Public Disclosure Synopsis
Protocol B1371013 – 18 June 2018 - Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
GENERIC DRUG NAME AND/OR COMPOUND NUMBER:
Glasdegib / PF-04449913
PROTOCOL NO.:
B1371013
PROTOCOL TITLE:
A Phase 2, Double-Blind, Randomized Safety and Efficacy Study of Glasdegib(PF-04449913) versus Placebo in Patients with Myelofibrosis Previously Treated with
Ruxolitinib

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Study Center(s):Ten centers took part in the study: 3 in Japan and 7 in the United States (US).
Study Initiation Date and Primary Completion or Final Completion Dates:
Study Initiation Date: 06 October 2014
Primary Completion Date: 14 December 2016
Last Patient Last Visit (LPLV): 31 January 2018
This study was to consist of an open-label lead-in cohort to evaluate the safety andtolerability of glasdegib in patients with myelofibrosis (MF) previously treated with ≥1 Janus
kinase inhibitor (JAKi), followed by a Phase 2, randomized portion. Although the drug wasconsidered safe and tolerable in MF, the key secondary efficacy endpoint was not met;
therefore, the double-blind, randomized phase was not initiated, with no patients enrolled.
As of the primary completion date, 3 patients from the lead-in cohort who continued toderive clinical benefit from treatment remained in the study. All 3 patients discontinued
from study or completed the protocol-specified follow-up period as of LPLV.
Phase of Development:
Phase 2

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Study Objectives:
Lead-In Cohort Objectives
The primary objective in the glasdegib lead-in cohort was to assess the safety and tolerabilityof glasdegib in patients with primary or secondary MF who had been previously treated with
≥1 JAKi.

090177e18eda26c5\Approved\Approved On: 04-Jul-2018 08:48 (GMT)The secondary objectives in the glasdegib lead-in cohort were as follows:•

To assess the effect of glasdegib on spleen volume reduction (SVR) in patients withprimary or secondary MF who had been previously treated with ≥1 JAKi;•

To assess the effect of glasdegib on patient-reported MF symptoms in patients withprimary or secondary MF who had been previously treated with ≥1 JAKi;•

To assess the effect of glasdegib on hematologic improvement (peripheral blood) inpatients with primary or secondary MF who had been previously treated with ≥1 JAKi;•

To characterize the pharmacokinetics (PK) of glasdegib.

Randomized Cohort Objectives
The primary objective in the randomized cohort was to compare the effect of glasdegib
versus placebo on SVR in patients with primary or secondary MF who had been previously
treated with ruxolitinib.
The secondary objectives in the randomized cohort were as follows:•

To compare the effect of glasdegib versus placebo on patient-reported MF symptoms inpatients with primary or secondary MF who had been previously treated with ruxolitinib;•

To compare the effect of glasdegib versus placebo on hematologic improvement(peripheral blood) in patients with primary or secondary MF who had been previously
treated with ruxolitinib;•

To compare changes in patient-reported outcomes (PROs) of health-related quality of life
(HRQoL) and health status between treatment arms;•

To evaluate duration of SVR within each treatment arm;•

To compare overall survival (OS) between treatment arms;•

To evaluate the overall safety profile in each treatment arm;•

To characterize the PK of glasdegib;

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Protocol B1371013 – 18 June 2018 - Final•

To psychometrically validate and analyze interpretability of scores for the
Myeloproliferative Neoplasm Symptom Assessment Diary (MPN-SAD).

METHODS
Study Design:
An open-label lead-in cohort of ≥20 MF patients previously treated with ≥1 licensed orexperimental JAKi was planned to evaluate the safety and tolerability of 100 mg glasdegib
once daily (QD). Following this, a Phase 2, randomized, double-blind, 2-arm study of oral
single-agent glasdegib 100 mg QD versus placebo on a continuous regimen of 28-day cycles
in primary or secondary symptomatic MF was to be initiated if the key secondary endpoint(≥50% reduction in MPN-SAD Total Symptom Score [TSS]) was met.

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Patients were screened at 1 visit or over multiple visits across a 4-week period. Following
this, patients entered the treatment phase of the study. Duration was up to 24 weeks andpatients were eligible to remain on treatment after this for as long as they tolerated andderived clinical benefit from the treatment.
For the randomized cohort, all treatments were to be unblinded at 24 weeks; patients
receiving placebo treatment were eligible to cross over to open-label glasdegib at this point
or at any point prior to this if disease progression occurred.
The planned schedule of assessments for both the glasdegib lead-in and randomized cohorts
is presented in Table 1. The PK and electrocardiogram (ECG) schedule of assessments forthe glasdegib lead-in cohort is presented in Table 2. For the randomized cohort, the planned
PK and ECG schedule of assessments for the majority of patients is presented in Table 3; inaddition to this, approximately 30 patients were planned to be evaluated at additional time
points, and patients in Japan were to follow a different schedule. The planned schedule ofassessments for the crossover cohort (which would have consisted of the patients whocrossed over to open-label glasdegib from previous placebo treatment) is presented inTable 4; the PK and ECG schedule for this cohort is provided in Table 5.

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Table 1.

Schedule of Activities for the Glasdegib Lead-In and Randomized Cohorts

Protocol Activity

Screening

28-Day Cycles
C2, 3, 5
and 6

C1

D-7

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Visit Window

Up to 28 days
beforeregistration/
randomization
X
X
X

Informed consentc
Medical history
Cancer historyd
Baseline signs andsymptomse
Physical examinationf
Vital signsg
Performance statush
Contraception checki
Laboratory
Hematologyj
Blood chemistryk
Coagulationl
Urinalysism
Pregnancy testn
Triplicate 12-lead ECGo
Randomization and treatment
Registration (lead-in)/randomizationp
Study treatmentq
Study drug compliancer
Disease response assessments
Spleen and liver
palpations

Table 1.

-

D1
(predose)-

C4 andC7

After C7
Q3M
(C10,
C13, etc.)
D1

D8

D15

D21

D1

D1

±1 day-±1 day±2 days±5 days(±7 daysforimaging)±7 days

X
X
X
X

X
X
X
X

X
X
X
X

X
X
X
X
X

X
X
X
X
X

X
X
X
X
X

QD, orally, on a continuous basis
X
X

X

X
X
X
X
X

X
X
X
X

X
X
X
X
X
X

X
X

X
X
X
X
X
X
X
X
X
Refer to Table 2 and Table 3

X
X

X

X
X

X

X

X

X

X

C4 andC7

After C7
Q3M
(C10,
C13, etc.)
D1

Schedule of Activities for the Glasdegib Lead-In and Randomized Cohorts

Protocol Activity

Screening

28-Day Cycles
C2, 3, 5
and 6

C1

D-7
Visit Window

Abdominal imagingt
Response assessment(revised IWG-MRT)uPROsv

Up to 28 days
beforeregistration/
randomization
Xt

-

D1
(predose)-

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D8

D15

D21

D1

D1

±1 day-±1 day±2 days±5 days(±7 daysforimaging)
X
X

Page 4±7 days

X
X

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eDiary device set-upw
Symptom score(MPN-SAD)x

X
X

X

X

X

X

X

X

X
(weekly)

PGIC
X
X
X
EQ-5D-5L
X
X
X
X
EORTC QLQ-30
X
X
X
X
Other clinical assessments
AEsy
X
X
X
X
X
X
X
Concomitant treatments
X
X
X
X
X
X
X
RBC and platelet
X
X
X
X
X
X
X
X
transfusionsz
Special laboratory assessments: blood samples
PK
Refer to Table 2 and Table 3
Survival follow-upb
Abbreviations: AE=adverse event; BICR=blinded independent central review; C=cycle; CRF=case report form; CT=computed tom
DIPSS=dynamic international prognosis scoring system; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group;
EORTC-QLQ=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EOT=end of treatmen
patient-reported outcomes; EQ-5D-5L=EuroQol 5 Dimensions Questionnaire 5-level version; IEC=Independent Ethics Committee
Board; IWG-MRT=International Working Group for Myelofibrosis Research and Treatment; JAKi=Janus kinase inhibitor; MF=m
MPN-SAD=Myeloproliferative Neoplasm Symptom Assessment Diary; MRI=magnetic resonance imaging; NCI CTCAE=Nationa
Terminology Criteria for Adverse Events; PGIC=Patient Global Impression of Change; PK=pharmacokinetics; PRO=patient-reporcontrol; QD=once daily; Q[X]M=every [X] months; QTc=corrected QT interval; QTcF= QT interval corrected by the Fridericia coblood cell; SAE=serious adverse event; SVR=spleen volume reduction; WBC=white blood cell.
a. EOT visit: Patients should have completed all assessments within 28 days of receiving last dose, unless otherwise specified. P
experience toxicity following discontinuation of treatment were to be followed by the investigator at least every 4 weeks until reso
further improvement was expected in the clinical judgment of the investigator.
b. Survival follow-up: Survival follow-up was not collected for patients enrolled to the glasdegib lead-in cohort. Following discfor patients enrolled to the randomized cohort, survival status was to be collected every 3 months until death or up to 20 months af
patient, whichever occurred first. Subsequent anticancer therapy(s) and relevant transplant information were also to be collected.
been acceptable for follow-up monitoring.
c. Informed consent: Had to be obtained prior to undergoing any study-specific procedure.
d. Cancer history: Date of initial diagnosis, risk category at time of enrollment (per DIPSS), a complete history of MF prior therduration of therapy), best response and reason for discontinuation. Events leading to intolerance of a prior JAKi therapy, including
events, were also collected.
e. Baseline signs and symptoms: Patients were asked about any signs and symptoms experienced within the 14 days prior to sta
signs and symptoms were recorded on the AE page of the CRF.
f. Physical examination: Included examination of all the major body systems. If a physical examination was obtained within 4evaluation did not need to be repeated. Weight had to be recorded at Screening and on Day 1 of each cycle. Height did not need tomeasurement.
g. Vital signs: Blood pressure and heart rate were recorded in the sitting position. If an assessment had been obtained within 48
collection, it did not need to be repeated.
h. Performance status: ECOG scale.
i. Contraception check: Male patients who were able to father children and female patients who were of childbearing potential
criteria for correct use of 2 of the selected methods of contraception. The investigator or designee discussed with the patient the necontraception methods consistently and correctly and documented such conversation in the patient’s chart. In addition, the investig
patient to call immediately if one or both selected contraception methods were discontinued, or if pregnancy was known or suspectpatient’s partner.
j. Hematology: Assessed locally by the site; laboratory certifications and normal ranges with units had to be provided to the spo
also be repeated as clinically indicated. All platelet, absolute neutrophils, WBC and hemoglobin values observed during the screen
the CRF.
k. Blood chemistry: Assessed locally by the site; laboratory certifications and normal ranges with units had to be provided to thetests could also be repeated as clinically indicated.
l. Coagulation: Assessed locally by the site. Coagulation tests could also be repeated as clinically indicated.

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Public Disclosure Synopsis
Protocol B1371013 – 18 June 2018 - Final

m. Urinalysis: Assessed locally by the site. Dipstick was acceptable. Microscopic analyses should have been performed if abnor
protein or blood). If a urinalysis was obtained within 7 days of the scheduled collection, it did not need to be repeated at C1D1.
n. Pregnancy test: For female patients of childbearing potential, a urine or serum pregnancy test, with sensitivity of at least 25 m
certified laboratory, was performed on 2 occasions prior to starting study therapy: once at the start of screening and once at the C1D
study treatment administration. Pregnancy tests were also routinely repeated at the beginning of every treatment cycle during the aend of study treatment, and additionally whenever one menstrual cycle was missed or when potential pregnancy was suspected. A
also have been undertaken if requested by IRB/IECs or if required by local regulations.
o. Triplicate 12-lead ECGs: At Screening, 3 consecutive 12-lead ECGs were performed approximately 2 minutes apart to deter(and derived QTcF). ECGs should have been assessed locally and were also submitted to a central vendor.
p. Registration/randomization: Patients had to meet all eligibility criteria prior to registration (glasdegib lead-in cohort) or randcohort).
q. Study treatment (glasdegib or placebo): Patients should have been reminded at each visit that the study treatment was to be
8 ounces (240 mL) of water at the same time each day. On protocol visit days, the patient was reminded that the study treatment shsite staff, to support specific time point assessments (ie, PK sampling).
r. Study drug compliance: All study treatment bottle(s) including any unused tablets and patient dosing diaries should have bee
compliance assessment and drug accountability.
s. Spleen and liver palpation: Spleen and liver measurement should ideally have been performed by the same medical professio
provide consistency for each patient assessment. Palpable spleen length below left costal margin was measured in centimeters.
t. Abdominal imaging: MRI of the spleen and the liver was collected at baseline, then every 12 weeks (ie, C4D1 and C7D1) whtreatment. In exceptional circumstances, patients unable to undergo an MRI could be assessed by CT scan, following consultation
method of assessment used at baseline should have been used for the duration of the trial to ensure consistency. Additional scans cinvestigator’s discretion. Patients should have refrained from eating or drinking and from exercise for at least 2 hours (preferably 4
exam. All scans were assessed by a BICR through a central imaging vendor. Baseline imaging should have been obtained at least
Phase 1b) or randomization (for Phase 2), to ensure acceptability of the scan by the central imaging vendor. Suspected disease pro
spleen size increase or symptomatic deterioration, was confirmed via imaging assessment, by the BICR. Scans that did not pass thprocess were repeated within 2 weeks and resubmitted to ensure readability. At the time of permanent study treatment discontinua
been collected within 2 weeks after last dose of study treatment was administered. Patients discontinuing treatment with document
need a repeat MRI/CT at the final visit.
u. Response assessment (revised IWG-MRT): At a minimum, evaluation of SVR, peripheral blood, and physical symptoms we
assessment. Where available, bone marrow samples were also evaluated for response.
v. PROs: All PROs were collected electronically. An eDiary device (similar to a smart phone) was used to capture MPN-SAD.
capture all other PRO data (eg, EORTC QLQ-30, EQ-5D-5L and PGIC) at the study visits. Site staff provided patient training on t
only used at the site.
w. eDiary: Site staff provided patient training on use of eDiary device, logged patients onto the device, and dispensed the device
enrollment. An eDiary device is physical hardware used by the patient to enter eDiary data from the MPN-SAD. Patients had to b
clinic visit to verify that the device was charging properly and to download accumulated data. The device was returned to the patie
study completion or discontinuation.
x. Daily symptom score: The total symptom score from the MPN-SAD was recorded daily each night beginning at least 7 days
through C7D1 (Week 24, for a total of 25 weeks). Thereafter, patients recorded their symptoms weekly until the time of treatment
treatment discontinuation, symptoms were to be recorded monthly by all patients participating in survival follow-up, through compstudy.
y. AE assessments: AEs should have been documented and recorded at each visit using the NCI CTCAE version 4.03. Patients
28 days after the last treatment administration or until all drug related toxicities had resolved, whichever was later, or earlier than 2commenced another anticancer therapy in the meantime. For SAEs, the active reporting period to Pfizer or its designated represen
the patient provided informed consent, which was obtained prior to the patient’s participation in the study, ie, prior to undergoing a
and/or receiving study treatment, through and including 28 calendar days after the last administration of the study treatment. SAEs
reporting period had ended should have been reported to the sponsor if the investigator became aware of them. At a minimum, allbelieved had at least a reasonable possibility of being related to the study drug were to be reported to the sponsor.
z. Transfusions: All RBC and platelet transfusions, including the date of each transfusion and number of RBC or platelet units t
the patient was on treatment. Transfusion histories for the 3 months prior to C1D1 were also recorded in the CRF. The number of
was recorded.

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Table 2.
Dose Day

Pharmacokinetics and Electrocardiogram – Glasdegib Lead-In Cohort
C1D1

C1D15

C1D16

C2 and C3,

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Hour
0a
0.25
1
2
4
0a
0.25 0.5
1
2
4
6
24
0a
1
PostdosePK plasma
X
X
X
X
X
X
X
X
X
X
X
X
X
X
sampleTriplicate
X
X
X
X
X
X
X
X
X
12-lead ECGb
Abbreviations: C=cycle; D=day; ECG=electrocardiogram; EOT=end of treatment; PK=pharmacokinetics; Q3M=every 3 months; Q
QTcF= QT interval corrected by the Fridericia correction formula.
a. In all instances, “0 hour” represents a predose collection. The PK sample should have been collected within 30 minutes prior
Patients should have been reminded not to take their study medication prior to arriving at the clinic on protocol scheduled visits.
b. At each time point, 3 consecutive 12-lead ECGs were performed approximately 2 minutes apart to determine the mean QTc in
ECGs should have been assessed locally and were also submitted to a central vendor. When coinciding with blood sample draws f
have been performed prior to blood sample collection, such that the blood sample was collected at the nominal time. Additional tr
performed as clinically indicated.

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Table 3.
Dose Day

Pharmacokinetics and Electrocardiogram – Randomized Cohort (General)
C1D1

C1D15

C2 and C3, D1

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Hour Postdose
0a
1
4
0a
1
4
0a
1
4
PK plasma sample
X
X
X
X
X
X
X
X
Triplicate 12-lead
X
X
X
X
X
X
X
X
X
ECGb
Abbreviations: C=cycle; D=day; ECG=electrocardiogram; EOT=end of treatment; PK=pharmacokinetics; Q3M=every 3 months; Q
QTcF= QT interval corrected by the Fridericia correction formula.
a. In all instances, “0 hour” represents a predose collection. The PK sample should have been collected within 30 minutes prior
Patients should have been reminded not to take their study medication prior to arriving at the clinic on protocol scheduled visits.
b. At each time point, 3 consecutive 12-lead ECGs were performed approximately 2 minutes apart to determine the mean QTc in
ECGs should have been assessed locally and were also submitted to a central vendor. When coinciding with blood sample draws f
have been performed prior to blood sample collection, such that the blood sample was collected at the nominal time. Additional tr
performed as clinically indicated.

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Table 4.

Schedule of Activities for the Crossover Cohort

Protocol
Activity

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Visit Window

Baseline

28-Day Cycles
C2,
3, 5
and
6

C1

Up to 14days
prior to
C1D1c-

C4, C7

After
C7,
Q3M
(C10,
C13)
D1

End of
Treat
menta

D1
Pred
ose

D8

D1
5

D21

D1

D1

-

±1
day

-

±1
day

±2
days

±7
days

X

X

PhysicalX
X
examinationd
Vital signse
X
X
PerformanceXstatusf
Contraception
X
X
checkgLaboratory assessments
Hematologyh
X
X
Blood
X
X
chemistryiCoagulationj
X
Urinalysisk
X
Pregnancy testl
X
X
Triplicate
X12-lead ECGm
Registration and study treatment
IRT
X
registrationn
Glasdegib
administrationo
Drugcompliancep
Spleen andXliver palpationq
Efficacy assessments
Abdominal
Xrr
MRI/CT
Response
assessment(revised
IWG-MRT)s
Patient-Reported Outcomes
Daily symptom
X
X
score
(MPN-SAD)t

X
X

X

X

±5 days±7 daysforimagin
g
X

X

X
X

X
X

X
X

X
X

X

X

X

X

X
X

X
X

X
X

X
X

X
X
X
X
X
X
Refer to Table 5

X
X
X

X
X
X

X
X

X
X

Survival
Follow
-Upb

±14
days

QD orally on a continuous basis
X
X

X

X

X

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X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X
(weekly)X(weeklythrough

X

Page 9X(monthly)

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final
visit)

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Table 4.

Schedule of Activities for the Crossover Cohort

Protocol
Activity

Baseline

Visit Window

Up to 14days
prior to
C1D1c-

28-Day Cycles
C2,
3, 5
and
6

C1

C4, C7

D1
Pred
ose

D8

D1
5

D21

D1

D1

-

±1
day

-

±1
day

±2
days

±5 days±7 daysforimagin
g
X
X
X

After
C7,
Q3M
(C10,
C13)
D1

±7
days

End ofTreat
menta

Survival
Follow
-Upb

±14
days

PGIC
X
X
X
EQ-5D-5L
X
X
X
X
EORTC QLQXXXX30Other clinical assessments
AEsu
X
X
X
X
X
X
X
X
Concomitant
X
X
X
X
X
X
X
X
treatments
Transfusionsv
X
X
X
X
X
X
X
X
Blood and plasma samples
PK
Refer to Table 5
Post-treatment
SurvivalX
follow-upb
Abbreviations: AE=adverse event; BICR= blinded independent central review; C=cycle; CT=computed
tomography; D=day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group;
eDiary=electronic diary; EORTC QLQ=European Organization for Research and Treatment of Cancer
Quality of Life Questionnaire; EQ-5D-5L=EuroQol 5 Dimensions Questionnaire 5-level version;
IEC=Independent Ethics Committee; IRB=Institutional Review Board; IRT=Interactive ResponseTechnology; IWG-MRT=International Working Group for Myelofibrosis Research and Treatment;
MPN-SAD=Myeloproliferative Neoplasm Symptom Assessment Diary; MRI=magnetic resonance imaging;
NCI CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events; PGIC=Patient
Global Impression of Change; PK=pharmacokinetics; QD=once daily; Q[X]M=every [X] months; RBC=red
blood cell; SAE=serious adverse event.
a. End of treatment visit: Patients were to have completed all assessments within 28 days of receiving
last dose, unless otherwise specified. Patients continuing to experience toxicity following discontinuation oftreatment were to be followed by the investigator at least every 4 weeks until resolution or determination, inthe clinical judgment of the investigator, that no further improvement was expected.
b. Survival follow-up: Following discontinuation of glasdegib, follow-up survival status was to becollected every 3 months until death or at least 20 months after randomization of the last patient.
Subsequent anticancer therapy(ies) and transplant information were also to be collected. Telephone contact
would have been acceptable for follow-up visits.
c. Assessments collected prior to crossover that fell within 2 weeks of crossover C1D1 would not haveneeded to be repeated, unless specifically indicated.
d. Physical examination: Was to include examination of all the major body systems. If physicalexamination had been obtained within 48 hours of crossover C1D1, the evaluation would not have needed tobe repeated. Weight was to be recorded at crossover baseline and on D1 of each cycle. Height would not

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Protocol B1371013 – 18 June 2018 - Final
have needed to be recorded after the first measurement.
e. Vital signs: Blood pressure and pulse rate were to be recorded in the sitting position. If an assessment
had been obtained within 48 hours of crossover C1D1 scheduled collection, it would not have needed to berepeated.
f. Performance status: ECOG scale.
g. Contraceptive check: Male patients who were able to father children and female patients ofchildbearing potential were to affirm that they met the criteria for correct use of 2 of the selected methods ofcontraception. The investigator or his or her designee was to discuss with the patient the need to use
2 highly effective contraception methods consistently and correctly, and document such conversation in thepatient’s chart. In addition, the investigator or his or her designee was to instruct the patient to call
immediately if 1 or both selected contraception methods were discontinued, or if pregnancy was known orsuspected in the patient or the patient’s partner.
h. Hematology: Assessed locally by the site; laboratory certifications and normal ranges with units were
to be provided to the sponsor. Hematology tests were to be repeated as clinically indicated.
i. Blood chemistry: Assessed locally by the site; laboratory certifications and normal ranges with units
were to be provided to the sponsor. Blood chemistry tests were to be repeated as clinically indicated.
j. Coagulation tests: Assessed locally by the site. Coagulation tests were to be repeated as clinicallyindicated.
k. Urinalysis: Assessed locally by the site. Dipstick was to be acceptable. Microscopic analyses were to
be done if results were abnormal (ie, presence of protein or blood). If urinalysis had been obtained within 7days of the scheduled collection, it would not have needed to be repeated at crossover C1D1.
l. Pregnancy test: For female patients of childbearing potential, a urine or serum pregnancy test, withsensitivity of at least 25 mIU/mL and assayed in a certified laboratory, were to be performed on 2 occasions
prior to starting study therapy, once at the start of screening and once at the crossover C1D1 visit,
immediately before glasdegib administration. Pregnancy tests were also to be routinely repeated at the
beginning of every treatment cycle during the active treatment period, at the end of study therapy, andadditionally whenever a menstrual cycle was missed or when potential pregnancy was suspected.
Additional pregnancy tests were also to be undertaken if requested by IRB/IECs, or if required by local
regulations.
m. Triplicate 12-lead ECGs: Refer to Table 5 for additional details.
n. IRT registration: Patients were to be reassigned from blinded treatment to open-label glasdegib via
IRT prior to crossover C1D1.
o. Glasdegib: Patients were to be reminded at each visit that glasdegib was to be taken at the same timeeach day, with approximately 8 oz (240 mL) of water. On protocol visit days, the patient was to bereminded that glasdegib will be administered by the site staff, to support specific time point assessments (ie,PK sampling).
p. Drug compliance: All glasdegib bottles including any unused tablets and patient dosing diaries were to
be returned to the clinic for compliance assessment and drug accountability.
q. Spleen and liver palpation: Spleen and liver size measurement by manual palpation were ideally to be
performed by the same medical professional at each assessment to provide consistency. Palpable spleen
length below the LCM was to be measured in centimeters.
r. Abdominal imaging: MRI (or CT if applicable) of the spleen and liver was to be collected andsubmitted to a central imaging vendor where a blinded independent central reader was to make volume
assessments. The last imaging scan collected during the randomized portion of the trial was to be used forcrossover baseline, after which an MRI/CT was to be collected every 12 weeks (eg, crossover C4D1,
crossover C7D1, etc) while the patient was on treatment. The same method of assessment used to establish
crossover baseline was to be used for the duration of the trial to ensure consistency. Patients were to refrainfrom eating or drinking and from exercise for at least 2 hours preferably 4 hours, prior to the MRI/CT exam.
Additional scans were to be performed at the investigator’s discretion. Suspected disease progression
identified by palpable spleen size increase or symptomatic deterioration was to be confirmed via imaging
assessment, by the BICR. Scans that were not accepted by the vendor were to be repeated within 2 weeks
and resubmitted to ensure readability. At the time of permanent study treatment discontinuation, MRI/CT
was to be collected within 2 weeks after last dose was administered. Patients discontinuing treatment with
documented disease progression would not have needed a repeat MRI/CT at the final visit.
s. Response assessment (Revised IWG-MRT): Evaluation of spleen volume, peripheral blood andphysical symptoms were to be required for response assessment.

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090177e18eda26c5\Approved\Approved On: 04-Jul-2018 08:48 (GMT)t. Daily symptom score: The total symptom score from the MPN-SAD was to be recorded daily eachnight, without interruption during transition from blinded treatment to open-label glasdegib, and continuing
through crossover C7D1. Thereafter, patients were to record their symptoms weekly until the time oftreatment discontinuation. Following treatment discontinuation, symptoms were to be recorded monthly by
all patients participating in survival follow-up, through completion or discontinuation of study. Patientswere to bring the eDiary device to each clinic visit to verify that the device was charging properly, and to
download accumulated data. The device was to be returned to the patients for continued use until study
completion or discontinuation.
u. AE assessments: AEs were to be documented and recorded at each visit using the NCI CTCAE version
4.03. Patients were to be followed for AEs for 28 days after the last treatment administration or until all
drug related toxicities had resolved, whichever was later; or earlier than 28 days should the patient havecommenced another anticancer therapy in the meantime. For SAEs, the active reporting period to Pfizer orits designated representative was to begin from the time that the patient provided informed consent, which
was obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related
procedure and/or receiving any investigational product, through and including 28 calendar days after the last
administration of the investigational product. SAEs occurring to a patient after the active reporting period
had ended were to be reported to the sponsor if the investigator became aware of them. At a minimum, all
SAEs that the investigator believed had at least a reasonable possibility of being related to theinvestigational product were to be reported to the sponsor.
v. Transfusions: All RBC and platelet transfusions, including the date of each transfusion and the numberof red cell or platelet units transfused were to be recorded while the patient was on treatment. Note that the
number of units, not the number of bags, was to be recorded.

Table 5.
Dose Day

Pharmacokinetics and Electrocardiogram - Crossover Cohort (Placebo
to Glasdegib)
Cycle 1 Day 1

Cycle 1 Day 15

Cycle 2 Day 1

Cycles
3, 5
and 6
Day 1
1

Cycles
4, 7,
then
Q3M
1

EO
T

Hour
0a
1
4
0a
1
4
0a
1
4
PostdosePK plasma
X
X
X
X
X
X
X
X
sampleTriplicate
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGb
Abbreviations: ECG=electrocardiogram; EOT=end of treatment; PK=pharmacokinetics; Q3M=every
3 months; QTc=corrected QT interval; QTcF=QT interval corrected by the Fridericia formula.
a. In all instances, “0 hour” represents a predose collection. The PK sample was to be collected within 30
minutes prior to dose administration. Patients were to be reminded not to take their study medication prior
to arriving at the clinic on protocol scheduled visits.
b. At each time point, 3 consecutive 12-lead ECGs were to be performed approximately 2 minutes apartto determine the mean QTc interval (and derived QTcF). ECGs were to be assessed locally and would also
have been submitted to a central vendor. When coinciding with blood sample draws for PK, ECG
assessment were to be performed prior to blood sample collection, such that the blood sample is collected at
the nominal time. Additional triplicate ECGs could have been performed as clinically indicated.

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Number of Patients (Planned and Analyzed):
The glasdegib lead-in cohort was planned to consist of ≥20 patients. A total of 21 patientsenrolled, of whom 16 patients were in the US and 5 patients were in Japan.
The randomized cohort, which was not initiated, was planned to consist of approximately
202 patients.
Diagnosis and Main Criteria for Inclusion and Exclusion:
MF patients, who had a spleen palpable ≥5 cm below the left costal margin and who had
previously been treated with ruxolitinib.

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Study Treatment:
In the glasdegib lead-in cohort, open-label oral glasdegib tablets (25 mg and 100 mg) were
supplied in bottles by the sponsor and administered 100 mg QD. Each bottle contained
enough medication for a 28-day cycle of dosing, plus an additional amount to cover potential
delays in visiting the study site. Treatment duration in the glasdegib lead-in cohort wasplanned to be at least 12 weeks followed by enrollment of the randomized cohort, where
patients planned to be assigned to double-blind glasdegib or matching placebo in a 2:1 ratio.
Patients were permitted to remain on glasdegib for as long as they continued to experience
clinical benefit.
Efficacy, Pharmacokinetic, and Outcomes Research Endpoints:
The primary efficacy endpoint was achieving ≥35% SVR at Week 24 from baseline in the
randomized cohort as assessed by magnetic resonance imaging (MRI), or computed
tomography (CT) when applicable, by a central, independent, blinded reader.
The key secondary efficacy endpoint for the randomized cohort was symptom improvement,
defined as achieving ≥50% reduction in TSS at Week 24 (Cycle 7 Day 1), as measured by the
MPN-SAD.
Additional secondary endpoints were as follows:•

Achieving ≥35% SVR at Week 24 from baseline in the glasdegib lead-in cohort asassessed by MRI, or CT when applicable, by a central, independent, blinded reader;•

Peripheral blood count improvement;•

Duration of SVR in the randomized cohort;•

OS in the randomized cohort;•

PK parameters of glasdegib;•

Overall TSS at Week 24 as measured by MPN-SAD;•

PROs of HRQoL and health status in the randomized cohort;
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Psychometric validation of the MPN-SAD in the randomized cohort.

Safety Evaluations:
The primary endpoint for the glasdegib lead-in cohort was safety: Adverse Events (AEs) as
characterized by type, frequency, severity (National Cancer Institute Common Terminology
Criteria for Adverse Events [NCI CTCAE] grades), timing, seriousness, and relationship to
study therapy, and laboratory abnormalities as characterized by type, frequency, severity(CTCAE grades, or categorized as normal, abnormal or not done for tests without CTCAE
definitions), and timing.
The timing of safety evaluations is provided in Table 1 through Table 5.

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Adverse Events
An AE was defined as any untoward medical occurrence in a clinical investigation patient
administered a product or medical device. The event need not necessarily have had a causal
relationship with the treatment or usage. AEs were graded by the investigator according to
the CTCAE version 4.03 and coded using the Medical Dictionary for Regulatory Activities(MedDRA) version 20.0 for tables produced based upon the primary completion date for the
study, and version 20.1 for data to LPLV. All observed or volunteered AEs regardless oftreatment group or suspected causal relationship to the investigational product were reported.
AEs should have been recorded from the time the patient had taken at least 1 dose ofinvestigational product through the patient’s last visit. The serious AE (SAE) reporting
period began when a patient provided informed consent (ie, prior to undergoing any
study-related procedure and/or receiving study treatment), through and including 28 calendar
days after the last dose of study treatment. If the investigator became aware of SAEs
occurring after the active reporting period had ended, the events should have been reported tothe sponsor; at a minimum, SAEs believed by the investigator to have at least a reasonable
possibility of being treatment-related were to be reported. If a patient began a new anticancer
therapy, the AE reporting period for non-serious AEs ended at the time the new treatment
was commenced. Death was reported if it occurred during the SAE reporting period after thelast dose of investigational product, irrespective of any intervening treatment.
Serious Adverse Events
An SAE was defined as any untoward medical occurrence at any dose that:•

Resulted in death;•

Was life-threatening (immediate risk of death);•

Required inpatient hospitalization or prolongation of existing hospitalization;•

Resulted in persistent or significant disability/incapacity (substantial disruption of theability to conduct normal life functions);

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Resulted in congenital anomaly/birth defect.

Medical and scientific judgment was exercised in determining whether an event was animportant medical event. An important medical event may not have been immediately
life-threatening and/or have resulted in death or hospitalization. However, if it wasdetermined that the event may have jeopardized the patient or have required intervention toprevent one of the other AE outcomes, then the important medical event should have beenreported as serious.
Treatment-Emergent Adverse Events

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Treatment-emergent AEs (TEAEs) were defined as follows:•

All deaths from start of treatment until 28 days after the final dose;•

All treatment-related SAEs even if occurring after 28 days after the final dose or after endof treatment;•

All treatment-unrelated SAEs from treatment start until 28 days after final dose oftreatment;•

All nonfatal AEs occurring after treatment start up until 28 days after final dose oftreatment or until start of new anticancer treatment, whichever was first.

Disease progression was not considered a TEAE unless the patient died of disease prior to
28 days after discontinuation of treatment. Events that were continuations of baseline
abnormalities were considered TEAEs only if there was an increase in grade over baseline.
Laboratory Evaluations
The following laboratory assessments were analyzed at local laboratories:•

Hematology (bands, basophils, blast count, eosinophils, lymphocytes, monocytes,
neutrophils, platelets, white blood cells, and hemoglobin);•

Blood chemistry (albumin, alkaline phosphatase, alanine aminotransferase, amylase,
aspartate aminotransferase, blood urea nitrate or urea, calcium, chloride, creatinine,creatine kinase/creatine phosphokinase, nonfasting glucose, lactate dehydrogenase,lipase, magnesium, phosphorus, potassium, sodium, total bilirubin, total protein, uricacid, and vitamin D);•

Urinalysis (dipsticks for urine protein and urine blood);•

Coagulation tests (activated partial thromboplastin time and international normalized
ratio).

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Vital Signs and Physical Examination
Vital signs included blood pressure (sitting) and heart rate. Patients also underwent aphysical examination which included examination of major body systems, measurement of
spleen and liver by palpation, weight, and assessment of Eastern Cooperative Oncology
Group status.
Electrocardiogram
Triplicate 12-lead (with a 10-second rhythm strip) tracing was performed for ECGs at every
time point and submitted to a central vendor for assessment. At each time point,
3 consecutive ECGs were performed approximately 2 minutes apart (but no longer than
5 minutes) to determine the mean QTcF intervals. Sites were provided with a simple
calculation tool which allowed for real-time assessment of mean QTcF values from thetriplicate QT interval and heart rate measurements.

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Transfusions
All red blood cell (RBC) and platelet transfusions while the patient was on treatment wererecorded, including the date and the number of RBC or platelet units transfused (as opposedto the number of bags).
Statistical Methods:
Only the statistical methodology for the glasdegib lead-in cohort is discussed below, as theother analyses were not performed. Summaries and statistical analyses were provided fordata up to the primary completion date. All data collected after the primary completion datewere provided as listings only.
The rates of binary endpoints were provided along with the corresponding two-sided 95%
confidence intervals (CIs) using normal approximation unless otherwise stated. Descriptive
statistics, such as the mean, standard deviation (SD), coefficient of variation (CV), median,minimum, and maximum values, were provided for continuous endpoints.
Efficacy Endpoints
The proportion of patients with ≥35% reduction in spleen volume at Week 24, the proportionof patients with ≥50% reduction in TSS at Week 24, and the proportion of patients everachieving peripheral blood count improvement (anemia response) were estimated with
two-sided 95% CI (using exact method).
The number and percentage of patients who completed the MPN-SAD were summarized.
MPN-SAD TSS was summarized using means, medians, SDs, and 95% CIs at each
assessment point based on the observed values as well as changes from baseline. The
number of patients with symptom improvement (≥50% TSS improvement) together with theestimated percentage and 95% CI was presented.

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Pharmacokinetic Endpoints
Standard plasma PK parameters including the maximum plasma concentration (Cmax), time tomaximum plasma concentration (Tmax), and area under the plasma concentration versus time
curve (AUC) for glasdegib were estimated using noncompartmental analysis. If data
permitted, or if considered appropriate, minimum plasma concentration (Cmin) and averageplasma concentration (Cavg) were to be estimated. Descriptive statistics were provided forthese PK parameters in tabular form (n, mean, SD, CV, median, minimum, maximum,
geometric mean and its associated CV) by dose, cycle and day.
For glasdegib concentrations, individual values and descriptive statistics (n, mean, SD, CV,median, minimum, maximum, geometric mean and its associated CV) were presented bydose, cycle, day of assessment, and nominal time in tabular form.
Outcomes Research Endpoints
MPN-SAD is discussed under Efficacy Endpoints.

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Safety Endpoints
AEs were summarized by the frequency of patients experiencing TEAEs corresponding to
MedDRA System Organ Class (SOC) and preferred term, and by worst NCI CTCAE(version 4.03) grade. Summaries of treatment-related TEAEs (TRAEs) were also provided.
The number and percentage of patients who experienced laboratory test abnormalities weresummarized according to worst toxicity grade observed for each assay, graded according to
NCI CTCAE version 4.03. The analyses summarized laboratory tests both on the entire
study period and by treatment cycle. Shift tables were provided to examine the distributionof laboratory toxicities. For laboratory tests without CTCAE grade definitions, results werecategorized as normal, abnormal, or not done.
The analysis of ECG results was based on patients with both baseline and on-treatment ECG
data. All ECGs obtained during the study were evaluated for safety. ECGs collected prior to
the first day of dosing were considered the baseline ECGs. The triplicate data were averaged
and all summary statistics and data presentations used the triplicate averaged data. Data weresummarized and listed for QT, heart rate, RR interval, PR interval, QRS, QTcF and QTinterval corrected by the Bazett formula; individual corrected QT intervals (all evaluatedcorrections) were listed by time.
Analysis Sets
The lead-in analysis set consisted of all patients treated in the lead-in portion of the study andwas used for all analyses conducted on the lead-in portion of the study.
Additional analysis sets were planned for the randomized cohort, which was not initiated.

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RESULTS
Patient Disposition and Demography:
A total of 21 patients were screened, all of whom were assigned to study treatment.

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Discontinuation from treatment signified that a patient had permanently stopped taking thestudy treatment. Up to the primary completion date, a total of 18 patients (85.7%)
discontinued from treatment. The most common reasons for discontinuing glasdegib
treatment were AEs considered related to glasdegib (10 patients; 47.6%), and insufficient
clinical response (3 patients; 14.3%). Of the 3 patients who remained in the study up to
LPLV, 1 patient each discontinued glasdegib treatment due to an AE, due to starting a newtreatment for the disease under study, and due to study termination by sponsor.
Discontinuation from the study signified that a patient had not only discontinued fromtreatment but had also discontinued from any follow-up. Ten (47.6%) patients discontinued
from the study by the primary completion date. In these 10 patients, the most common
reasons for discontinuing participation in the study were patient refused further follow-up(5 patients; 23.8%) and other reasons (4 patients; 19.0%). The “other reasons” were reported
as follows: 1 patient was unable to return to the treatment center due to poor condition(considered possibly related to glasdegib), and 3 patients terminated early (survival follow-up
was not required for the glasdegib lead-in cohort).
After the primary completion date, an additional 7 patients discontinued from the study:
5 patients due to AEs, and 1 patient each due to study termination by sponsor and startingnew treatment for disease under study. In addition, 1 patient previously classified as having
refused further follow-up was reclassified as having discontinued due to AE.
A total of 4 patients completed the protocol-specified follow-up period and, therefore, were
not classified as having discontinued from the study (Table 15).
Of 21 patients, 13 were male (Table 6); the majority of patients were white (66.7%) and themean (SD) age was 69.3 (7.0) years.
Table 6.

Demographic Characteristics

Number (%) of patientsAge (years)
Mean (SD)
Range
Race
White
Asian

Male
13

Glasdegib Lead-In
Female8Total
21

68.2 (7.6)
58-81

71.0 (6.1)
65-83

69.3 (7.0)
58-83

10 (76.9)
3 (23.1)

4 (50.0)
4 (50.0)

14 (66.7)
7 (33.3)

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Efficacy, Pharmacokinetic, and Outcomes Research Results:
Efficacy: Primary
The primary efficacy endpoint (achieving ≥35% SVR at Week 24 from baseline in the
randomized cohort as assessed by MRI, or CT when applicable, by a central, independent,
blinded reader) was not analyzed, as the randomized cohort was not initiated.
Efficacy: Secondary

090177e18eda26c5\Approved\Approved On: 04-Jul-2018 08:48 (GMT)The following secondary efficacy endpoints were not analyzed: duration of SVR in the
randomized cohort and OS in the randomized cohort. Symptom improvement (defined asachieving ≥50% reduction in TSS at Week 24 as measured by the MPN-SAD), peripheral
blood count improvement, and overall TSS at Week 24 as measured by MPN-SAD wereanalyzed only in the glasdegib lead-in cohort, as the randomized cohort was not initiated.
For the secondary endpoint of achieving ≥35% SVR at Week 24 from baseline in theglasdegib lead-in cohort as assessed by MRI, or CT when applicable, by a central,
independent, blinded reader, there were no responders (Table 7). Mean spleen volume at
Week 24 was increased from baseline for the 6 patients evaluated: mean (SD) absolutechange from baseline was 116712.14 (148671.45) mm3; mean (SD) percentage change frombaseline was 8.79% (9.01%).
Table 7.

Responders: Percent Change from Baseline in Spleen Volume Reduction≥35% at Week 24
Glasdegib Lead-In (N = 21)
Change from Baseline
mm3%

Result (mm3)n (%)
6 (28.57)
Number of responders at Week 24
0
Mean (SD)
1542870.340
116712.137
8.793(719261.9024)(148671.4471)(9.0111)
1st quartile
1012712.520-31031.960-1.993
Median1402613.570
95869.740
12.337
3rd quartile
2123824.340
273661.900
13.564
Minimum, Maximum
727734.38,-43179.41, 309082.81-2.72, 19.24
2587723.66
Patients who were not known to have achieved ≥35% reduction of spleen volume at Week 24 were counted as
nonresponders.
The window for Weeks 12 and 24 was -1/+2 weeks.
Overall represents the maximum change from baseline at any postbaseline visit (prior to any further anticancer
therapy).
Patients were censored after starting anticancer therapy on another treatment as indicated on the follow-up
therapy case report form page - further systemic therapy.
Abbreviations: N=number of patients in the population; n=number of patients in the analysis; SD=standard
deviation.

There were no patients who achieved ≥35% SVR during the study.

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For the secondary endpoint of reduction from baseline of ≥50% in TSS at Week 24, therewas 1 (4.8%) MPN-SAD TSS responder who had a mean change from baseline of -55.0%(Table 8).
Table 8.

Percentage of MPN-SAD TSS Responders – 28-Day Average at Week 24
ResultGlasdegib Lead-In (N = 21)
Change from% Reduction
Baselinefrom Baseline

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Number of responders with TSS reduction
1
from baseline ≥50%
% (CI) of responders with TSS reduction
4.8(0.1, 23.8)
from baseline ≥50%
Overall mean of responders
11.3
-13.6
-55.0
Responders were those patients with change from baseline in TSS ≤-50% (reduction of ≥50%).
Patients were censored after starting anticancer therapy on another treatment as indicated on the follow-up
therapy case report form page - further systemic therapy.
Abbreviations: CI=confidence interval; MPN-SAD=Myeloproliferative Neoplasm Symptom Assessment Diary;
N=number of patients in the population; n=number of patients in the analysis; TSS=Total Symptom Score.

Peripheral blood count was measured by anemia response, which was defined astransfusion-independent patients with a ≥20 g/L increase in hemoglobin level where baseline
hemoglobin level was <100 g/L, or transfusion-dependent patients becomingtransfusion-independent). Up to the primary completion date, anemia response was observedin 1 (5.9%) patient (Table 9). The data were not updated after the primary completion date.

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Table 9.

Anemia Response (Transfusion-Dependent versus Independent)
Glasdegib Lead-In (N = 21)
Transfusion-Dependent at Transfusion-Independent
Baseline (N2 = 4)
at Baseline (N2 = 17)090177e18eda26c5\Approved\Approved On: 04-Jul-2018 08:48 (GMT)

Postbaseline≥20 g/L increase in hemoglobinn (%)
95% CI-

1 (5.9)0.1, 28.7

Duration of ≥20 g/L increase in hemoglobinfrom baseline (days)
Mean (SD)Minimum, Maximum-

92.0 (-)
92, 92

Number of patients transfusion-independent
postbaseline among patients dependent atbaselinen (%)
0
95% CI
Transfusion dependency before start of study treatment was defined as transfusions of ≥6 units of PRBC in
the 12 weeks prior to start of study treatment, for a final pretreatment hemoglobin of <85 g/L. In addition,
the most recent transfusion episode must have occurred in the 28 days prior to study enrollment.
Response in transfusion-dependent patients required absence of any PRBC transfusions during any
consecutive rolling 12-week interval during the treatment phase, capped by a hemoglobin level of ≥85 g/L.
Denominator for percentages was the number of patients in the lead-in analysis set. Exact CIs forpercentages were calculated using the Clopper-Pearson method.
Abbreviations: CI=confidence interval; N=number of patients in the analysis set; N2=number of patients inthe subset; n=number of patients with the characteristic; PRBC=packed red blood cells; SD=standard
deviation.

For overall TSS at Week 24 as measured by MPN-SAD (Table 10), the monthly meanchange from baseline was -4.95 (5.78) in the lead-in cohort.
Table 10. Overall MPN-SAD TSSn13

Glasdegib Lead-In (N = 21)
Mean (SD) Change from Baseline-2.74 (14.07)

Monthly mean at Week 12(Days 57 – 84)
Monthly mean at Week 24
6-4.95 (5.78)(Days 141 – 168)Monthly mean at Week 36
1-4.11 (-)
(Days 225 - 252)
Monthly mean at Week 48
2-8.39 (11.52)(Days 309 – 336)
Patients were censored after starting anticancer therapy on another treatment as indicated on the follow-up
therapy case report form page - further systemic therapy.
Abbreviations: CI=confidence interval; MPN-SAD=myeloproliferative neoplasm symptom assessment diary;
N=number of patients in the population; n=number of patients in the analysis; TSS=Total Symptom Score.

Pharmacokinetics
As the randomized cohort was not initiated, PK was only analyzed in the glasdegib lead-incohort.

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Following administration of 100 mg QD oral dose of glasdegib for 15 days in the glasdegib
lead-in cohort, Cmax generally occurred at 1 hour postdose (Tmax; Table 11). The geometricmean area under the concentration-time profile from time zero to time τ, the dosing interval,
where tau = 24 hours for QD dosing (AUCtau) and Cmax values were 13150 ng.hr/mL and
996.8 ng/mL, respectively. Interpatient variability for glasdegib exposure (based on %CV ofgeometric means) in this study was 50% for AUCtau and 45% for Cmax. The glasdegib
predose concentrations (Ctrough) for the dose-compliant group were consistent over multiple
cycles. At Cycle 1 Day 15 (number of patients = 19), Cycle 2 Day 1 (number ofpatients = 17), and Cycle 3 Day 1 (number of patients = 15), the geometric mean (%CVgeometric mean) Ctrough values were 204.1 ng/mL (61%), 201.0 ng/mL (63%), and
189.5 ng/mL (57%), respectively; 2 patients were dose reduced to 75 mg prior to the Cycle 3
Day 1 PK collection.
Table 11. Summary of Steady State Plasma Glasdegib Pharmacokinetic Parameter
Values Following 100 mg QD Oral Dose of Glasdegib for 15 Days
(Dose-Compliant Patients)
Parameter Summary Statisticsa by Treatment
Glasdegib Lead-In Cohort
N, n
19, 17
AUCtau, ng.hr/mL*
13150 (50)Cav, ng/mL*
548.0 (50)
Cmax, ng/mL
996.8 (45)
Ctrough, ng/mL
204.1 (61)Cmin, ng/mL
191.9 (68)Tmax, hr1.02 (0.483-4.00)*
Two patients were excluded from AUCtau and Cav calculation due to truncated pharmacokinetic profiles up
to 6 hours.
Abbreviations: %CV=percent coefficient of variation; AUCtau=area under the concentration-time profile fromtime zero to time τ, the dosing interval, where tau = 24 hours for once daily dosing; Cav=average
concentration at steady state; Cmax=maximum plasma concentration; Cmin=lowest concentration observed
during dosing interval τ; if measured at end of dosing interval; Ctrough=minimum plasma concentration before
next dose; N=number of patients in the treatment group and contributing to the statistical summary;n=number of patients with reportable AUCtau and Cav; QD=once daily; Tmax=time to Cmax.
a. Geometric mean (%CV) for all except: median (range) for Tmax.

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Parameter, Unit

Outcomes Research
The secondary outcomes research endpoints (PROs of HRQoL and health status, andpsychometric validation of the MPN-SAD) were not analyzed, as the randomized cohort was
not initiated.
Safety Results:
The primary endpoint in the glasdegib lead-in cohort was safety. Up to the primary
completion date, all 21 (100%) patients experienced at least 1 TEAE (Table 12). Of these,
4 (19.0%) patients experienced treatment-emergent SAEs; 1 (4.8%) experienced a Grade 5
TEAE, and 14 (66.7%) patients experienced Grade 3 or 4 TEAEs. Over the entire study
duration up to LPLV, a total of 5 (23.8%) patients experienced SAEs.

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Up to the primary completion date, 12 (57.1%) patients permanently discontinued from study
treatment due to TEAEs (there is a discrepancy in the results in terms of 1 patient who
discontinued treatment due to Grade 1 pyrexia; however, the reason for discontinuation wasrecorded as progressive disease). After the primary completion date, 1 additional patient
discontinued from treatment due to AEs.
Table 12. Treatment-Emergent Adverse Events up to the Primary Completion Date
(All Causalities)

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Glasdegib Lead-In(N = 21)
Number (%) of patients
Patients evaluable for AEs
21
Number of AEs
190
Patients with AEs
21 (100.0)
Patients with SAEs
4 (19.0)
Patients with Grade 3 or 4 AEs
14 (66.7)
Patients with Grade 5 AEs
1 (4.8)
Patients discontinued due to AEs
12 (57.1)
Patients with dose reduced due to AEs
1 (4.8)
Patients with temporary discontinuations due to AEs
4 (19.0)
Patients with dose reduced and temporary discontinuation due to AEs
4 (19.0)
Includes data up to 28 days after last dose of study drug.
Except for the number of AEs, patients were counted only once per treatment in each row.
SAEs - according to the investigator’s assessment.
Severity counts were based on the maximum severity or grade of events.
MedDRA (version 20.0) coding dictionary applied.
Abbreviations: AE=adverse event; MedDRA=Medical Dictionary for Regulatory Activities; N=number ofpatients in the population; SAE=serious adverse event.

There was 1 study-emergent death reported. The death was due to disease progression.
Table 13 summarizes the SAEs reported during the study. Five patients experienced a totalof 15 SAEs, of which 8 were TRAEs.
By SOC, the most commonly reported SAEs were: Respiratory, thoracic and mediastinal
disorders (2 patients [9.52%] who experienced 3 SAEs, 1 of which [Hypoxia] was a TRAE),
General disorders and administration site conditions (2 patients [9.52%] who experienced
2 SAEs, 1 of which [Fatigue] was a TRAE), and Psychiatric disorders (2 patients [9.52%]
who experienced 2 SAEs, both of which [Confusional state and Mental status changes] were
TRAEs).
By preferred term, no SAE was reported in >1 patient; 1 patient experienced 2 SAEs of
Respiratory failure.

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Table 13. Treatment-Emergent Serious Adverse Events by System Organ Class andPreferred Term (All-Causality and Treatment-Related)
System Organ Class
Glasdegib Lead-In Cohort (N = 21)
Preferred Term
n
%
n1
n2
Number (%) of Patients:
Evaluable for AEs
21
With AEs5
23.81
Cardiac disorders
1
4.76
1
1
Sinus tachycardia
1
4.76
1
1
Gastrointestinal disorders
1
4.76
2
0
Gastric varices haemorrhage
1
4.76
1
0
Varices oesophageal
1
4.76
1
0
General disorders and administration site
2
9.52
2
1
conditions
Disease progression
1
4.76
1
0
Fatigue
1
4.76
1
1
Hepatobiliary disorders
1
4.76
1
0
Portal hypertension
1
4.76
1
0
Infections and infestations
1
4.76
1
1
Bronchitis
1
4.76
1
1
Injury, poisoning and procedural complications
1
4.76
1
1
Postoperative ileus
1
4.76
1
1
Metabolism and nutrition disorders
1
4.76
1
0
Failure to thrive
1
4.76
1
0
Nervous system disorders
1
4.76
1
1
Memory impairment
1
4.76
1
1
Psychiatric disorders
2
9.52
2
2
Confusional state
1
4.76
1
1
Mental status changes
1
4.76
1
1
Respiratory, thoracic and mediastinal disorders
2
9.52
3
1
Hypoxia14.76
11Respiratory failure
1
4.76
2
0
Except for ’n1’ and ’n2’, patients are only counted once per treatment for each row.
MedDRA (version 20.1) coding dictionary applied.
Includes data up to 28 days after last dose of study drug.
Abbreviations: AE=adverse event; N=number of patients in the analysis set; n=number of patients with thecharacteristic; n1=the number of occurrences of treatment-emergent all-causality AEs; n2=the number ofoccurrences of treatment-emergent causally related to treatment AEs.

Table 14 summarizes non-serious TEAEs reported in >5% of patients in the glasdegib lead-incohort.
The most common all-causality TEAEs by SOC were Musculoskeletal and connective tissue
disorders (reported in 15 patients [71.43%] who experienced 40 TEAEs, of which 28 wereconsidered TRAEs) and Skin and subcutaneous tissue disorders (reported in 15 patients[71.43%] who experienced 25 TEAEs, of which 12 were considered TRAEs). The third
most common SOC was Nervous system disorders (reported in 14 patients [66.67%] who
experienced 26 TEAEs, of which 21 were considered TRAEs).
By preferred term, the most common all-causality TEAEs were Dysgeusia (reported in
13 patients [61.90%] who experienced 17 TEAEs, all of which were considered TRAEs),
Muscle spasms (reported in 12 patients [57.14%] who experienced 20 TEAEs, of which

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18 were considered TRAEs), and Alopecia (8 patients [38.10%] who experienced 10 TEAEs,
all of which were considered TRAEs).

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Table 14. Treatment-Emergent Non-Serious Adverse Events by System OrganClass and Preferred Term (All-Causality and Treatment-Related)
Reported in >5% of Patients
System Organ Class
Preferred Term
Number (%) of Patients:
Evaluable for AEs
With AEs
Blood and lymphatic system disorders
Anaemia
Neutropenia
Thrombocytopenia
Gastrointestinal disorders
Abdominal pain
Abdominal pain upper
Constipation
Diarrhoea
Dry mouth
NauseaGeneral disorders and administration site
conditions
Asthenia
FatiguePyrexia
Infections and infestations
Upper respiratory tract infection
Injury, poisoning and procedural complications
Fall
Investigations
Electrocardiogram QT prolonged
Lipase increased
Lymphocyte count decreased
Weight decreased
Metabolism and nutrition disorders
Decreased appetite
Dehydration
Hyperglycaemia
Hyperuricemia
Musculoskeletal and connective tissue disorders
Back pain
Muscle spasms
Myalgia
Pain in extremity
Nervous system disorders
Dizziness
Dysgeusia
Respiratory, thoracic and mediastinal disorders
Cough
Dyspnoea exertional
Skin and subcutaneous tissue disorders
Alopecia

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nGlasdegib Lead-In Cohort (N = 21)
%
n1
n2

21
21
9
5
2
3
12
2
2
3
2
2
4
11

100.00
42.86
23.81
9.52
14.29
57.14
9.52
9.52
14.29
9.52
9.52
19.05
52.38

16
6
3
4
24
2
2
3
2
2
4
27

8
3
2
1
12
0
1
2
2
2
2
9

3
7
4
6
3
4
2
13
3
5
3
6
12
7
3
2
4
15
2
12
3
3
14
3
13
7
3
2
15
8

14.29
33.33
19.05
28.57
14.29
19.05
9.52
61.90
14.29
23.81
14.29
28.57
57.14
33.3
14.29
9.52
19.05
71.43
9.52
57.14
14.29
14.29
66.67
14.29
61.90
33.33
14.29
9.52
71.43
38.10

5
9
6
11
5
6
3
26
5
10
3
8
21
7
3
2
4
40
2
20
3
3
26
4
17
12
3
3
25
10

3
5
0
3
0
2
2
20
5
8
0
7
11
7
0
0
1
28
1
18
3
2
21
3
17
4
0
1
12
10

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Table 14. Treatment-Emergent Non-Serious Adverse Events by System OrganClass and Preferred Term (All-Causality and Treatment-Related)
Reported in >5% of Patients
System Organ Class
Glasdegib Lead-In Cohort (N = 21)
Preferred Term
n
%
n1
n2
Night sweats
2
9.52
2
0
Pruritus
2
9.52
3
1
Pruritus generalised
2
9.52
2
0
Rash
3
14.29
3
1
Except for ’n1’ and ’n2’, patients are only counted once per treatment for each row.
MedDRA (version 20.1) coding dictionary applied.
Includes data up to 28 days after last dose of study drug.
Abbreviations: AE=adverse event; N=number of patients in the analysis set; n=number of patients with thecharacteristic; n1=the number of occurrences of treatment-emergent all-causality AEs; n2=the number ofoccurrences of treatment-emergent causally related to treatment AEs.

Table 15 summarizes discontinuations from the study. In total, 17 patients discontinued fromthe study. The most common reason for discontinuation was other (11 patients [52.4%]).

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Table 15. Discontinuations from Study
Glasdegib Lead-In Cohort (N = 21)n%Patient died1
4.8
Relationship to glasdegib not defined
16
76.2
Other
11
52.4
Study terminated by sponsor
1
4.8
Patient refused further follow-up
4
19.0
Completed
4
19.0
Total
21
100.0
Abbreviations: N=number of patients in the analysis set; n=number of patients with the characteristic.

CONCLUSION(S):•

There was 1 study-emergent death due to disease progression. A total of 5 patients
experienced SAEs. By preferred term, no SAE was reported in >1 patient; 1 patient
experienced 2 SAEs of Respiratory failure.

•

The safety profile of glasdegib is manageable in this population. No new safety concerns
have arisen during this study.

•

Extended exposure to glasdegib in this population was not accompanied by any observed
increase in toxicity and there have been no consistent patterns of AEs or abnormal
laboratory results.

•

Although the key secondary efficacy endpoint of SVR was not met, glasdegib may
improve MF symptoms in this population of pretreated patients based upon PRO
measures.

•

In conclusion, further study of glasdegib in MF patients may be warranted.

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