be kept secure and available only to the Principal Investigator or selected members 
of the study team. Any information that can identify you will remain confidential. 
The records for this trial will be stored in locked cabinets and/or offices and password protected 
computers. The study team will only give this coded information to others to carry out this research 
study or to sponsor representatives to comply with federal laws and regulations. It is anticipated 
that records containing the information that links you to your coded information will be maintained 
indefinitely, as there are no plans at this time to destroy these records at the end of the study.  
Information about your study participation will be entered into your Electronic Medical Record 
(EMR). Once placed in your EMR, these results are accessible to all of your providers who 
participate in the EMR system. Information within your EMR may also be shared with others who 
are appropriate to have access to your EMR (e.g., health insurance company, disability provider.)
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 18 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
Information about you and your health which might identify you may be used by or given to: 

The U.S. Department of Health and Human Services (DHHS) agencies

Representatives from Yale University and the Human Investigation Committee (the 
committee or Institutional Review Board that reviews, approves, and monitors research 
on human subjects), who are responsible for ensuring research compliance.  These 
individuals are required to keep all information confidential

Your providers who are participants in the Electronic Medical Record (EMR) system

Those individuals at Yale who are responsible for the financial oversight of research 
including billings and payments

The study doctor, Dr. Amer Zeidan, and the Yale study team

The U.S. Food and Drug Administration (FDA).  This is done so that the FDA can review 
information about the new drug product involved in this research.  The information may 
also be used to meet the reporting requirements of drug regulatory agencies.  

The study sponsor or manufacturer of study drug, Pfizer, Inc. and/ or their representatives

Drug regulatory agencies in other countries

Governmental agencies to whom certain diseases (reportable diseases) must be reported

Health care providers who provide services to you in connection with this study.

Laboratories and other individuals and organizations that analyze your health information 
in connection with this study, according to the study plan.

Data and Safety Monitoring Boards and others authorized to monitor the conduct of the 
Study 
By signing this form, you authorize the use and/or disclosure of the information described above 
for this research study.  The purpose for the uses and disclosures you are authorizing is to ensure 
that the information relating to this research is available to all parties who may need it for research 
purposes.
All health care providers subject to HIPAA (Health Insurance Portability and Accountability Act) 
are required to protect the privacy of your information.  The research staff at Yale School of 
Medicine and Yale-New Haven Hospital is required to comply with HIPAA and to ensure the 
confidentiality of your information.  Some of the individuals or agencies listed above may not be 
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 19 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
subject to HIPAA and therefore may not be required to provide the same type of confidentiality 
protection. They could use or disclose your information in ways not mentioned in this form.  
However, to better protect your health information, agreements are in place with these individuals 
and/or companies that require that they keep your information confidential. 
Authorized representatives of the Food and Drug Administration (FDA) and the manufacturer of 
the study drug being tested, Pfizer, Inc., may need to review records of individual subjects.  As a 
result, they may see your name, but they are bound by rules of confidentiality not to reveal your 
identity to others.
The sponsor will see the research information we collect about you when they come to Yale to 
monitor the conduct of this research study.  The “Sponsor” includes any persons that work for or 
are hired by the sponsor to conduct research activities related to this study.    For this study the 
sponsor is Yale Cancer Center. Yale researchers will also send the sponsor your health information 
during the study or at the end of the study.  When Yale researchers send information about you to 
the sponsor, they will not send information that directly identifies you such as your name.
You have the right to review and copy your health information in your medical record in 
accordance with institutional medical records policies.  However, you will not be allowed to look 
at or copy your study related information until after the research is completed.  
This authorization to use and disclose your health information collected during your participation 
in this study will never expire.
A description of this clinical trial will be available on, as required by U.S. Law. This Web site will 
not include information that can identify you.  At most, the Web site will include a summary of 
the results. You can search this Web site at any time.
IN CASE OF INJURY
It is important that you follow carefully all the instructions given by the Study Doctor and his/her 
staff regarding this study.
If you encounter a physical injury or illness while on this study, you should seek prompt medical 
treatment and contact your study doctor right away to be treated or referred for treatment. You 
may seek treatment at any medical facility.
Yale Cancer Center, Yale University and Pfizer, Inc. do not provide funds for the treatment of 
research-related injury.  If you are injured as a result of your participation in this study, treatment 
will be provided.  You or your insurance carrier will be expected to pay the costs of this treatment.  
No additional financial compensation for injury or lost wages is available.
You do not give up any of your legal rights by signing this form.
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 20 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
VOLUNTARY PARTICIPATION AND WITHDRAWAL
Participation in this study is voluntary. You are free to choose not to take part in this research 
study.  Refusing to take part in this research study will not lead to penalty or loss of benefits to 
which you are otherwise entitled (such as your health care outside the study, the payment for your 
health care, and your health care benefits). However, you will not be able to enroll in this research 
study and will not receive study procedures as a study participant if you do not allow use of your 
information as part of this study.
Withdrawing from the Study:
If you decide to participate in this research study, you are free to stop and withdraw from this study 
at any time during its course. To withdraw from the study, you can call a member of the research 
team at any time and tell them that you no longer want to take part.  They will make sure that 
proper procedures are followed and a final visit is made for your safety.
You may request that the Sponsor destroy your blood sample(s) by contacting your study site.  As 
long as it is possible to identify your samples (i.e., your samples have not been anonymized or the 
study site has not destroyed the first key), then the Sponsor will destroy the sample.  However, 
data obtained from your samples prior to receiving your request for destruction will not be deleted.   
If you request destruction of your sample(s), you will not lose any benefits, medical treatment or 
legal rights to which you are otherwise entitled.
The researchers may withdraw you from participating in the research if necessary.  The study 
doctor or the study sponsor may decide to take you out of the study without your agreement if: 

You do not follow the directions of the study team;

The study doctor decides that the study is not in your best interest;

The study is stopped by the study sponsor, the institutional review board (IRB) or 
independent ethics committee (IEC) (a group of people who review the research to protect 
your rights), or by a regulatory agency;  

You become pregnant, intend to become pregnant or are breast feeding a child during this 
study.  
To help you leave the study safely, the study doctor may ask you to have more tests.  The study 
doctor may also ask if you wish to take part in the follow up portion of the study.  If you agree to 
continue with the follow up portion of the study, information about your health will continue to be 
collected as described above in the Follow Up Procedures section.  The study doctor will discuss 
with you the different withdrawal options.  
Withdrawing from the study will involve no penalty or loss of benefits to which you are otherwise 
entitled. It will not harm your relationship with your own doctors or with Yale-New Haven 
Hospital.  
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 21 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
If you choose not to give your consent by not signing this document, or if you cancel your consent 
later, then you will not be eligible to participate in this study and will not receive any treatment 
provided as part of the study. Unless and until you do cancel the consent, it will remain valid and 
effective.
Withdrawing Your Authorization to Use and Disclose Your Health Information:
You may withdraw or take away your permission to use and disclose your health information at 
any time. You do this by telling the study staff or by sending written notice to the study doctor, 
Amer Zeidan, MBBS, MhS, at the address listed on page one of this form.  If you withdraw your 
permission, you will not be able to stay in this study.
When you withdraw your permission, no new health information identifying you will be gathered 
after that date.  Information that has already been gathered may still be used and given to others 
until the end of the research study, as necessary to ensure the integrity of the study and/or study 
oversight.  
OPTIONAL SPECIMENS FOR FUTURE STORAGE/GENETIC TESTING
You are invited to allow some of your blood and bone marrow samples (called specimens) and 
related information to be stored (banked) for future research. Your blood and bone marrow samples 
collected will be shipped to, analyzed by, and temporarily stored at Yale University or at a 
laboratory selected by the Yale University. Most testing samples will be destroyed at the end of 
the testing process, but some samples may be kept and analyzed at a later time to learn more about 
your disease and its treatment.
The samples that are stored after the testing will be kept for an unlimited time at Yale University 
or a laboratory selected by Yale University. The tests that might be done at a later time will include 
looking for changes in the cancer cell genetic make-up and/or proteins inside the cancer cells that 
might be involved with your response to cancer therapy. Your genes are made up of DNA. DNA 
is short for deoxyribonucleic acid and contains information that determines, in part, the traits, such 
as eye color, height, or disease risk, that are passed on from parent to child. This study will not 
analyze your body’s DNA. It will only look at changes in the DNA of your cancer cells to better 
understand your response to therapy. RNA is made from DNA. RNA is short for ribonucleic acid. 
RNA is a genetic material that has a major role in making proteins. Proteins are the building blocks 
of your body, cells, and organs. Future tests may include looking at the RNA or proteins inside 
your cancer cells. Afterwards, the samples are discarded by a certified hazardous waste 
management company.
When your specimens and information are stored, we are careful to try to protect your identity 
from discovery by others. Your samples and information will receive a unique code. Other 
researchers will only receive coded samples and information, and will not be able to link the code 
to you. Strict security safeguards are in place to reduce the chance of misuse or unplanned release 
of information.
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 22 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
Using your specimens for research will probably not help you. We do hope the research results 
will help people in the future.
There is a risk that your information could be misused. The chance of this happening is very small, 
and we have protections in place to lower this risk. There can also be a risk in uncovering genetic 
information. New health information about inherited traits that might affect you or your blood 
relatives could be found during a research study. Very rarely, health or genetic information could 
be misused by employers, health insurance companies, and others. There is a federal law called 
the Genetic Information Nondiscrimination Act (GINA) that, in general, makes it illegal for health 
insurance companies, group health plans, and most employers (except those with fewer than 15 
employees) to discriminate against you based on your genetic information. However, it does not 
protect you against discrimination by companies that sell life insurance, disability insurance, or 
long-term care insurance.
Your specimens and information will be used for research and will not be sold. There is a 
possibility that this research may lead to development of products that will be commercialized. If 
this happens, there is no plan to share any financial gain with you or your family.
Research results will not be returned to you or your doctor. If research results are published, your 
name and other personal information will not be given.
The choice to take part is up to you. You may choose not to let us store and use your samples, and 
your care will not be affected by this decision. If you decide that your samples can be kept, you 
may change your mind at any time. To withdraw your samples from the study, you can call a 
member of the research team or you may write to the Principal Investigator using the contact 
information on page one of this form at any time and tell them you do not want your samples used 
any longer. If your sample has not already been anonymized it will be destroyed.
Please indicate your choice below by checking yes or no:
Yes, I agree to allow my samples to be kept at Yale University or a laboratory chosen by 
Yale University for analysis at a later time.
No, I do not agree to allow my samples to be kept at Yale University or a laboratory chosen 
by Yale University for analysis at a later time.
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 23 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
QUESTIONS
We have used some technical terms in this form. Please feel free to ask about anything you don't 
understand and to consider this research and the consent form carefully – as long as you feel is 
necessary – before you make a decision.
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020


APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020
Principal Investigator:
Amer Zeidan, MBBS, MhS
Sponsor Protocol/HIC #: 
2000024738
Funding Source:
Yale University
Protocol Number:
PF-04449913
Sponsor ICF Template Version:
05/31/2019
Sponsor Protocol Date:
31-May-2019
Page 24 of 24
YCC v1.0 (16-July-2019) 
Main Compound and Authorization Form  
Authorization and Permission
I have read (or someone has read to me) this form and have decided to participate in the project as 
described above.  Its general purposes, the particulars of my involvement and possible hazards and 
inconveniences have been explained to my satisfaction.  My signature also indicates that I have 
received a copy of this consent form.
By signing this form, I give permission to the researchers to use and give out information about 
me for the purposes described in this form.  By refusing to give permission, I understand that I will 
not be able to participate in this research. 
I also confirm that I have received a Trial Alert Card providing contact details of the study doctor 
and agree to carry this card with me at all times. 
Study Participant (print name)
Signature
Date
Person obtaining consent (print 
name)
Signature
Date
Person obtaining consent (print 
name) – only if applicable, otherwise 
blank
Signature
Date
Interpreter/ Witness (print name) 
– only if applicable, otherwise blank
Signature
Date
 
If after you have signed this form you have any questions about your privacy rights, please contact 
the Yale Privacy Officer at (203) 432-5919.
If you have further questions about this project or if you have a research-related problem, you 
may contact the Principal Investigator, Dr. Amer Zeidan, at (203) 737-7078.  If you would like to 
talk with someone other than the researchers to discuss problems, concerns, and questions you 
may have concerning this research, or to discuss your rights as a research subject, you may 
contact the Yale Human Investigation Committee at (203) 785-4688
APPROVED BY THE YALE UNIVERSITY IRB 7/17/2020