Conditions: Chronic Graft Versus Host Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
This pilot clinical trial studies how well vismodegib works in treating patients with chronic graft-versus-host disease that did not respond to previous steroid treatment. Chronic graft-versus-host disease can cause a build-up of scar tissue under the skin and lead to symptoms such as sclerodermatous skin changes, dry mouth, dry eye, narrowing of the esophagus, or vaginal graft-versus-host disease. Vismodegib may work against the build-up of scar tissue and be a better treatment for chronic graft-versus-host disease caused by a hematopoietic stem cell transplant.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the clinical effects of GDC-0449 (vismodegib), in steroid-refractory chronic graft-versus-host disease (GVHD).

SECONDARY OBJECTIVES:

I. To determine the safety of GDC-0449 in patients with steroid-refractory GVHD.

II. To determine the change in National Institutes of Health (NIH) Consensus Criteria (CC) global score of chronic GVHD at 6 and 12 months from baseline.

III. To determine one-year non relapse mortality (NRM) and one-year relapse rate.

IV. To determine one-year failure free survival (FFS) and one-year overall survival (OS).

V. To determine baseline clinical characteristics that may be associated with decreased FFS.

OUTLINE:

Patients receive vismodegib orally (PO) daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 6 months.

Arms:
arm 1: Patients receive vismodegib PO daily, every other day, every three days, or twice weekly for 6-12 months in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Vismodegib
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO

Protocol document:
Prot_SAP_000.pdf: 
Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
i 
 
SUMMARY OF CHANGES 
 
Date: 
 
05APR2019 
Document: 
NCI Protocol 9664: “Pilot Study for the Treatment of Steroid-Refractory 
Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-0449 (GDC-
0449).” 
Note: 
The following is a Summary of Changes for the 05APR2019 protocol version #13 
 
Protocol Changes: 
 
Section 
Description of Change  
All pages 
Updated to reflect current version date. 
Title Page 
Updated to reflect current version information and update study staff 
9.1.2 Definition 
of Response to 
Therapy 
Added definitions for GVHD assessments to define response to therapy. 
10.1 Study 
Design/Study 
Endpoints 
Added a secondary endpoint to clarify that response to therapy is a secondary endpoint. 
10.2 Sample 
Size/Accrual 
Rate/Other 
Statistical 
Considerations 
Updated to describe how response assessment data will be reported. 
ICF 
No changes to the Informed Consent Document.  ICF version date has been updated to 05APR2019 
 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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NCI Protocol #: 
9664 
 
IRB #: 
84584 
 
Lead Org. ID #: 
Huntsman Cancer Institute/University of Utah 
 
TITLE:  PILOT STUDY FOR THE TREATMENT OF STEROID-REFRACTORY 
SCLERODERMATOUS CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD) WITH 
GDC-0449 (GDC-0449)  
 
 
 
Principal Investigator 
 
Daniel Couriel, M.D, MS. 
Huntsman Cancer Institute/University of 
Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Daniel.Couriel@hci.utah.edu  
Sub-Investigators 
Tibor Kovacsovics  
Huntsman Cancer Institute/University of 
Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Tibor.Kovacsovics@hci.utah.edu  
 
 
 
Michael Deininger 
Huntsman Cancer Institute/University of 
Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
michael.deininger@hci.utah.edu 
 
Ahmad Halwani 
Huntsman Cancer Institute/University of 
Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
ahmad.halwani@hci.utah.edu 
 
Catherine Lee 
Huntsman Cancer Institute/University of 
Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
Page 2 of 80 
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catherine.lee@hci.utah.edu 
Matthew T. Rondina, M.D., M.S. 
(Laboratory) 
George and Dolores Eccles Institute of 
Human Genetics 
15 N 2030 E 
Salt Lake City, UT 84112 
Matthew.Rondina@hsc.utah.edu 
Statistician 
Ken Boucher, PhD 
Huntsman Cancer Institute  
2000 Circle of Hope 
Salt Lake City, UT 84112 
Kenneth.Boucher@hci.utah.edu 
NCI Supplied Agent:  GDC-0449 (NSC 747691) 
  
  
Historical Protocol Versions 
Original (NCI Version 4): 6-14-2015 
Version #5:   07-16-2015 
Version #6:   08-03-2015 
Version #7:   08-10-2015 
Version #8:   11-24-2015 
Version #9:   05-17-2016 
Version #10: 06-29-2017 
Version #11: 04-12-2018 
Version #12: 07-09-2018 
Version #13: 04-05-2019 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
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TABLE OF CONTENTS 
TITLE:  Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host 
Disease (GVHD) with GDC-0449 (GDC-0449)..................................................................1 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................6 
PROTOCOL SIGNATURE .............................................................................................................9 
STUDY SUMMARY 10 
SCHEMA 
13 
1 
OBJECTIVES 14 
1.1 
Primary Objectives....................................................................................................14 
1.1.1 To determine the clinical effects of GDC-0449, in steroid-refractory 
chronic graft versus host disease (GVHD) ............................................................14 
1.2 
Secondary Objectives................................................................................................14 
1.1.2 To determine the safety of GDC-0449 in patients with steroid-refractory 
GVHD 14 
1.1.3 To determine the change in National Institutes of Health (NIH) Consensus 
Criteria (CC) global score of chronic GVHD at 6 and 12 months from 
baseline ..................................................................................................................14 
1.1.4 To determine one-year non relapse mortality (NRM) and one-year relapse 
rate 
14 
1.1.5 To determine one-year failure-free survival (FFS) and one-year overall 
survival (OS) ..........................................................................................................14 
1.1.6 To determine baseline clinical characteristics that may be associated with 
decreased FFS ........................................................................................................14 
2 
BACKGROUND ...............................................................................................................14 
2.1 
Chronic GVHD .........................................................................................................14 
2.2 
CTEP Agent ......................................................................................................15 
2.3 
Hedgehog (HH) pathway and fibrosis ......................................................................20 
2.4 
Rationale for HH pathway inhibition as a new therapeutic target ............................20 
2.5 
GDC-0449 in steroid-refractory sclerodermatous chronic GVHD ...........................21 
2.6 
Correlative Studies/Biomarkers Background ...........................................................22 
3 
STUDY DESIGN...............................................................................................................23 
3.1 
Description ................................................................................................................23 
3.2 
Number of Patients ...................................................................................................24 
3.3 
Number of Study Centers..........................................................................................24 
3.4 
Study Duration ..........................................................................................................24 
4 
Eligibility Criteria ..............................................................................................................24 
4.1 
Inclusion Criteria ......................................................................................................24 
4.2 
Exclusion Criteria .....................................................................................................26 
4.3 
Inclusion of Women and Minorities .........................................................................28 
5 
TREATMENT PLAN ........................................................................................................28 
5.2 
CTEP  Agent ......................................................................................................29 
5.3 
Other Immunosuppression ........................................................................................31 
5.4 
General Concomitant Medication and Supportive Care Guidelines .........................32 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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5.5 
Duration of Therapy ..................................................................................................35 
5.6 
Duration of Follow Up ..............................................................................................35 
5.7 
Criteria for Removal from Study ..............................................................................35 
6 
DOSING DELAYS, DOSE MODIFICATIONS AND EARLY STOPPING CRITERIA35 
6.1 
Dose Modifications ...................................................................................................35 
7 
STUDY CALENDAR .......................................................................................................37 
8 
STUDY Procedures ...........................................................................................................38 
8.1 
Screening Procedures ................................................................................................38 
8.2 
Procedures During Treatment ...................................................................................39 
8.3 
Follow-Up Procedures ..............................................................................................39 
8.4 
Time and Events Table .............................................................................................39 
9 
Criteria For Evaluation and endpoint .................................................................................39 
9.1 
Measurement of Effect ..............................................................................................39 
9.2 
Safety ........................................................................................................................41 
9.3 
Stopping Rules/Interim Analysis ..............................................................................41 
10 
STATISTICAL CONSIDERATIONS...............................................................................42 
10.1 
Study Design/Study Endpoints .................................................................................42 
10.2 
Sample Size/Accrual Rate/Other Statistical Considerations.....................................44 
10.3 
Stratification Factors .................................................................................................44 
10.4 
Analysis of Secondary Endpoints .............................................................................44 
11 
REGISTRATION Guidelines ............................................................................................44 
11.1 
Investigator and Research Associate Registration with CTEP .................................44 
11.2 
Patient Registration: ..................................................................................................45 
12 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................46 
12.1 
Data Reporting ..........................................................................................................46 
12.2 
CTEP Multicenter Guidelines ...................................................................................47 
12.3 
Collaborative Agreements Language ........................................................................47 
13 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................49 
13.1 
Biomarker Studies .....................................................................................................49 
14 
Adverse Events ..................................................................................................................53 
14.1 
Adverse Events / Serious Adverse Events ................................................................53 
14.2 
Huntsman Cancer Institute SAE Reporting Requirements .......................................55 
14.3 
CTEP Notification and Reporting Requirements .....................................................55 
14.4 
Expedited Adverse Event Reporting .........................................................................60 
14.5 
Routine Adverse Event Reporting ............................................................................63 
14.6 
Secondary Malignancy..............................................................................................63 
14.7 
Second Malignancy ...................................................................................................64 
15 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................64 
15.1 
Informed consent ......................................................................................................64 
15.2 
Institutional Review ..................................................................................................64 
15.3 
Data and Safety Monitoring Plan ..............................................................................64 
15.4 
Protocol Amendments ...............................................................................................64 
15.5 
Protocol Deviations ...................................................................................................64 
16 
REFERENCES ..................................................................................................................66 
17 
Appendix 
70 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................70 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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APPENDIX B   DEFINITION OF WOMEN OF CHILDBEARING POTENTIAL AND  ACCEPTABLE 
AND UNACCEPTABLE FORMS OF CONTRACEPTION ...........................................71 
APPENDIX C  
POSSIBLE PRENATAL EXPOSURE TO TERATOGEN REPORT ......73 
APPENDIX D 
PATIENT’S MEDICATION DIARY .......................................................74 
APPENDIX E 
INFORMATION ON POSSIBLE DRUG INTERACTIONS ...................76 
APPENDIX F 
GVHD Chronic flowsheet..........................................................................78 
 
 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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LIST OF ABBREVIATIONS 
 
Abbreviation or 
Term1 
Definition/Explanation 
AE 
Adverse event 
Allo 
Allogeneic 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
β-HCG 
Beta-human chorionic gonadotropin 
BCC 
Basal Cell Carcinoma 
BID 
Twice daily 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRC 
Colorectal Cancer 
CRF 
Case report form 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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Abbreviation or 
Term1 
Definition/Explanation 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CRF 
Case report form 
CSS 
Clinical Study Synopsis 
CV 
Curriculum Vitae 
CYP 
Cytochrome P450 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
ECM 
Extra Cellular Matrix 
EMA 
European Medicines Agency 
FACS 
Fluorescence Activated Cell Sorting  
FDA 
Food and Drug Administration 
FFS 
Failure-Free Survival 
GGT 
Gamma glutamyl transferase 
GI 
Gastrointestinal 
GLP 
Good laboratory practice  
GVHD 
Graft-Versus-Host Disease 
HDL 
High Density Lipoprotein 
HH/h 
Hedgehog Signaling Pathway 
HIV 
Human immunodeficiency virus 
hr 
Hour or hours 
HSCT 
Hematopoietic Stem Cell Transplantation 
i.e. 
Id est (that is) 
INR 
International normalized ratio 
IPF 
Interstitial Pulmonary Fibrosis 
IRB 
Institutional review board 
LDH 
Lactate dehydrogenase 
LDL 
Low Density Lipoprotein 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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Abbreviation or 
Term1 
Definition/Explanation 
MMH 
Mohs Micrographic Surgery 
MTD 
Maximum tolerated dose  
NIH 
National Institutes of Health 
NRM 
Non-Relapse Mortality 
OS 
Overall Survival 
PD 
Progressive Disease 
PDE 
Prednisone Dose Equivalent 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
QOL 
Quality of Life 
QTc 
QT interval corrected  
RSS 
Regulatory Support System 
SAE 
Serious adverse event 
SD 
Standard deviation or stable disease 
SMO 
Smoothened 
T1/2 
Terminal elimination half-life 
Tmax 
Time of maximum observed concentration 
ULN 
Upper limit of normal 
WOCBP 
Women of childbearing potential 
All of these abbreviations may or may not be used in protocol.  
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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PROTOCOL SIGNATURE 
 
 
I confirm that I have read this protocol, and I will conduct the study as outlined herein and 
according to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practice, and the applicable laws and regulations of 
the federal government.  I will promptly submit the protocol to the IRB for review and approval.  
Once the protocol has been approved by the IRB, I understand that any modifications made 
during the course of the study must first be approved by the IRB prior to implementation except 
when such modification is made to remove an immediate hazard to the subject. 
 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study.  I will discuss this material with them to ensure that 
they are fully informed regarding the study treatment, the conduct of the study, and the 
obligations of confidentiality. 
 
Note: This document is signed electronically through submission and approval by the Principal 
Investigator in the University of Utah IRB Electronic Research Integrity and Compliance 
Administration (ERICA) system. 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
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STUDY SUMMARY 
Title 
Pilot Study for the Treatment of 
Steroid-Refractory Sclerodermatous 
Chronic Graft-Versus-Host Disease 
(GVHD) with GDC-0449   
Short Title 
GDC-0449 for the treatment of GVHD 
IRB Number 
84584 
 
 
Phase 
Pilot 
Design 
This is an open label non-randomized 
pilot study to the clinical effects and 
safety of GCD-0449 in patients with 
hematologic malignancies who have 
undergone Allogeneic Hematopoietic 
Stem Cell Transplantation (HSCT) and 
have been diagnosed with chronic 
GVHD. 
Study Duration 
Two years 
Study Center(s) 
Single Center – Huntsman Cancer 
Institute 
Objectives 
Primary Objectives: 
•
To determine the clinical effects of
GDC-0449, in steroid-refractory
chronic graft versus host disease
(GVHD)
Secondary Objectives: 
•
To determine the safety of GDC-
0449 in patients with steroid-
refractory GVHD
•
To determine the change in National
Institutes of Health (NIH)
Consensus Criteria (CC) global
score of chronic GVHD at 6 and 12
months from baseline
•
To determine one-year non relapse
mortality (NRM) and one-year
relapse rate
•
To determine one-year failure-free
survival (FFS) and one-year overall
survival (OS)
•
To determine baseline clinical
characteristics that may be
associated with decreased FFS


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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Number of Subjects 
12 patients 
Diagnosis and Main Eligibility Criteria Inclusion: 
1. Patients with chronic GVHD 
diagnosed within 3 years after 
hematopoietic stem cell transplant 
(HSCT) for any disease, with any 
graft, and any conditioning regimen 
with at least one manifestation 
secondary to fibrosis, including: 
sclerodermatous skin changes, dry 
mouth, dry eye, esophageal 
strictures, or vaginal GVHD 
2. Failure to respond to corticosteroids, 
defined as: 
• Progression of chronic GVHD 
despite optimal first line therapy 
(> 0.5 mg/kg/day of prednisone 
dose equivalent (PDE) for two 
weeks) or; 
• No improvement after 4-8 
weeks of sustained therapy. 
Sustained therapy should 
include 2 weeks of > 0.5 
mg/kg/day of PDE or;  
• Inability to taper steroid dosage 
to less than 0.5 mg/kg/day of 
PDE without worsening of 
chronic GVHD or; 
• Need for second or third line 
therapy beyond corticosteroids 
and calcineurin inhibitors or 
sirolimus, irrespective of other 
criteria listed under the current 
section 
 
Exclusion: 
1. Patients who have had 
chemotherapy or radiotherapy 
within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior 
to entering the study or those who 
have not recovered from adverse 
events due to agents administered 
more than 4 weeks earlier. 
2. More than 2 lines of therapy beyond 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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corticosteroids with or without 
calcineurin inhibitors or sirolimus 
3. Relapsed malignancy after 
transplantation 
Study Product, Dose, Route, Regimen 
GDC-0449 will be given orally at 150 
mg daily for a total of 6 months. Dosing 
will start at 150 mg daily.  Dose 
reductions may be made in the case of 
intolerable toxicities that do not meet 
discontinuation criteria.  
Dose Level -1: 150 mg every other day 
Dose Level -2: 150 mg every three days 
Dose Level -3: 150 mg twice a week 
 
In patients who are responsive to 
therapy with acceptable toxicity, the 
treatment period will be extended to 12 
months. 
Statistical Methodology 
This is a pilot study that will include 12 
patients. FFS, the primary endpoint, 
will be evaluated using the Kaplan-
Meier method. The impact of different 
covariates on FFS will be analyzed 
using descriptive statistics, t-test, and 
Fisher’s exact test where applicable. 
Differences in NIH scores will be 
analyzed using Wilcoxon signed-rank 
test. Differences in biomarkers will be 
assessed using Wilcoxon rank-sum test. 
 
The proportion of subjects who 
experience adverse events and serious 
adverse events will be summarized 
descriptively; no inferential tests will be 
performed. 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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SCHEMA 
 
 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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1 
OBJECTIVES 
 
1.1 Primary Objectives 
 
1.1.1 To determine the clinical effects of GDC-0449, in steroid-refractory chronic graft 
versus host disease (GVHD) 
1.2 Secondary Objectives 
 
1.1.2 To determine the safety of GDC-0449 in patients with steroid-refractory GVHD 
1.1.3 To determine the change in National Institutes of Health (NIH) Consensus 
Criteria (CC) global score of chronic GVHD at 6 and 12 months from baseline 
1.1.4 To determine one-year non relapse mortality (NRM) and one-year relapse rate 
1.1.5 To determine one-year failure-free survival (FFS) and one-year overall survival 
(OS)  
1.1.6 To determine baseline clinical characteristics that may be associated with 
decreased FFS  
 
2 
BACKGROUND 
 
2.1 Chronic GVHD 
 
Allogeneic (Allo) Hematopoietic Stem Cell Transplantation (HSCT) is a potentially curative 
treatment modality for patients with hematologic malignancies who would otherwise have a 
poor outcome with other conventional treatment approaches alone. Allo HSCT causes donor-
derived immune responses that can result in the desired graft-versus-tumor effect as well as 
the undesired complication, Graft versus Host Disease (GVHD). Chronic GVHD is the main 
complication for long term survivors of a successful AlloHSCT. Chronic GVHD occurs in 
more than 50 % of all patients who undergo an allo HSCT and the majority of patients who 
develop acute GVHD as a complication of their allo HSCT. Chronic GVHD can involve 
multiple organs and require prolonged immunosuppressive therapy. Advanced chronic GVHD 
is typically manifested by significant fibrous tissue deposition in different organs, leading to 
disabling symptoms, most commonly as a consequence of sicca syndrome and 
sclerodermatous forms of the disease. Sicca syndrome can lead to severe pain, visual 
impairment, and mucositis leading to malnutrition. Sclerodermatous chronic GVHD can cause 
dramatic limitations in the range of motion, with different degrees of immobility, and 
occasionally restrictive pulmonary disease. At this stage, current treatment strategies are 
almost always ineffective, at least in part due to the irreversibility of manifestations related to 
fibrosis. The mainstay of first-line immunosuppressive therapy in patients with chronic 
GVHD is systemic glucocorticoids and there are no standard second-line therapies. Systemic 
glucocorticoids have limited efficacy and significant long term complications. Despite the 
many alternative immunosuppressive agents to systemic glucocorticoids, no single class of 
immunosuppressive agents has persistently produced a steroid-sparing effect in patients with 
chronic GVHD [1-7]. In conclusion, Chronic GVHD and its current standard therapy have a 
major negative impact on the quality of life (QOL) and survival in patients in whom allo 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
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HSCT was able to achieve a cure from their original hematologic malignancy. Therefore, 
there is a desperate need for more effective agents in treating chronic GVHD. 
2.2 CTEP Agent 
2.2.1 GDC-0449 
The hedgehog (Hh) signaling pathway is a crucial mediator of embryogenesis [8].  
Signaling is initiated by the binding of the secreted morphogen, Hh, to its receptor, 
patched 1 (Ptch1).  In the unbound state, Ptch1 inhibits Smoothened (SMO), a G-protein 
coupled phosphoprotein receptor, by preventing its localization to the cell surface; 
however, in the presence of the Hh ligand, the Hh-Ptch1 complex is internalized and the 
repression of Ptch1 on SMO is relieved.  Surface localization of SMO is thought to 
initiate a signaling cascade, leading to the activation of the glioma-associated (Gli) family 
of zinc finger transcription factors, many of which are involved in proliferation, survival, 
and angiogenesis. 
Aberrant activation of the Hh pathway in cancers is caused by mutations in the pathway 
or through Hh overexpression, termed either ligand-independent or ligand-dependent, 
respectively [9, 10]. Past studies have identified mutations in the Hh receptor 
components, Ptch1 or SMO in basal cell carcinoma (BCC) and medulloblastoma, 
resulting in constitutive pathway activation [11, 12].  Excessive or inappropriate 
expression of the Hh ligand has been found in a significant proportion of patients with 
sporadic cancers of the gastrointestinal tract, pancreas, lung and prostate, suggesting that 
disruption of Hh signal transduction could potentially be beneficial in a broad array of tumor 
types [13-16]. Evidence suggests that antagonism of excessive Hh signaling may provide 
a route to unique mechanism-based anticancer therapies, blocking tumor growth and 
stimulating tumor regression without toxic effects on normal adjacent tissue [17]. 
GDC-0449 binds to and inhibits SMO, whose only established function is to transmit the 
Hh signal. Specific SMO mutations have been identified that alter the ability of GDC-
0449 to bind and inhibit the activity of SMO, thereby directly linking the action of GDC-
0449 to SMO (Investigator’s Brochure, 2015).GDC-0449 has demonstrated efficacy 
against a variety of primary human tumor xenografts, including colorectal cancer (CRC) 
and pancreatic adenocarcinoma, and tumor cell-line xenograft models.  Inhibition of Hh 
signaling in xenograft models has been correlated with a decrease in tumor growth. 
GDC-0449 has been studied in a number of Phase I and Phase II studies. These studies 
have evaluated the dose and schedule, pharmacokinetic (PK) profile, and efficacy of 
GDC-0449 in a number of indications, including first-line metastatic colorectal cancer 
(mCRC), ovarian cancer in second or third complete remission, and advanced basal cell 
carcinoma (aBCC). Clinical pharmacology studies have examined the potential of GDC-
0449 for DDIs; dose-schedule optimization; effect of GDC-0449 on QTc interval 
prolongation; effect of food on the PK of GDC-0449; and the absorption, distribution, 
metabolism, and excretion of GDC-0449. A Phase I study in patients with varying 
degrees of renal and hepatic function has also been completed (Study GP27839). On 30 








Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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evaluating the efficacy and safety of vismodegib in first-line mCRC (Study SHH4429g), 
ovarian cancer in second or third complete remission (Study SHH4489g), and in aBCC 
(Study SHH4476g) have been completed. The expanded access study in the United States 
(Study SHH4811) has been completed, because vismodegib is available commercially. 
The global safety study (Study MO25616) continues after conditional approval in the EU 
to further evaluate safety and efficacy of vismodegib in aBCC. Studies analyzing 
vismodegib in operable BCC (Study SHH4812g) and drug-drug interactions of 
vismodegib with a combined P-glycoprotein (P-gp)/cytochrome P450 (CYP) 3A4 
inhibitor or a CYP2C9 inhibitor (Study GP28465) have been completed. A Phase Ib, 
open-label, PK and safety study (Study GP27839) of vismodegib in patients with 
advanced solid tumors, including hepatocellular carcinoma, with varying degrees of renal 
or hepatic function has been completed. An extension study (Study SHH4437g) has been 
completed, which had been opened to permit patients deriving clinical benefit at the time 
of closure of Genentech-sponsored parent studies to continue receiving vismodegib. 
Other Phase II and IV studies evaluating the efficacy and safety of vismodegib in 
multiple BCC (Study MO28295) and in BCC preceding excision by Mohs micrographic 
surgery (MMS), as well as an observational study of treatment patterns, effectiveness, 
and safety outcomes in advanced BCC and BCCNS patients (Study 
ML28296/RegiSONIC) are ongoing. Additionally, vismodegib is being studied in 15 
clinical trials under a Collaborative Research and Development Agreement Letter of 
Intent with the NCI Division of Cancer Treatment and Diagnosis and under agreements 
for four ISTs, which comprise multiple Phase I and Phase II studies. For a current list of 
NCI-sponsored and investigator-sponsored studies, refer to http://www.clinicaltrials.gov. 
A Phase II study (Study GB29298) that will evaluate the efficacy and safety of 
vismodegib in patients with IPF is being planned. 
 
Reproductive and Developmental Toxicity 
 
Fertility 
Dedicated studies to assess the potential of vismodegib to affect fertility have not been 
performed. However, data from studies in rats and dogs indicate that male and female 
fertility may be compromised by treatment with vismodegib. 
  
Increased numbers of degenerating germ cells and hypospermia were observed in 
relatively young dogs treated for 4 weeks at ≥ 50 mg/kg/day (corresponding to 2.2-fold 
greater than the average AUC0-24h steady-state exposure at the recommended human 
dose), which were not fully reversed by the end of a 4-week recovery period. No 
corresponding findings were observed at similar doses in 13-week and 26-week toxicity 
studies with sexually mature dogs. A relative decrease in percent motile sperm was 
observed in some male rats treated for 26 weeks at ≥ 15 mg/kg/day (corresponding to 
34% of the average AUC0-24h steady-state exposure at the recommended human dose), 
which was not reversed by the end of an 8-week recovery period. No corresponding 
microscopic changes in the testis or epididymis or changes in sperm count, staging, or 
morphology were observed. A decrease in the number of corpora lutea was observed in 
female rats treated for 26 weeks at 100 mg/kg/day (corresponding to 1.1-fold of the 
average AUC0-24h steady-state exposure at the recommended human dose), which was 
not reversed by the end of an 8-week recovery period. 




Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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As aforementioned, activation of the HH pathway has recently been linked to carcinogenesis 
and fibro proliferative disorders. In basal cell carcinoma of the skin, significant advancement 
has been made in understanding the role of HH signaling pathway[35]. This advancement has 
led to the rapid development of preclinical and clinical testing of targeted hedgehog pathway 
inhibitors which led to the US Food and Drug Administration (FDA) approval of GDC-0449, 
the first hedgehog pathway inhibitor for the treatment of advanced basal cell carcinoma[40, 
41]. In a vital phase 2 trial, GDC-0449 was associated with tumor responses in 96 patients 
with locally advanced or metastatic basal-cell carcinoma[18].In systemic sclerosis, Shh was 
found to be overexpressed, with accumulation of Gli-1 and Gli-2. This activated phenotype 
led to the differentiation of resting fibroblasts into my fibroblasts, and in turn increased 
production of collagen [36]. Therefore, the HH pathway is a profibrotic pathway in systemic 
sclerosis. Furthermore, HH pathway inhibition had strong antifibrotic effects in preclinical 
models of systemic sclerosis in both the preventive and therapeutic settings [37]. In IPF, cross 
talk between TGF-B1, a central profibrotic cytokine, and the HH pathway was described in 
normal and IPF fibroblasts, where TGF-B1 modulated the expression of key components of 
the HH pathway. In addition, a functional HH pathway as well as GLI-dependent transcription 
in the nucleus was required for TGF-B1 effects on both normal and IPF fibroblasts during 
myofibroblastic differentiation [38] . Therefore, these data identified the GLI transcription 
factors as potential therapeutic targets in IPF. In human and murine chronic GVHD, HH 
pathway signaling was recently found to be activated with increased expression of Shh and 
accumulation of the transcription factors Gli-1 and Gli-2 [34]. Inhibition of the HH pathway 
with selective Smo inhibitor, LDE223 had effective antifibrotic effects both in the preventive 
and therapeutic settings of murine sclerodermatous chronic GVHD without affecting the 
potential benefits of a graft-versus leukemia response [34]. In conclusion, HH pathway 
activation has profibrotic effects and targeted HH pathway inhibition has potential antifibrotic 
effects in basal cell carcinoma, systemic sclerosis, IPF and sclerodermatous chronic GVHD.   
 
2.5 GDC-0449 in steroid-refractory sclerodermatous chronic GVHD 
 
Inhibition of the HH pathway has emerged as a new therapeutic target with antifibrotic 
effects. GDC-0449, a small molecule that binds and inhibits Smo, has been approved by the 
FDA for the treatment of advanced basal cell carcinoma [40]. As aforementioned, Active Smo 
signals downstream promoting the release of Gli family transcription factors which activate 
transcription of multiple target genes, including key regulators of the HH pathway, notably 
Gli1 and Ptch-1 (Figure adapted from [40]). 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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GDC-0449 binds to the extracellular domain of SMO, markedly inhibiting downstream 
signaling, even in the absence of Ptch-1. The first documented mechanism of clinical acquired 
resistance to GDC-0449 is a secondary mutation in the extracellular domain of Smo, D473H 
(indicated in the inset in the figure as a red circle), which prevents GDC-0449 binding. GDC-
0449’s safety was assessed in phase 1 trials in patients with refractory, locally advanced or 
metastatic solid tumors and in patients with advanced basal cell carcinoma [42, 43]. There 
was no maximum tolerated dose (MTD) reached. The recommended phase 2 trials dose was 
150 mg/day, based on maximal plasma concentration achievement and pharmacodynamic 
response at this dose. In a phase 2 trial of GDC-0449 in patients with locally advanced or 
metastatic basal-cell carcinoma, all patients had at least one adverse effect [18]. More than 
half the treated patients (57%) had only grade 1 or 2 adverse events. Adverse events occurring 
in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), 
weight loss, and fatigue. Serious adverse events were reported in 25% of patients, but the 
relationship between the drug and these deaths is unknown. In summary, given the need for 
more effective agents in treating chronic GVHD, the potential antifibrotic effect of HH 
inhibition in chronic GVHD, and the established safety and efficacy of GDC-0449, a SMO 
inhibitor, we hypothesize that target therapy of steroid refractory sclerodermatous chronic 
GVHD with GDC-0449 has the potential of preventing or reversing fibrosis and sparing 
steroid use. 
 
2.6 Correlative Studies/Biomarkers Background 
 
The pathophysiology of chronic GVHD is poorly understood, to date biomarkers to predict 
the disease course or guide therapy are not available. Moreover, the current therapeutic 
approaches have limited efficacy, particularly in patients with advanced chronic GVHD. 
Advanced chronic GVHD is defined by extensive fibrous tissue deposition in different organs, 
leading to considerable morbidity and mortality. Therefore, early diagnosis and treatment of 
chronic GVHD could prevent irreversible fibrotic damage and decrease morbidity and 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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mortality. Thus, this emphasizes the need for biomarkers to risk stratify patients with chronic 
GVHD and guide the optimal timing and intensity of therapy in these patients.  
 
We hypothesize that chronic GVHD is a fibro proliferative process and thus patients with 
chronic GVHD will have changes in the production and/or turnover of the ECM. These 
changes can provide more understanding of the pathophysiology of chronic GVHD and 
introduce biomarkers for risk stratification and targeted therapy. We previously evaluated 
ECM turnover biomarkers in 112 patients with newly diagnosed chronic GVHD. Biomarkers 
were classified according to their role in fibrogenesis. Levels of three profibrotic proteins 
(CCL2, IGF-1, IL-13Ra) significantly correlated with TGF-B levels. TGF-B provided the 
strongest association with clinical outcomes one year after the diagnosis of chronic GVHD. 
Low levels of TGF-B were associated with more relapse, more NRM, lower progression free 
survival (PFS), and lower overall survival (OS) than high levels of TGF-B. High TGF-B 
levels and high IL-13 levels were associated with development of sclerotic chronic GVHD. 
Low levels of MMP2, an antifibrotic metalloproteinase, were associated with development of 
sclerotic chronic GVHD. These results suggested that ECM turnover is active at the time of 
chronic GVHD onset, even prior to the development of clinically apparent sclerosis [44]. 
Therefore, further investigation of changes in the production and/or turnover of the ECM at 
baseline, and following treatment may provide a better understanding of the pathophysiology 
of chronic GVHD and help develop new biomarker opportunities for risk stratification and 
targeted treatment of chronic GVHD. 
 
3 
STUDY DESIGN 
 
3.1 Description 
This is an open label non-randomized pilot study to determine the clinical effects and safety 
of GCD-0449 in patients with hematologic malignancies who have undergone Allogeneic 
Hematopoietic Stem Cell Transplantation (HSCT) and have been diagnosed with chronic 
GVHD. 
 
GDC-0449 will be given orally for a total of 6 months. In patients who are responsive to 
therapy with acceptable toxicity, the treatment period will be extended to 12 months. The 
initial dose will be given at 150 mg po daily. If Grade 2 hematologic or non-hematologic 
toxicities attributable to the study drug are observed, three different, consecutive dose 
reduction levels may be utilized: 
 
• Level -1 (150 mg po every other day) 
• Level -2 (150 mg po every three days) 
• Level -3 (150 mg po twice a week) 
 
All initial dose reductions will start at Level -1 and proceed to the next level if the toxicity in 
question persists. Dosing schedules will be dependent on what day of the week the patient 
starts the dose reduction level; for example, patients on Dose Level -1 with a Monday start 
would dose on Wednesday, Friday, Sunday, and so on.  


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
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Principal Investigator: Daniel Couriel, MD 
 
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3.2 Number of Patients 
Twelve patients will be enrolled in this study. Sample size: 12 patients. Accrual rate: 1-2 
patients monthly. 
 
3.3 Number of Study Centers 
 This will be a single center study performed at the Huntsman Cancer Institute.  
 
3.4 Study Duration  
Estimated duration for the main protocol (e.g. from start of screening to last subject processed 
and finishing the study) is approximately two years. The accrual rate is estimated to be 1-2 
patients per month. Patients will remain on study treatment for 6-12 months and will complete 
all study procedures in 12-18 months.  
 
4 
ELIGIBILITY CRITERIA 
 
This eligibility checklist is used to determine patient eligibility and filed with signature in the 
patient research chart.  
  
Patient No. ______________________ 
Patient’s Initials: (L,F,M) _________________ 
 
4.1 Inclusion Criteria 
Yes/No  (Response of “no” = patient ineligible) 
 
4.1.1 _____ Age ≥18 years.   
Because no dosing or adverse event data are currently available on the use of 
GDC-0449 in patients <18 years of age, children are excluded from this study. 
 
4.1.2 _____ ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
4.1.3 _____ Life expectancy of greater than 12 months 
 
4.1.4 _____ Patients must have normal organ and marrow function as defined below: 
 
 Leukocytes 
≥3,000/mcL 
 Absolute neutrophil count 
≥1,500/mcL 
 Platelets 
 
 
≥50,000/mcL 
 Total Bilirubin 
within normal institutional limits 
 AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of      
normal 
 Creatinine 
 
≤1.5 mg/dl 
 
OR 
 Creatinine Clearance 
≥55 mL/min using the Cockcroft-Gault 
equation for patients with creatinine 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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levels above 1.5 mg/dl. 
 
4.1.5 _____ Patients with chronic GVHD diagnosed within 3 years after hematopoietic 
stem cell transplant (HSCT) for any disease, with any graft, and any conditioning 
regimen with at least one manifestation secondary to fibrosis, including: 
sclerodermatous skin changes, dry mouth, dry eye, esophageal strictures, or 
vaginal GVHD 
 
4.1.6 _____ Failure to respond to corticosteroids, defined as: 
 Progression of chronic GVHD despite optimal first line therapy (> 0.5 
mg/kg/day of prednisone dose equivalent (PDE) for two weeks) or; 
 No improvement after 4-8 weeks of sustained therapy. Sustained therapy 
should include 2 weeks of > 0.5 mg/kg/day of PDE or;  
 Inability to taper steroid dosage to less than 0.5 mg/kg/day of PDE without 
worsening of chronic GVHD or; 
 Need for second or third line therapy beyond corticosteroids and calcineurin 
inhibitors or sirolimus, irrespective of other criteria listed under the current 
section. 
 
4.1.7 _____ The effects of GDC-0449 on the developing human fetus at the 
recommended therapeutic dose are unknown.  For this reason and because Hh 
signal pathway inhibitors are known to cause interruption of the embryonic 
signaling pathway and may lead to serious or life-threatening birth defects, 
including brain deformities, facial malformation, heart problems, or abnormal 
organs.  Therefore, women of child-bearing potential and men must use two forms 
of contraception (i.e., barrier contraception and one other method of 
contraception) at least 4 weeks prior to study entry, for the duration of study 
participation, and for at least 24 months post-treatment.  For appropriate methods 
of contraception considered acceptable see Appendix B.  Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately.   
 
Pregnancy Testing.  Women of childbearing potential are required to have a 
negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 7 
days prior to the first dose of GDC-0449 (serum or urine).  A pregnancy test 
(serum or urine) will be administered every 4 weeks if their menstrual cycles are 
regular or every 2 weeks if their cycles are irregular while on study within the 24-
hour period prior to the administration of GDC-0449.  A positive urine test must be 
confirmed by a serum pregnancy test.  Prior to dispensing GDC-0449, the 
investigator must confirm and document the patient’s use of two contraceptive 
methods, dates of negative pregnancy test, and confirm the patient’s understanding 
of GDC-0449 cause serious or life-threatening birth defects. Patients must continue 
highly effective contraception during therapy and for 24 months after the last dose 
of GDC-0449 
 
Women of childbearing potential are defined as follows: 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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• Patients with regular menses 
• Patients with amenorrhea, irregular cycles, or using a contraceptive method that 
precludes withdrawal bleeding 
• Women who have had a tubal ligation 
 
Women are considered not to be of childbearing potential for the following 
reasons: 
• The patient has undergone hysterectomy and/or bilateral oophorectomy. 
• The patient is post-menopausal defined by amenorrhea for at least 12 months in a 
woman > 45 years old. 
 
Male patients should use condoms with spermicide, even after a vasectomy, during 
sexual intercourse with female partners while being treated with GDC-0449 and 
for 3 months after the last dose to avoid exposing an embryo or fetus to GDC-0449 
 
4.1.8 _____HIV-positive patients on combination antiretroviral therapy are eligible 
provided that they meet the following criteria in addition to the other protocol 
criteria:  
 Cancer as the only AIDS-defining condition 
 CD4 cell count ≥250,  
 Treatment sensitive HIV and prospects for long term survival on the basis 
of HIV disease alone 
 Willing to take anti-HIV therapy that will have minimal potential for 
pharmacokinetic interactions with GDC-0449.  
4.2 Exclusion Criteria 
 
4.2.1 _____ Patients who have had chemotherapy or radiotherapy within 4 weeks (6 
weeks for nitrosoureas or mitomycin C) prior to entering the study or those who 
have not recovered from adverse events due to agents administered more than 4 
weeks earlier. 
 
4.2.2 _____ Patients who are receiving any other investigational agents. 
 
4.2.3 _____ Patients with known brain metastases should be excluded from this clinical 
trial because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and 
other adverse events. 
 
4.2.4 _____ History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to GDC-0449  
 
4.2.5 _____ Patients receiving any medications or substances that are strong 
inducers/inhibitors or substrates of CYP3A4/5, CYP2C9, CYP2C8, or CYP2C19 
are ineligible.  Because the lists of these agents are constantly changing, it is 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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important to regularly consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such 
as the Physicians’ Desk Reference may also provide this information.  As part of 
the enrollment/informed consent procedures, the patient will be counseled on the 
risk of interactions with other agents, and what to do if new medications need to 
be prescribed or if the patient is considering a new over-the-counter medicine or 
herbal product.   
 
4.2.6 _____ Patients with malabsorption syndrome or other condition that would 
interfere with intestinal absorption.  Patients must be able to swallow capsules. 
 
4.2.7 _____ Patients with clinically important history of liver disease, including viral or 
other hepatitis or cirrhosis are ineligible. 
 
4.2.8 _____ Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia 
or hypokalemia defined as less than the lower limit of normal for the institution, 
despite adequate electrolyte supplementation are excluded from this study. 
 
4.2.9 _____ Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
4.2.10 _____ Pregnant women are excluded from this study because GDC-0449 is a Hh 
pathway inhibiting agent with the potential for serious or life-threatening birth 
defects or abortifacient effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with GDC-
0449, breastfeeding should be discontinued if the mother is treated with GDC-
0449.  These potential risks may also apply to other agents used in this study. 
 
4.2.11 _____ More than 2 lines of therapy beyond corticosteroids with or without 
calcineurin inhibitors or sirolimus. 
 
4.2.12 _____ Relapsed malignancy after transplantation 
 
 
I certify that this patient meets all inclusion and exclusion criteria for enrollment onto this 
study.  
 
______________________________ 
 
_________ 
_______ 
Investigator Signature  
 
 
Date  
Time 
 
 
 
 




Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
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•
Investigators may dispense no more than a 32-day supply of GDC-0449.
• GDC-0449 will be given orally for a total of 6 months. In patients who are responsive
to therapy with acceptable toxicity, the treatment period will be extended to 12
months. The initial dose will be given at 150 mg po daily. If Grade 2 hematologic or
non-hematologic toxicities attributable to the study drug are observed, three different,
consecutive dose reduction levels may be utilized:
•
Level -1 (150 mg po every other day)
•
Level -2 (150 mg po every three days)
•
Level -3 (150 mg po twice a week)
All initial dose reductions will start at Level -1 and proceed to the next level if the 
toxicity in question persists. Dosing schedules will be dependent on what day of the 
week the patient starts the dose reduction level; for example, patients on Dose Level -1 
with a Monday start would dose on Wednesday, Friday, Sunday, and so on.  
5.2 CTEP Agent 
5.2.1 GDC-0449 (NSC 747691) 
Chemical Name or Amino Acid Sequence:  2-chloro-N-[4-chloro-3-pyridin-2-yl-phenyl]-
4-(methanesulfonyl)benzamide 
Other Names:  Systemic Hedgehog Pathway Antagonist, G-025897, G-025897.1, and 
GDC-0449.1, GDC-0449 
Classification:  Hedgehog Pathway Antagonist 
CAS Registry Number:  879085-55-9 
Molecular Formula:  C19H14Cl2N2O3S 
M.W.:  421.3 g/mol 
Mode of Action:  GDC-0449 provides anticancer responses by inhibiting the hedgehog 
pathway. The Hedgehog signaling pathway controls cell differentiation, growth, and 
proliferation. It is most active during embryogenesis but may also play a role in the 
regulation of adult stem cells involved in the maintenance and regeneration of adult tissues. 
How Supplied:  GDC-0449 is supplied by Genentech and distributed by the CTEP, NCI. It 
is available as 150-mg grey and pink size 1 capsules containing microcrystalline cellulose, 
lactose monohydrate, sodium lauryl sulfate, povidone K29/32, talc, sodium starch glycolate, 
and magnesium stearate. The capsule shell consists of gelatin, red iron oxide, black iron 
oxide, and titanium dioxide. A compendial-grade black printing ink may be used. 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
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Principal Investigator: Daniel Couriel, MD 
 
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Capsules are packaged in 75-mL round, white, high-density polyethylene (HDPE) bottles 
and closed with 38/400 two-piece HDPE child-resistant caps.  Each bottle contains 
32 capsules.   
 
Storage:  Store GDC-0449 at room temperature between 59°F and 86°F (15°C and 30°C).  
 
Stability:  Stability testing is ongoing. 
 
Route(s) of Administration:  Oral 
 
5.2.2 Preparation and Administration 
 
Drug Administration:  Patients should take GDC-0449 at approximately the same time 
according to their dose level, with or without food.  If a patient misses a dose (e.g., due to 
emesis), he or she should be instructed not to take or make up that dose and to resume 
dosing with the next scheduled dose.  Missed doses should not be made up.  
 
Patient Care Implications:  The terminal half-life of GDC-0449 is currently unknown, but 
is expected to be longer than 1 week, and may be as high as 2 to 3 weeks.  If plasma levels 
of GDC-0449 need to be lowered emergently, animal studies suggest that oral 
administration of activated charcoal may lower drug plasma levels more quickly than dose 
cessation alone. 
 
Drug Interactions:  Avoid any concurrent drug metabolized by cytochrome P450 that has a 
narrow therapeutic index. 
 
5.2.3 Accountability and Compliance 
 
GDC-0449 is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
GDC-0449 is provided to the NCI under a Collaborative Agreement between Genentech 
and the DCTD, NCI (see Section 12.3). 
 
Agent Ordering and Agent Accountability 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical 
Management Branch (PMB) policy requires that agent be shipped directly to the 
institution where the patient is to be treated.  PMB does not permit the transfer of 
agents between institutions (unless prior approval from PMB is obtained).  The 
CTEP-assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents.  The responsible investigator at each participating 
institution must be registered with CTEP, DCTD through an annual submission 
of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental 
Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If there are 
several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can submit agent requests through the PMB 
Online Agent Order Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account 
status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
Agent Inventory Records – The investigator, or a responsible party designated by 
the investigator, must maintain a careful record of the inventory and disposition 
of all agents received from DCTD using the NCI Oral Drug Accountability 
Form.  (See the NCI Investigator’s Handbook for Procedures for Drug 
Accountability and Storage.) 
 
5.3 Other Immunosuppression 
 
5.3.1 Corticosteroids 
Corticosteroids at a dose of >0.5 mg/kg/d PDE for at least 1 week prior to initiation of 
GDC-0449. After initiation of GDC-0449, the corticosteroids will be tapered according to 
protocol guidelines in the following table, in order to minimize heterogeneity and 
subsequent potential for confounding: 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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5.3.2 Calcineurin inhibitor and sirolimus 
Therapy will continue at a dose which achieves the following trough serum levels:  
• Tacrolimus: 5-10 ng/mL 
• Cyclosporine: 120-200 ng/mL 
• 
Sirolimus: 5-10 ng/mL 
 
5.4 General Concomitant Medication and Supportive Care Guidelines 
Because there is a potential for interaction of GDC-0449 with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must capture 
the concurrent use of all other drugs, over-the-counter medications, or alternative therapies.  
The Principal Investigator should be alerted if the patient is taking any agent known to affect 
or with the potential to affect selected CYP450 isoenzymes.  Appendix E presents guidelines 
for identifying medications/substances that could potentially interact with the study agent(s). 
 
5.4.1 Concomitant Medications 
 
GDC-0449 inhibits CYP2C8, CYP2C9, and CYP2C19 drug metabolism enzymes in vitro 
at concentrations that may be clinically relevant.  Caution should be exercised when 
dosing GDC-0449 concurrently with medications that are substrates of CYP2C8, 
CYP2C9, and CYP2C19 and have narrow therapeutic windows.  The table below lists 
clinically significant substrates of CYP2C8, CYP2C9, and CYP2C19.  The table below 
represents medications to be used with caution.  Only medications or substances that are 
strong inducers/inhibitors or strong substrates of CYP3A4/5, CYP2C9, CYP2C8, or 
CYP2C19 are prohibited. See exclusion criteria 4.2.5 for additional information. 
 
2C8 
2C9 
2C19 
Miscellaneous 
 
Repaglinide 
 
Rosiglitazone 
NSAIDs 
 
Diclofenac 
 
Ibuprofen 
 
Piroxicam 
 
Naproxen 
Proton-pump inhibitors 
 
Omeprazole 
 
Lansoprazole 
 
Pantoprazole 
 
Rabeprazole 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Celecoxib 
Oral hypoglycemic agents 
 
Glipizide 
 
Tolbutamide 
Angiotensin II blockers 
 
Irbesartan 
 
Iosartan 
 
NOT candesartan 
 
NOT valsartan 
Miscellaneous 
 
Fluvastatin 
 
Phenytoin 
 
Sulfamethoxazole 
 
Tamoxifen 
 
Torsemide 
 
Warfarin 
 
Esoprazole 
Anti-epileptics 
 
Diazepam 
 
Phenytoin 
 
Phenobarbitone 
Miscellaneous 
 
Amitriptyline 
 
Clomipramine 
 
Clopidogrel 
 
Cyclophosphamide 
NSAIDs = Non-steroidal anti-inflammatory drugs 
 
Clinically significant PK interactions between vismodegib and CYP450 
inhibitors are not expected. Results from Study GP28465 demonstrated no 
clinically significant PK interaction between vismodegib and fluconazole (a 
moderate CYP2C9 inhibitor) or itraconazole (a strong CYP3A4 inhibitor) in 
healthy volunteers. Inducers of CYP3A4 are not predicted to alter vismodegib 
systemic exposure since similar steady-state plasma vismodegib concentrations 
were observed in patients in clinical studies concomitantly treated with CYP3A4 
inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly 
treated with CYP3A4 inhibitors (i.e.,erythromycin, fluconazole).  
 
If plasma levels need to be lowered emergently, animal studies have suggested 
that oral administration of activated charcoal may lower drug plasma levels more 
quickly than drug cessation alone. 
 
5.4.2   Pregnancy and Reproductive Concerns 
 
Women of childbearing potential (defined in Appendix B) are required to have a 
negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 7 
days prior to the first dose of GDC-0449 (serum or urine).  A pregnancy test 
(serum or urine) will be administered every 4 weeks if their menstrual cycles are 
regular or every 2 weeks if their cycles are irregular while on study within the 
24-hour period prior to the administration of GDC-0449.  Prior to dispensing 
GDC-0449, the investigator must confirm and document the patient’s use of two 
contraceptive methods, dates of negative pregnancy test, and confirm the 
patient’s understanding of the of GDC-0449 to cause spontaneous abortion or 
birth defects. 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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Female patients are required to use two forms of acceptable contraception (refer 
to Appendix B), including one barrier method during participation in the study 
and for the 24 months following the last dose.  All patients should receive 
contraceptive counseling either by the investigator, or by an obstetrician 
(OB)/gynecologist or other physician who is qualified in this area of expertise.  If 
a woman of childbearing potential believes that her contraceptive method has 
failed, emergency contraception should be considered. 
 
If a patient is suspected to be pregnant, GDC-0449 should be immediately 
discontinued.  In addition, a positive urine test must be confirmed by a serum 
pregnancy test.  If it is confirmed that the patient is not pregnant, the patient may 
resume dosing with GDC-0449.   
 
If a female patient becomes pregnant during therapy or within 24 months 
after the last dose of GDC-0449, or if the female partner of a male patient 
exposed to the drug becomes pregnant while the male patient is receiving 
GDC-0449 or within 3 months after the last dose of GDC-0449, the 
investigator must be notified in order to facilitate outcome follow-up. 
 
Abortion, whether accidental, therapeutic, or spontaneous, should always be 
classified as serious.  Any congenital anomaly/birth defect in a child conceived 
during the study or within 24 months after the last dose of GDC-0449 to a female 
patient or to a female partner of a male patient exposed to the agent during 
treatment or within 3 months after the last dose of GDC-0449 should be recorded 
and reported as an SAE. 
 
• 
Female patients should not breastfeed a baby while on this study.   
 
• 
Female patients must NEVER donate ova while being treated with GDC-
0449. 
 
• 
All sexually active male subjects (including those who have undergone 
vasectomy) should utilize a barrier form of contraception during study 
treatment and for 3 months after the last dose as it is not known whether 
GDC-0449 that may be present in seminal fluid would cause serious or life-
threatening birth defects in a fetus born to the female partner of a male subject.  
Males should also not donate sperm during treatment or up to 3 months after the 
last dose. 
 
• 
All patients are prohibited from donating blood for 24 months after the last 
dose of GDC-0449. 
 
5.4.3   Supportive Care Guidelines 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Supportive care, including infection prophylaxis will be conducted as per the 
current University of Utah institutional BMT program clinical practice 
guidelines. 
 
Steroids can be re-introduced for supportive care once the taper begins as long as 
it is cleared with the Principle Investigator, is not for the treatment of GVHD 
progression AND does not exceed 0.5 mg/kg/d PDE. 
 
5.5 Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue for up to 
12 cycles (i.e. 12 months) if there is clinical benefit (i.e. PR or CR) after the first 6 cycles, 
(i.e. 6 months) or until one of the following criteria applies: 
 
• 
Chronic GVHD or malignancy progression, 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s) (see section 6.1) 
 
• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.6 Duration of Follow Up 
Patients will be followed for a total of 6 months after removal from study treatment or until 
death, whichever occurs first.  Patients removed from study for unacceptable adverse event(s) 
will be followed until resolution or stabilization of the adverse event. 
 
5.7 Criteria for Removal from Study 
Patients will be removed from study when any of the criteria listed in Section 5.5 applies.  
The reason for study removal and the date the patient was removed must be documented in 
the Case Report Form. In addition, early stopping criteria are defined in Section 9. 
 
6 
DOSING DELAYS, DOSE MODIFICATIONS AND EARLY STOPPING CRITERIA 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 4.0 for adverse event and serious adverse event reporting.  A copy of the CTCAE 
Version 4.0 can be downloaded: (http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx). 
 
6.1 Dose Modifications 
 
In the case of any Grade 2 hematologic or non-hematologic toxicity attributable to the 
study drug, dose reductions can be performed to up to 3 different, consecutive levels 
as detailed below. All initial dose reductions will start at level -1, and proceed to the 
immediately lower level if the toxicity in question persists for at least 1 week. Dosing 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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schedules will be dependent on what day of the week the patient starts the dose 
reduction level; for example, patients on Dose Level -1 with a Monday start would 
dose on Wednesday, Friday, Sunday, and so on.  
 
 Dose reduction levels are: 
 
o Level -1 (150 mg every other day)  
o Level -2 (150 mg every three days) 
o Level -3 (150 mg twice a week) 
 
• GDC-0449 will be discontinued under the following circumstance: 
 
• Grade 3 or 4 non-hematologic or hematologic toxicity attributable to study 
treatment by Common Terminology Criteria for Adverse Events (CTCAE) version 
4. 
 
 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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7 
STUDY CALENDAR 
 
 
*These represent the minimum number of visits per protocol 
**Pulmonary function tests during these time points are only performed in patients with a diagnosis of chronic 
GVHD of the lung 
3*These are monitoring time points for patients receiving 12 months of therapy. Patients will be followed every 3 
months for 6 months after discontinuation of study treatment. 
4* Adverse Events are monitored while the patient is receiving study drug (i.e. up to 12 months for those patients 
receiving 1 year of therapy) until 30 days post the last dose of study treatment. 
5*Women of childbearing potential (defined in Appendix B) are required to have a negative serum pregnancy test 
(with a sensitivity of at least 25 mIU/mL) within 7 days prior to the first dose of GDC-0449 (serum or urine). A 
pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 
weeks if their cycles are irregular while on study within the 24-hour period prior to the administration of GDC-0449. 
Prior to dispensing GDC-0449, the investigator must confirm and document the patient’s use of two contraceptive 
methods, dates of negative pregnancy test, and confirm the patient’s understanding of the of GDC-0449 to cause 
spontaneous abortion or birth defects 
6* Blood and Plasma will be collected at baseline, 3, 6, 9, and 12 months post first dose.  Skin punch biopsies will be 
collected at baseline and 6 months post first dose. See table in section 13.1 for additional details.  
7 The AM-PAC score (Activity Measure for Post-Acute Care) will be captured at each designated study visit as part 
of routine clinical assessment.  
 
 
 
 
Screening/ 
baseline 
Monthly for 3 
months* 
 
At 4 and 6 
months* 
 
At 8, 10 
and 12 
months3* 
1 month 
after last 
date of 
treatment 
9 months/ 
15 
months3* 
 
12 months/ 
18 months3* 
 
Informed consent 
x 
 
 
 
 
 
 
Medical history 
x 
x 
x 
x 
 
x/x 
x/x 
Demographics 
x 
 
 
 
 
 
 
Eligibility criteria 
x 
 
 
 
 
 
 
Concomitant 
Medications 
x 
x 
x 
x 
x 
x 
x 
Physical exam 
x 
x 
x 
x 
 
x/x 
x/x 
Vital signs 
x 
x 
x 
x 
 
x/x 
x/x 
Performance status 
x 
 
 
 
 
 
 
Pregnancy test5* 
x 
 
 
 
 
 
 
Hematology 
x 
x 
x 
x 
 
x/x 
x/x 
Serum chemistries 
x 
x 
x 
x 
 
x/x 
x/x 
Pulmonary function 
tests 
x 
x** 
x** 
x** 
x** 
x** 
x** 
Correlative studies6* 
x 
At 3 months 
At 6 months 
 
 
x 
x 
Chronic GVHD 
assessment 
x 
x 
x 
x 
 
x/x 
x/x 
Endpoint 
assessments 
Primary & 
secondary 
 
x 
x 
x 
 
x/x 
x/x 
Adverse events4* 
x 
x 
x 
x 
x 
x 
x 
AM-PAC7 
 
x 
x 
x 
x 
x 
x 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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8 
STUDY PROCEDURES 
 
Patient registration for this trial will be managed by the Research Compliance Office at the 
Huntsman Cancer Institute. 
 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
8.1 
Screening Procedures 
All screening procedures must be performed within 7 days prior to registration unless otherwise 
stated. The screening procedures include: 
• Informed Consent 
• Medical history - Complete medical and surgical history, including history of 
infections 
• Demographics - Age, gender, race, ethnicity 
• Review subject eligibility criteria 
• Review previous and concomitant medications 
• Physical exam including vital signs, height and weight - Vital signs (temperature, 
pulse, respirations, blood pressure) 
• Performance status - Evaluated prior to study entry according to Appendix A. 
• Adverse event assessment - Baseline adverse events will be assessed. See Section 
14.0 for Adverse Event monitoring and reporting. 
• Hematology 
o Complete blood count (CBC) with differential and platelet count.  
• Blood draw for correlative studies 
o See Section 13.0 for details. 
• Blood Serum chemistries 
o Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphates, 
Alanine Amino transferase/Serum Glutamic Pyruvic Transaminase(ALT/SGPT), 
Aspartate Amino transferase/ Serum Glutamic Oxaloacetic 
Transaminase(AST/SGOT), BUN, creatinine, electrolytes (sodium, potassium, 
calcium, chloride, bicarbonate), glucose, and total bilirubin. 
o Serum Magnesium (Mg) and Phosphorus (Phos). 
o Serum Lactate dehydrogenase (LDH). 
o Pregnancy test (for females of child bearing potential) 
• Chronic GVHD assessment 
• To be performed using the NIH global score which will be defined by using the NIH 
consensus criteria for assessment of chronic GVHD severity [46].  
 
Other tests 
• Baseline pulmonary function tests. 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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8.2 
Procedures During Treatment 
Clinical assessment visits - Will be scheduled monthly for the first 3 months, then months 4, 6, 8 
10, 12 while patients are receiving GDC-0449 and will include history and physical exam (H&P) 
including vital signs, height and weight, directed evaluation of chronic GVHD assessment as per 
8.1, directed evaluation of treatment effect as per  9.0, directed evaluation of adverse events as 
per 14.0, hematology as per 8.1, serum chemistries as per Section 8.1. 
 
Study endpoint assessments - Will be study specific and will include comprehensive evaluations 
of chronic GVHD and evaluations of correlative studies as in table in section 7. 
8.3 
Follow-Up Procedures 
 
Patients will be followed every 3 months from the first day the patient is no longer receiving 
GDC-0449 through 6 months from the completion of GDC-0449.  
 
Follow-up visits will include H&P including vital signs, height and weight, directed evaluation 
of chronic GVHD assessment, directed evaluation of treatment effect, directed evaluation of 
adverse events, hematology and serum chemistries following the same guidelines above in 
section 8.1. 
8.4 Time and Events Table 
The time of assessments is shown in months, as it facilitates better comprehension, preventing 
potential errors, in the interpretation of the exact timing for each assessment. On the other 
hand, in order to facilitate integration with the weekly-based schedule of corticosteroids taper, 
and also budget considerations, we use the following transformation between weeks and 
months when addressing the schedule of assessments: 
 
1 month: Week 4+/-1 week 
2 months: Week 8+/-1 Week 
3 months: Week 12+/-1 week 
4 months: Week 16+/-1 week 
6 months: Week 24 +/-1week 
8 months: Week 32+/- 1 week 
9 months: Week 36 +/-1 week 
10 months: Week 40 +/- 1 week 
12 months or 1 year: Week 52 +/-1week 
15 months: Week 64 +/-1 week 
18 months: Week 72+/-1 week 
 
9 
CRITERIA FOR EVALUATION AND ENDPOINT 
9.1 Measurement of Effect 
Response to therapy will be assessed at clinical assessment visits every 3 months from the 
first day of treatment with GDC-0449 through 12 months from the initiation of GDC-0449. 
Response will be defined as FFS at 6 months [23].  


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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9.1.1 Failure Free Survival Definition 
FFS is defined as being alive and:  
• No relapse of malignancy  
• No addition of any other systemic treatment for chronic GVHD 
• Steroid dose at 6 months ≤ 0.2 mg/kg/day PDE 
 
The need for addition of therapy while on GDC-0449 is one of the criteria for failure, and 
consequently the patient will be taken off study. In order to minimize differences in practice 
that might impact the primary endpoint, we established minimal indispensable criteria to 
initiate additional immunosuppressive therapy during the first six months of GDC-0449 
treatment.  
 
9.1.2 Definition of Response to Therapy 
1. Stable disease (SD) (no change in chronic GVHD) according to NIH consensus 
response criteria for a total of 1month [46]. This criteria is irrespective of any 
response obtained initially, prior to the month of stability. 
2. Progressive Disease: This is defined as any one of the following: 
• Skin: Increase in NIH Skin Score by 1 or more points, except 0 to 1. 
• Eyes: Increase in NIH Eye Score by 1 or more points, except 0 to 1. 
• Mouth: Increase in NIH Modified Oral Mucosa Rating Score of 2 or more points. 
• Esophagus: Increase in NIH Esophagus Score by 1 or more points, except 0 to 1. 
• Upper GI: Increase in NIH Upper GI Score by 1 or more points, except 0 to 1. 
• Lower GI: Increase in NIH Lower GI Score by 1 or more points, except from 0 to 
1. 
• Liver: Increase by 2x ULN ALT, alkaline phosphatase, and Total bilirubin.  
• Lungs: 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: 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 increases by 2 or more points on a 0 – 10 
scale 
3. Partial Response: This is defined as any one of the following: 
• Skin: Decrease in NIH Skin Score by 1 or more points 
• Eyes: Decrease in NIH Eye Score by 1 or more points 
• Mouth: Decrease in NIH Modified Oral Mucosa Rating Score of 2 or more points. 
• Esophagus: Decrease in NIH Esophagus Score by 1 or more points. 
• Upper GI: Decrease in NIH Upper GI Score by 1 or more points 
• Lower GI: Decrease in NIH Lower GI Score by 1 or more points. 
• Liver: Decrease by 50% ALT, alkaline phosphatase, and Total bilirubin. 
• Lungs: Increase by 10% predicted absolute value of %FEV1. If PFTs not 
available, decrease in NIH Lung Symptom Score by 1 or more points. 
• Joints and Fascia: Decrease in NIH Joint and Fascia Score by 1 or more points or 
increase in P-ROM score by 1 point for any site. 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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• Global: Clinician overall severity score decreases by 2 or more points on a 0 – 10 
scale. 
4. Complete Response: This is defined as any one of the following: 
• Skin: NIH Skin Score 0 after previous involvement. 
• Eyes: NIH Eye Score 0 after previous involvement. 
• Mouth: NIH Modified Oral Mucosa Rating Score 0 after previous involvement. 
• Esophagus: NIH Esophagus Score 0 after previous involvement. 
• Upper GI: NIH Upper GI Score 0 after previous involvement. 
• Lower GI: NIH Lower GI Score 0 after previous involvement. 
• Liver: Normal ALT, alkaline phosphatase, and Total bilirubin after previous 
elevation of one or more. 
• Lungs: Normal %FEV1 after previous involvement. If PFTs not available, NIH 
Lung Symptom Score 0 after previous involvement. 
• Joints and Fascia: Both NIH Joint and Fascia Score 0 and P-ROM score 25 after 
previous involvement by at least one measure. 
• Global: Clinician overall severity score 0. 
 
Patients under categories 1 and 2 require the addition of other systemic treatment for chronic 
GVHD. These conditions should be attributable to chronic GVHD, with exclusion of other 
relevant causes in the differential diagnosis when applicable. The addition of other systemic 
treatment excludes the patient from the current clinical study. 
9.2 Safety 
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, and clinical laboratory 
test results. More frequent safety evaluations may be performed if clinically indicated or at the 
discretion of the investigator. 
  
Physical Examination 
Complete and symptom-directed physical examinations will be performed by a licensed 
physician (or physician’s assistant or nurse practitioner). 
 
Vital Signs 
Vital signs (blood pressure, respiratory rate, pulse rate and temperature) will be obtained per 
the study calendar. 
 
Safety Laboratory Determinations 
Laboratory evaluations will be performed as noted on the study calendar.  
9.3 Stopping Rules/Interim Analysis 
Safety was assessed after 1 cycle in the first 4 subjects to ensure that no more than one grade 
3-5 drug reaction occurred and that no more than 4 of 6 subjects required a dose reduction for 
grade 2-4 drug reactions. At the initial dose of 150 mg daily, dose reductions to 150 mg every 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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other day for Grade 2 drug reactions were required. As such, the dosing schema was updated 
to the following: 
 
The initial dose will be given at 150 mg po daily. If Grade 2 hematologic or non-
hematologic toxicities attributable to the study drug are observed, three different, 
consecutive dose reduction levels may be utilized (below). All initial dose reductions 
will start at Level -1 and proceed to the next level if the toxicity in question persists. 
Dosing schedules will be dependent on what day of the week the patient starts the dose 
reduction level; for example, patients on Dose Level -1 with a Monday start would 
dose on Wednesday, Friday, Sunday, and so on.  
 
o Level -1 (150 mg po every other day)  
o Level -2 (150 mg po every three days) 
o Level -3 (150 mg po twice a week) 
Starting with patient 05, safety will be assessed to ensure that no more than 4 subjects (50% 
of the number of patients left to meet the enrollment target of 12) discontinue GDC-0449 after 
reducing to Level -3 due to adverse effects attributable to study drug. Safety will be reviewed 
monthly and at the time of each grade 3-5 reaction. 
 
GDC-0449 will be discontinued under the following circumstance: 
 
• If no more than 4 subjects (50% of the number of patients left to meet the enrollment 
target of 12) enrolled discontinue GDC-0449 after reducing to Level -3 due to 
adverse effects attributable to study drug. 
 
10 STATISTICAL CONSIDERATIONS 
 
10.1   Study Design/Study Endpoints 
 
This is a pilot study of GDC-0449 in steroid refractory chronic GVHD. This is a single- 
institution study that will be performed at the Huntsman Cancer Institute. Total duration 
of study will be 2 years. 
 
10.1.1 
Primary Endpoint 
 
 
• FFS at 6 months after initiation of therapy with GDC-0449 
FFS is defined as absence of NRM, no recurrent malignancy, steroid dose at 6 months 
≤ 0.2 mg/kg/d of PDE, and no addition of new systemic treatment for chronic GVHD 
(Adapted from [45]). Criteria for addition of new systemic treatment for chronic 
GVHD are defined as per section 9.0. 
 
10.1.2 Secondary Endpoints 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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• Safety of GDC-0449 in patients with steroid-refractory chronic GVHD 
 
• Change in NIH global score of chronic GVHD from baseline at 6 and 12 months after 
the initiation of the protocol therapy 
  
o NIH global score will be defined by using the NIH consensus criteria for 
assessment of chronic GVHD severity [46].  
 
• One-year NRM and one-year relapse rate 
  
o Relapse will be defined as malignancy relapse or as the initiation of any 
unintended intervention including an unplanned taper of immunosuppressant 
therapy to prevent malignancy progression due to any signs of recurrent, 
residual or new malignant disease after transplantation.  
 
• One-year FFS and one-year OS 
  
o FFS is defined as in section 10.1.1 (Primary Endpoint). 
 
• Clinical characteristics that may be associated with decreased FFS including the 
presence of high-risk disease at transplantation; high-intensity conditioning with 
total-body irradiation; > 3 involved sites with chronic GVHD, lower gastrointestinal 
involvement by GVHD and severe NIH global score at initiation of protocol 
treatment; and thrombocytopenia, hyperbilirubinemia, and steroid doses >1 mg/kg per 
day immediately before treatment failure requiring treatment change. 
  
• Clinical response to GDC-0449 at 6 months as defined in section 9.1.2. 
 
 
10.1.3 Exploratory Endpoints 
 
• Fibrocyte numbers, leukocyte subsets and T cell cytokine profiles will be determined 
at baseline and in response to GDC-0449 at 3, 6, 9 and 12 months using flow 
cytometry. 
• Cytokine profiles and ECM biomarkers present in plasma will be determined at 
baseline and in response to GDC-0449 at 3, 6, 9 and 12 months using ELISA and the 
fibroplex assay 
• Mesenchymal cell phenotypes cultured from skin biopsies of cutaneous cGVHD 
patients pre- and post-GDC-0449 will be determined at baseline and in response to 
GDC-0449 at 6 months using immunohistochemistry studies and mesenchymal cell 
cultures 
• Levels of TGFβ and hedgehog activation will be determined on skin biopsies at 
baseline and in response to GDC-0449 at 6 months, using different staining and other 
techniques. 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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10.2    Sample Size/Accrual Rate/Other Statistical Considerations 
 
 
 
Sample size: 12 patients. Accrual rate: 1-2 patients monthly. 
This is a pilot study that will include 12 patients. FFS, the primary endpoint, will be 
evaluated using the Kaplan-Meier method. The impact of different covariates on FFS will 
be analyzed using descriptive statistics, t-test, and Fisher’s exact test where applicable. 
Differences in NIH scores will be analyzed using Wilcoxon signed-rank test. Differences 
in biomarkers will be assessed using Wilcoxon rank-sum test. 
 
Overall clinical response (PD, SD, PR, CR) according to NIH criteria will be tabulated 
and described based on organ response and overall response. 
 
The proportion of subjects who experience adverse events and serious adverse events will 
be summarized descriptively; no inferential tests will be performed. 
 
10.3   Stratification Factors 
 
N/A 
 
10.4   Analysis of Secondary Endpoints 
 
See Sections 10.1. 
 
11 REGISTRATION GUIDELINES 
 
11.1  Investigator and Research Associate Registration with CTEP 
 
11.1.1 CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
 
Registration requires the submission of: 
 
• a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• a current Curriculum Vitae (CV) 
• a completed and signed Supplemental Investigator Data Form (IDF) 
• a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
http://ctep.cancer.gov/investigatorResources/investigator registration.htm. 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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For questions about Investigator Registration, please contact the CTEP Investigator 
Registration Help Desk by email at pmbregpend@ctep.nci.nih.gov 
 
11.1.2 CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only.  (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
 
An active CTEP-IAM user account is required to access all CTEP applications and, if 
applicable (e.g., all Network trials), all Cancer Trials Support Unit (CTSU) applications 
and websites. 
 
Additional information can be found on the CTEP website at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm. 
 
11.2  Patient Registration: 
 
Patients must meet all of the eligibility requirements listed in Section 4 prior to 
registration.   
 
Study related screening procedures can only begin once the patient has signed a consent 
form.  Patients must not begin protocol treatment prior to registration. 
 
Treatment should start within 5-7 business days after registration. 
 
To register eligible patients on study, complete a Clinical Trials Office Patient Registration 
Form and submit to: CTORegistrations@hci.utah.edu.  
 
IWRS 
Patient Enrollment will be facilitated using the Interactive Web Response System (IWRS).  
IWRS is a web-based registration system available to users on a 24/7 basis.  On a successful 
registration, IWRS will assign a patient number and assign the treatment.  Patient enrollment 
data entered by Registrars in IWRS will automatically transfer to the NCI’s clinical data 
management system, Medidata Rave.  IWRS will provide a printable confirmation of 
registration and treatment information.  Please print this confirmation for your records. 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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• Users must have a valid CTEP-IAM account (i.e., CTEP username and password) to 
access the IWRS system. 
• Users defined with the Registrar role will have the ability to register patient in the 
study. 
• Users defined with the Client Administrator role will have the ability to manage 
accrual limits, open and close treatment assignments as well as approve slot 
reservations, if applicable to the study. 
• For trials with slot reservation requirements, Registrars will have the ability to request 
to reserve a slot, which may require approval from users at the lead institution defined 
as a ‘Client Administrator’ for the study. 
 
12 DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
14.0 (Adverse Events: List and Reporting Requirements). 
 
12.1  Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the 
site user must have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Read-Only, or Site Investigator) on either the 
Corresponding Organization or Participating Organization roster at the enrolling site.   
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To 
accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, 
and click on the “accept” link in the upper right-corner of the iMedidata page.  Please note, 
site users will not be able to access the study in Rave until all required Medidata and study 
specific trainings are completed.  Trainings will be in the form of electronic learnings 
(eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website under the Rave tab or by contacting the CTSU Help Desk at 1-888-
823-5923 or by e-mail at ctsucontact@westat.com. 
 
12.1.1  Method 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will 
be submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/CTMS.  On-site audits will be conducted three times annually (one 
annual site visit and two data audits).  For CTMS monitored studies, after users have 
activated their accounts, please contact the Theradex Help Desk at (609) 799-7580 or by 
email at ctms@theradex.com for additional support with Rave and completion of CRFs. 
12.2  CTEP Multicenter Guidelines 
 
N/A 
 
12.3  Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators.  The protocol documents for 
studies utilizing Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI.  If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement.  A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design 
of the proposed combination protocol, and the existence of any obligations that 
would tend to restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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other Collaborator to develop, obtain regulatory approval or commercialize its own 
Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication.  Collaborator(s) will have 
30 days from the date of receipt for review.  Collaborator shall have the right to 
request that publication be delayed for up to an additional 30 days in order to ensure 
that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and 
preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings.  Press releases and other 
media presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/ proprietary information. 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
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Principal Investigator: Daniel Couriel, MD 
 
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13 BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
13.1  Biomarker Studies 
All studies in this section are ancillary/exploratory. The aim of these studies is to determine 
the impact of GDC-0449 treatment on parameters of ECM turnover and immunologic changes 
in the circulation, as well as on markers of HH signaling in cGVHD skin biopsies.  
13.1.1 Proteomic chronic GVHD analysis in Plasma: 
Plasma will be collected for proteomic analysis of chronic GVHD biomarkers and 
extracellular matrix production and turnover. Analysis will include, but not be limited to, 
osteopontin, ST2, BAFF, MMP3, TGF-, and CXCL9.  
13.1.2 Immunologic Monitoring in Peripheral Blood: 
Immunological monitoring will be performed using peripheral blood mononuclear cells collected 
prior to the initiation of therapy and then at 3, 6, 9 and 12 months (5 time points per patient)  
 
13.1.2.1 
Immune Cell Subsets:  
The main objectives of the monitoring will be to characterize changes in immune subsets with 
well-defined or emerging roles in immunopathology of chronic GVHD (T cells, B cells, and 
monocytes/dendritic cells) and correlate findings with the clinical outcome. . Analyses will 
utilize multicolor flow cytometry to profile helper and regulatory CD4+ T cells, effector CD8+ T 
cells, circulating monocytes, and B cells and define impact of GDC-0449.. 
  
Regulatory T cell analyses (CD3+ CD4+ CD25+ Foxp3+) will focus on markers of their 
suppressive potential with likely functional impact in chronic GVHD (such as Helios and CTLA- 
[53-57]. Th1/Th2/Th17 polarization among helper T cells will be analyzed by flow cytometry, 
evaluating canonical transcription factors Tbet, GATA3, and RORγ and cytokine production in 
re-stimulated T cells. In addition, sort purified CD4+ and CD8+ T cells will be transcriptionally 
profiled for broader cytokine production and changes that occur under GDC-0449. 
 
B cells are well documented mediators of chronic GVHD and represent an intermediary step in 
triggering fibrotic tissue response. We will provide immunophenotypic analyses and focus on 
characterization of GDC-0449 impact on defined subsets with pathogenic relevance in chronic 
GVHD, including “autoreactive” CD27negCD21low, pre-germinal center CD27+IgD+CD38hi, and 
plasmablast-like CD27+IgDlowCD38hi B cells in peripheral blood. In addition, B cells will be sort 
purified to evaluate transcriptionally impact of GDC-0449 on Hh target genes. 
 
Emerging evidence supports key role for alternative macrophage activation and polarization in 
fibrotic tissue remodeling in chronic GVHD, and pre-clinical studies have identified early 
monocyte polarization is essential for fibrotic GVHD onset. We will profile impact of GDC-
0449 on subsets of patrolling (CX3CR1highCD14dimCD16+) and classical 
(CCR2highCD14+CD16−) monocytes by flow cytometry. In addition, we will sort purify bulk 
monocytes and transcriptionally analyze for regulation of Hh target genes and classicall vs 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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alternative polarization towards macrophages. 
  
The effect of GDC-0449 on immune subsets remains uncharacterized aside for pre-clinical 
reports of no impact on leukocyte tissue infiltration in models of chronic fibrotic GVHD. Pre-
clinical data suggest impact of Hh signaling on innate immunity, thus, if clinical benefit is 
documented, we hypothesize biggest differences will be seen in the pool of peripheral blood 
monocytes. While Hh pathway has been shown to play a role in T cell development its impact on 
mature T cell responses remains undefined. We postulate that Hh will not influence T cell 
polarization or function, nor B cell responses directly, and possible clinical benefits will be 
largely derived through its impact on myeloid regulation and/or terminal tissue remodeling 
functions. Importantly, our studies will document the effects of GDC-0449 on adaptive immunity 
and thus inform of the possible immunosuppressive effects of this therapy that could pose further 
risks to patients with chronic GVHD. 
 
Flow Cytometry panels: 
 
Panel 1: 
Treg 
Panel 2: 
T helper 
Panel 3: B cells 
/ Monocytes 
Panel 4: 
Sort 
41BB 
IL-17 
CD3 
CD3 
CD4 
CD4 
CCR2 
CD4 
CD127 
  
  
  
ICOS 
IFNg 
CD14 
CD14 
FoxP3 
RORc 
CD64 
CD64 
PD-1 
  
CD20 
CD20 
Helios 
GATA3 
CD38 
  
OX40 
IL-4 
CD16 
CD16 
  
  
IgD 
  
CD25 
Tbet 
CX3CR1 
  
CD3 
CD3 
  
  
CTLA-4 
  
CD27 
  
CD8 
  
CD21 
CD8 
Viability 
Viability 
Viability 
Viability 
 
13.1.2.2 
Platelet Function Assay  
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Assay description 
Proposed candidates 
Whole blood flow cytometric assay for platelet activation 
CD41, P-selectin, PAC-1, CD154 (CD40L). 
Isolated platelets flow cytometric assay for platelet 
apoptosis and immune functions 
Annexin V, Caspase-3, Bcl-2, MHC class I, 
CXCR4, CCL5 (RANTES), PDGF, 
PF4(CXCL4), TGF-β, TNF-α. 
Ex vivo stimulated platelets flow cytometric assay for 
platelet activation and immune functions 
CD41, P-selectin, PAC-1, CD154 (CD40L), 
CXCR4, CCL5, PDGF, VEGF, PF4, TGF-β, 
TNF-α. 
ELISA for the quantification of platelet released cytokine 
and growth factors upon stimulation ex vivo 
VEGF, PDGF, TGF-β, TNF-α, IL-1, IL-6, 
serotonin. 
Western immunoblotting of isolated platelet lysates and ex 
vivo stimulated platelet lysates for the characterization of 
Wnt/Shh signaling pathway 
Wnt, β-Catenin and phospho-β-Catenin. 
RNA sequencing of platelets 
Global genetic signature characterization of 
platelets. 
Validation at protein level of candidates screemed from 
RNA sequencing data 
Dependent on the RNA sequencing data. 
 
 
Abbreviations: 
CCL5: Chemokine ligand 5 
CXCR4: C-X-C chemokine receptor type 4 
ELISA: Enzyme-linked immunosorbent assay 
PDGF: Platelet derived growth factor 
PF4: Platelet factor 4 
TGF-β: Transforming growth factor-beta 
TNF-α: Tumur necrosis factor 
VEGF: Vascular endothelial growth factor 
 
 
Whole blood will be drawn from consenting patients and controls using sterile, ACD-containing, 
BD vacutainer tubes.  We will draw approximately 40mLs of whole blood from each patient or 
control at each time point.  Blood will be used immediately for real-time assays (e.g. whole 
blood flow cytometry and platelet stimulation assays) and cells and plasma components will also 
be isolated (e.g. platelets, PBMCs, plasma, plasma-derived microparticles) for studies performed 
in batches to minimize variability.  Table 1 is a proposed list of assays and target candidates.  
These candidates include canonical indices of platelet activation (e.g. P-selectin, PAC-1), 
immune and inflammatory molecules expressed by or secreted from platelets (e.g. TNF, CD154, 
MHC Class I, CCL5), apoptosis markers (e.g. Annexin V), and growth factors (e.g. VEGF).  We 
will also interrogate candidates involved in the hedgehog pathway including Wnt and beta-
catenin (both unphosphorylated and phosphorylated forms).  Other assays may be included as 
new targets are identified.  Next-generation RNA-sequencing will be done on a subset of patients 
and controls (n=5-10/group) as a discovery tool to interrogate other genes differentially 
expressed in patients with GHVD. 
 
13.1.3 Skin Biopsies: 
 
Four mm punch biopsies will be collected at baseline and 6 months from patients enrolled in the 
study.  Biopsies will be cut in half and one half will be fixed and embedded in paraffin for 
immunohistochemistry studies for the HH stabilized transcription factors GLI-1 and GLI-2. The 
other half will be used to obtain RNA to test for mRNA expression of SHH, GLI-1, GLI-2, 




Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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NIH funded. His lab has contributed a novel understanding of platelets, 
magakaryocytes, and platelet-leukocyte interactions during health and disease.   
Whole blood and plasma samples will be analyzed in the University of Utah 
Molecular Medicine Program in the Rondina Lab at the Eccles Institute of Human 
Genetics.  
 
13.1.5  Overall Anticipated Results, Interpretations and Pitfalls:  
In all analyses, each patient will serve as their own control by comparing 
baseline measures with longitudinal results post-treatment.  GDC-0449 may have 
little impact on inflammatory cell numbers in the peripheral blood or IHC 
specimens based on previous murine results [34].  Whether GDC-0449 will alter 
T cell cytokine profiles in circulation or in skin is unknown.  Patients responding 
well to this SMO inhibitor may show reduced IL-17 and IFNγ in circulation as 
these cytokines have been associated with cutaneous manifestations of cGVHD 
[47].  These same studies showed Th2 cytokines (IL-4/13) were associated with 
aGVHD.  If therapy fails to mediate clinical improvement, it may be due to an 
inability to inhibit these T cell responses. If GDC-0449 is effective, we anticipate 
reduced expression of GLI-1, GLI-2, PTCH-1 and PTCH-2 in skin. Because 
GLI-1 can activate IL-6 and IL-8 [63], these cytokines may be reduced in plasma 
post-GDC-0449 treatment and this may offer an assay to look for HH activity 
indirectly. Patients who do not respond may show no reductions in HH signaling 
(e.g. GLI-1) and this may indicate that drug levels were insufficient.  It is also 
possible that patients may acquire SMO mutations that make them resistant to 
GDC-0449 [64, 65].  This could be determined by sequence analysis of SMO in 
those patients.  We believe systemic markers of ECM synthesis, turnover and 
degradation will also be altered by GDC-0449 treatment in patients showing 
signs of clinical efficacy.  We realize that these analyses are exploratory in 
nature given the relatively small sample size (n=12) for which CTEP agreed to 
provide study drug.  However, these studies are highly significant as they are 
likely to identify relevant biomarkers that correlate with clinical efficacy or that 
may explain therapeutic futility.  These will be critical insights into designing 
larger future trials. 
 
14 ADVERSE EVENTS 
 
14.1 Adverse Events / Serious Adverse Events 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 4.0 for AE and SAE reporting.  An electronic copy of the CTCAE Version 4.0 can be 
downloaded from: http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx 
 
14.1.1 Adverse Events (AE) 
An adverse event is the appearance or worsening of any undesirable sign, 
symptom, or medical condition occurring after starting the study drug even if the 
event is not considered to be related to study drug. For the purposes of this study, 
the terms toxicity and adverse event are used interchangeably. Medical 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
 
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conditions/diseases present before starting study drug are only considered adverse 
events if they worsen after starting study drug. Abnormal laboratory values or test 
results constitute adverse events only if they induce clinical signs or symptoms, 
are considered clinically significant, or require therapy. 
 
The collection of adverse events will begin after the first dose of study treatment 
and end 30 days post the last dose of study treatment.  
 
Information about all adverse events, whether volunteered by the subject, 
discovered by investigator questioning, or detected through physical examination, 
laboratory test or other means, will be collected and recorded and followed as 
appropriate. 
 
The occurrence of adverse events should be sought by non-directive questioning 
of the patient at each visit or phone contact during the study. Adverse events also 
may be detected when they are volunteered by the patient during or between visits 
or through physical examination, laboratory test, or other assessments. As far as 
possible, each adverse event should be evaluated to determine: 
 
1. the severity grade based on CTCAE v.4 (grade 1-5) 
2. its relationship to the study drugs (definite, probable, possible, unlikely, 
not related)  
3. its duration (start and end dates or if continuing at final exam) 
4. action taken (no action taken; study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication taken; non-drug therapy given; 
hospitalization/prolonged hospitalization) 
5. whether it constitutes an SAE 
 
All adverse events will be treated appropriately. Such treatment may include 
changes in study drug treatment as listed in the dose modification section of this 
protocol (see section 6 for guidance). Once an adverse event is detected, it should 
be followed until its resolution, or until the end of the follow-up period (6 months 
after removal from study treatment or until death, whichever occurs first) and 
assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome. 
 
Information about common side effects already known about the investigational 
drug is described in the Drug Information (section 3) and the most recent 
Investigator Brochure. This information will be included in the patient informed 
consent and will be discussed with the patient during the study as needed. 
 
All adverse events will be immediately recorded in the patient research chart.  
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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14.1.2 Serious Adverse Event (SAE) 
Information about all serious adverse events will be collected and recorded. Refer 
to section 14.3 for NCI serious adverse event guidelines.  
 
14.2  Huntsman Cancer Institute SAE Reporting Requirements 
SAEs must be reported to the DSMC, the FDA, the IRB, and the NCI, according to the 
requirements described below: 
 
A CTEP-AERS form must be completed per NCI guidelines listed in section 14.3. At the 
completion of the online submission, the SAE report should be exported to a PDF and printed. 
The PI should sign and date the report which will then be submitted to 
compliance@hci.utah.edu as soon as possible, but no later than 10 days of first knowledge or 
notification of event (5 days for fatal or life threatening event). 
 
DSMC Notifications: 
• An HCI Research Compliance Officer (RCO) will process and submit the CTEP-
AERS form to the proper DSMC member as necessary for each individual study.  
• The RCO will summarize and present all reported SAEs according to the Data and 
Safety Monitoring Plan at the quarterly DSMC meeting. 
 
IRB Notification: 
• Events 
meeting 
the 
University 
of 
Utah 
IRB 
reporting 
requirements 
(http://www.research.utah.edu/irb/) will be submitted through the IRB’s electronic 
reporting system within 10 working days. 
14.3  CTEP Notification and Reporting Requirements   
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs and the characteristics of an observed AE will determine whether the 
event requires expedited reporting (via CTEP-AERS) in addition to routine reporting.   
 
14.3.1 Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
GDC-0449 (Vismodegib, NSC 747691) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 1893 patients. Below is the CAEPR for GDC-
0449 (Vismodegib).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 




Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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2Irregular menstruation was observed in 30% (3 of 10) women of child bearing age and/or in 28% (18 of 
64) women who had menses at baseline who were enrolled in studies of advanced BCC. 
 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on GDC-0449 (Vismodegib) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that GDC-0449 (Vismodegib) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Febrile neutropenia; Thrombotic 
thrombocytopenic purpura 
 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Heart failure; Myocardial 
infarction; Pericardial tamponade; Sinus bradycardia 
 
EYE DISORDERS - Keratitis; Retinal vascular disorder 
 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Dry mouth; Dysphagia; 
Esophageal pain; Esophagitis; Flatulence; Gastritis; Gastroesophageal reflux disease; Gastrointestinal 
disorders - Other (thrush); Gastrointestinal hemorrhage3; Gastrointestinal pain; Ileus; Mucositis oral; 
Pancreatitis; Stomach pain 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Facial 
pain; Fever; Injection site reaction; Non-cardiac chest pain; Pain 
 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Portal hypertension 
 
INFECTIONS AND INFESTATIONS - Infection4 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Hip fracture 
 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Blood bilirubin increased; Cholesterol high; Creatinine increased; GGT 
increased; INR increased; Investigations - Other (brain natriuretic peptide increased); Investigations - 
Other (elevated LDH); Lipase increased; Lymphocyte count decreased; Neutrophil count decreased; 
Platelet count decreased; White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperglycemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; 
Hypomagnesemia; Hyponatremia; Hypophosphatemia 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
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Principal Investigator: Daniel Couriel, MD 
 
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MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Flank 
pain; Generalized muscle weakness; Muscle weakness lower limb; Musculoskeletal and connective tissue 
disorder -  Other (muscle tightness/stiffness); Myalgia; Neck pain; Pain in extremity; Trismus 
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Leukemia secondary to oncology chemotherapy; Treatment related secondary malignancy 
 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dizziness; Dysesthesia; 
Headache; Intracranial hemorrhage; Movements involuntary; Nervous system disorders - Other (amimia); 
Olfactory nerve disorder; Paresthesia; Peripheral motor neuropathy; Peripheral sensory neuropathy; 
Seizure; Stroke; Syncope; Tremor 
 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Hallucinations; Insomnia; 
Psychosis 
 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal hemorrhage 
 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Aspiration; Cough; Dyspnea; 
Epistaxis; Hiccups; Hypoxia; Pleural effusion; Pneumonitis; Postnasal drip; Pulmonary edema; 
Respiratory, thoracic and mediastinal disorders - Other (COPD); Respiratory, thoracic and mediastinal 
disorders - Other (oropharyngeal pain); Sneezing; Sore throat 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Nail ridging; Pruritus; Rash 
acneiform; Rash maculo-papular; Skin and subcutaneous tissue disorders - Other (hair color changes); 
Skin and subcutaneous tissue disorders - Other (psoriasis); Skin and subcutaneous tissue disorders - Other 
(skin exfoliation); Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event; Vasculitis 
 
Note: GDC-0449 (Vismodegib) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
Additional Adverse Events 
 
Serious or Life-threatening Birth Defect Effects of GDC-0449 
Studies have demonstrated that inhibition of the Hh pathway in embryos results in 
brain, facial, and other midline defects, including holoprosencephaly or 
microencephaly, cyclopia, absent nose, cleft palate, tooth abnormalities, and bone 
development abnormalities (Bale, 2002).  While the effects of GDC-0449 on the 
developing human fetus at the recommended therapeutic dose are unknown, women 
of childbearing potential and men must agree to use two methods of contraception 
(i.e., barrier contraception and another method of contraception) prior to study entry, 
for the duration of study participation, and for 24 months following treatment. 
 
Women of childbearing potential are defined as follows: 
• Patients with regular menses 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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• Patients with amenorrhea, irregular cycles, or using a contraceptive method that 
precludes withdrawal bleeding 
• Women who have had a tubal ligation 
 
Women are considered not to be of childbearing potential for the following reasons: 
• The patient has undergone hysterectomy and/or bilateral oophorectomy. 
• The patient is post-menopausal defined by amenorrhea for at least 12 months in a 
woman > 45 years old. 
 
Women of childbearing potential are required to use two forms of acceptable 
contraception (refer to Appendix B), including one barrier method during 
participation in the study and for the 24 months following the last dose.  All patients 
should receive contraceptive counseling either by the investigator or by an 
OB/gynecologist or other physician who is qualified in this area of expertise.  If a 
woman of childbearing potential believes that her contraceptive method has failed, 
emergency contraception should be considered. 
 
If a patient is suspected to be pregnant, GDC-0449 should be IMMEDIATELY 
discontinued and the study physician contacted.  A positive urine test must be 
confirmed by a serum pregnancy test.  If it is confirmed that the patient is not 
pregnant, the patient may resume dosing with GDC-0449.   
 
If a female patient becomes pregnant during therapy or within 24 months after 
the last dose of GDC-0449, or if the female partner of a male patient exposed to 
the drug becomes pregnant while the male patient is receiving GDC-0449 or 
within 3 months after the last dose of GDC-0449, the investigator must be notified 
in order to facilitate outcome follow-up. 
 
Abortion, whether accidental, therapeutic, or spontaneous, should always be 
classified as serious.  Any congenital anomaly/birth defect in a child conceived 
during the study or within 24 months after the last dose of GDC-0449 to a female 
patient or to a female partner of a male patient exposed to the agent during treatment 
or within 3 months after the last dose of GDC-0449 should be recorded and reported 
as an SAE. 
 
In addition, it is not known whether GDC-0449 that may be present in seminal fluid 
would cause serious or life-threatening birth defects in a fetus born to the female 
partner of a male subject.  Sexually active male subjects should utilize a barrier form 
of contraception, even those who have had a vasectomy, during study treatment and 
for 3 months after the last dose.  Male patients should advise their partners to use an 
additional method of contraception during the study and for at least 3 months after 
discontinuation of GDC-0449.  Male subjects should also not donate sperm during 
treatment or up to 12 months after the last dose. 
 
Risk of Male Germ Cell Degeneration 








Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Principal Investigator: Daniel Couriel, MD 
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•
Pregnancies that occur up to 24 months after the last dose of GDC-0449 will be
followed until the outcome of the pregnancy is known.
•
The adverse event (pregnancy) should be reported as a Grade 4 event using CTCAE
4.0 as follows:
➢Endocrine disorders- Other (Prenatal exposure to a possible teratogen)
➢A completed “Possible Prenatal Exposure to Teratogen Report” Form
(Appendix C) should be attached to the complete CTEP-AERS Report.  This
form may also be faxed to CTEP along with any relevant supporting medical
information at 301-230-0159 (alternative FAX Number:  301-897-7404).
➢This form should be submitted for any female patient or any female partner of
a male patient who becomes pregnant during therapy or up to 12 months after
the last dose of GDC-0449.
•
Any congenital anomaly/birth defect in a child conceived to a female patient or to a
female partner of a male patient exposed to GDC-0449 during treatment or within 24
months after the last dose of GDC-0449 should be reported as an expedited adverse
event to CTEP-AERS as a 24-hour notification followed by a complete report within
5 calendar days.
•
Abortion, whether accidental, therapeutic, or spontaneous, should always be
classified as serious.  Any abortion occurring during the study or within 24 months
after the last dose of GDC-0449 to a female patient or to a female partner of a male
patient exposed to the agent during treatment or within 24 months after the last dose
of GDC-0449 should be reported as an expedited adverse event to CTEP-AERS as a
24-hour notification followed by a complete report within 5 calendar days.
14.5   Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
through CTEP-AERS must also be reported in routine study data submissions. 
14.6   Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IDE be reported via CTEP-AERS. Three options are available to describe the 
event:  
•
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia
[AML])
•
Myelodysplastic syndrome (MDS)
•
Treatment-related secondary malignancy


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
14.7  Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified.  
 
15 ETHICAL AND REGULATORY CONSIDERATIONS 
 
15.1  Informed consent  
Informed consent will be obtained from all research participants prior to performing any 
study procedures using the most recent IRB approved version.  
 
15.2  Institutional Review 
Study will be approved by the Institutional Review Board of University of Utah. 
 
15.3  Data and Safety Monitoring Plan 
A Data and Safety Monitoring Committee (DSMC) is established at Huntsman Cancer 
Institute (HCI) and approved by the NCI to assure the well-being of patients enrolled on 
Investigator Initiated Trials that do not have an outside monitoring review.  Roles and 
responsibilities of the DSMC are set forth in the NCI approved plan.  The activities of this 
committee include a quarterly review of adverse events including SAEs, important medical 
events, significant revisions or amendments to the protocol, and approval of cohort/dose 
escalations.  If the DSMC and/or the PI have concerns about unexpected safety issues, the 
study will be stopped and will not be resumed until the issues are resolved. The DSMC also 
reviews and approves audit reports generated by the Research Compliance Office.  
 
 
  
This study will be reviewed by the full committee at each quarterly DSMC meeting. This 
includes a review of all serious adverse events (SAEs) occurring in patients treated at HCI or 
its affiliates as well as all grade 3 or greater toxicities for patients on treatment and within 30 
days follow-up window (only if possibly, probably or definitely related).  
15.4  Protocol Amendments 
Any amendments or administrative changes in the research protocol during the period, for 
which the IRB approval has already been given, will not be initiated without submission of 
an amendment for IRB review and approval.    
 
These requirements for approval will in no way prevent any immediate action from 
being taken by the investigator in the interests of preserving the safety of all patients 
included in the trial.  
15.5  Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and 
treatment plans as outlined in the protocol version submitted and previously approved by the 
IRB. Protocol deviations have the potential to place participants at risk and can also 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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undermine the scientific integrity of the study thus jeopardizing the justification for the 
research.  Protocol deviations are unplanned and unintentional events.  
 
Because some protocol deviations pose no conceivable threat to participant safety or 
scientific integrity, reporting is left to the discretion of the PI within the context of the 
guidelines below. The IRB requires the prompt reporting of protocol deviations which are: 
• 
Exceptions to eligibility criteria. 
• 
Intended to eliminate apparent immediate hazard to a research participant or  
• 
Harmful (caused harm to participants or others, or place them at increased risk of 
harm - including physical, psychological, economic, or social harm), or  
• 
Possible serious or continued noncompliance  
 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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Pierucci-Alves, F., A.M. Clark, and L.D. Russell, A developmental study of the Desert 
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Turner, T.T., et al., Sonic hedgehog pathway inhibition alters epididymal function as 
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Sekulic, A., et al., Advanced basal cell carcinoma of the skin: targeting the hedgehog 
pathway. Curr Opin Oncol, 2013. 25(3): p. 218-23. 
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Cigna, N., et al., The hedgehog system machinery controls transforming growth factor-
beta-dependent myofibroblastic differentiation in humans: involvement in idiopathic 
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One, 2011. 6(9): p. e23943. 
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Dlugosz, A., S. Agrawal, and P. Kirkpatrick, Vismodegib. Nat Rev Drug Discov, 2012. 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
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11(6): p. 437-8. 
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Guha, M., Hedgehog inhibitor gets landmark skin cancer approval, but questions remain 
for wider potential. Nat Rev Drug Discov, 2012. 11(4): p. 257-8. 
42. 
Von Hoff, D.D., et al., Inhibition of the hedgehog pathway in advanced basal-cell 
carcinoma. N Engl J Med, 2009. 361(12): p. 1164-72. 
43. 
LoRusso, P.M., et al., Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-
0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin 
Cancer Res, 2011. 17(8): p. 2502-11. 
44. 
Kitko, C., Saliba, R., Choi, S. et al. Biomarkers of Extracellular Matrix Remodelling in 
Chronic GVHD. 2013. Biol Blood Marrow Transplant. 
45. 
Inamoto, Y., et al., Failure-free survival after second-line systemic treatment of chronic 
graft-versus-host disease. Blood, 2013. 121(12): p. 2340-6. 
46. 
Filipovich, A.H., et al., National Institutes of Health consensus development project on 
criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging 
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Bruggen, M.C., et al., Diverse T-cell responses characterize the different manifestations 
of cutaneous graft-versus-host disease. Blood, 2014. 123(2): p. 290-9. 
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Koreth, J., et al., Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl 
J Med, 2011. 365(22): p. 2055-66. 
49. 
Zorn, E., et al., Reduced frequency of FOXP3+ CD4+CD25+ regulatory T cells in 
patients with chronic graft-versus-host disease. Blood, 2005. 106(8): p. 2903-11. 
50. 
Borie, R., et al., Detection of alveolar fibrocytes in idiopathic pulmonary fibrosis and 
systemic sclerosis. PLoS One, 2013. 8(1): p. e53736. 
51. 
Mathai, S.K., et al., Circulating monocytes from systemic sclerosis patients with 
interstitial lung disease show an enhanced profibrotic phenotype. Lab Invest, 2010. 
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Russell, T.M., E.L. Herzog, and R. Bucala, Flow cytometric identification of fibrocytes in 
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Kisielewicz, A., et al., A distinct subset of HLA-DR+-regulatory T cells is involved in the 
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Schober, L., et al., Term and preterm labor: decreased suppressive activity and changes 
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Mandapathil, M., et al., Increased ectonucleotidase expression and activity in regulatory 
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Zabransky, D.J., et al., Phenotypic and functional properties of Helios+ regulatory T 
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57. 
Schuler, P.J., et al., Phenotypic and functional characteristics of CD4+ CD39+ FOXP3+ 
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Curti, B.D., et al., OX40 is a potent immune-stimulating target in late-stage cancer 
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Chen, Y.B. and C.S. Cutler, Biomarkers for acute GVHD: can we predict the 
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60. 
Vokes, S.A., et al., Genomic characterization of Gli-activator targets in sonic hedgehog-
mediated neural patterning. Development, 2007. 134(10): p. 1977-89. 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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61. 
Moore, B.B., et al., Bleomycin-induced E prostanoid receptor changes alter fibroblast 
responses to prostaglandin E2. J Immunol, 2005. 174(9): p. 5644-9. 
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Yauch, R.L., et al., Smoothened mutation confers resistance to a Hedgehog pathway 
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65. 
Chang, A.L. and A.E. Oro, Initial assessment of tumor regrowth after vismodegib in 
advanced Basal cell carcinoma. Arch Dermatol, 2012. 148(11): p. 1324-5. 
 


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17 APPENDIX 
 
Refer to pages 69 – 82 for Appendices 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry 
on normal activity or to do 
active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable to 
carry out any work activities.  Up and 
about more than 50% of waking hours. 
60 
Requires occasional 
assistance, but is able to care 
for most of his/her needs. 
50 
Requires considerable 
assistance and frequent 
medical care. 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
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Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
Page 71 of 80 
Template version date: 12-21-11 
 
 
APPENDIX B   DEFINITION OF WOMEN OF CHILDBEARING POTENTIAL AND  
ACCEPTABLE AND UNACCEPTABLE FORMS OF CONTRACEPTION 
 
Women of childbearing potential are defined as follows: 
• Patients with regular menses 
• Patients with amenorrhea, irregular cycles, or using a contraceptive method that 
precludes withdrawal bleeding 
• Women who have had a tubal ligation 
Women are considered not to be of childbearing potential for the following reasons: 
• The patient has undergone hysterectomy and/or bilateral oophorectomy. 
• The patient is post-menopausal defined by amenorrhea for at least 12 months in a woman 
 45 years old. 
Determine pregnancy status within 10-14 days prior to initiation of treatment in 
females of reproductive potential. For females with a negative pregnancy test, initiate a 
highly effective form of contraception (failure rate of less than 1%) 4 weeks prior to the 
first dose. Continue highly effective contraception during therapy and for 24 months 
after the last dose of GDC-0449 
 
The following are acceptable forms of barrier contraception: 
• Latex condom (always used with spermicide) 
• Diaphragm (always used with spermicide) 
• Cervical cap (always used with spermicide) 
The following are acceptable forms of secondary contraception, when used with a barrier 
method: 
• Tubal ligation  
• Partner’s vasectomy 
• Hormonal contraception including birth control pills, patches, rings, or injections, 
with the exception of the progesterone-only “mini pill”  
• Intrauterine device (non–progesterone T) 
• Vaginal sponge (containing spermicide) 
In addition, 100% commitment to abstinence is considered an acceptable form of 
contraception. 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
Page 72 of 80 
Template version date: 12-21-11 
 
The following are unacceptable forms of contraception for women of childbearing potential: 
• IUD progesterone T  
• Progesterone-only “mini pill” 
• Female condom 
• Natural family planning (rhythm method) or breastfeeding 
• Fertility awareness 
• Withdrawal 
• Cervical shield 
 




Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
Page 74 of 80 
Template version date: 12-21-11 
 
 
APPENDIX D 
PATIENT’S MEDICATION DIARY 
 
PATIENT’S MEDICATION DIARY 
 
Today’s date _____________________ 
Agent:  GDC-0449 
Patient Name_____________________(initials acceptable)  
 Patient Study ID __________________________ 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle of treatment. 
2. 
You will take GDC-0449 capsules once daily.  You should take the capsules at approximately the same 
time each day. 
 
Dose:  take  ___ 150 mg capsules. 
3. 
If you have any comments or notice any side effects, please record them in the Comments column.   
4. 
Please bring this form and your bottles of GDC-0449 capsules when you return for each appointment. 
 
Day 
 
Date 
 
Time of 
dose  
# of capsules 
taken 
Comments 
 
150 mg 
 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
 
Patient’s signature  _________________________________________________________________________ 
 
CTEP-assigned Protocol #___________ 
 
Local Protocol # ___________________ 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
Page 75 of 80 
Template version date: 12-21-11 
 
 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment _________________________________________________________
2. Date patient was removed from study __________________________________________________________
3. Total number of capsules taken this month  _____________________________________________________
4. Physician/Nurse/Data Manager’s Signature  _____________________________________________________


 
 
DEPARTMENT OF HEALTH & HUMAN SERVICES 
 
Public Health Service 
 
 
National Institutes of Health  
National Cancer Institute 
Bethesda, Maryland 20892 
 
Revision or Amendment Review Template Version 10-26-2011  
73 
APPENDIX E 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers and Non-Study 
Healthcare Team 
 
The patient ____________________________________ is enrolled on a clinical trial using the experimental agent 
GDC-0449. This clinical trial is sponsored by the National Cancer Institute. This form is addressed to the patient, 
but includes important information for others who care for this patient.  A convenient wallet-sized information card 
is also included for the patient to clip out and retain at all times.  
 
GDC-0449 interacts with many drugs that are processed by your liver. Because of this, it is very important to tell 
your study doctors about all of your medicine before you start this study. It is also very important to tell them if you 
stop taking any regular medicine, or if you start taking a new medicine while you take part in this study. When you 
talk about your medicine with your study doctor, include medicine you buy without a prescription at the drug store 
(over-the counter remedy), or anything that you buy from the health food store or grocery store (herbal supplement).  
 
Many health care prescribers can write prescriptions. You must also tell your other prescribers (doctors, physicians’ 
assistants or nurse practitioners) that you are taking part in a clinical trial. Bring this paper with you. These are the 
thing that you and they need to know:  
 
• 
GDC-0449 is a CYP3A4/5 and CYP2C9 substrate.  GDC-0449 also inhibits CYP2C8, CYP2C9, and CYP2C19.  
These CYPs are enzymes in your liver. GDC-0449 must be used very carefully with other medicines that need 
certain liver enzymes to be effective or to be cleared from your system.  
o 
The specific enzymes are CYP3A4/5, CYP2C9, CYP2C8, and CYP2C19.  
o 
You and healthcare providers who prescribe drugs for you must be careful about adding or removing any drug 
in this category.  
o 
Before you start the study, your study doctor will work with your regular prescriber to switch any medicines 
that are considered “strong inducers/inhibitors or substrates of CYP3A4/5, CYP2C9, CYP2C8, or CYP2C19.” 
o 
Your regular prescribers should look at this web site http://medicine.iupui.edu/clinpharm/ddis/table.asp to see if 
any medicine they want to prescribe is on a list of drugs to avoid.   
o 
Please be very careful! Over-the-counter drugs have a brand name on the label—it’s usually big and catches 
your eye. They also have a generic name—it’s usually small and printed on the ingredient list. Find the generic 
name (your pharmacist can help) and look at the table on the back of this page. Be careful:  
▪ 
If you take acetaminophen regularly:  You should not take more than 4 grams a day if you are an 
adult or 2.4 grams a day if you are older than 65 years of age.  Read labels carefully!  
Acetaminophen is an ingredient in many medicines for pain, flu, and cold.  
▪ 
If you take herbal medicine regularly.  You should not take St. John’s wort while you are taking 
GDC-0449. 
 
Other medicines can be a problem with your study drugs.  
 
• 
You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement.  
 
• 
Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you.  Your study doctor’s name is  
 
_________________________________________________  
 
and he or she can be contacted at  
 
_________________________________________________


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
Revision or Amendment Review Template 
 
77 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent GDC-
0449.  This clinical trial is sponsored by the NCI.  GDC-0449 
interacts with drugs that are processed by your liver.  Because of this, 
it is very important to: 
➢ Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
GDC-0449 interacts with specific liver enzymes named CYP3A4/5, 
CYP2C9, CYP2C8, and CYP2C19, and must be used very carefully with 
other medicines that interact with these enzymes.  
➢ Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP______.” 
➢ Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a 
list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
Revision or Amendment Review Template 
 
78 
APPENDIX F 
GVHD CHRONIC FLOWSHEET 
 
Chronic GVHD Flowsheet GDC-0449, IRB 84584 
MOUTH 
 
0=None 1= 
Mild  
2= 
Moderate 
3=Severe 
 
Erythema 
 
 
 
 
 
Licheniods 
 
 
 
 
 
Ulcers 
 
 
 
 
 
Mucosal Changes 
 
 
 
 
GI-
ESOPHAGEAL 
 
 
 
 
 
 
Dysphagia 
 
 
 
 
 
Odynophagia 
 
 
 
 
GI-UPPER GI 
 
 
 
 
 
 
Early Satiety 
 
 
 
 
 
Anorexia 
 
 
 
 
 
Nausea/Vomiting 
 
 
 
 
GI-LOWER GI 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
SKIN 
 
 
 
 
 
 
Maculopapular 
Rash/Erythema 
 
 
 
 
 
Lichen Planus Features 
 
 
 
 
 
Sclerotic Features 
 
 
 
 
 
Papulosquamous Lesions  
 
 
 
 
 
Ichthyosis 
 
 
 
 
 
Karatosis Pilaris-like 
 
 
 
 
 
Non-GVHD Abnormality 
Present 
 
 
 
 
EYES 
 
 
 
 
 
 
Eyes 
 
 
 
 
 
Non-GVHD Abnormality 
Present 
 
 
 
 
LUNGS 
 
 
 
 
 
 
FEF 1  
 
 
 
 
 
Lungs 
 
 
 
 
 
Non-GVHD Abnormality 
Present 
 
 
 
 
JOINTS/ 
FASCIA 
 
 
 
 
 
 
Joints and Fascia 
 
 
 
 
 
Non-GVHD Abnormality 
Present 
 
 
 
 
 
Shoulder - Right 
 
 
 
 
 
Shoulder - Left 
 
 
 
 


Protocol name: Pilot Study for the Treatment of Steroid-Refractory Sclerodermatous Chronic Graft-Versus-Host Disease (GVHD) with GDC-
0449  
Version Date: 05APR2019 
Principal Investigator: Daniel Couriel, MD 
 
Revision or Amendment Review Template 
 
79 
 
Elbow – Right 
 
 
 
 
 
Elbow - Left 
 
 
 
 
 
Wrist/Fingers – Right  
 
 
 
 
 
Wrist/Fingers – Left  
 
 
 
 
 
Ankle – Right  
 
 
 
 
 
Ankle – Left  
 
 
 
 
GRADE  
 
 
 
 
 
 
Health Care Provider Global 
Rating 
 
 
 
 
 
Overall Severity Chronic 
GVHD