Clinical trial NCT04111497
Conditions: Chronic Graft Versus Host Disease Fasciitis
Sponsor: Fred Hutchinson Cancer Center
Start date: 2019-12-03; Completion date: 2023-08-23
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies whether glasdegib is helpful in treating sclerosis associated with chronic graft-versus-host disease. It will also investigate the safety of glasdegib in treating patients with chronic graft-versus-host disease.

Detailed description:
OUTLINE: This is a phase I/II study.

Patients receive glasdegib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Arms: arm 1: Patients receive glasdegib PO QD on days 1-28. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Glasdegib
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_001.pdf: 
 
 
Official Title: 
A Single-Arm, Open-Label, Phase I/II Study of Glasdegib for 
Sclerotic Chronic Graft-vs-Host Disease 
NCT Number: 
NCT04111497 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
8-May-2023  
 
 


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PROTOCOL 
TITLE: 
A Single-Arm, Open-Label, Phase I/II Study of Glasdegib 
for Sclerotic Chronic Graft-vs-Host Disease 
PROTOCOL NUMBER: 
FH8771                        
STUDY DRUG: 
Glasdegib (PF-04449913) 
IND NUMBER: 
145532 
PRINCIPAL INVESTIGATOR: 
 
Stephanie Lee, MD, MPH 
1100 Fairview Ave N, D5-290 
Seattle, WA 98109  
Email: sjlee@fredhutch.org 
COORDINATING STUDY 
CENTER: 
Fred Hutchinson Cancer Research Center 
 
PARTICIPATING SITES: 
Duke University – Duke Cancer Institute 
University of Utah – Huntsman Cancer Institute 
PROTOCOL VERSION 
HISTORY: 
Version 1.3         September 9, 2019 
Version 1.4         April 7, 2020 
Version 1.5         July 8, 2020 
Version 1.6         August 3, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
STUDY SYNOPSIS ................................................................................................... 6 
1.0 
BACKGROUND INFORMATION .................................................................. 10 
1.1 
Chronic graft-versus-host disease ................................................................ 10 
1.2 
Chronic GVHD diagnosis and classification .................................................. 10 
1.3 
Therapy of established chronic GVHD .......................................................... 11 
1.4 
Assessment of therapeutic response in chronic GVHD ................................ 12 
1.5 
GLASDEGIB (PF-04449913, Daurismotm) .................................................... 12 
1.5.1 
Mechanism of Action ....................................................................... 12 
1.5.2 
Safety Pharmacology ...................................................................... 13 
1.5.3 
Drug-drug Interaction Potential ....................................................... 14 
1.6 
Clinical Experience – GLASDEGIB ............................................................... 14 
1.6.1 
Clinical Efficacy ............................................................................... 14 
1.6.2 
Adverse Events ............................................................................... 14 
1.6.3 
Warnings and Precautions .............................................................. 15 
2.0 
STUDY OBJECTIVES ................................................................................... 17 
2.1 
Primary Objective: ......................................................................................... 17 
2.2 
Secondary Objectives: .................................................................................. 17 
3.0 
STUDY DESIGN ........................................................................................... 17 
3.1 
Study Parameters ......................................................................................... 20 
3.1.1 
Efficacy Parameters ........................................................................ 20 
3.1.2 
Safety Parameters ........................................................................... 20 
3.2 
Rationale for Study Design and Dosing Regimen ......................................... 20 
3.3 
Selection of Study Population ....................................................................... 20 
3.3.1 
Inclusion Criteria .............................................................................. 20 
3.3.2 
Exclusion Criteria ............................................................................. 21 
3.3.3 
Enrollment Procedures .................................................................... 22 
3.4 
Study Drug .................................................................................................... 23 
3.4.1 
Premedications ................................................................................ 23 
3.4.2 
Formulation, Packaging, and Storage ............................................. 23 
3.4.3 
Administration of Study Drug ........................................................... 24 


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3.4.4 
Assuring Subject Compliance ......................................................... 24 
3.5 
Study Treatment Schedule ........................................................................... 25 
3.6 
Duration of Therapy ...................................................................................... 25 
3.7 
Dosing Delays and Modifications .................................................................. 25 
3.8 
Concomitant Therapy .................................................................................... 25 
3.8.1 
Permitted Concomitant Therapy ...................................................... 25 
3.8.2 
Prohibited or Restricted Concomitant Therapy ............................... 25 
3.9 
Precautions ................................................................................................... 26 
3.9.1 
Pregnancy Prevention ..................................................................... 26 
3.9.2 
Overdose Instructions ..................................................................... 27 
3.10 
DISCONTINUATION OF Study Treatment ................................................... 28 
3.11 
Removal from study ...................................................................................... 28 
3.12 
Data and Safety Monitoring .......................................................................... 28 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS ................................................. 31 
4.1 
Description of Procedures ............................................................................. 31 
4.1.1 
Informed Consent ............................................................................ 31 
4.1.2 
Medical History ................................................................................ 32 
4.1.3 
Adverse Events ............................................................................... 32 
4.1.4 
Concomitant Medications and Therapy ........................................... 32 
4.1.5 
Confirmation of Eligibility ................................................................. 32 
4.1.6 
Karnofsky Performance Status ........................................................ 32 
4.1.7 
Physical Examination, Vital Signs, Height & Weight ....................... 32 
4.1.8 
Serum Pregnancy Test .................................................................... 32 
4.1.9 
Hematology ..................................................................................... 32 
4.1.10 Serum Chemistry ............................................................................. 33 
4.1.11 Pulmonary Function Tests and Spirometry ..................................... 33 
4.1.12 Patient-Reported Outcomes ............................................................ 33 
4.1.13 Clinician-Reported Outcomes ......................................................... 33 
4.1.14 Biologic Studies ............................................................................... 34 
4.1.15 Study Drug Accountability ............................................................... 34 
4.2 
Assessment of Response to Treatment ........................................................ 34 
4.3 
END OF Treatment VISIT and Safety Follow-up .......................................... 34 
4.4 
Follow-up for New Systemic Treatment, Disease Relapse, and Survival ..... 34 
4.4.1 
Long-term Follow-up ....................................................................... 34 
4.5 
Missed Evaluations ....................................................................................... 35 
5.0 
STATISTICAL METHODS OF ANALYSIS .................................................... 35 
5.1 
General Considerations ................................................................................ 35 
5.2 
Rationale for Sample Size ............................................................................ 35 
5.3 
Analysis POPULATIONS .............................................................................. 35 


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5.4 
Missing Data Handling .................................................................................. 35 
5.5 
Endpoint Data Analysis ................................................................................. 36 
5.5.1 
Study Treatment Administration and Compliance ........................... 36 
5.5.2 
Analysis of Endpoints ...................................................................... 36 
6.0 
SAFETY MONITORING ................................................................................ 37 
6.1 
Definitions ..................................................................................................... 37 
6.1.1 
Severity ............................................................................................ 38 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events ......... 39 
6.2.1 
Adverse Event Reporting Period ..................................................... 40 
6.2.2 
Assessment of Adverse Events ....................................................... 40 
6.2.3 
Pregnancy, lactation, and occupational exposure ........................... 40 
6.2.4 
Hy’s Law Cases ............................................................................... 41 
6.2.5 
IND Safety Reporting ...................................................................... 41 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ............ 41 
7.1 
Informed Consent and Protected Subject Health Information Authorization . 42 
7.2 
Record Retention .......................................................................................... 42 
8.0 
REFERENCES .............................................................................................. 44 
APPENDIX 1.  NIH GLOBAL SEVERITY OF CHRONIC GVHD ............................. 47 
APPENDIX 2.  SCHEDULE OF ASSESSMENTS ................................................... 48 
APPENDIX 3.  SUBJECT DRUG DIARY ................................................................. 50 
APPENDIX 4.  KNOWN STRONG IN VIVO INHIBITORS OR INDUCERS OF CYP3A
 ...................................................................................................................... 52 
APPENDIX 5.  KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS 
RATING (%) CRITERIA ................................................................................ 53 
APPENDIX 6.  NIH RESPONSE ASSESSMENT .................................................... 54 
APPENDIX 7.  RESPONSE DETERMINATION ...................................................... 60 
APPENDIX 8.  ADVERSE EVENT ASSESSMENT OF CAUSALITY ...................... 61 
APPENDIX 9.  DRUGS WITH A KNOWN RISK OF TORSADES DE POINTES .... 62 
APPENDIX 10.  PATIENT-REPORTED OUTCOMES ............................................. 64 
 
 
 
 


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STUDY ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
cGVHD 
Chronic graft-versus-host disease 
CR 
complete response  
CRF 
case report form 
CTCAE 
Common Terminology Criteria For Adverse Events 
DSMB 
Data and Safety Monitoring Board  
ECG 
electrocardiogram 
EOT 
End of treatment 
FFS 
failure-free survival (survival free from addition of another systemic chronic 
GVHD treatment, relapse or death) 
GVHD 
graft-versus-host disease 
Hh 
Hedgehog 
ICF 
informed consent form 
IRB 
institutional review board 
KPS 
Karnofsky Performance Status 
MR 
mixed response 
NIH 
National Institutes of Health 
ORR 
overall response rate (complete plus partial remission) 
PD 
progressive disease 
PR 
partial response  
SAE 
serious adverse event 
SMO 
smoothened 
TdP 
Torsades de pointes 


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STUDY SYNOPSIS 
Study Title: 
A Single-Arm, Open-Label, Phase I/II Study of Glasdegib for 
Sclerotic Chronic Graft-vs-Host Disease 
Protocol Number: 
FH8771 
Sponsor: 
Stephanie J. Lee, M.D., M.P.H. 
Study Drug: 
Glasdegib (PF-04449913) 
Phase: 
I/II 
Study Centers: 
3  
Study Objectives: 
Primary Objective: 
• 
Determine whether 50 mg daily of glasdegib is safe and 
tolerable in the cGVHD population. 
Secondary Objectives: 
• 
Determine best overall response rate by 12 months (complete 
response + partial response) for sclerotic manifestations of 
cGVHD. 
• 
Determine best overall response rate by 12 months (complete 
response + partial response) for all manifestations of cGVHD. 
• 
Examine the safety profile of glasdegib in the cGVHD 
population.  
• 
Bank blood and skin biopsy material for future biologic 
studies.  
 
Study Design: 
This phase I/II trial will examine the safety, tolerability and 
efficacy of glasdegib in cGVHD treatment.  This is a single-arm, 
open-label study. 
Dose Regimen/Route 
of Administration: 
Glasdegib will be administered orally at a dose of 50 mg once 
daily for 28 days, for a total of up to 24 monthly cycles of 
treatment. 
Safety Parameters: 
Grade 3-5 adverse events and all serious adverse events will be 
collected. 
Number of Subjects: 
20 
Inclusion Criteria: 
1. At least 18 years old 
2. Diagnosed with moderate or severe cGVHD according to 
the 2014 NIH Consensus Criteria 
3. Diagnosed with cGVHD-related sclerosis or fasciitis 


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• 
Skin feature score of at least 2 OR 
• 
Joints and fascia score of at least 1 
4. New, stable or progressive sclerosis/fasciitis despite 
treatment with at least one prior line of systemic therapy 
for cGVHD. 
5. Female patients who: 
• 
Are documented to be postmenopausal or are 
surgically sterile, OR 
• 
If of childbearing potential, agree to use at least 1 
highly effective method of contraception from the time 
of signing the informed consent form through 30 days 
after the last dose of study drug, OR agree to practice 
true abstinence or exclusively non-heterosexual 
activity when this is in line with the preferred and usual 
lifestyle of the subject 
6. Male patients who: 
• 
Are surgically sterile (vasectomized) OR 
• 
Agree to use at least 1 highly effective method of 
contraception during the entire study treatment period 
and through 30 days after the last dose of study drug, 
OR agree to practice true abstinence or exclusively 
non-heterosexual activity when this is in line with the 
preferred and usual lifestyle of the subject, AND   
• 
Agree to use a condom to prevent potential 
transmission of investigational drug in seminal fluid 
7. Patients who meet the following clinical laboratory criteria: 
• 
Absolute neutrophil count (ANC) > 1000/µL, platelet 
count > 50 x 109/mL 
• 
ALT and AST < 2x ULN and normal total bilirubin 
unless attributed to cGVHD 
• 
Creatinine < 2.0 mg/dl 


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Exclusion Criteria: 
1. Hospitalization for evaluation or management of an 
infection within the last 8 weeks 
2. Known organ dysfunction 
• 
uncontrolled cardiovascular disease, including 
arrhythmias, congestive heart failure 
• 
oxygen requirement 
3. Addition of any new systemic immunosuppressive 
treatment within the last 2 weeks. 
• 
Addition of new systemic immunosuppressive 
treatment along with glasdegib is also prohibited 
4. QTc interval > 480 ms 
5. Female patients who are lactating or have a positive 
serum pregnancy test 
6. Major surgery within 14 days before enrollment 
• 
Does not include placement of venous access 
device, bone marrow biopsy, GVHD diagnostic 
biopsy, or other routine procedures in cGVHD or 
post-transplantation care 
7. Use of any concomitant medications that are prohibited 
within the past 7 days 
8. Any serious medical or psychiatric illness that could, in the 
investigator’s opinion, potentially interfere with the 
completion of treatment according to this protocol 
9. Known intolerance to glasdegib, sonidegib, or vismodegib  
10. Non-hematologic malignancy within the past 2 years with 
the exception of: 
• 
adequately treated basal cell carcinoma, 
squamous cell skin cancer, or thyroid cancer 
• 
carcinoma in situ of the cervix or breast 


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• 
prostate cancer of Gleason Grade 6 or less with 
stable prostate-specific antigen levels 
• 
cancer considered cured by surgical resection or 
unlikely to impact survival during the duration of 
the study 
11. Treatment with non-FDA approved drug within 28 days of 
start of this trial 
12. Evidence of recurrent or progressive underlying malignant 
disease 
13. Karnofsky performance status (KPS) < 70% 
14. History of non-compliance 
15. Life expectancy < 6 months 
16. Grade 2 or 3 muscle cramping, or grade 1 muscle 
cramping that occurs at least weekly. 
 
Concomitant 
Medications: 
Permitted Concomitant Therapy 
• 
Ongoing systemic treatment for acute GVHD prophylaxis, 
acute GVHD treatment, or cGVHD treatment 
• 
Prophylaxis against infection 
Prohibited Concomitant Therapy 
• 
moderate/strong CYP3A4 inducers  
Avoid Unless No Other Alternative 
• 
moderate/strong CYP3A4 inhibitors  
• 
drugs with known risk of Torsades de Pointes 
• 
QT prolonging medications 
 


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1.0 
BACKGROUND INFORMATION 
1.1 
CHRONIC GRAFT-VERSUS-HOST DISEASE 
Chronic graft vs. host disease (cGVHD) is a major late complication of allogeneic hematopoietic 
cell transplantation (HCT) that affects up to 50% of HCT survivors. The syndrome is associated 
with major transplant-related morbidity, mortality, infectious complications, prolonged duration of 
immune suppression, and impaired patient-reported quality of life.1-8  Thus, it represents a major 
obstacle to recovery and survival following HCT, and its prevention and treatment are of 
significant importance. Chronic GVHD is characterized by diverse clinical manifestations, but 
the most commonly affected organs are the skin, eyes, mouth, and liver.9 However, most organs 
can be involved, with parallels to other systemic immune-mediated disorders.   
Sclerotic GVHD is a distinctive phenotype of cGVHD that usually begins in the superficial layers 
of the skin and then extends to deeper layers but it may also only involve deeper structures 
such as fascia with normal overlying skin. Sclerotic GVHD can severely affect patients’ mobility 
and quality of life, and it is often refractory to standard and secondary therapies. The presence 
of sclerosis after allogeneic HCT is considered diagnostic for cGVHD.10 Progressive or poorly 
controlled sclerotic GVHD results in joint contractures, chronic skin ulcers, and pulmonary 
restriction, causing major disability. A prospective multicenter observational study found a 
cumulative incidence of 8% sclerosis with a median onset of 14 months.11 In a large study from 
Fred Hutchinson Cancer Research Center, the cumulative incidence of sclerosis was 20% at 3 
years. Of the patients who developed sclerosis, 13% had only skin sclerosis, 33% had only joint 
contracture or fasciitis, and 53% had both clinical manifestations. The development of sclerosis 
was associated with a reduced rate of withdrawal of immunosuppressive treatment.12 These 
findings as well as clinical experience indicate that patients with sclerotic chronic GVHD have 
poor quality of life, often require multiple sequential therapies, and frequently exhaust available 
treatment options.13-15  
1.2 
CHRONIC GVHD DIAGNOSIS AND CLASSIFICATION 
Diagnosis and classification of cGVHD has undergone major revision following the 2005 and 
2014 NIH Consensus Conferences on Chronic GVHD. The diagnosis of cGVHD is based on the 
presence of diagnostic manifestations of the syndrome or distinctive manifestations supported 
by confirmatory biopsy or testing. Chronic GVHD severity is scored according to objective 
criteria for each organ involved, which is summarized by an overall global severity score of mild, 
moderate, or severe (Appendix 1).10,16 Mild disease is generally well-tolerated and may 
sometimes be managed with topical or local therapies. Moderate and severe disease is 


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associated with higher mortality and requires systemic treatments.17 Patients with moderate-
severe disease and sclerosis will be enrolled in this trial. 
1.3 
THERAPY OF ESTABLISHED CHRONIC GVHD 
Accepted standard primary therapy for cGVHD includes 0.5-1 mg/kg of prednisone or equivalent 
with or without a calcineurin inhibitor.1,18,19 The addition of other systemic immune-suppressive 
agents to initial therapy has not provided benefit, as evidenced by trials adding azathioprine, 
thalidomide, hydroxychloroquine, mycophenolate mofetil and entospletinib to initial treatment 
with steroids.20-23 Published primary cGVHD therapy trials demonstrate that on average 27% will 
achieve complete response, and 60% will achieve overall response (complete + partial 
response) by 6-9 months after starting initial therapy.18,20-24 A study testing the addition of 
ibrutinib to standard primary therapy has almost finished accrual as of December 2018. 
Based on insufficient response to primary therapy or a flare of cGVHD after tapering of initial 
therapy, many will go on to require additional immune-suppressive agents for cGVHD control. 
“Steroid-refractory” cGVHD has most commonly been defined as either progressive 
manifestations despite one month of treatment, or incomplete response despite two months of 
1-2 mg/kg of prednisone or equivalent.1 In addition to steroid-refractoriness, other clinical 
indications for additional lines of systemic immune suppressive therapy include steroid 
dependence and steroid intolerance. Patients with steroid-dependent cGVHD can’t tolerate 
tapering prednisone due to recurrent cGVHD manifestations. Steroid intolerant patients have 
medical complications of steroid therapy (e.g. hyperglycemia, edema, psychosis, osteoporosis), 
and thus require additional immune-suppressive agents to control GVHD and facilitate taper of 
prednisone. Multiple immune-suppressive therapies, including pharmacologic agents, 
monoclonal antibodies, and strategies such as extracorporeal photopheresis have 
demonstrated moderate activity in this setting, both ameliorating objective cGVHD 
manifestations, as well as facilitating taper of systemic steroids.25 Their effectiveness is 
suboptimal, however, and many patients will require multiple agents to achieve disease control. 
A retrospective study showed that patients with cGVHD received a median of three lines of 
treatment and were on systemic immunosuppression for a median of 5 years. When patients 
stopped systemic treatment, between 30-50% of patients needed to restart treatment a median 
of 3-6 months later for recurrent symptoms.26 
In August 2017, the FDA approved ibrutinib, a Bruton’s tyrosine kinase inhibitor, for the 
treatment of adult patients with cGVHD after failure of one or more lines of systemic 
immunosuppressive therapy.27 There were 24 patients with skin involvement and an 88% 
response rate in skin was reported; however, skin involvement was not subclassified into 


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inflammatory manifestations (which usually respond to treatment) or sclerotic forms (which are 
much harder to treat).  
The overall burden of cGVHD despite routine pharmacologic GVHD prophylaxis, limited 
response to primary and secondary therapy, and the attendant morbidity and mortality all 
support the need for novel approaches in cGVHD treatment, particularly the sclerotic forms. 
1.4 
ASSESSMENT OF THERAPEUTIC RESPONSE IN CHRONIC GVHD 
Following the 2014 NIH Consensus Conference, most clinical trials use the recommended 
response criteria to calculate response based on change scores in nine organ-specific 
measures, assessed prior to study treatment and at defined points afterwards. The organ-
specific change scores are used to classify responses into complete (CR, resolution of all 
cGVHD manifestations), partial (PR, partial resolution of cGVHD manifestations without 
significant worsening in any organ), stable (SD, no change in organ involvement), mixed 
response (MR, improvement and worsening in different organs) and progressive (PD, significant 
worsening in at least one organ). The overall response rate (ORR) is the CR plus PR rate.28  
Interpretation of previously published trials for secondary cGVHD treatment is limited by a 
number of factors, most notably heterogeneity in response determination. In the Phase 2 
ibrutinib study that led to regulatory approval (N=42), the best ORR was 67%. Adverse events 
were common including fatigue, diarrhea, muscle spasms, nausea and bruising.27 The 
publication reported that at a median follow-up of 13.9 months, 30 (70%) had stopped 
treatment.  
1.5 
GLASDEGIB (PF-04449913, DAURISMOTM) 
Glasdegib (DaurismoTM) is a potent and selective oral inhibitor of the Hh (Hedgehog) 
signaling pathway. It is FDA-approved for use in combination with low-dose cytarabine 
for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adult patients 
who are ≥ 75 years old or who have comorbidities that preclude use of intensive 
induction chemotherapy. It is being tested for other hematologic malignancies and solid 
tumors.   
1.5.1 
Mechanism of Action 
Hedgehog activation of Gli1 has been implicated in fibrotic diseases through stimulation of 
mesenchymal stromal cells29 or fibroblasts to differentiate into myofibroblasts which produce 
collagen and fibrosis. There is growing evidence of the relevance of this pathway in systemic 
sclerosis30-34 and efforts to block this pathway therapeutically using agents such as oral 


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hedgehog pathway inhibitors.35  Studies in murine models of cGVHD36 and human clinical trials 
of sonidegib37 and vismodegib38 suggest that Hh pathway inhibitors may improve fibrosis. 
Glasdegib binds to its target Smo (smoothened), a cell membrane protein in the Hh signaling 
pathway, interfering with activation of Gli1 and blocking effects of aberrant Hh signaling. 
1.5.2 
Safety Pharmacology 
Glasdegib has been extensively characterized in nonclinical safety studies in rats, dogs 
and rabbits. Glasdegib was evaluated in safety pharmacology studies (cardiovascular, 
neurofunctional, respiratory), definitive toxicology assessments of up to 6- and 9-months 
duration, in vitro and in vivo genetic toxicity studies, local irritation study and embryo-fetal 
developmental toxicity studies. The primary target organs in rat included kidney, bone, and 
tooth. The primary target organs in the dog included kidney and liver. Additional observations of 
alopecia and skin irritation/inflammation, and QTc prolongation were identified in the dog.  
In general, many findings in the rat and dog predict drug reactions reported in the clinic with 
glasdegib; these include muscle spasms, alopecia and QTc prolongation.  However; not all the 
organ toxicities observed in animals have been observed in humans when treated with 
glasdegib. The kidney is a target organ in rat and dog.  In the clinical program, at the 100 mg 
dose, acute kidney injury has been reported, primarily Grade 1-2. These events were often 
associated with prerenal confounders or consequent to or exacerbated by other glasdegib 
effects (e.g., diarrhea, vomiting, and/or decreased oral intake).  
There have not been any liver events or significant increases in liver transaminases 
reported in the clinic. Findings in bone, teeth and testis are considered a potential concern 
only for pediatric patients, as Hh signaling is important in growth and development of these 
tissues. These effects have not been seen in adult patients and are not a risk for adults 
being treated with glasdegib. 
Based on the available clinical data, the safety profile of glasdegib as a single agent 
administered orally on a once daily continuous dosing regimen is characterized by 
manageable and potentially reversible toxicities that are generally mild to moderate in 
severity. The key observed toxicities are: muscle spasms, dysgeusia, decreased appetite, 
and alopecia. Glasdegib can cause embryo-fetal death or severe birth defects when 
administered to a pregnant woman. Glasdegib is embryotoxic, fetotoxic, and teratogenic in 
animals.  
For further details on the safety pharmacology of glasdegib, refer to the Investigator Brochure.   


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1.5.3 
Drug-drug Interaction Potential 
For more detailed information on drug-drug interaction potential for glasdegib, refer to the 
Investigator Brochure. 
Please refer to Section 3.8 Concomitant Therapy for guidance on drugs that may cause drug-
drug interactions. 
1.6 
CLINICAL EXPERIENCE – GLASDEGIB 
For more detailed information on the clinical experience for glasdegib, please refer to the 
Investigator Brochure.   
1.6.1 
Clinical Efficacy  
There have been no reports of the use of glasdegib for cGVHD. Glasdegib is FDA-approved at 
a dose of 100 mg daily in combination with low-dose cytarabine for the treatment of adult 
patients with acute myeloid leukemia for whom intensive chemotherapy is not an option. It is 
currently under investigation as treatment for hematologic and solid tumor malignancies. An 
ongoing Spanish study of glasdegib for sclerotic cGVHD identified 50 mg daily at the 
recommended dose (JA Perez Simon, personal communication). However, the Spanish study 
will not be sufficient to confirm the tolerability of glasdegib at this dose or provide robust efficacy 
data, so the present study is still warranted. 
1.6.2 
Adverse Events  
The table below lists the most common treatment emergent/treatment-related adverse events 
(AE) of special interest seen thus far in 5 or more patients receiving glasdegib alone or in 
combination with chemotherapy (N=241). Most studies combined glasdegib with other 
chemotherapy making it difficult to ascertain toxicities due to glasdegib itself. Liver toxicity and 
neuropathy have not been identified as drug-related in the clinical program. 
 
 
 
 
 
 
 
 
 
 


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TABLE 2. The most common adverse events seen with glasdegib.  
 
 
1.6.3 
Warnings and Precautions 
1.6.3.1 
Cytopenias 
Febrile neutropenia was reported in 41% of patients being treated for myeloid malignancies, 
usually in combination with other chemotherapy. In patients receiving single agent glasdegib, 
cytopenias were reported only sporadically, with no Grade 3 / 4 events. Complete blood counts 
(CBC) will be monitored in this study. 
1.6.3.2 
QT/QTc 
QTc prolongation has been observed in studies with glasdegib although usually in patients with 
multiple comorbidities, including significant cardiovascular medical history, and/or in patients 
taking concomitant therapy with QT prolonging potential. None of the events were accompanied 
by serious cardiac arrhythmias. Although the likelihood of QT prolongation is low, ECGs will be 
monitored in this study and patients with significant cardiac histories excluded.  
1.6.3.3 
Renal impairment 
The incidence of grade 3 or higher creatinine levels was less than 5% and occurred in patients 
with multiple potential other contributing factors. Renal function will be monitored in this study 
and patients with significant baseline renal dysfunction excluded. 


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1.6.3.4 
Muscle spasms 
Muscle spasms are on-target adverse events and are considered a class effect for SMO 
inhibitors. No cases of rhabdomyolysis have been reported with glasdegib. In prior studies, 
grade 3 muscle spasms were seen in 1.2%. Patients with muscle spasms should receive 
adequate hydration and electrolyte imbalances should be corrected. Stretching may be helpful. 
Some have tried low-dose calcium channel blockers. Approximately 18% of those who had 
muscle cramps had ongoing symptoms at the time of treatment discontinuation, although mostly 
at low level. 
1.6.3.5 
Hyponatremia 
Hyponatremia was observed in some patients, usually grade 3 or less. There was a single case 
of grade 4 hyponatremia that could have been related to a concurrent medication that resolved 
the next day. Electrolytes will be monitored in this study.  
1.6.3.6 
Dysgeusia 
Dysgeusia is an on-target adverse event and is considered a class effect for SMO inhibitors 
reported in about 40% of patients, although almost always grade 1/2 and infrequently leading to 
treatment discontinuation. Approximately 41% of patients who had dysgeusia had ongoing 
symptoms at the time of treatment discontinuation. 
1.6.3.7 
Alopecia 
Alopecia is an on-target adverse event and is considered a class effect for SMO inhibitors with 
19.9% reported events, although almost always grade 1/2 and rarely leading to discontinuation. 
Of patients with alopecia, 75% had ongoing symptoms at the time of treatment discontinuation. 
 
1.6.3.8  
Dental effects 
 
Loose teeth and toothache were observed in fewer than 10% patients taking glasdegib in 
combination with chemotherapy. 


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2.0 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE: 
Determine whether 50 mg daily of glasdegib is safe and tolerable in the cGVHD population. 
2.2 
SECONDARY OBJECTIVES: 
2.2.1. Determine best overall response rate by 12 months (complete response + partial 
response) for sclerotic manifestations of cGVHD. 
2.2.2. Determine best overall response rate by 12 months (complete response + partial 
response) for all manifestations of cGVHD. 
2.2.3. Examine the safety profile of glasdegib in the cGVHD population.  
2.2.4. Bank blood and skin biopsy material for future biologic studies. 
3.0 
STUDY DESIGN 
This is a single-arm, open-label, phase I/II trial examining the efficacy and safety of glasdegib 
50 mg daily for treatment of sclerotic cGVHD. The FDA approved dose is 100 mg of glasdegib 
daily in the treatment of AML. The MTD in other glasdegib studies in healthy and cancer 
patients is 400 mg daily. 
Twenty subjects will be enrolled. A subject is considered enrolled the day the informed consent 
form is signed. To control the speed of enrollment and ensure that no more than 20 subjects are 
enrolled across the study, each participant must be approved by the coordinating center at Fred 
Hutchinson Cancer Research Center prior to enrollment. 
Eligible subjects will undergo up to 24 cycles of study therapy. At this point, there is no study 
support for longer glasdegib administration or monitoring. If study drug is discontinued 
prematurely, subjects will still complete remaining study assessments every 3 months through 
24 months, unless they refuse continued active participation, relapse, or start a new systemic 
immunosuppressive treatment, in which case they are followed by chart review only. If subjects 
discontinue study drug within the first 6 months of study participation (prior to C7D1), they 
should be seen next at the time point that coincides with an overall every-3-month visit cadence 
(i.e. C4D1 or C7D1, whichever is next). Any monthly visits in the interim are not required for 
patients who have stopped glasdegib. 
Refer to Appendix 2 for a comprehensive list of study assessments and their timing.  The study 
schema is provided below (FIGURE 1).  


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Figure 1.  Study Schema 
 
                 
 
 


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3.1 
STUDY PARAMETERS 
3.1.1 
Efficacy Parameters 
See Section 5.5.1 for definitions. 
3.1.2 
Safety Parameters 
The safety of glasdegib will be characterized by the type, frequency, severity, timing of onset, 
duration, and relationship to study drug of any treatment-emergent grade 3 or higher AEs, any 
severe adverse events (SAE) or AEs leading to discontinuation of study treatment or death.  
The severity of AEs will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE), version 5.0.  Standard definitions for seriousness will be applied (see Section 6.1). 
3.2 
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN 
A single arm, open-label trial is justified by the rarity of cGVHD and no prior published 
experience for this indication. 100 mg daily is the approved dose for acute myeloid leukemia. 
We will use the lower dose of 50 mg daily for 28 days to assess tolerability based on the 
preliminary experience of a Spanish group conducting a similar trial.  Only adults will be enrolled 
given the lack of data in pediatric populations. 
3.3 
SELECTION OF STUDY POPULATION 
3.3.1 
Inclusion Criteria 
Eligible subjects will be considered for inclusion in this study if they meet all of the following 
criteria: 
1. At least 18 years old 
2. Diagnosed with moderate or severe cGVHD according to the 2014 NIH Consensus 
Criteria 
3. Diagnosed with cGVHD-related sclerosis or fasciitis 
• 
Skin feature score of at least 2 OR 
• 
Joints and fascia score of at least 1 
4. New, stable or progressive sclerosis/fasciitis despite treatment with at least one prior line 
of systemic therapy for cGVHD. 
5. Female patients who: 
• 
Are documented to be postmenopausal or are surgically sterile, OR 


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• 
If of childbearing potential, agree to use at least 1 highly effective method of 
contraception from the time of signing the informed consent form through 30 
days after the last dose of study drug, OR agree to practice true abstinence or 
exclusively non-heterosexual activity when this is in line with the preferred and 
usual lifestyle of the subject 
6. Male patients who: 
• 
Are surgically sterile (vasectomized) OR 
• 
Agree to use at least 1 highly effective method of contraception during the entire 
study treatment period and through 30 days after the last dose of study drug, OR 
agree to practice true abstinence or exclusively non-heterosexual activity when 
this is in line with the preferred and usual lifestyle of the subject, AND   
• 
Agree to use a condom to prevent potential transmission of investigational drug 
in seminal fluid 
7. Patients who meet the following clinical laboratory criteria: 
• 
Absolute neutrophil count (ANC) >1000/µL, platelet count >50 x 109/mL 
• 
ALT and AST < 2x ULN and normal total bilirubin unless attributed to cGVHD 
• 
Creatinine < 2.0 mg/dl 
3.3.2 
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. Hospitalization for evaluation or management of an infection within the last 8 weeks 
2. Known organ dysfunction  
• 
Uncontrolled cardiovascular disease, including arrhythmias, congestive heart 
failure 
• 
Oxygen requirement 
3. Addition of any new systemic immunosuppressive treatment within the last 2 weeks 
• 
Addition of new systemic immunosuppressive treatment along with glasdegib is 
also prohibited. 


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4. QTc interval >480 ms 
5. Female patients who are lactating or have a positive serum pregnancy test 
6. Major surgery within 14 days before enrollment 
• 
Does not include placement of venous access device, bone marrow biopsy, 
GVHD diagnostic biopsy, or other routine procedures in chronic GVHD or post-
transplantation care 
7. Use of any concomitant medications meds that are prohibited within the past 7 days 
8. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol 
9. Known intolerance to glasdegib, sonidegib, or vismodegib 
10. Non-hematologic malignancy within the past 2 years with the exception of: 
• 
adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid 
cancer 
• 
carcinoma in situ of the cervix or breast 
• 
prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen 
levels 
• 
cancer considered cured by surgical resection or unlikely to impact survival 
during the duration of the study 
11. Treatment with non-FDA approved drug within 28 days of start of this trial 
12. Evidence of recurrent or progressive underlying malignant disease 
13. Karnofsky performance status < 70% 
14. History of non-compliance 
15. Life expectancy <6 months 
16. Grade 2 or 3 muscle cramping, or grade 1 muscle cramping that occurs at least weekly 
 
3.3.3 
Enrollment Procedures 
Potentially eligible patients will be approached at participating study centers. The treating 
clinician will review the informed consent document with them. After the subject has signed and 


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dated the Informed Consent Form (ICF), screening may begin. Once all screening procedures 
have been completed and eligibility has been confirmed, the subject can be enrolled into the 
study. The screening period lasts from the date the subject signs consent until they complete 
the enrollment visit and start study drug, which may be up to 28 days. 
Once 15 patients have been enrolled on study, the Coordinating center at Fred Hutchinson will 
assign screening slots to ensure that the study does not over-enroll. 
3.4 
STUDY DRUG 
3.4.1 
Premedications 
No specific premedications or supporting medications are required in conjunction with glasdegib 
administration. 
3.4.2 
Formulation, Packaging, and Storage 
Glasdegib tablets will be provided by Pfizer Worldwide Research and Development from clinical 
supply.  The study drug will be labeled and handled as open-label material, and packaging 
labels will fulfill all requirements specified by governing regulations.  Glasdegib will be supplied 
as 25 mg tablets for oral administration.  
 
Glasdegib will be packaged in high-density polyethylene bottles and should be handled with 
care. Each bottle will contain enough medication for the appropriate number of doses 
between study visits (one cycle worth dispensed at cycles 1-6, and three cycles’ worth 
dispensed at cycles 7 and beyond), plus an additional amount to cover the allowed time 
windows around visit scheduling. 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. 
 
Investigational product should be dispensed by an appropriately qualified and experienced 
member of the study staff (e.g., physician, nurse, physician's assistant, practitioner, or 
pharmacist) as allowed by local, state, and institutional guidance. 
Investigational glasdegib that will not be used (expired, returned, or leftover at end of study) 
should be destroyed on site according to the institution’s standard operating procedure, and 
removal and destruction must be documented on drug accountability logs. 


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3.4.3 
Administration of Study Drug  
Glasdegib will be administered at a dose of 50 mg once daily by mouth. Up to 24 months of 
glasdegib treatment will be administered on study. Glasdegib is 77% bioavailable with a time to 
peak concentration of less than 2 hours. The drug is metabolized through the CYP3A4 pathway 
with a half life of 17 hours. Steady state is reached after 8 days.  
 
At any time, patients may hold glasdegib because of side effects, toxicity or for logistic reasons. 
Any number of doses may be held as long as drug is resumed within 28 days. If glasdegib is 
held for longer than 28 days, it should not be restarted and the patient is just followed for clinical 
endpoints.  
 
All protocol-specific criteria for administration of study drug must be met and documented before 
drug is started.  Study drug will be administered or dispensed under the supervision of the 
investigator or identified sub-investigators.  Subjects should be monitored for toxicity, and doses 
of glasdegib should be modified as needed to accommodate subject tolerance to treatment. 
 
Glasdegib will be self-administered by the patient at home, unless otherwise specified. 
Glasdegib will be administered orally with approximately 8 ounces (240 mL) of water and 
should be taken in the morning, at the same time each day with or without food. Tablets 
must not be crushed or cut; they must be swallowed whole, not manipulated or chewed 
prior to swallowing. Patients should be instructed to not to 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 10 hours have passed since the scheduled dosing time, that dose should be 
taken as soon as possible. If more than 10 hours have passed since the scheduled dosing 
time, the dose should be skipped and the 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 subsequent doses the next day as prescribed. If a patient 
inadvertently takes 1 extra dose during a day, the patient should not take the next dose of 
glasdegib.  
3.4.4 
Assuring Subject Compliance 
Study patients will document their compliance through medication logs. The subject study drug 
diary is provided in Appendix 3.  


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3.5 
STUDY TREATMENT SCHEDULE 
Glasdegib will be administered at a dose of 50 mg once daily by mouth. Up to 24 months of 
glasdegib treatment will be administered on study. 
3.6 
DURATION OF THERAPY 
Subjects will be treated with glasdegib for up to 24 months depending on tolerability and 
response.  
3.7 
DOSING DELAYS AND MODIFICATIONS 
Subjects should be followed closely for AEs or laboratory abnormalities that might indicate 
glasdegib-related toxicity.  If a subject experiences a treatment-related toxicity of grade 3 or 
higher or other intolerable treatment-related AE of any grade during the course of therapy, then 
glasdegib should be withheld or the dose reduced, as necessary, until the AE resolves to grade 
≤ 2 or stabilizes to an acceptable degree.  
 
As appropriate, certain laboratory abnormalities may warrant more frequent monitoring (e.g., 
once per week) until abnormalities have recovered to Grade ≤ 1.   
Treatment with glasdegib should be withheld for any unmanageable, potentially study-drug-
related toxicity that is Grade ≥ 3 in severity or for QTc greater than 500 ms.  Any other clinically 
important events where dose delays may be considered appropriate must be discussed with the 
Principal Investigator. If glasdegib needs to be held for more than 28 days for a treatment-
related toxicity, it should not be restarted. 
3.8 
CONCOMITANT THERAPY 
3.8.1 
Permitted Concomitant Therapy 
Standard supportive care medications are permitted as per institutional standards. These 
include infectious prophylaxis and symptomatic management, as well as ongoing (begun prior to 
study enrollment) systemic and topical therapies for acute or chronic GVHD. New topical 
therapies for cGVHD are also permitted and will not constitute treatment failure. 
3.8.2 
Prohibited or Restricted Concomitant Therapy 
 
Other investigational agents are prohibited during the course of the study. Additionally, the co-
administration of glasdegib and strong CYP3A4 inducers is not permitted because this 
decreases glasdegib levels. While this situation is of less concern in the cGVHD 


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population than in the acute myeloid leukemia indication, we will follow the FDA-
approved guidance regarding CYP3A4 inducers. A list of strong CYP3A4 inducers and 
inhibitors is provided in Appendix 4. 
 
The potential exists for drug-drug interactions with CYP3A4/5 inhibitors, and co-administration 
of glasdegib in combination with moderate/strong CYP3A4/5 inhibitors is not recommended 
because this could lead to increased glasdegib levels. Moderate/strong CYP3A4/5 inhibitors 
(Appendix 4) should be used with caution and only if considered medically necessary. If 
a moderate/strong CYP3A4/5 inhibitor is to be initiated in addition to glasdegib, please 
contact the principal investigator for guidance. ECGs should be checked prior to 
addition of the CYP3A4/5 inhibitor and weekly afterwards x 2 weeks to ensure the QTc 
interval is < 500 ms. Empiric observations in healthy people and modeling simulation 
suggest no more than a 12 ms increase in QTc when glasdegib and a CYP3A4/5 
inhibitor are combined. 
 
The concomitant administration of glasdegib and drugs with a known risk of Torsades 
de Pointes (TdP) should be avoided whenever possible because the combination may 
increase the risk of QTc prolongation. A list of such drugs is provided in Appendix 9. 
Use of these drugs is not recommended unless there are no alternatives. If a TdP drug 
is to be initiated in addition to glasdegib, please contact the principal investigator for 
guidance. ECGs should be checked prior to addition of the TdP drug and weekly 
afterwards x 2 weeks to ensure the QTc interval is < 500 ms.  
 
3.9 
PRECAUTIONS 
3.9.1 
Pregnancy Prevention 
In this study, male subjects who are able to father children and female subjects who are of 
childbearing potential will receive glasdegib, a compound which has been associated with 
teratogenic risk. Subjects who are, in the opinion of the investigator, sexually active and at risk 
for pregnancy with their partner(s) must agree to use at least 1 highly effective form of 
contraception throughout the study and for at least 30 days after the last dose of 
investigational product. Male subjects must, additionally, use a condom to prevent potential 
transmission of investigational product in seminal fluid. The investigator or his or her 
designee, in consultation with the subject, will confirm that the subject has selected at least 
1 appropriate method of contraception from the list of permitted contraception methods (see 


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Table 2 below) and will confirm that the subject has been instructed in its consistent and 
correct use.  In addition, the investigator or designee will instruct the subject to call 
immediately if the selected contraception method is discontinued or if pregnancy is known 
or suspected in the subject or partner. 
 
TABLE 2  Highly effective methods of contraception  
Highly effective (failure rate <l % if used consistently and correctly) 
Low user dependency 
High user dependency 
• 
Progestogen-only contraceptive implant 
• 
Intrauterine hormone releasing 
system (IUS) 
 
• 
Intrauterine device (IUD) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Combined hormonal contraception 
(estrogen and progestogen) 
• 
Oral, intravaginal, transdermal, 
injectable 
• 
Progestogen-only hormonal contraception 
• 
Oral, injectable 
 
3.9.2 
Overdose Instructions 
Clinical information relevant to overdose is not available. For results from nonclinical overdose 
studies in rats and dogs, please refer to the Investigator Brochure. 
Study drug overdose is the accidental or intentional use of the drug in an amount higher than 
the dose being studied. An overdose or incorrect administration of study drug is not an AE 
unless it results in untoward medical effects. 
Any study drug overdose or incorrect administration of study drug should be noted on the 
appropriate CRF. 
All Grade ≥3 AE’s and all SAE’s associated with an overdose or incorrect administration of 
study drug should be recorded.   
In the event of subject ingestion of more than the recommended glasdegib dosage, observation 
for any symptomatic side effects should be instituted, and vital signs, biochemical and 
hematologic parameters should be followed closely (consistent with the protocol or more 
frequently, as needed).  Appropriate supportive management to mitigate adverse effects should 
be initiated.  If the overdose ingestion of glasdegib is recent and substantial, and if there are no 
medical contraindications, use of gastric lavage or induction of emesis may be considered. 


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3.10 DISCONTINUATION OF STUDY TREATMENT 
The investigator may discontinue study treatment for any subject, if, in the investigator’s opinion, 
it is not in the subject’s best interest to continue. Additionally, a subject has the right to stop 
study treatment at any time.  In addition, subjects may be withdrawn from study treatment for 
the following reasons: 
• 
Study treatment should be discontinued if the drug is held for a treatment-related toxicity 
lasting > 28 days as defined above.   
• 
Any subject who starts new systemic immunosuppressive therapy for the treatment of 
chronic GVHD, becomes pregnant, or is significantly noncompliant should stop study 
treatment. 
The End of Treatment visit should occur 28 days after the last dose of study drug. Patients 
should be followed on the study schedule, every 3 months (see Section 3.0), unless they start a 
new systemic immunosuppressive treatment for cGVHD, relapse, or refuse to continue 
participation. Patients will continue to be followed by chart review for survival, relapse and 
cGVHD outcomes unless they withdraw consent. 
Note that cGVHD progression itself does not require that subjects stop glasdegib unless a new 
systemic immune-suppressive medication is started. In some circumstances, investigators and 
subjects may want to continue glasdegib despite documented cGVHD progression if other 
options are not available. 
3.11 REMOVAL FROM STUDY 
Reasons for removal of a subject from the study are below. The End of Treatment visit should 
still be completed approximately 28 days after the last dose, if possible. 
• 
Subject’s withdrawal of consent from study 
• 
Decision by sponsor 
• 
Subject lost to follow-up 
• 
Relapse of malignancy 
• 
Death 
3.12 DATA AND SAFETY MONITORING 
This trial will be monitored in accordance with the Pfizer’s Pharmacovigilance procedures.  
Adverse events, and SAEs will be reviewed internally as part of ongoing safety surveillance.   


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Monthly communications with the investigators and applicable site staff will be conducted to 
discuss study progress, obtain investigator feedback and exchange, and discuss "significant 
safety events" (i.e., AEs leading to dose reductions, related SAEs, and deaths). 
In addition, an external DSMB will monitor the study every 6-12 months until the last patient has 
received 2 months of therapy, unless there are concerns that require ongoing monitoring.  
While glasdegib has demonstrated safety, it has not been previously studied in cGVHD therapy 
after allogeneic hematopoietic cell transplantation. Current evidence suggests that mortality 
after initiation of cGVHD therapy may be as high as 20% at 56 days in some high-risk patient 
groups (Blood and Marrow Transplant Clinical Trial Network Protocol 0801). No interim analysis 
is planned during this trial, but there will be continuous monitoring for a stopping rule if an exact 
1-sided 80% confidence interval for the true non-relapse mortality exceeds 10% -- for example, 
if 2 of first £ 8, 3 of first £ 15, 4 of first £ 20 experience non-relapse mortality in the first 2 
months. If the true probability of non-relapse mortality is 5%, the probability of study suspension 
under the above rule is approximately 0.08; if the true probability is 40%, the probability of 
suspension is approximately 0.99, estimated from 5,000 simulations, using R version 3.5.0.  
Further details of the stopping rule include the following: 
• 
Treatment-related mortality is any death occurring while receiving study drug, or within 30 
days after discontinuation of study drug, that is possibly, probably or definitely related to the 
drug 
• 
Relapse or progressive disease will factor into the attribution of cause but will not 
automatically prevent a death from being classified as treatment-related 
• 
For purposes of this stopping rule, the count of patients (8, 15, etc) will reflect the order in 
which patients start treatment 
• 
If a DSMB review is required because the stopping rule is triggered, patients who are 
already enrolled and taking glasdegib may continue treatment, pending the outcome of that 
review. Any enrolled patient who has consented but not started study drug may not start 
glasdegib treatment, pending the outcome of that review. 
• 
The DSMB may, after review, recommend to stop the trial or continue it with or without 
modifications. 
We will also include a stopping rule for grade >3 AEs that are known to be adverse reactions to 
glasdegib and hedgehog inhibitor pathway class drugs, such as musculoskeletal pain, muscle 
spasm, QT prolongation, anorexia, nausea, diarrhea, dizziness, elevated creatinine, elevated 


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transaminases, and tooth problems. If the lower bound of an 80% exact binomial confidence 
interval is > 20%, operationally given the total sample size 20, if any 2 of the first 4 or fewer 
subjects or any 3 of the first 7 or fewer subjects or any 4 of the first 11 or fewer subjects or any 
5 of the 15 or fewer subjects or 6 of the first 20 or fewer subjects have unacceptable toxicity or 
Grade 3 or higher severity AEs, then enrollment will be halted while the DSMB reviews the 
study. If the true probability of Grade 3 or higher AE is 5%, the probability of study suspension 
under the above rule is approximately 0.02; if the true probability is 40%, the probability of 
suspension is approximately 0.85 (probabilities estimated from 5,000 simulations, using R 
version 3.5.0). 
 
Since 2 of the first 4 patients experienced grade 3 muscle cramping, the stopping rule was 
triggered. Of note, these 2 patients had cramping prior to enrollment. The DSMB reviewed the 
data and allowed enrollment to continue but with an exclusion criterion for pre-enrollment grade 
2 or 3 muscle cramps, or grade 1 cramps that occur at least weekly.  For the purposes of the 
stopping rule, we will start again with subject #5, so if 2 of the next 4 or fewer, 3 of the next 7 or 
fewer, 4 of the next 10 or fewer, or 5 of the next 15 have unacceptable toxicity or grade 3 or 
higher severity AEs, then enrollment will be halted again while the DSMB reviews the study. If 
the true probability of Grade 3 or higher AE is 5%, the probability of study suspension under the 
above rule is approximately 0.02; if the true probability is 40%, the probability of suspension is 
approximately 0.85 (probabilities estimated from 5,000 simulations, using R version 3.5.0). 
 
 
At the recommendation of the FDA, this trial will include a futility stopping rule for overall 
response rate by 12 months based on Simon’s two-stage design.39 If the null hypothesis is that 
the true overall response rate (CR+PR) is <20% and the alternative hypothesis is that the 
response rate is greater than 50%, in the first stage, at least 10 patents will be accrued, and if 2 
or fewer responses are observed in the first 10, the study will be suspended. Otherwise, a total 
of 19-20 patients will be accrued, and the null hypothesis will be rejected if 8 or more responses 
are observed in 19 patients. This design yields a one-sided type I error rate of 0.025 and power 
of 80% by minimax. The calculation used R version 3.5.0 and Simon’s two-stage design from 
the following website: 
(http://cancer.unc.edu/biostatistics/program/ivanova/SimonsTwoStageDesign.aspx). This 
stopping rule will be evaluated by the DSMB at each meeting but would not be invoked unless 
the first 10 patients are fully evaluable for overall response rate by 12 months, acknowledging 


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that that trial may be fully accrued before then. All enrolled and treated patients will be included 
in this futility analysis. 
At the coordinating center at Fred Hutch, the study will be reviewed annually by the Consortium 
Data and Safety Monitoring Committee (DSMC) according to current Institutional policies. The 
DSMC will review accrual, unanticipated problems, SAE’s, and DSMB reports.  
As the Coordinating Center PI and IND holder, the Fred Hutch PI will obtain copies of all local 
site IRB approvals, will receive and review adverse event reports, and will disseminate that 
information to the appropriate committees and the DSMB. The Fred Hutch PI will also have 
responsibility for establishing and carrying out procedures for assessing protocol compliance, 
data accuracy and completeness, and full and timely reporting of safety data to outside sites.  
In addition to continuous safety monitoring by the Investigators, internal monitoring will occur at 
each site by staff independent of the study team using monitoring plans approved by the 
National Cancer Institute (since all sites will be Comprehensive Cancer Centers) and reviewed 
by Fred Hutchinson.  
The initial monitoring visit will occur no later than 6 months after the first subject has begun 
study treatment. Subsequent visits will occur approximately every 6-12 months while subjects 
are enrolling and receiving study treatment. Monitoring reports will be reviewed by the Fred 
Hutch PI. 
 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS 
The schedule of events is provided in Appendix 2.  Descriptions of the scheduled evaluations 
are outlined below and complete information on study drug and dosing is provided in Section 
3.4.  
4.1 
DESCRIPTION OF PROCEDURES 
4.1.1 
Informed Consent 
The subject must read, understand and sign the ICF approved by the institutional review board 
or independent ethics committee (IRB/IEC), confirming his or her willingness to participate in 
this study before initiating any screening activity that is not standard of care.  Subjects must also 
grant permission to use protected health information, if required by local regulations. 


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4.1.2 
Medical History 
Collect and record the subject’s relevant medical history through review of medical records and 
by interview.  Concurrent medical signs and symptoms must be documented to establish 
baseline severities.  A disease history, including the date of initial diagnosis and list of all prior 
systemic chronic GVHD treatments also will be recorded. 
4.1.3 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 6.1. AEs will be recorded 
using CTCAE version 5.0 criteria. Important additional requirements for reporting SAEs are 
explained in Section 6.2.4. 
4.1.4 
Concomitant Medications and Therapy 
Document all concomitant systemic medications and procedures from within 21 days before the 
start of study drug administration through 28 days after the last dose of study drug. 
4.1.5 
Confirmation of Eligibility 
Subject eligibility for enrollment will be assessed per Section 3.3.1 and 3.3.2.  All screening 
procedures, unless otherwise indicated, should be completed within 28 days of the first dose of 
study drug. 
4.1.6 
Karnofsky Performance Status 
The Karnofsky performance index is provided in Appendix 5 and must be captured at enrollment 
to confirm eligibility. 
4.1.7 
Physical Examination, Vital Signs, Height & Weight 
The screening physical examination will include, at a minimum, the height (screening only) and 
weight, blood pressure and general physical examination. 
Symptom-directed and response assessment physical exams will be done during the treatment 
period and at the End of Study visit. 
4.1.8 
Serum Pregnancy Test 
Pregnancy tests will be required for women of childbearing potential during screening.   
4.1.9 
Hematology 
Hematology studies must include complete blood count (CBC) with differential, including 
hemoglobin, hematocrit, platelet count, and ANC.    


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4.1.10 
Serum Chemistry 
Chemistry panel must include alkaline phosphatase, ALT, creatinine, total bilirubin, sodium, 
potassium, magnesium. 
4.1.11 
Pulmonary Function Tests and Spirometry 
Full pulmonary function testing is required at Cycle 1 Day 1.  Only spirometry is required at day 
1 of cycles 4, 7, 10, and 13, and EOT. Spirometry is required at day 1 of cycles 16, 19, and 22 if 
a patient has bronchiolitis obliterans syndrome or as clinically indicated.  
4.1.12 
Patient-Reported Outcomes  
Subjects will complete the Lee Chronic GVHD Symptom Scale and the Patient-reported 
Outcomes Measurement Information System (PROMIS)-29 survey (See Appendix 10) at Day 1 
of cycles 1, 4, 7, 10, 13, 16, 19, 22 and End of Treatment.  
 
The Lee Chronic GVHD symptom scale (LSS) is a 30 item measure with one summary score 
and 7 domains: skin, mouth, eye, lung, psychoemotional, vitality and nutrition.40,41 Higher scores 
indicate higher symptom burden. Scores may be calculated if more than half of items in a 
subscale are answered. Scores range from 0-100 with higher scores indicated greater symptom 
burden. A difference of 6-7 points on the summary score is considered clinically meaningful but 
since this scale measures cGVHD symptoms, general population norms are not available. 
 
The PROMIS-29 contains 29 scored items and 7 subscales: for the physical and social 
functioning scales, higher scores indicate better functioning; for fatigue, pain, anxiety, 
depression, and sleep scales, higher scores indicate a higher symptom burden.42 Similar to the 
SF-36, scores are normalized to 50 with a STD of 10 with higher scores indicating better 
functioning, and scores greater than 0.5 times STD (i.e., <45 or >55, compared to the general 
population) are considered clinically meaningful. 
 
 
4.1.13 
Clinician-Reported Outcomes 
The NIH Chronic GVHD Response Assessment (Appendix 6) will be completed monthly, based 
on physical exam findings, testing and patient interviews. The assessment must be completed 
by a clinician.  


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4.1.14 
Biologic Studies 
These studies aim to discern the biologic impact of Hedgehog pathway inhibition in the 
treatment of cGVHD. Peripheral blood samples (20 mL in a heparinized tube and 4 mL in an 
EDTA tube) will be obtained on day 1 of cycles 1, 2, 4, and 7 and processed into peripheral 
blood mononuclear cells and plasma. Samples will be frozen and batch shipped to Fred Hutch 
for storage and potential study later depending on the clinical results of the trial. Four-millimeter 
punch biopsies will be obtained before and after 6 months of treatment with glasdegib in 
consenting patients. Patients may still participate in the trial if they refuse the research skin 
biopsies. Biopsies are bisected, with half stored in RNAlater, and half embedded in OCT 
(optimal cutting temperature compound), for later analysis.  Skin biopsies will not be performed 
if there are contraindications as outlined in Manual of Operations. 
4.1.15 
Study Drug Accountability 
Subjects will return unused medication at each study visit. 
4.2 
ASSESSMENT OF RESPONSE TO TREATMENT 
Response assessments will be evaluated based on NIH Criteria (refer to Appendix 7). 
4.3 
END OF TREATMENT VISIT AND SAFETY FOLLOW-UP  
An End of Treatment (EOT) visit is required for safety assessments for any subjects who 
permanently discontinue study drug for any reason, including after completing 24 months of 
treatment on study.  The EOT visit should be scheduled within 28 days (with +/- 7-day window) 
after the last dose of study drug but is not required for subjects who discontinue from the study 
within 10 days of a completed, scheduled study visit.  
If a patient is not willing or able to return for evaluation or is seen prior to 28 days after the last 
dose of study medication, study staff will call the patient to document any new events occurring 
within 28 days of the last dose (safety follow-up).  
4.4 
FOLLOW-UP FOR NEW SYSTEMIC TREATMENT, DISEASE RELAPSE, AND 
SURVIVAL 
4.4.1 Long-term Follow-up 
Once subjects discontinue glasdegib and start a new systemic immunosuppressive treatment, 
refuse to continue participation, or are diagnosed with relapsed malignancy, they will be 
followed via medical record review for new systemic cGVHD treatment, disease relapse, and 
survival. 


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4.5 
MISSED EVALUATIONS 
Missed evaluations should be rescheduled and performed as close to the original scheduled 
date as possible.  An exception is made when rescheduling becomes, in the investigator’s 
opinion, unsafe or medically unnecessary because it is too close in time to the next scheduled 
evaluation.  In that case, the missed evaluation should be abandoned and the reason for the 
missed visit recorded in the database. 
5.0 
STATISTICAL METHODS OF ANALYSIS  
5.1 
GENERAL CONSIDERATIONS 
This is a Phase I/II, single-arm trial designed to assess the safety and efficacy of glasdegib in 
subjects with sclerotic cGVHD.  
5.2 
RATIONALE FOR SAMPLE SIZE 
With a sample size of 20 patients, the best ORR will be estimated with an 80% exact binomial 
confidence intervals (CIs).43  If glasdegib is more effective than ibrutinib, the lower bound of the 
CIs will be used to provide evidence that the true ORR is greater than a specific response rate.  
For instance, if there are 17 response (CR+PR) out of 20 patients (85%), the corresponding 
80% CI will exclude 67% which is greater than the published historical chronic GVHD trials with 
ORR 67%. However, even if glasdegib is not statistically more effective than ibrutinib, it may still 
be a preferable treatment if the toxicity is less or the response rate for sclerotic features is 
encouraging.  
5.3 
ANALYSIS POPULATIONS 
All efficacy and safety analysis will be performed using the treated population, which consists of 
all subjects who receive any amount of study treatment. The characteristics of this population 
will be described. The analysis of duration of response will only include subjects who have 
achieved objective response. 
5.4 
MISSING DATA HANDLING 
No imputation of values for missing data will be performed except: missing or partial start and 
end dates for AEs and concomitant medication will be imputed according to prespecified, 
conservative imputation rules. Subjects lost to follow-up (or drop out) will be included in 
statistical analyses to the point of their last evaluation. 


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5.5 
ENDPOINT DATA ANALYSIS 
5.5.1 
Study Treatment Administration and Compliance 
Descriptive information will be provided regarding the number of glasdegib cycles completed 
and the number and timing of prescribed dose delays, reductions and interruptions.   
5.5.2 
Analysis of Endpoints 
5.5.2.1 
Primary Endpoint 
 
The primary endpoint is the safety and tolerability of glasdegib in the cGVHD population. This 
will be reported as the type and severity of adverse events, severe adverse events and number 
of cycles completed and reasons for discontinuation. 
5.5.2.2 
Secondary Endpoints 
The secondary endpoints are best overall Response Rate (ORR) in sclerotic manifestations, 
best ORR in all cGVHD manifestations, and safety.  
Overall Response Rate (ORR) in sclerotic manifestations 
Best ORR of sclerotic manifestations by 12 months after the initiation of glasdegib and before 
another systemic immunosuppressive regimen is started represents the composite outcome of 
complete and partial response (CR + PR). ORR will be calculated according to (1) the response 
definitions of the NIH Consensus Conference for (a) skin or joint scores (0-3), where 
improvement by at least 1 point is a PR and return to score 0 is a CR, or (b) the photographic 
range of motion scale (0-25) where improvement by at least 1 point is a PR and return to score 
25 is a CR; and (2) change in the 0-10 sclerotic severity scale where at least a 2 point 
improvement is a PR or return to 0 (CR). 
Overall Response Rate (ORR) in all cGVHD manifestations 
Best ORR of all cGVHD manifestations by 12 months after the initiation of glasdegib and before 
another systemic immunosuppressive regimen is started represents the composite outcome of 
complete and partial response (CR + PR). ORR will be calculated according to the response 


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definitions of the NIH Consensus Conference. ORR both including and excluding skin sclerotic 
features will be reported. 
Safety 
Safety assessments will consist of monitoring and recording adverse events. See section 6.0 
below. 
In addition, we will describe the following exploratory endpoints: 
Failure-Free Survival  
This endpoint will be estimated at 12 months with events considered death, relapse, or start of 
another systemic immunosuppressive agent. Patients lost to follow-up or who withdraw consent 
will be censored.  
Patient-reported outcomes  
Subjects will provide assessments of their symptom burden and quality of life using a validated 
instrument recommended by the NIH Consensus on Chronic GVHD (Lee Chronic GVHD 
Symptom Scale) and the NIH-endorsed PROMIS-29 (See Appendix 10). These will be collected 
before starting glasdegib on day 1 of cycle 1, and again on D1, cycles 4, 7, 10, 13, 16, 19, 22  
and EOT. Scores will be calculated for each instrument based on published algorithms with 
absolute changes from baseline and clinically meaningful changes described for the population 
as a whole and based on CR+PR vs. SD+MR+PD. 
Biologic studies 
These studies aim to discern the biologic impact of Hedgehog pathway inhibition in the 
treatment of cGVHD and may include the following skin assays as well as others: expression of 
Shh, Gli1, Gli2, ptch-2, collagen, TGFb, and Smo. Immunohistochemistry may be performed for 
Patched, Shh, Snail, GSK3-b, b-catenin, or Ihh as well as other markers.  
6.0 
SAFETY MONITORING 
6.1 
DEFINITIONS 
Adverse Event 
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans, whether considered drug related or not. It can be any unfavorable and unintended sign 
(e.g., an abnormal laboratory finding), symptom, or disease, temporally associated with the use 
of a drug whether it is related to the drug or not.  This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency. 


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Unexpected Adverse Event 
An adverse event is considered unexpected if it is not listed in the investigator brochure or is not 
listed at the specificity or severity that has been observed in the event.  “Unexpected” also 
refers to adverse events that are mentioned in the investigator brochure as occurring with a 
class of drugs or as anticipated from the pharmacological properties of the drug but are not 
specifically mentioned as occurring with the drug under investigation.  
Serious Adverse Event 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to the grade 
of an AE (see below).  “Serious” is a regulatory definition and is based on subject or event 
outcome or action criteria usually associated with events that pose a threat to a subject’s life or 
functioning.  Seriousness (not severity) serves as the guide for defining regulatory reporting 
obligations from the Sponsor to applicable regulatory authorities. A serious adverse event (SAE) 
is any adverse event, without regard to causality, that includes any of the following: 
• 
Death 
• 
A life-threatening adverse event (places the subject at an immediate risk of death) 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant disability or incapacitation (substantial disruption of the ability 
to conduct normal life functions) 
• 
A congenital anomaly or birth defect 
• 
Is a medically important event.  This refers to an AE that, in the medical judgment of 
the Principal Investigator, may jeopardize the subject, or may require medical or surgical 
intervention to prevent one of the outcomes listed above.  
 
A planned medical or surgical procedure is not, it itself, an SAE. 
6.1.1 
Severity 
The study site will grade the severity of adverse events experienced by study participants 
according to CTCAE version 5.0.  Grade 1 and grade 2 adverse events do not require reporting 
in this study. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of 
severity for each referenced AE.  Should a subject experience any AE not listed in the CTCAE, 
the following grading system should be used to assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience 
or concern to the subject, and which may interfere with daily activities, but are 
usually ameliorated by simple therapeutic measures 


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• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, 
significantly interrupt the subject’s usual daily activity, and require systemic drug 
therapy or other treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject 
to be in imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in subject death 
6.2 
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS ADVERSE 
EVENTS 
The study will collect all Grade 3 and above adverse events, regardless of relationship to study 
therapy or study procedures, unless the event is one of the exceptions listed below.  Severity 
grading will be based on CTCAE version 5.0. Grade 1 and 2 events will not be collected. 
The following will NOT be collected as adverse events: 
• An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. Any 
laboratory value meeting seriousness criteria must also be reported. 
• Manifestations of chronic GVHD will not be collected as AE’s unless they meet 
seriousness criteria.  
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an adverse event. 
Non-serious, Grade 3 and above adverse events must be recorded in the database within 20 
days of becoming aware of the event. Non-serious adverse events collected in the database will 
be compiled by the coordinating center and reported to the DSMB at regularly scheduled 
meetings.  
Reporting procedures: All serious adverse events must be reported to Pfizer within 24 hours of 
first awareness of the event. If the event is fatal or life-threatening, it must be reported 
immediately. SAEs should be reported as soon as they are determined to meet the definition, 
even if complete information is not yet available. Sites must notify the coordinating center at 
Fred Hutchinson, and the study staff at Fred Hutchinson will prepare the report for Pfizer. 
Reports will be submitted on the Pfizer-provided Investigator-Initiated Research Serious 
Adverse Event Report Form, and faxed to Pfizer along with the Reportable Event Fax Cover 
Sheet.  The Sponsor-Investigator at Fred Hutchinson will determine whether the event meets 
the criteria for expedited reporting, and will prepare the IND Safety Report as necessary. 
Significant and relevant follow-up information should also be reported to Pfizer as soon as 


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possible. Fred Hutchinson and the sites will assist Pfizer in investigating any SAE and will 
provide any follow-up information reasonably requested by Pfizer.  
6.2.1 
Adverse Event Reporting Period 
The AE reporting period for this study begins when the subject receives the first dose of study 
drug and ends with the EOT visit, or 28 days after the last dose of study drug, whichever is later.  
Exception to this reporting period are (a) any AE occurring due to a protocol-specific screening 
procedure; and (b) if any SAE occurs beyond 28 days after the last dose of glasdegib AND it is 
assessed by the investigator as possibly related to glasdegib, it must be reported as an SAE.  
6.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation timepoints 
during the study.  All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, or detected through physical examination, or other means, will be 
recorded in the subject’s medical record and on the AE CRF.  
Each recorded AE or SAE will be described by its diagnostic term, duration (eg, start and end 
dates), severity, regulatory seriousness criteria, if applicable, suspected relationship to the study 
drug (see following guidance), and any actions taken.  The relationship of AEs to the study drug 
will be assessed by means of the question: ‘Is there a reasonable possibility that the event may 
have been caused by the study drug?’ per FDA guidance on safety reporting requirements (FDA 
Guidance 2012).  
See Appendix 8 for more detail on assessing relationship. 
6.2.3 
Pregnancy, lactation, and occupational exposure 
Even though there may not be an associated SAE, exposure to glasdegib during pregnancy, 
exposure during lactation, and occupational exposure are all reportable, and reporting 
procedures should follow those for SAEs.   
All pregnancies and partner pregnancies that are identified during or after this study, wherein 
the estimated date of conception is determined to have occurred from the time of consent to 30 
days after the last dose of study medication will be reported, followed to conclusion, and the 
outcome reported. 
Subjects should be instructed to immediately notify the investigator of any pregnancies.  Any 
female subjects receiving study drug who become pregnant must immediately discontinue study 
drug. The investigator should counsel the subject, discussing any risks of continuing the 
pregnancy and any possible effects on the fetus. 


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6.2.4 
Hy’s Law Cases 
Cases of potential drug-induced liver injury as assessed by laboratory values are also 
reportable to Pfizer as SAEs. If a study subject develops abnormal values in AST and/or ALT, 
concurrent with abnormal elevations in total bilirubin and no other known cause of livery injury, 
that event is classified as a Hy’s Law Case and must be reported.  
6.2.5 
IND Safety Reporting 
An event must meet all three of the following criteria in order to qualify for expedited reporting to 
the FDA in an IND Safety Report: 
• 
Serious 
• 
Unexpected 
• 
Suspected adverse reaction (i.e. there is a reasonable possibility that the drug 
caused the event) 
 
The Sponsor-Investigator is ultimately responsible for determining whether all criteria are met. 
Details are as follows: 
 
• 
Seriousness: If either the sponsor-investigator or local investigator believes that an event is 
serious, it must be considered serious and evaluated by the sponsor-investigator for expedited 
reporting. Similarly, if either the sponsor-investigator or local investigator believes that an event 
is life threatening, it must be considered life threatening for reporting purposes. 
 
• 
Expectedness: The sponsor-investigator is responsible for determining whether an event is 
unexpected. 
 
• 
Causality: Although local investigators are required to provide a causality assessment for each 
serious adverse event originating from their sites, it is ultimately the sponsor-investigator who 
decides whether the event meets the definition of a suspected adverse reaction.  
 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
The Sponsor retains the right to terminate the study and remove all study materials from a study 
site at any time.  Specific circumstances that may precipitate such termination are: 
• 
Unsatisfactory subject enrollment with regard to quality or quantity 


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• 
Significant or numerous deviations from study protocol requirements, such as failures to 
perform required evaluations on subjects and maintain adequate study records 
• 
Inaccurate, incomplete and/or late data recording on a recurrent basis 
• 
The incidence and/or severity of AEs in this or other studies indicating a potential health 
hazard caused by the study treatment 
7.1 
INFORMED CONSENT AND PROTECTED SUBJECT HEALTH INFORMATION 
AUTHORIZATION 
The investigator, or designee, must explain to each subject the purpose and nature of the study, 
the study procedures, the possible adverse effects, and all other elements of consent as defined 
in § 21 Code of Federal Regulations (CFR) Part 50, and other applicable national and local 
regulations governing informed consent form.  Each subject must provide a signed and dated 
informed consent before enrollment into this study.  In the case of a subject who is incapable of 
providing informed consent, the investigator (or designee) must obtain a signed and dated 
informed consent form from the subject’s legal guardian.  Signed consent forms must remain in 
each subject’s study file and be available for verification by study monitors at any time. 
In accordance to individual local and national subject privacy regulations, the investigator or 
designee must explain to each subject that for the evaluation of study results, the subject’s 
protected health information obtained during the study may be shared with regulatory agencies 
and IRBs/IECs. It is the investigator’s or designee’s responsibility to obtain written permission to 
use protected health information from each subject, or if appropriate, the subject’s legal 
guardian.  If a subject or subject’s legal guardian withdraws permission to use protected health 
information, it is the investigator’s responsibility to obtain the withdrawal request in writing from 
the subject or subject’s legal guardian and to ensure that no further data will be collected from 
the subject.  Any data collected on the subject before withdrawal will be used in the analysis of 
study results. 
7.2 
RECORD RETENTION 
The investigators and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study.  Mandatory documentation includes copies of study 
protocols and amendments, each Form FDA 1572, IRB/IEC approval letters, signed ICFs, drug 
accountability records, SAE information, subject files (source documentation) that substantiate 
database entries, all relevant correspondence and other documents pertaining to the conduct of 
the study. 


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The investigator shall retain study records in accordance with institutional and/or national/local 
regulations, whichever is longer. 


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2016;22(4):752-758. 
42. 
Jensen RE, Potosky AL, Moinpour CM, et al. United States Population-Based Estimates 
of Patient-Reported Outcomes Measurement Information System Symptom and Functional 
Status Reference Values for Individuals With Cancer. J Clin Oncol. 2017;35(17):1913-1920. 
43. 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika. 1934;38 (1):404-413. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 1.  NIH Global Severity of Chronic GVHD 
Mild chronic GVHD 
 
 
1or 2 organs involved with no more than score 1 plus 
 
Lung score 0  
 
Moderate chronic GVHD 
 
 
3 or more organs involved with no more than score 1 
 
 
 
OR 
 
 
At least 1 organ (not lung) with a score of 2 
 
 
 
OR 
 
 
Lung score 1 
 
 
Severe chronic GVHD 
 
 
At least 1 organ with a score of 3 
 
 
 
OR 
 
 
Lung score of 2 or 3 
 
 
Key points: 
1. In skin: higher of the two scores to be used for calculating global severity. 
 
2. In lung: FEV1 is used instead of clinical score for calculating global 
severity. 
 
3. If the entire abnormality in an organ is noted to be unequivocally explained 
by a non-GVHD documented cause, that organ is not included for 
calculation of the global severity.  
 
4. If the abnormality in an organ is attributed to multifactorial causes (GVHD 
plus other causes) the scored organ will be used for calculation of the 
global severity regardless of the contributing causes (no downgrading of 
organ severity score). 


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Appendix 2.  Schedule of Assessments 
 
 
SCR 
C1D1 
C1D8 
C1D 
15, 22 
C2D1 
C2D15 
C3D1 
C4D1 
C5D1 
C6D1 
C7D1 
C10D1, 
C13D1, 
C16D1, 
C19D1, 
C22D1 
EOT 
Visit Windows 
-28 days 
-7 
days* 
+/- 3 days 
+/- 7 days 
Signed informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam and GVHD evaluation 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Clinical labs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram5 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Research blood samples5 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Skin biopsy 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Pulmonary function test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Spirometry5 
 
 
 
 
 
 
 
X 
 
 
X 
X4 
X 
Patient-reported outcomes3 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
Chronic GVHD Provider Assessment 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Dispense glasdegib study drug 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
1 Clinical labs to include CBC, ALT, AlkPhos, Total bilirubin, Creatinine, Sodium, Potassium, Magnesium.  Verify that creatine kinase 
is normal prior to first dose. 
2 Serum pregnancy test required for women of childbearing potential within -7 days of C1D1. 
3 Patient-reported outcomes to include: Lee Chronic GVHD Symptom Scale and PROMIS-29 (Appendix 10) 
4 Spirometry required for cycles 10 and 13. Spirometry at cycles 16, 19, 22 is required only if a patient has BOS, otherwise as 
clinically indicated 
5 Not required for patients who have discontinued glasdegib. (Spirometry is still required at EOT, unless it has already been done 
within the past 3 months.) 


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*Everything within this column can be done within the 7 days prior to the first dose, or on the actual Day 1. Do not need to repeat 
physical exam, clinical labs, or ECG if done within -7 days for screening. In all cases, study staff will check in with the patient by 
phone or in person within 48 hours prior to the first dose in order to confirm that there have been no significant changes to the 
patient’s GVHD or overall health. 
 
Target visit dates will be calculated based on a 28-day treatment cycle, and with C1D1 as the starting date.  
 
End of Treatment (EOT) visit should occur 28 days (+/- 7 days) from last dose of study drug. 
 


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Appendix 3.  Subject Drug Diary 
 
 
 
 


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Appendix 4.  Known Strong in Vivo Inhibitors or Inducers of CYP3A 
 
Strong Inhibitors of CYP3Aa 
Strong Inducers of CYP3Ad 
boceprevir 
carbamazepinee 
clarithromycinb 
phenytoine 
conivaptinb 
rifampine 
indinavir 
St John's worte  
itraconazoleb 
 
ketoconazoleb 
 
lopinavir/ritonavirb (combination drug) 
 
mibefradilc 
 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavirb 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
voriconazole 
 
  
a. 
A strong inhibitor is defined as an inhibitor that increases the AUC of a substrate by ≥ 5-fold. 
b. 
In vivo inhibitor of P-glycoprotein. 
c. 
Withdrawn from the United States market because of safety reasons. 
d. 
A strong inducer is defined as an inducer that results in ≥ 80% decrease in the AUC of a substrate. 
e. 
In vivo inducer of P-glycoprotein.   
 
Note: The list of drugs in these tables is not exhaustive.  Any questions about drugs not on this list should be addressed to the 
Sponsor of the protocol. 
Source: 
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers . Web link Accessed 11 June 2015: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#inViv
o 
 
 
 


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Appendix 5.  Karnofsky Performance Status Scale Definitions Rating (%) 
Criteria  
Able to carry on normal activity and to work; no 
special care needed. 
  100   Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs 
or symptoms of disease.  
Unable to work; able to live at home and care 
for most personal needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but is 
able to care for most of his personal 
needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission 
is indicated although death not 
imminent. 
20 
Very sick; hospital admission 
necessary; active supportive 
treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
References: 
Crooks, V, Waller S, et al. The use of the Karnofsky Performance Scale in determining 
outcomes and risk in geriatric outpatients. J Gerontol. 1991; 46: M139-M144. 
de Haan R, Aaronson A, et al. Measuring quality of life in stroke. Stroke. 1993; 24:320- 327. 
Hollen PJ, Gralla RJ, et al. Measurement of quality of life in patients with lung cancer in 
multicenter trials of new therapies. Cancer. 1994; 73: 2087-2098. 
O'Toole DM, Golden AM. Evaluating cancer patients for rehabilitation potential. West J Med. 
1991; 155:384-387. 
Oxford Textbook of Palliative Medicine, Oxford University Press. 1993;109. 
Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: Reliability, validity, 
and guidelines. J Clin Oncology. 1984; 2:187-193. 


 
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Appendix 6.  NIH Response Assessment 
 


 
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Appendix 7.  Response Determination 
Response determination for chronic GVHD clinical trials based on clinician assessments 
Organ 
Complete Response 
Partial Response 
Progression 
Skin 
NIH Skin Score 0 after previous 
involvement 
Decrease in NIH Skin Score by 1 
or more points 
Increase in NIH Skin Score by 1 
or more points, except 0 to 1 
Eyes 
NIH Eye Score 0 after previous 
involvement 
Decrease in NIH Eye Score by 1 
or more points 
Increase in NIH Eye Score by 1 
or more points, except 0 to 1 
Mouth 
NIH Modified Oral Mucosa 
Rating Score 0 after previous 
involvement 
Decrease in NIH Modified Oral 
Mucosa Rating Score of 2 or 
more points 
Increase in NIH Modified Oral 
Mucosa Rating Score of 2 or 
more points 
Esophagus 
NIH Esophagus Score 0 after 
previous involvement 
Decrease in NIH Esophagus 
Score by 1 or more points 
Increase in NIH Esophagus 
Score by 1 or more points, 
except 0 to 1 
Upper GI 
NIH Upper GI Score 0 after 
previous involvement 
Decrease in NIH Upper GI Score 
by 1 or more points 
Increase in NIH Upper GI Score 
by 1 or more points, except 0 to 1 
Lower GI 
NIH Lower GI Score 0 after 
previous involvement 
Decrease in NIH Lower GI Score 
by 1 or more points 
Increase in NIH Lower GI Score 
by 1 or more points, except from 
0 to 1 
Liver 
Normal ALT, alkaline 
phosphatase, and Total bilirubin 
after previous elevation of one or 
more 
Decrease by 50% 
Increase by 2x ULN 
Lungs 
-Normal %FEV1 after previous 
involvement 
-If PFTs not available, NIH Lung 
Symptom Score 0 after previous 
involvement 
-Increase by 10% predicted 
absolute value of %FEV1 
-If PFTs not available, decrease 
in NIH Lung Symptom Score by 
1 or more points 
-Decrease by 10% predicted 
absolute value of %FEV1 
-If PFTs not available, increase in 
NIH Lung Symptom Score by 1 
or more points, except 0 to 1 
Joints and 
Fascia 
Both NIH Joint and Fascia Score 
0 and P-ROM score 25 after 
previous involvement by at least 
one measure 
Decrease in NIH Joint and 
Fascia Score by 1 or more points 
or increase in P-ROM score by 1 
point for any site 
Increase in NIH Joint and Fascia 
Score by 1 or more points or 
decrease in P-ROM score by 1 
point for any site 
Global 
Clinician overall severity score 0 
Clinician overall severity score 
decreases by 2 or more points 
on a 0–10 scale 
Clinician overall severity score 
increases by 2 or more points on 
a 0–10 scale 


 
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Appendix 8.  Adverse Event Assessment of Causality 
Is there a reasonable possibility that the event may have been caused by study drug?  No___ Yes___ 
The descriptions provided below will help guide the principal investigator in making the decision to choose 
either “yes” or “no”: 
No = There is no reasonable possibility that the event may have been caused by study drug. 
The adverse event: 
• 
may be judged to be due to extraneous causes such as disease or environment or toxic factors 
• 
may be judged to be due to the subject’s clinical state or other therapy being administered 
• 
is not biologically plausible 
• 
does not reappear or worsen when study drug is re-administered 
• 
does not follow a temporal sequence from administration of study drug 
Yes = There is a reasonable possibility that the event may have been caused by study drug. 
The adverse event: 
• 
follows a temporal sequence from administration of study drug 
• 
is a known response to the study drug based on clinical or preclinical data 
• 
could not be explained by the known characteristics of the subject’s clinical state, environmental or 
toxic factors, or other therapy administered to the subject 
• 
disappears or decreases upon cessation or reduction of dose of study drug 
• 
reappears or worsens when study drug is re-administered 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 9.  Drugs with a Known Risk of Torsades de Pointes 
   Generic Name 
    Drug Class 
   Therapeutic Use 
Amiodarone 
Antiarrhythmic 
Arrhythmia 
Anagrelide 
Phosphodiesterase 3 inhibitor 
Thrombocythemia 
Arsenic trioxide 
Anti-cancer 
Cancer (leukemia) 
Azithromycin 
Antibiotic 
Bacterial infection 
Bepridil 
Antianginal 
Angina pectoris 
Chloroquine 
Antimalarial 
Malaria 
Chlorpromazine 
Antipsychotic / Antiemetic 
Schizophrenia, nausea, many others 
Cilostazol 
Phosphodiesterase 3 inhibitor 
Intermittent claudication 
Ciprofloxacin 
Antibiotic 
Bacterial infection 
Citalopram 
Antidepressant, SSRI 
Depression 
Clarithromycin 
Antibiotic 
Bacterial infection 
Cocaine 
Local anesthetic 
Anesthesia (topical) 
Disopyramide 
Antiarrhythmic 
Arrhythmia 
Dofetilide 
Antiarrhythmic 
Arrhythmia 
Domperidone 
Antiemetic 
Nausea, vomiting 
Donepezil 
Cholinesterase inhibitor 
Dementia (Alzheimer's Disease) 
Dronedarone 
Antiarrhythmic 
Arrhythmia 
Droperidol 
Antipsychotic / Antiemetic 
Anesthesia (adjunct), nausea 
Erythromycin 
Antibiotic 
Bacterial infection, increase GI motility 
Escitalopram 
Antidepressant, SSRI 
Depression (major), anxiety disorders 
Flecainide 
Antiarrhythmic 
Arrhythmia 
Fluconazole 
Antifungal 
Fungal infection 
Halofantrine 
Antimalarial 
Malaria 
Haloperidol 
Antipsychotic 
Schizophrenia, agitation 
Hydroquinidine 
Antiarrhythmic 
Arrhythmia 
Hydroxychloroquine 
Antimalarial, anti-inflammatory 
Malaria, SLE, rheumatoid arthritis 
Ibutilide 
Antiarrhythmic 
Arrhythmia 
Levofloxacin 
Antibiotic 
Bacterial infection 
Levomepromazine 
(methotrimeprazine) 
Antipsychotic 
Schizophrenia 
Levosulpiride 
Antipsychotic 
Schizophrenia 
Methadone 
Opiate 
Narcotic dependence, pain 
Moxifloxacin 
Antibiotic 
Bacterial infection 
Ondansetron 
Antiemetic 
Nausea, vomiting 
Oxaliplatin 
Anti-cancer 
Cancer 
Papaverine HCl 
(Intra-coronary) 
Vasodilator, Coronary 
Diagnostic adjunct 
Pentamidine 
Antifungal 
Fungal infection (Pneumocystis pneumonia) 
Pimozide 
Antipsychotic 
Tourette's Disorder 
Procainamide 
Antiarrhythmic 
Arrhythmia 
Propofol 
Anesthetic, general 
Anesthesia 
Quinidine 
Antiarrhythmic 
Arrhythmia 
Roxithromycin 
Antibiotic 
Bacterial infection 
Sevoflurane 
Anesthetic, general 
Anesthesia 


 
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Sotalol 
Antiarrhythmic 
Arrhythmia 
Sulpiride 
Antipsychotic, atypical 
Schizophrenia 
Sultopride 
Antipsychotic, atypical 
Schizophrenia 
Terlipressin 
Vasoconstrictor 
Septic shock 
Terodiline 
Muscle relaxant 
Bladder spasm 
Thioridazine 
Antipsychotic 
Schizophrenia 
Vandetanib 
Anti-cancer 
Cancer (thyroid) 
Source: crediblemeds.org, Drugs with Known TdP Risk, accessed 7-April-2020. 


 
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Appendix 10.  Patient-Reported Outcomes 
 


 
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ICF_002.pdf: 
 
 
Official Title: 
A Single-Arm, Open-Label, Phase I/II Study of Glasdegib 
for Sclerotic Chronic Graft-vs-Host Disease 
NCT Number: 
NCT04111497 
Document Type:  
Informed Consent Form 
Date of the 
Document: 
6/9/2022 
 
 


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FH8771 ICF version 1.5    
Fred Hutchinson Cancer Research Center 
Consent to take part in a research study: 
A Single-Arm, Open-Label, Phase I/II Study of Glasdegib 
for Sclerotic Chronic Graft-vs-Host Disease 
Principal Investigator: Stephanie Lee, MD, MPH. University of Washington; Fred 
Hutchinson Cancer Research Center. 206-667-5160 
Emergency number (24 hours): (206) 598-8902 
Ask to page the Long-Term Follow-Up Attending 
Important things to know about this study. 
You are invited to participate in a research study. The purpose of this research is 
to see if a medication called glasdegib (DaurismoTM) is helpful in treating skin 
thickening that can happen as part of chronic graft-versus-host disease (GVHD). 
People who agree to join the study will be asked to attend up to 18 visits over 24 
months. The study involves taking an oral medication (glasdegib) and attending 
regular study visits for physical exams, blood draws, lung function testing, and 
other assessments. 
We do not know if glasdegib will help treat chronic GVHD, and it could even 
make your condition/disease worse. Glasdegib could cause side effects such as 
low blood counts, muscle spasms, and kidney impairment, as described below in 
this form.  
You do not have to join this study. You can choose to receive standard methods 
to treat chronic GVHD instead of participating in this study. We will give you 
details about the purposes, procedures, risks and possible benefits related to this 
study. We will explain other choices that you have. We will also give you any 
other information that you need in order to make an informed decision about 
joining this study.  
The following is a more complete description of this study. Please read this 
description carefully. You can ask any questions you want to help you decide 
whether to join the study. If you join this study, we will give you a signed copy of 
this form to keep for future reference.  
IRO REC'D MAY 10  2022


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We invite you to join this research study. 
We invite you to join this research study because you have skin thickening 
and/or joint tightening caused by chronic GVHD, and it has not responded to 
at least one prior medication. Up to 20 people will join this study. 
Research is not the same as treatment or medical care. The purpose of a 
research study is to answer scientific questions.  
You do not have to be in the study. You are free to say “yes” or “no”, or to 
drop out after joining. If you say “no,” you would have no penalty or loss of 
benefits. Whatever you decide, your regular medical care would not change.  
Why are we doing this study? 
We are doing this study to see if glasdegib is helpful in the treatment of 
chronic GVHD. The study will enroll people who have active GVHD-related 
sclerosis or fasciitis despite at least one prior chronic GVHD treatment.  
In this study, we want to learn what effects, good or bad, glasdegib has on 
people with chronic GVHD. If you join this study, we would give you glasdegib 
and watch carefully for any side effects.  
What research tests, procedures, and treatments are done in this study? 
If you join this study, we would do these tests and procedures: 
• 
Questionnaire - We would ask you to fill out five questionnaires—one 
when you start taking glasdegib, then one every three months, plus 
one more when you finish treatment. Each questionnaire has questions 
about your GVHD symptoms and general health. Some of the 
questions may be sensitive. You can choose not to answer any 
questions that make you feel uncomfortable. 
• 
Physical exam – You will have a physical exam at each study visit, 
and we will pay special attention to any signs or symptoms of GVHD 
that you may be having. A member of the study team will fill out a form 
about your GVHD. 
• 
Clinical labs – We will do blood tests to check for GVHD and overall 
health. Most of the time, these labs will be done as part of your normal 
medical care. 
• 
Research blood samples – We will collect 24 ml (about 1.5 
tablespoons) of blood four times for research.  
• 
Electrocardiogram – We will perform an electrocardiogram (ECG) 
fourteen times during the study to check your heart rate and rhythm. 
• 
Pulmonary function test and spirometry – When you enroll on the 
study, we will do full pulmonary function tests, which checks how well 


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your lungs work. Eight more times during the study, we will ask you to 
do just the spirometry part of the test, which involves blowing into a 
small hand-held device. 
• 
Skin biopsies – Before you start taking glasdegib, and about 6 
months later, we will ask if we can take a skin biopsy for research. This 
is optional and you can still be in the study if you decide not to do the 
biopsies.  
• 
Pregnancy test – If you are a woman of childbearing potential, we will 
do a blood test to check for pregnancy before you begin taking 
glasdegib.  
If you need to stop taking glasdegib early, we would still ask you to complete 
the study visits and assessments at 3, 6, 9, 12, 15, 18, 21 and 24 months 
unless you start a new medication for chronic GVHD. After about two years of 
active study participation, you would no longer have study visits, but we would 
still like to follow your health and GVHD by looking at your medical records 
periodically.  
How long would you stay in this study? 
If you join this study, you would have study visits for about 26 months. After 
that, we would continue to look at your medical records periodically.  
You would receive glasdegib for up to 24 months. After your last dose of 
glasdegib, you would have a follow-up exam about one month later. 
Doctors could take you out of this study at any time. This would happen if: 
• 
They think it is in your best interest not to continue in the study. 
• 
You are not able or willing to follow study procedures. 
• 
You start a new medication for your chronic GVHD. 
• 
The whole study is stopped.   
If you withdraw from the study for any reason, previously collected information 
would remain in the study records and would be included in the analysis of 
results. This information could not be removed from the study records.  
Long-term follow-up means keeping track of someone’s medical condition 
for a long time. If you join this study, we would review your medical records a 
few times per year to see how you are doing. If you are not seen at the study 
center, we might also ask your local doctor to send a copy of your medical 
records. This information will help us learn about the long-term effects of 
glasdegib and chronic GVHD treatment in general.  
You do not have to be in long-term follow-up. You could say “yes” or “no”. 
Either way, you could still join this study. If you drop out of the study, you 
would be asked if we could continue to review your medical records.  


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If you choose not to join long-term follow-up, you would not be contacted 
regularly, and we would not ask your doctor to send medical records, but we 
might still need to contact you for some other reason. 
What are the side effects (risks)? 
In this part of the consent form, we describe the side effects we expect from 
the tests and treatments in this study. Glasdegib could cause side effects we 
do not know about yet. We will carefully watch everyone in the study for side 
effects.   
If you join this study, we would tell you if we discover new side effects that 
could affect you.  
This form lists the most common side effects of glasdegib. Other side effects 
could occur when glasdegib is used together with other drugs.  
Side effects may be mild or very serious. Medicines could be given to help 
lessen side effects. Many side effects go away soon after you stop taking 
glasdegib. In some cases, side effects can last a long time or never go away. 
There also is a risk of death with any medication. 
 
Low cell counts (cytopenias) 
Low cell counts can make you get infections more easily and can cause low 
energy. We will monitor your blood counts during the study to watch for this 
complication. 
 
Heart rhythm changes (QT/QTc prolongation) 
This can be seen in people who already have heart disease, or who are 
taking other medications that also affect their heart rhythm. We will do 
electrocardiograms to watch for this complication.  
 
Kidney impairment 
Some people who take glasdegib have decreased kidney function, and this 
usually happens in patients who already have a risk of kidney problems. We 
will monitor your kidney function with blood tests during the study.  
 
Muscle spasms or cramps 
Some people who take glasdegib experience muscle spasms or cramps. 
These cramps might be severe enough to interfere with your daily activities 
or sleep. If this happens, please tell your study doctor right away.  
 
Low sodium (hyponatremia) 
We will monitor your blood levels of sodium during the study.  


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Taste changes (dysgeusia) 
This is a common side effect with glasdegib and is usually not bad enough to 
make people stop taking glasdegib. If you have taste changes that are 
bothersome, please tell the study doctor.  
 
Hair loss (alopecia) 
Some people notice hair loss when they are taking glasdegib. Please tell 
your study doctor if you notice new hair loss.  
 
Dental effects 
Glasdegib has been associated with loose teeth and toothache in some 
studies. You should see your dentist regularly and report any symptoms. 
Reproductive risks 
Taking glasdegib involves risks to an embryo, fetus (unborn baby) or nursing 
infant; it can cause the child to die before it is born (be stillborn) or have 
severe birth defects. Therefore, you could not join this study if you are 
pregnant, if you are planning to become pregnant, or if you are breast-
feeding.   
If you became pregnant after joining this study, you would have to notify the 
study doctor immediately. Participation in this study would end, and you 
would receive counseling and follow-up throughout the pregnancy and for 
about 6 months after the child is born.  
 
For females who can become pregnant:  
• You should talk to the study doctor about the risks of glasdegib to your 
unborn child.  
• You will be asked to undergo a pregnancy test within 7 days before you 
start glasdegib.  
• You should not use glasdegib during pregnancy.  
• You should use effective birth control during treatment and for at least 30 
days after your last dose of glasdegib. Talk with the study doctor about 
what birth control method is right for you during this time. If you are 
already using a method of birth control, you would have to check with the 
study doctor or a member of the study staff to make sure it is acceptable.  
• Talk to the study doctor right away if you have unprotected sex or if you 
think that your birth control has failed.  
• Tell the study doctor right away if you become pregnant or think that you 
may be pregnant. 


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For males:  
• It is not known if glasdegib is present in semen. Do not donate semen 
during treatment with glasdegib and for at least 30 days after your last 
dose.  
• You should always use effective birth control, including a condom, even if 
you have had a vasectomy, during sex with female partners who are 
pregnant or who are able to become pregnant, during treatment with 
glasdegib and for at least 30 days after your last dose to protect your 
female partner from being exposed to glasdegib.  
• Tell the study doctor right away if your partner becomes pregnant or thinks 
she is pregnant while you are taking glasdegib.   
Exposure to glasdegib during pregnancy: 
If you think that you or your female partner may have been exposed to 
glasdegib during pregnancy, tell the study doctor right away. If you become 
pregnant during treatment with glasdegib, you or the study doctor would need 
to report your pregnancy to Pfizer at 1-800-438-1985. 
 
Other risks involved with the study 
• The blood draw may briefly cause you to feel faint, lightheaded, or 
nauseated. There is a risk of bleeding, bruising, and rarely, infection.  
• There is a risk of discomfort, bleeding, infection, and scarring from the 
optional skin biopsies. 
• The breathing tests can cause you to cough or feel lightheaded. 
• The survey questions we ask about your symptoms and quality of life may 
make you feel uncomfortable. You can skip any question you do not want 
to answer.  
• There is a slight risk of loss of confidentiality. 
What are the benefits? 
We do not know if this study would help you. We are testing glasdegib to see 
its effects on people with chronic GVHD, and to find the safest dose in people 
with chronic GVHD.  You might get better if you receive glasdegib, but your 
condition could stay the same or even get worse. We hope the information 
from this study will help other people with chronic GVHD in the future. 


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You have other choices besides this study. 
You do not have to join this study. You are free to say “yes” or “no”. Your 
regular medical care would not change if you decide to say “no”.  
You have other choices for treatment.  Each of these choices has risks and 
benefits. You should talk to your doctor or healthcare provider about these 
choices.   
Your other choices may include: 
• 
Continue routine treatment or care for your cGVHD without being in 
a clinical study 
• 
Ibrutinib, an FDA approved drug for the treatment of cGVHD if you 
have had at least one prior line of therapy 
• 
Take part in another clinical study 
• 
No treatment 
Enrollment in this study may exclude you from other research studies.  
Protecting Privacy as an Individual and the Confidentiality of Personal 
Information  
If you join this study, some people or organizations might need to look at your 
medical records and research records for quality assurance or data analysis. 
They include:  
• 
Researchers involved with this study. 
• 
Pfizer and their agents.  
• 
Institutional Review Boards (IRB), including the Fred Hutchinson 
Cancer Research Center IRB. An IRB is a group that reviews the study 
to protect the rights and welfare of research participants. 
• 
Fred Hutchinson Cancer Research Center, University of Washington, 
and Seattle Cancer Care Alliance. 
• 
Office for Human Research Protections, Food and Drug 
Administration, and other regulatory agencies as required. 
We will do our best to keep personal information confidential. But we cannot 
guarantee total confidentiality.  Personal information may be given out if 
required by law.  For example, workplace safety rules may require health 
workers to contact you about lab tests. Or a court may order study information 
to be disclosed. Such cases are rare. 
We will not use personal information in any reports about this study, such as 
journal articles or presentations at scientific meetings. 
If you join this study, information about your participation would be made part of 
your permanent medical record. This information would include a copy of this 
consent form. If an insurance company or employer or anyone else were 


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authorized to see your medical record, they would see a copy of this consent 
form.  
How is my genetic information protected? 
 
A federal law called the Genetic Information Nondiscrimination Act (GINA) 
helps protect genetic information about people who join research studies.  
 
GINA restricts access to genetic information so that it cannot be used for 
health insurance coverage decisions. GINA prevents health insurance 
companies or group health plans from:  
 
• Asking for genetic information obtained in research studies, or 
• Using genetic information when making decisions regarding your 
eligibility or premiums  
GINA does not help or protect against genetic discrimination by companies 
that sell life, disability or long-term care insurance.  
Would we pay you if you join this study? 
There is no payment for being in this study.  
Would you have extra costs if you join this study?  
You or your insurance company will not be billed for tests and procedures 
done specifically for this study (i.e., extra blood drawn for research, 
pregnancy tests, or questionnaires). Glasdegib will be provided free of 
charge from Pfizer for up to 24 months.  
There are some extra costs for being in this study. You or your insurer will 
have to pay these costs. Some insurers will not pay for research. Check with 
your insurer before you join this study. 
The extra costs are: 
• 
Cost of tests that are given more often than usual. 
• 
Cost of standard doctor visits and lab tests. 
• 
Cost of any other medical care you may need because of this study. 
Whether you are in the study or not, you or your insurance company will be 
responsible for medications, tests, clinic and hospital visits as part of your 
routine care as a transplant recipient. Pfizer will not pay any money to you or 
pay any of your medical bills. 
What if you get sick or hurt after you join this study? 
 


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For a life threatening problem, call 911 right away or seek help 
immediately.  Contact your study doctor when the medical emergency is over 
or as soon as you can.    
 
For all other medical problems or illness related to this research, immediately 
contact Dr. Lee at 206-667-5160.  She will treat you or refer you for 
treatment.  You or your health insurance will have to pay for the treatment. 
There are no funds to pay you for a research-related injury, added medical 
costs, loss of a job, or other costs to you or your family.  State or national law 
may give you rights to seek payment for some of these expenses.  You do not 
waive any right to seek payment by signing this consent form. 
 
You or your insurer will be billed for treatment of problems or complications 
that result from your condition or from standard clinical care. 
You would not lose any legal right to seek payment for treatment if you sign 
this form. 
What will my information and/or tissue samples be used for? 
Your information and tissue samples (such as blood and skin biopsies) will be 
used for the purposes of this study. 
Your tissue samples might help researchers develop new products. This 
research could be done by for-profit companies. There is no plan to share 
with you any revenue generated from products developed using your tissue 
samples. 
During this study, if the researchers learn new information that may be 
important to your general health or to your disease or condition, they will 
share that information with you. For example, if your physical exam, clinical 
blood tests, ECG, or pulmonary function tests show abnormalities, we would 
discuss those with you. The research blood samples and optional skin 
biopsies will be stored and analyzed later. The results of any testing on those 
samples would not be available to you.  
In addition, be aware that by agreeing to participate in this study, your 
information or tissue samples could be used for future research studies or 
sent to other investigators for future research studies without additional 
consent from you. These future research studies will be reviewed by an 
oversight group known as an institutional review board if required by law. The 
information that identifies you will first be removed from your information or 
tissue samples. If you do not want your information or tissue samples to be 
used for future research studies without your consent, you should not 
participate in this study. 


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We invite you to donate tissue samples for other research. 
After we do tests on tissue (blood or skin) in this study, some tissue may be 
left over. We invite you to donate this leftover tissue for future research. This 
may include genetic research. 
If you join this study, you would not have to donate tissue for future research. 
You would be free to say “yes” or “no.” Regular medical care would not 
change if you say “no.”  
If you donate tissue, it would be stored in a secure location. If we want to use 
your tissue for other research or share it with other scientists for research, an 
ethics review committee (IRB) would review the request. The IRB would 
decide if we need to ask you for permission to do the research.  
Your donated tissue would be used only for research. This research could be 
done by for-profit companies. Researchers would not report their results to 
you or your doctors. The research results would not be included in medical 
records. The results would not affect your medical care.  
Research with tissue might help develop new products. If these products 
make money, there is no plan to share the money with the participants who 
donate the tissue.  
If you donate tissue for research, you could withdraw the donation at any time 
by calling Dr. Stephanie Lee at 206-667-5160. You would have no penalty for 
withdrawing the donation, and regular medical care would not change. We 
could not return donated tissue, but we might be able to destroy the donated 
tissue. We could not destroy tissue if it is stored or shared without any label 
saying who donated it. In this case, it could still be used for research.   
Your rights 
• 
You do not have to join this study. You are free to say “yes” or “no”.  
• 
If you get sick or hurt in this study, you do not lose any of your legal 
rights to seek payment by signing this form. 
• 
During the study, we might learn new information that you need to 
know. For example, some information may affect your health or well-
being. Other information might make you change your mind about 
being in this study. If we learn these kinds of information, we would tell 
you. 
• 
If you join this study, you would not have to stay in it. You could stop at 
any time (even before you start). Your regular medical care would not 
change. You would have no penalty for stopping, but it would be better 
not to join the study if you think that you would change your mind later.   


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• 
If you decide to drop out, we would want you to tell the study doctor. 
The doctor could tell you about the effects of stopping glasdegib. You 
and the doctor could talk about the follow-up care and testing that 
would help the most.  
• 
Before you leave the study, the doctor might ask you to continue in the 
follow-up part of the study (we would review your medical records 
periodically).  
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, 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.  
Your responsibilities 
If you join this study, you would have some responsibilities.  
• 
Follow the schedule of study visits and procedures. 
• 
Take study medications as directed.  
• 
Prevent pregnancy. 
• 
Tell us about side effects.    
For more information 
If you have questions or concerns about this study, you can talk to your 
doctor anytime. Other people you could talk to are listed below. 
 


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If you have questions about: 
 
Call: 
This study (including 
complaints and requests 
for information) 
 
(206) 667-6190 (Dr. Stephanie Lee) 
(206) 667-7010 (Research Coordinator) 
If you get sick or hurt in this 
study 
 
(206) 667-6190 (Dr. Lee) 
Your rights as a research 
participant 
 
206-667-5900 or email 
irodirector@fredhutch.org (Director of 
Institutional Review Office, Fred Hutchinson 
Cancer Research Center) 
Your bills and health 
insurance coverage 
 
(206) 606-6226 or toll free at (800) 804-8824 
Emergency number (24 hours): (206) 598-8902 
Read each question and think about your choice. When you decide on each 
question, please circle YES or NO. 
 
Do you agree to donate your leftover tissue for future studies of GVHD? 
(circle one) 
YES  
NO  
 
 


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Signatures 
Please sign below if you:  
• have read this form (or had it read to you); 
• had the opportunity to ask any questions you have; 
• had the opportunity to discuss the research with the person obtaining 
consent; and  
• agree to participate in this study. 
 
Participant: 
 
 
 
 
 
Printed Name 
 
Signature 
 
Date 
Researcher’s statement 
I have discussed the research study, including procedures and risks, with the 
person signing above. A copy of the signed consent form will be given to the 
participant. 
 
Person obtaining consent signature: 
 
 
 
 
 
Printed Name 
 
Signature 
 
Date 
 
 
Protocol: 8771 
Current consent version date: 09-Jul-2020 
Previous consent version date: 17-Dec-2019 
Copies to: research coordinator, HIM, patient