Clinical trial NCT05673876
Conditions: Acute Graft-versus-host Disease
Sponsor: Genentech, Inc.
Start date: 2023-04-06; Completion date: 2024-01-15
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of the study is to assess the safety and pharmacokinetics (PK) of GDC-8264 in participants with acute graft-versus-host disease (aGVHD).

Detailed description:

Arms: arm 1: Participants will receive oral GDC-8264, 35 milligrams (mg), once daily (QD) for 28 days. arm 2: Participants will receive oral GDC-8264, 75 mg, PO, QD for 28 days.
Interventions: intervention 1: GDC-8264
Intervention descriptions: intervention 1: GDC-8264 tablets will be administered as per the schedule specified in the respective arms.

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: 
A Phase Ib, Open-Label, Randomized, Dose-Finding, Multicenter 
Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of 
GDC-8264 in Combination with Standard of Care in the Treatment of 
Acute Graft-Versus-Host Disease in Patients who have Undergone 
Allogeneic Hematopoietic Stem Cell Transplantation 
NCT Number: 
NCT05673876 
Document Date: 
Protocol Version 4: 20-Jul-2023 


CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
GDC-8264—Genentech, Inc. 
Protocol GA43861, Version 4 
PROTOCOL 
TITLE: 
A PHASE Ib, OPEN-LABEL, RANDOMIZED, 
DOSE-FINDING, MULTICENTER STUDY TO 
EVALUATE THE SAFETY, PHARMACOKINETICS, 
AND EFFICACY OF GDC-8264 IN COMBINATION 
WITH STANDARD OF CARE IN THE TREATMENT 
OF ACUTE GRAFT-VERSUS-HOST DISEASE IN 
PATIENTS WHO HAVE UNDERGONE 
ALLOGENEIC HEMATOPOIETIC STEM CELL 
TRANSPLANTATION  
PROTOCOL NUMBER: GA43861 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
161860 
TEST PRODUCT: 
GDC-8264 (RO7288817) 
SPONSOR NAME and 
ADDRESS: 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA  94080 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document 


GDC-8264—Genentech, Inc. 
2/Protocol GA43861, Version 4 
PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
4 
See electronic signature and date 
stamp on the final page of this 
document 
3 
26 August 2022 
2 
22 July 2022 
1 
2 February 2022 
 
 
 
 




GDC-8264—Genentech, Inc. 
4/Protocol GA43861, Version 4 
• 
Instructions have been added to clarify how to report significant non-serious events 
and conditions that occur after informed consent but prior to initiation of GDC-8264 
(Sections 4.5.2 and 5.4.2.1). 
• 
Electrocardiogram procedures have been updated to align with guidance on ECG 
measurements of the QT interval corrected through use of Fridericia's formula 
(Sections 4.5.10 and 5.1.2.3). 
• 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 4.5.13.6). 
• 
A criterion has been added for study drug discontinuation for newly discovered brain 
lesion associated with a higher risk of seizure (e.g., new mass lesion with 
surrounding vasogenic edema) (Section 4.6.1). 
• 
Since patients with Minnesota High Risk aGVHD are acutely ill with a 
life-threatening condition, accurate documentation of adverse events prior to and 
after study treatment is critical.  The reporting of adverse events prior to initiation of 
GDC-8264 has been updated to all serious adverse events (Sections 5.3.1 and 
5.4.2.1; Appendix 1). 
• 
Text has been removed describing the use of a single Institutional Review Board 
(IRB) by all sites for centralizing review efforts.  This change acknowledges that 
more than a single IRB/Ethics Committee may be used by the sites within their 
respective countries (Section 9.4). 
• 
Text has been modified to clarify that summaries of clinical study results may be 
available for public access in health authority databases (Section 9.5). 
 
Additional minor changes have been made to improve clarity and consistency.  New 
changes appear in italics.  This amendment represents cumulative changes to the 
original protocol. 
Reference 
Basak GW, Wiktor-Jedrzejczak W, Labopin M, et al. Allogeneic hematopoietic stem cell 
transplantation in solid organ transplant recipients: a retrospective, multicenter 
study of the EBMT. Am J Transplant 2015;15:705−14. 
 






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7/Protocol GA43861, Version 4 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 56 
4.5.3 
Physical Examinations ............................................................. 57 
4.5.4 
Vital Signs ................................................................................ 57 
4.5.5 
Clinical Response Assessment ................................................ 58 
4.5.6 
MAGIC Acute Graft-versus-Host Disease Target Organ 
Staging .................................................................................... 58 
4.5.7 
Chronic Graft-versus-Host Disease Staging ............................ 58 
4.5.8 
Corticosteroid-Refractory Acute Graft-versus-Host Disease 
Assessment ............................................................................. 58 
4.5.9 
Laboratory, Biomarker, and Other Biological Samples ............ 58 
4.5.10 
Electrocardiograms .................................................................. 61 
4.5.11 
Use of Screen-Fail Samples (Patients at Participating 
Sites) ....................................................................................... 61 
4.5.12 
Buccal Scraping Samples for Whole Genome Sequencing 
or Whole Exome Sequencing (Patients at Participating 
Sites) ....................................................................................... 61 
4.5.13 
Optional Samples for Research Biosample Repository and 
Mount Sinai Acute GVHD International Consortium 
Biorepository ............................................................................ 63 
4.5.13.1 
Overview of the Research Biosample Repository and 
Mount Sinai Acute GVHD International Consortium 
Biorepository ............................................................................ 63 
4.5.13.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 63 
4.5.13.3 
Sample Collection .................................................................... 64 
4.5.13.4 
Data Protection, Use, and Sharing .......................................... 64 
4.5.13.5 
Consent to Participate in the Research Biosample 
Repository and Mount Sinai Acute GVHD International 
Consortium Biorepository ........................................................ 65 
4.5.13.6 
Withdrawal from the Research Biosample Repository and 
Mount Sinai Acute GVHD International Consortium 
Biorepository ............................................................................ 66 
4.5.13.7 
Monitoring and Oversight ......................................................... 66 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 67 
4.6.1 
Study Drug Discontinuation ..................................................... 67 
4.6.2 
Patient Discontinuation from the Study .................................... 67 


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8/Protocol GA43861, Version 4 
4.6.3 
Study Discontinuation .............................................................. 68 
4.6.4 
Site Discontinuation ................................................................. 68 
5. 
ASSESSMENT OF SAFETY ......................................................... 68 
5.1 
Safety Plan .............................................................................. 68 
5.1.1 
Potential Risks Associated with GDC-8264 ............................. 69 
5.1.1.1 
Serious Bacterial or Viral Infections with Blunted Clinical 
Response................................................................................. 69 
5.1.1.2 
Seizures (Convulsions) ............................................................ 71 
5.1.2 
Management of Patients Who Experience Adverse Events ..... 72 
5.1.2.1 
Dose Modifications .................................................................. 72 
5.1.2.2 
Treatment Interruption ............................................................. 72 
5.1.2.3 
Management Guidelines .......................................................... 72 
5.2 
Safety Parameters and Definitions .......................................... 75 
5.2.1 
Adverse Events ........................................................................ 75 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 76 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 77 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 77 
5.3.1 
Adverse Event Reporting Period .............................................. 77 
5.3.2 
Eliciting Adverse Event Information ......................................... 78 
5.3.3 
Assessment of Severity of Adverse Events ............................. 78 
5.3.4 
Assessment of Causality of Adverse Events............................ 79 
5.3.5 
Procedures for Recording Adverse Events .............................. 79 
5.3.5.1 
Diagnosis versus Signs and Symptoms ................................... 80 
5.3.5.2 
Adverse Events That Are Secondary to Other Events ............. 80 
5.3.5.3 
Persistent or Recurrent Adverse Events .................................. 80 
5.3.5.4 
Abnormal Laboratory Values ................................................... 81 
5.3.5.5 
Abnormal Vital Sign Values ..................................................... 81 
5.3.5.6 
Abnormal Liver Function Tests ................................................ 82 
5.3.5.7 
Deaths ..................................................................................... 82 
5.3.5.8 
Preexisting Medical Conditions ................................................ 83 


GDC-8264—Genentech, Inc. 
9/Protocol GA43861, Version 4 
5.3.5.9 
Lack of Efficacy or Worsening of Acute Graft-Versus-Host 
Disease .................................................................................... 83 
5.3.5.10 
Hospitalization or Prolonged Hospitalization ............................ 83 
5.3.5.11 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ............................................................................. 84 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 86 
5.4.1 
Emergency Medical Contacts .................................................. 86 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 87 
5.4.2.1 
Events That Occur prior to GDC-8264 Initiation....................... 87 
5.4.2.2 
Events That Occur after GDC-8264 Initiation........................... 87 
5.4.3 
Reporting Requirements for Pregnancies ................................ 87 
5.4.3.1 
Pregnancies in Female Patients .............................................. 87 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................... 88 
5.4.3.3 
Abortions.................................................................................. 89 
5.4.3.4 
Congenital Anomalies/Birth Defects ........................................ 89 
5.5 
Follow-Up of Patients after Adverse Events............................. 89 
5.5.1 
Investigator Follow-Up ............................................................. 89 
5.5.2 
Sponsor Follow-Up .................................................................. 89 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 90 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 90 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 90 
6.1 
Determination of Sample Size ................................................. 91 
6.2 
Summaries of Conduct of Study .............................................. 91 
6.3 
Summaries of Demographic and Baseline Characteristics ...... 91 
6.4 
Safety Analyses ....................................................................... 91 
6.5 
Pharmacokinetic Analyses ....................................................... 92 
6.6 
Efficacy Analyses ..................................................................... 92 
6.6.1 
Secondary Efficacy Endpoints ................................................. 93 
6.6.2 
Exploratory Efficacy Endpoints ................................................ 93 
6.7 
Biomarker Analyses ................................................................. 94 




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11/Protocol GA43861, Version 4 
Table 7 
Guidelines for Management of Patients Who Experience 
Adverse Events ........................................................................... 73 
Table 8 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 78 
Table 9 
Causal Attribution Guidance ....................................................... 79 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 37 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 107 
Appendix 2 
Schedule of Pharmacokinetic and Exploratory 
Biomarker Samples ................................................................... 112 
Appendix 3 
Ann Arbor Scoring ..................................................................... 115 
Appendix 4 
Mount Sinai Acute GVHD International Consortium (MAGIC) 
Acute GVHD Target Organ Staging .......................................... 116 
Appendix 5 
National Institutes of Health Chronic GVHD Diagnosis and 
Staging ...................................................................................... 118 
Appendix 6 
Primary Disease Relapse or Progression Guidance ................. 121 
Appendix 7 
Blood and Marrow Transplant Clinical Trials Network 
Severity Grading Table and Recurrence Interval Definitions .... 124 
 
 


 
GDC-8264—Genentech, Inc. 
12/Protocol GA43861, Version 4 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE Ib, OPEN-LABEL, RANDOMIZED, 
DOSE-FINDING, MULTICENTER STUDY TO 
EVALUATE THE SAFETY, PHARMACOKINETICS, 
AND EFFICACY OF GDC-8264 IN COMBINATION 
WITH STANDARD OF CARE IN THE TREATMENT 
OF ACUTE GRAFT-VERSUS-HOST DISEASE IN 
PATIENTS WHO HAVE UNDERGONE 
ALLOGENEIC HEMATOPOIETIC STEM CELL 
TRANSPLANTATION 
PROTOCOL NUMBER: GA43861 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
161860 
TEST PRODUCT: 
GDC-8264 (RO7288817) 
SPONSOR: 
Genentech, Inc. 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your assigned study monitor or CRO staff. 


 
GDC-8264—Genentech, Inc. 
13/Protocol GA43861, Version 4 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE Ib, OPEN-LABEL, RANDOMIZED, DOSE-FINDING, 
MULTICENTER STUDY TO EVALUATE THE SAFETY, 
PHARMACOKINETICS, AND EFFICACY OF GDC-8264 IN 
COMBINATION WITH STANDARD OF CARE IN THE TREATMENT 
OF ACUTE GRAFT-VERSUS-HOST DISEASE IN PATIENTS WHO 
HAVE UNDERGONE ALLOGENEIC HEMATOPOIETIC STEM 
CELL TRANSPLANTATION 
PROTOCOL NUMBER: 
GA43861 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
161860 
TEST PRODUCT: 
GDC-8264 (RO7288817) 
PHASE: 
Phase Ib 
INDICATION: 
Graft-versus-host disease 
SPONSOR: 
Genentech, Inc. 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety, pharmacokinetics, and efficacy of GDC-8264 given in 
combination with standard-of-care corticosteroid treatment in patients with high-risk acute 
graft-versus-host disease (aGVHD).  The overall purpose of the study is to identify an optimal 
dose for GDC-8264 for future studies, using all available safety, pharmacokinetic (PK), and 
efficacy data.  Specific objectives and corresponding endpoints for the study are outlined below.   
 
Co-Primary Objectives 
Corresponding Endpoint 
• To evaluate the safety of GDC-8264 
• Incidence and severity of adverse events, with 
severity determined according to the NCI CTCAE 
v5.0 grading scale 
• To characterize the pharmacokinetics 
of GDC-8264  
• Plasma concentration of GDC-8264 at specified 
timepoints, and relevant PK parameters 
aGVHD = acute graft-versus-host disease; BMT CTN = Blood and Marrow Transplant Clinical Trials 
Network; CR = complete response; DOR = duration of response; FFS = failure-free survival; 
MAP = Mount Sinai Acute GVHD International Consortium [MAGIC] algorithm probability; 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events v5.0; 
NRM = non-relapse mortality; ORR = overall response rate; OS = overall survival; 
PK = pharmacokinetic; PR = partial response; VGPR = very good partial response. 
a Responses are determined by the investigator. 
b Baseline defined as last value prior to initiation of GDC-8264. 
 
 














 
GDC-8264—Genentech, Inc. 
20/Protocol GA43861, Version 4 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The co-primary objectives of this study are to evaluate the safety and pharmacokinetics of 
GDC-8264.  The safety analysis population will consist of all patients who received at least one 
dose of GDC-8264, with patients grouped according to treatment received.  The PK analysis 
population will consist of patients who have received at least one dose of GDC-8264 and have 
at least one evaluable postdose PK concentration. 
DETERMINATION OF SAMPLE SIZE 
This study is exploratory in nature.  The overall purpose of the study is to identify an optimal 
dose for GDC-8264 for future studies, using all available safety, PK, and efficacy data.  A 
sample size of approximately 20 patients per dose cohort is believed to be clinically appropriate 
to assess the preliminary safety, pharmacokinetics, and efficacy in this initial study in patients 
with aGVHD and to inform future development of GDC-8264.  The sample size calculation is not 
based on a statistical power consideration. 
 


 
GDC-8264—Genentech, Inc. 
21/Protocol GA43861, Version 4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
aGVHD 
acute graft-versus-host disease 
ASCO 
American Society of Clinical Oncology 
AUC 
area under the concentration–time curve 
AUC0−24 hr 
AUC from 0 to 24 hours 
AUC0–24 hr,ss 
AUC from 0 to 24 hours at steady state 
AUC0–last 
AUC from Time 0 to last measurable concentration 
AUCinf 
AUC from Time 0 to infinity 
BMT 
bone-marrow transplant 
BMT CTN 
Blood and Marrow Transplant Clinical Trial Network 
CBR1 
carbonyl reductase 1 
Cmax 
maximum plasma concentration observed 
Cmax,ss 
Cmax at steady state 
Cmin 
minimum plasma concentration under steady-state 
conditions within a dosing interval 
Cmin,ss 
Cmin at steady state 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRO 
contract research organization 
CV 
coefficient of variation 
DAP 
Data Analysis Plan 
DCC 
Data Coordinating Center 
DOR 
duration of response 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
EC90 
90% effective concentration level 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ESMO 
European Society for Medical Oncology 
FDA 
(U.S.) Food and Drug Administration 
FFS 
failure-free survival 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice  
GVHD 
graft-versus-host disease 
H antigen 
histocompatibility antigen 
HIPAA 
Health Insurance Portability and Accountability Act 
HLA 
human leukocyte antigen 


 
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22/Protocol GA43861, Version 4 
Abbreviation 
Definition 
HR 
hazard ratio 
HSCT 
hematopoietic stem cell transplantation 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
KD 
kinase dead 
KLH 
keyhole limpet hemocyanin 
LPLV 
last patient, last visit 
MAD 
multiple ascending dose 
MAGIC 
Mount Sinai Acute GVHD International Consortium 
MAP 
MAGIC algorithm probability 
MDZ 
midazolam 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NK 
natural killer (cell) 
NOAEL 
no-observed-adverse-effect level 
NOEL 
no-observed-effect level 
NR 
no response 
NRM 
non-relapse mortality 
ORR 
overall response rate 
OS 
overall survival 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PO 
orally, by mouth 
pop-PK 
population-pharmacokinetic 
PR 
partial response 
pRIP1 
autophosphorylated receptor-interacting protein 1 
QD 
once a day 
QTcF 
QT interval corrected through use of Fridericia's 
formula 
RBR 
Research Biosample Repository 
REG3α 
regenerating islet-derived 3-alpha 
RIP1 
receptor-interacting protein 1 
SAD 
single ascending dose 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2  
ST2 
suppressor of tumorigenesis 2 
t1/2 
elimination half-life 


 
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Abbreviation 
Definition 
tmax 
time to maximum concentration 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
USPI 
U.S. Prescribing Information 
VGPR 
very good partial response 
WT 
wild type 


 
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24/Protocol GA43861, Version 4 
1. 
BACKGROUND 
1.1 
BACKGROUND ON ACUTE GRAFT-VERSUS-HOST DISEASE  
Acute graft-versus-host disease (aGVHD) is a common and life-threatening complication 
of allogeneic hematopoietic stem cell transplantation (HSCT).  aGVHD occurs in nearly 
60% of patients receiving allogeneic HSCT (Jagasia et al. 2012) and aGVHD remains 
the second leading cause of death after disease relapse (Aziz et al. 2020).   
Current understanding of aGVHD pathophysiology is based primarily on murine models 
(Naymagon et al. 2017; Zeiser and Blazar 2017).  aGVHD occurs as a result of host 
(recipient) tissue damage caused by the underlying hematologic disease and associated 
treatments, infection, and the conditioning regimen (Ghimire et al. 2017).  Damaged host 
tissues release signals, including proinflammatory cytokines, which activate host 
antigen-presenting cells (APCs).  Conditioning regimen−mediated damage to the 
gastrointestinal (GI) tract allows translocation of microbes and microbial products that 
amplifies host APC activation and causes infection.  Host APCs activate donor T cells 
that destroy healthy host tissue, resulting in aGVHD (Naymagon et al. 2017).  Risk 
factors for developing aGVHD include degree of human leukocyte antigen (HLA) 
mismatch, relatedness of the donor, intensity of conditioning regimen, source of graft, 
and aGVHD prophylactic regimen (Zeiser and Blazar 2017).  
The most common organs affected by aGVHD are the skin, liver, and GI tract (Zeiser 
and Blazar 2017).  Lower GI aGVHD is the most difficult form of aGVHD to treat and is 
the greatest cause of GVHD-related morbidity and mortality (Naymagon et al. 2017).  
Signs and symptoms associated with aGVHD include rash, dermatitis, hepatitis, 
jaundice, abdominal pain, and diarrhea.  Diagnosis of aGVHD depends on the clinical, 
laboratory, and pathologic assessment of target organs.  The Mount Sinai Acute GVHD 
International Consortium (MAGIC) (Harris et al. 2016) provides a standardized approach 
to aGVHD clinical staging criteria and grading based on the Glucksberg scale 
(Glucksberg et al. 1974).  Severity is categorized as Grade I−IV, depending on the 
degree of skin, GI and/or liver involvement, with Grade IV representing the most severe 
disease. 
aGVHD treatment is tailored to address the severity of the presentation and 
management of symptoms.  Initial treatment ranges from simple observation or topical 
corticosteroids for Grade I aGVHD presenting with skin symptoms or aGVHD limited to 
the upper GI tract (a subset of Grade II aGVHD), to systemic corticosteroid treatment for 
Grade II−IV aGVHD (Nassereddine et al, 2017; NCCN 2021).  Corticosteroid treatment 
is continued for several weeks in responders and then gradually tapered over a period of 
months.  Corticosteroid treatment, especially at higher doses and with prolonged 
duration of treatment, has many well-documented side effects, some of which may 
increase the risk of complications after HSCT and negatively impact non-relapse 
mortality (NRM) (Matsumura-Kimoto et al, 2016; Fuji et al. 2021; RAYOS U.S. 
Prescribing Information [USPI]; SOLU-MEDROL USPI).  Side effects include 


 
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osteoporosis, hypertension, adrenal suppression, cataracts, hyperglycemia and 
diabetes mellitus, avascular necrosis, and myopathy, and impaired neutrophil function 
and lymphocytopenia contributing to increased susceptibility to serious infection 
(Dignass et al. 2010, Matsumura-Kimoto et al. 2016; Fuji et al. 2021).  Balancing 
immunosuppression to control aGVHD while maintaining a degree of 
immunocompetence against infection is critical (Hooker et al. 2021).  In one Phase III 
study, after initiation of high-dose corticosteroids (prednisone 2 mg/kg/day or 
methylprednisolone 1.6 mg/kg/day) at the time of aGVHD diagnosis, 64.7% of patients 
experienced at least one infection through Day 56, and the cumulative incidence of a 
severe, life-threatening, or fatal infection at 12 months was 42.9% (95% CI: 33.9 to 52.0; 
p = 0.83) (Bolaños-Meade et al. 2014).  In a retrospective study in patients with 
Grade III−IV aGVHD, the cumulative dose of corticosteroids during the first 4 weeks of 
aGVHD treatment was associated with an increased risk of fungal disease (hazard ratio 
[HR]: 3.65; 95% CI: 1.17 to 11.4; p = 0.03) and non-cytomegalovirus viral diseases (HR: 
4.14; 95% CI: 1.25 to 13.7, p=0.02) (Matsumura-Kimoto et al. 2016).  First-line 
treatments administered in addition to corticosteroids have been studied, including 
etanercept, mycophenolate, denileukin, and pentostatin (Alousi et al. 2009), infliximab 
(Couriel et al. 2009), and natalizumab (Kekre et al. 2021), but no treatment has 
established a significant benefit compared with standard first-line corticosteroid 
treatment alone.   
Despite recent advances in aGVHD prevention that permit the use of highly 
HLA-mismatched donors, data from almost 4000 patients enrolled in the MAGIC Natural 
History Study (a database and biorepository that contains detailed longitudinal biomarker 
and clinical data prospectively obtained according to an Institutional Review 
Board−approved protocol at each MAGIC participating center) reveal that the 
percentage of patients requiring high-dose corticosteroids has not changed since 2015.  
Moreover, the incidence of severe (Grade III−IV) aGVHD remains high (13% in 2020), 
despite the dramatic increase in post-transplant cyclophosphamide prophylaxis from 9% 
to 22%.  As a result, the incidence of NRM driven by aGVHD of the GI tract remains 
unacceptably high at 15% (Aziz et al. 2020). 
A major barrier to improving aGVHD treatment is that aGVHD symptom severity 
(i.e., grade) at presentation does not reliably predict treatment response or long-term 
outcomes (Levine et al. 2015).  Maximum aGVHD grade, which can be determined only 
retrospectively after response to treatment is known, does correlate with NRM 
(Przepiorka et al. 1995; Rowlings 1997).  Thus, patients who present with mild to 
moderate (Grade I−II) clinical symptoms at time of diagnosis and have higher risk for 
severe disease are under-treated.   
1.1.1 
Background on Minnesota Risk Score 
The Minnesota group has defined an aGVHD risk score based on the number of 
involved organs and severity of aGVHD at the time of initiation of corticosteroid therapy 


 
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26/Protocol GA43861, Version 4 
(MacMillan et al. 2015; Macmillan et al. 2020), with staging determined through use of 
the MAGIC aGVHD Target Organ Staging criteria (see Appendix 4).  The refined 
definition of high-risk aGVHD includes either single-organ involvement with Stage 4 skin, 
Stage 3−4 lower GI, or Stage 1−4 liver; or multiple-organ involvement with Stage 1−2 
lower GI plus any liver, Stage 2 lower GI plus any skin, Stage 3−4 lower GI plus any liver 
or skin, or any three-organ involvement.  Standard-risk aGVHD includes single-organ 
involvement (either Stage 1−3 skin or stage 1−2 GI) or two-organ involvement (either 
Stage 1 GI plus Stage 1−3 skin; or Stage 1−3 skin plus Stage 1−4 liver).  In a large 
cohort of patients from multiple centers (n = 1723) from 1990 to 2007, overall response 
(complete response and partial response) rate 28 days after initiation of corticosteroid 
therapy for aGVHD was lower for the high-risk aGVHD population (44% [95% CI: 38% to 
50%; p < 0.001]) compared with the standard-risk aGVHD population (68% [95% CI: 
66% to 70%; p < 0.001]) (MacMillan et al. 2015).  Patients with high-risk aGVHD were 
less likely to respond at Day 28 (odds ratio 0.3, 95% CI:0.2 to 0.4; p < 0.001) and had 
higher risks of mortality (relative risk 2.1, 95% CI: 1.7 to 2.6; p < 0.001) and transplant-
related mortality (relative risk 2.5, 95% CI: 2.0% to 3.2%; p < 0.001) compared with 
patients with standard-risk aGVHD (MacMillan et al. 2015).  The Minnesota risk score 
was validated in a more contemporary cohort from 2007 to 2016, confirming that patients 
with high-risk aGVHD, the proposed population for this study, were less likely to respond 
at Day 28 and had higher risk of 2-year transplant−related mortality and overall mortality 
than patients with standard-risk aGVHD (MacMillan et al. 2020).  The Minnesota risk 
score represents a valuable tool to identify patients at high risk with standard care who 
stand to benefit from novel treatment approaches.  
1.1.2 
Background on MAGIC Algorithm Probability 
MAGIC has recently introduced a major innovation in aGVHD treatment by validating a 
biomarker−based risk stratification system, referred to as the MAGIC algorithm 
probability (MAP) (Hartwell et al. 2017; Major-Monfried et al. 2018; Srinagesh et al. 
2019; Aziz et al. 2020).  MAP combines the concentrations of two serum biomarkers to 
separate patients into three distinct risk strata, referred to as Ann Arbor scores 1, 2, and 
3, with each representing a single probability of 6-month NRM (Hartwell et al. 2017; Aziz 
et al. 2018, Zhao et al. 2018; Srinagesh et al. 2019) (see Appendix 3).  The two serum 
biomarkers (together known as MAGIC biomarkers) are interleukin (IL)-33 receptor 
suppressor of tumorigenesis 2 (ST2) and regenerating islet-derived 3-alpha (REG3α).  
Lethal aGVHD almost always results from extensive damage to the GI crypt, which is the 
primary source of ST2 and REG3α, and the presence of GI crypt damage portends a 
worse outcome, even when GI symptoms are minimal or absent (Levine et al. 2013; 
Levine et al. 2015; Hartwell et al. 2017).  Hence, serum concentrations of ST2 and 
REG3α measured after transplant can predict outcomes through use of MAP and the 
resulting Ann Arbor score (Ferrara et al. 2011; Zhang 2015; Ferrara and Chaudhry 
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virus (Western Reserve strain) (Webster et al. 2020).  Taken together, data from multiple 
nonclinical studies clearly indicate the absence of immunosuppressive activity of 
GDC-8264 and other RIP1 inhibitors. 
Refer to the GDC-8264 Investigator's Brochure for additional detail on nonclinical 
studies. 
1.2.2 
Clinical Background 
The experience with GDC-8264 in humans consists of one Phase I study in healthy 
subjects (GP41678) and one Phase 1 study in subjects with kidney failure requiring 
dialysis and matched healthy controls (GP42995).  
Study GP41678 is a first-in-human, single-center, randomized, double-blinded, 
placebo-controlled study evaluating the safety, tolerability, and pharmacokinetics of oral 
GDC-8264 in healthy subjects.  The single ascending dose (SAD) stage evaluated 
doses from 5 mg to 225 mg; the multiple ascending dose (MAD) stage evaluated 50 mg 
once a day (QD) and 100 mg QD for 14 days.  The study also explored the effect of food 
on the pharmacokinetics of GDC-8264 and the CYP3A induction effect of GDC-8264.  
GDC-8264 was well tolerated at all dose levels evaluated in Study GP41678.  No 
individual or group stopping criteria were met; there were no deaths, no serious or 
severe adverse events, and no clinically significant laboratory, ECG, or vital sign findings 
related to GDC-8264.  Treatment-related adverse events were generally of mild severity.  
Pharmacokinetic (PK) analyses from the SAD portion of Study GP41678 indicate that 
GDC-8264 peak concentrations (Cmax) were observed at 1.29−4.00 hours (median tmax) 
after the administration of GDC-8264 as single doses over the dose range from 5 mg to 
225 mg.  The geometric mean elimination half-life (t1/2) after single-dose administration 
ranged from 10.4 to 13.3 hours over this dose range, indicating that once-daily dosing is 
appropriate and that the t1/2 is independent of dose and formulation.  Exposure 
parameters Cmax, AUC0-24 hr, and AUC from Time 0 to infinity [AUCinf]) for the tablet 
formulation at single doses of 75 mg, 150 mg, and 225 mg increased proportionally with 
dose.  Inter-individual exposure variability is low to moderate and ranges from 6.70% to 
52.9%.  Under fed conditions, Cmax is approximately 21% higher and median tmax 
increases from 3 to 4 hours, compared with fasted administration, but overall exposure 
(AUC0-24 hr and AUCinf) is comparable under fasted and fed conditions.  Hence, 
GDC-8264 can be given without regard to food.  Low renal excretion of unchanged 
GDC-8264 was observed at all doses (mean % of GDC-8264 dose excreted in urine of 
0.16%−0.22%).  Geometric mean renal clearance was similar for all doses and ranged 
from 0.00901 L/h after 5 mg of GDC-8264 to 0.0119 L/h after 75 mg of GDC­8264 (fed).  
Estimated accumulation ratios in the MAD stage after multiple daily dosing of GDC-8264 
at 100 mg and 50 mg were 1.41 and 1.37, respectively, based on Cmax and 1.31 and 
1.39, respectively, based on AUC0-24 hr, consistent with the estimated half-life.  The 






 
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Table 1 
Objectives and Corresponding Endpoints 
Co-Primary Objectives 
Corresponding Endpoint 
• To evaluate the safety of GDC-8264 
• Incidence and severity of adverse events, with 
severity determined according to the NCI CTCAE 
v5.0 grading scale 
• To characterize the pharmacokinetics 
of GDC-8264  
• Plasma concentration of GDC-8264 at specified 
timepoints, and relevant PK parameters 
Secondary Objectives 
Corresponding Endpoints 
• To evaluate the efficacy of GDC-8264  • ORR, defined as the proportion of patients with a CR, 
VGPR, or PR on Day 29 with no intervening 
additional line of aGVHD therapy, as determined by 
the investigator a  
• DOR, defined as the time from response (CR, VGPR 
or PR) on Day 29 to aGVHD progression from nadir 
in any organ, new systemic therapy for aGVHD, or 
death from any cause (whichever occurs first), as 
determined by the investigator a 
• Cumulative incidence of aGVHD flares by Day 56 
• Cumulative incidence of NRM by Day 180  
aGVHD = acute graft-versus-host disease; BMT CTN = Blood and Marrow Transplant Clinical Trials 
Network; CR = complete response; DOR = duration of response; FFS = failure-free survival; 
MAP = Mount Sinai Acute GVHD International Consortium [MAGIC] algorithm probability; 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events v5.0; 
NRM = non-relapse mortality; ORR = overall response rate; OS = overall survival; 
PK = pharmacokinetic; PR = partial response; VGPR = very good partial response. 
a Responses are determined by the investigator.  See Section 3.1.4 for key definitions and details 
on response criteria. 
b Baseline defined as last value prior to initiation of GDC-8264. 
 
 




























 
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• 
Diagnosis of post−allogeneic HSCT aGVHD at screening, with the following aspects 
of HSCT permissible: 
– 
Any malignant or non-malignant indication leading to HSCT  
– 
Any HSCT donor type (e.g., related, unrelated) or stem cell source (i.e., bone 
marrow, peripheral blood, cord blood)  
– 
Any GVHD prophylaxis regimen  
– 
Any conditioning regimen (i.e., myeloablative, reduced intensity, and 
non-myeloablative) 
• 
Evidence of engraftment post-transplant, as indicated by the following values:  
ANC ≥ 500/µL (0.5 × 109/L) and platelet count ≥ 10,000/µL (100 × 109/L) 
ANC and platelet counts may be repeated once during screening. 
Use of growth-factor supplementation to maintain neutrophil count is allowed. 
If platelet-transfusion refractoriness is suspected, platelet count will be 
measured approximately 1 hour after transfusion. 
• 
Diagnosis of high-risk aGVHD, defined as meeting any one criterion from either of 
the following sets of refined Minnesota high-risk aGVHD criteria during screening, 
with staging determined through use of MAGIC aGVHD Target Organ Staging: 
(see Appendix 4) 
– 
Single-organ involvement 
Stage 4 skin 
Stage 3−4 lower GI 
Stage 1−4 liver 
– 
Multiple-organ involvement 
Stage 1−2 lower GI plus any liver 
Stage 2 lower GI plus any skin 
Stage 3−4 lower GI plus any liver or skin 
Any three-organ involvement 
• 
Initiation of treatment with systemic corticosteroids for aGVHD at a dose of 
prednisone ≥ 2 mg/kg/day PO or methylprednisolone ≥2 mg/kg/day intravenously (or 
equivalent) in divided doses at diagnosis and up to 3 days prior to or on the same 
day as initiation of GDC-8264 (Day 1), with no taper planned prior to Day 3  
As clinically indicated, corticosteroid treatment may be initiated at a lower dose 
and increased on Day 1 to the doses specified above. 






















 
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4.5.5 
Clinical Response Assessment 
Overall response will be determined by the investigator at specified timepoints 
according to the response criteria as defined in Section 3.1.4.  Assessments should be 
performed by the same individual, if possible, to ensure internal consistency across 
visits. 
Endpoints (e.g., ORR, DOR, OS, NRM) will be calculated programmatically on the basis 
of investigator assessments of response at each specified timepoint. 
4.5.6 
MAGIC Acute Graft-versus-Host Disease Target Organ Staging 
The MAGIC aGVHD Target Organ Staging (see Appendix 4) assigns a stage to each of 
four aGVHD target organs (skin, liver, upper GI tract, and lower GI tract) based on 
severity of organ involvement.  The stages range from 0 to 4, with Stage 4 being the 
most severe, except for upper GI that is 0 or 1 (yes or no).  An overall grade ranging 
from 0 to IV is then determined on the basis of stages for the four target organs, with 
Grade IV being the most severe (Harris et al. 2016). 
4.5.7 
Chronic Graft-versus-Host Disease Staging 
Chronic GVHD severity will be independently assessed according to the National 
Institutes of Health Chronic GVHD Diagnosis and Staging score (see Appendix 5) on the 
basis of Karnofsky Performance Score and investigator quantification of patient chronic 
GVHD signs and symptoms.  The chronic GVHD target organs (skin, mouth, eyes, GI 
tract, liver, lungs, joints and fascia, and genital tract) are scored from 0 to 3, with 3 as the 
most severe (Jagasia et al. 2015). 
4.5.8 
Corticosteroid-Refractory Acute Graft-versus-Host Disease 
Assessment 
Assessment of aGVHD severity (grade) and patient response to treatment will be 
performed after the initiation of study treatment.  Patients who demonstrate 
progression of disease or non-response according to the criteria in Sections 3.1.4.7 
and 3.1.4.4, respectively, should be evaluated for corticosteroid-refractory aGVHD.  
If criteria for corticosteroid-refractory aGVHD are met (see Section 3.1.4.5), the 
investigator should evaluate the patient's condition to guide the clinical decision on 
initiation of second-line therapy.  The MAGIC Principal Investigator may be consulted.  
Initiation of any second-line therapy will require discontinuation of GDC-8264 (see 
Section 4.6.1). 
4.5.9 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
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• 
Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if 
considered standard of care for the region), sodium, potassium, chloride, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total and direct 
bilirubin, ALP, ALT, and AST 
• 
Coagulation:  INR, aPTT, and PT 
• 
Pregnancy test 
All women of childbearing potential (defined in Section 4.1.1) will have a serum 
pregnancy test performed at screening.  If obtaining results from a serum 
pregnancy test would delay enrollment, a urine pregnancy test is acceptable.  
 
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
• 
Plasma samples for PK analysis 
• 
Serum samples for biomarker analysis of ST2 and REG3α to calculate MAP  
• 
Serum samples for exploratory research on biomarkers (including biomarker assay 
development) 
• 
Residual biopsy tissue samples from involved aGVHD target organs (e.g., GI, skin) 
obtained up to 2 weeks prior to study enrollment or during the study for exploratory 
research on biomarkers 
Patients may undergo biopsies of involved organs to inform the diagnosis of 
aGVHD and/or to inform clinical management decisions according to 
institutional guidelines.  Biopsies of involved aGVHD target organs are 
encouraged but not required for this study.   
For patients with residual biopsy tissue samples available, the samples will be 
submitted to the Sponsor or designated laboratory only after the tissue samples 
are no longer required for clinical care 
• 
Buccal scraping sample for exploratory research on biomarkers 
 
Exploratory biomarker research may include, but will not be limited to, analysis of 
ATG16L1 polymorphisms and protein biomarkers.  Research may involve extraction of 
DNA, cell-free DNA, or RNA; analysis of mutations, single nucleotide polymorphisms, 
and other genomic variants; and genomic profiling.  Genomic research may include 
exploration of germline variants.  Genomic profiling may include whole genome 
sequencing (WGS) or whole exome sequencing (WES) of buccal scraping samples, but 
only at participating sites (see Section 4.5.12). 
Residual plasma PK samples may be used for exploratory biomarker research described 
above.  
For sampling procedures, storage conditions, and shipment instructions, see the 
appropriate laboratory manual. 


 
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Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.13), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions: 
• 
Plasma samples collected for PK analysis may be needed for additional PK and 
biomarker research and biomarker assay development and validation; therefore, 
these samples will be destroyed no later than 5 years after the final Clinical Study 
Report has been completed. 
• 
Serum samples collected for biomarker analysis of ST2 and REG3α to calculate 
MAP will be destroyed no later than10 years after the final Clinical Study Report has 
been completed.  However, the storage period will be in accordance with the 
IRB/EC−approved Informed Consent Form and applicable laws (e.g., health 
authority requirements).   
• 
Serum samples collected for biomarker research (including biomarker assay 
development) will be destroyed no later than 10 years after the final Clinical Study 
Report has been completed.  However, the storage period will be in accordance with 
the IRB/EC−approved Informed Consent Form and applicable laws (e.g., health 
authority requirements). 
• 
Residual biopsy tissue samples that are shared for biomarker research will be 
returned to the site upon request or no later than 5 years after the final Clinical 
Study Report has been completed.   
• 
Buccal scraping samples collected for biomarker research will be destroyed no later 
than 5 years after the final Clinical Study Report has been completed, with the 
exception of samples that undergo WGS or WES, which will be stored until they are 
no longer needed or until they are exhausted.  However, the storage period will be 
in accordance with the IRB/EC−approved Informed Consent Form and applicable 
laws (e.g., health authority requirements). 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to investigators or patients 
unless required by law.  The aggregate results of any conducted research will be 
available in accordance with the effective Sponsor policy on study data publication. 


 
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4.5.10 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal, if possible.  Circumstances that may induce changes in heart rate, 
including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings will be stored at the site. 
If at a particular postdose timepoint the mean QTcF is > 500 ms and > 60 ms longer than 
the baseline value, another ECG must be recorded, ideally within the next 5 minutes, 
and ECG monitoring should continue until QTcF has stabilized on two successive ECGs.  
The MAGIC Principal Investigator and the Medical Monitor should be notified.  Standard-
of-care treatment may be instituted per the discretion of the investigator.  If a PK sample 
is not scheduled for that timepoint, a PK sample may be obtained, at the discretion of the 
MAGIC Principal Investigator or the Medical Monitor.  A decision on GDC-8264 
discontinuation should be made, as described in Section 5.1.2.3.  The investigator 
should also evaluate the patient for potential concurrent risk factors (e.g., electrolyte 
abnormalities, co-medications known to prolong the QT interval, severe bradycardia). 
4.5.11 
Use of Screen-Fail Samples (Patients at Participating Sites)  
At participating sites, screening blood samples collected from patients who do not enroll 
in the study (screen-fail samples) may be used for research related to the disease under 
study and the development of disease-related tests or tools. 
If a site does not permit research on screen-fail samples, this section of the protocol 
(Section 4.5.11) will not be applicable at that site. 
4.5.12 
Buccal Scraping Samples for Whole Genome Sequencing or 
Whole Exome Sequencing (Patients at Participating Sites) 
At participating sites, buccal scraping samples will be collected for DNA extraction to 
enable WGS or WES to identify variants that are predictive of response to GDC-8264, 
are associated with progression to a more severe disease state, are associated with 
susceptibility to developing adverse events, can lead to improved adverse event 
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biology and drug safety.  Research will include exploration of germline variants.  The 
samples may be sent to one or more laboratories for analysis. 
Collection and submission of buccal scraping samples for WGS or WES is contingent 
upon the review and approval of the exploratory research by each site's Institutional 
Review Board or Ethics Committee (IRB/EC) and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for WGS or WES, this section 
of the protocol (Section 4.5.12) will not be applicable at that site. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  Data will be analyzed in the context of this study but may also 
be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
appropriate laboratory manual.   
Buccal scraping samples collected for WGS or WES are to be stored until they are no 
longer needed or until they are exhausted.  However, the storage period will be in 
accordance with the IRB/EC−approved Informed Consent Form and applicable laws 
(e.g., health authority requirements). 
Refer to Section 4.5.9 for details on use of samples after patient withdrawal and 
confidentiality standards for data. 
Data generated from buccal scraping samples collected for WGS or WES will be 
analyzed in aggregate rather than on an individual patient basis.  Thus, there will be no 
identification and reporting of incidental findings to investigators or patients.   
If permitted by local law, a patient may request access to uninterpreted WGS or WES 
data derived from analysis of his or her buccal scraping sample.  If a patient wishes to 
access these data, the investigator must inform the Sponsor, using the following email 
address:  global.return-genomics-results@roche.com.  The Sponsor will provide 
available data to the investigator in the form of a raw genomic sequencing data file, but 
will not provide any interpretation of the data.  The investigator should not include the 
data file in the patient's medical record.  Samples may be stored and analyzed in the 
future, and some samples may never be analyzed.  Thus, data may not be available at 
the time of the request or may never be available. 


 
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The aggregate results of any conducted research will be available in accordance with 
the effective Sponsor policy on study data publication. 
4.5.13 
Optional Samples for Research Biosample Repository and 
Mount Sinai Acute GVHD International Consortium 
Biorepository 
4.5.13.1 
Overview of the Research Biosample Repository and Mount 
Sinai Acute GVHD International Consortium Biorepository 
The Research Biosample Repository (RBR) is a centrally administered group of 
facilities used for the long-term storage of human biological specimens, including body 
fluids, solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of 
new pharmaceutical agents and the development of diagnostic tests, which may 
allow for individualized drug therapy for patients in the future. 
RBR samples will be analyzed to achieve one or more of the following objectives: 
• 
To study the association of biomarkers with efficacy or disease progression 
• 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
• 
To increase knowledge and understanding of disease biology and drug safety 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
The MAGIC Natural History Study is a database and biorepository that contains detailed 
longitudinal biomarker and clinical data prospectively obtained according to an 
institutional review board−approved protocol at each MAGIC participating center.  
Samples retained in the MAGIC biorepository will be used for research activities related 
to GVHD.   
Samples for the RBR and the MAGIC biorepository will be collected from patients who 
give specific consent to participate in this optional research. 
4.5.13.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR and MAGIC biorepository samples is 
contingent upon the review and approval of the exploratory research and the RBR 
portion of the Informed Consent Form by the Institutional Review Board or Ethics 
Committee (IRB/EC) and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR and MAGIC biorepository sampling, this section of the 
protocol (Section 4.5.13) will not be applicable at that site. 


 
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4.5.13.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to GVHD or GDC-8264, or 
drug safety: 
• 
Leftover blood, serum, plasma, and tissue samples (with the exception of residual 
biopsy tissue samples from involved aGVHD target organs, which will be returned to 
sites) and any derivatives thereof (e.g., DNA, RNA, proteins, peptides)  
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods.  Genomics is 
increasingly informing researcher's understanding of disease pathobiology.  WGS and 
WES provide a comprehensive characterization of the genome and exome, respectively, 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which patients are more likely to respond to a drug or develop 
adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
The following samples will be stored in the MAGIC biorepository and used for research 
purposes, including, but not limited to, research on GVHD or complications of HSCT that 
mimic GVHD: 
• 
Leftover serum samples for biomarker analysis of ST2 and REG3α to calculate 
MAP 
 
Alongside samples, the information collected from patients during the trial may also be 
shared with MAGIC, but only after personal information that can identify the patient has 
been removed. 
For sampling procedures, storage conditions, and shipment instructions, see the 
appropriate laboratory manual.   
RBR and MAGIC biorepository samples are to be stored until they are no longer needed 
or until they are exhausted.  However, the RBR and MAGIC biorepository storage period 
will be in accordance with the IRB/EC−approved Informed Consent Form and applicable 
laws (e.g., health authority requirements). 
4.5.13.4 
Data Protection, Use, and Sharing 
RBR and MAGIC biorepository samples and associated data will be labeled with a 
unique patient identification number. 


 
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Patient medical information associated with RBR and MAGIC biorepository samples is 
confidential and may be disclosed to third parties only as permitted by the Informed 
Consent Form (or separate authorization for use and disclosure of personal health 
information) signed by the patient, unless permitted or required by law. 
Data generated from RBR and MAGIC biorepository samples will be analyzed in 
aggregate rather than on an individual patient basis.  Thus, there will be no identification 
and reporting of incidental findings to investigators or patients.  In addition, given the 
complexity and exploratory nature of the analyses of RBR and MAGIC biorepository 
samples, data derived from these analyses will generally not be provided to study 
investigators or patients, unless required by law, with the exception of data generated 
from blood samples collected for WGS or WES as described below. 
If permitted by local law, a patient may request access to uninterpreted WGS or WES 
data derived from analysis of his or her blood sample.  If a patient wishes to access 
these data, the investigator must inform the Sponsor, using the following email address:  
global.return-genomics-results@roche.com.  The Sponsor will provide available data to 
the investigator in the form of a raw genomic sequencing data file, but will not provide 
any interpretation of the data.  The investigator should not include the data file in the 
patient's medical record.  Samples may be stored and analyzed in the future, and some 
samples may never be analyzed.  Thus, data may not be available at the time of the 
request or may never be available.  
The aggregate results of any conducted research will be available in accordance with 
the effective Sponsor policy on study data publication. 
Data generated from RBR and MAGIC biorepository samples must be available for 
inspection upon request by representatives of national and local health authorities, and 
Sponsor monitors, representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR and MAGIC biorepository data will become and remain the exclusive 
and unburdened property of the Sponsor and MAGIC, respectively, except where agreed 
otherwise. 
4.5.13.5 
Consent to Participate in the Research Biosample Repository 
and Mount Sinai Acute GVHD International Consortium 
Biorepository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR and the MAGIC biorepository.  The investigator or authorized designee will 
explain to each patient the objectives, methods, and potential hazards of participation in 
the RBR and the MAGIC biorepository.  Patients will be told that they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the 
storage period.  A separate, specific signature will be required to document a patient's 


 
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agreement to provide optional RBR and MAGIC biorepository samples.  Patients who 
decline to participate will not provide a separate signature.  The investigator should 
document whether or not the patient has given consent to participate and (if applicable) 
the date of consent, by completing the appropriate eCRF. 
In the event of an RBR and MAGIC biorepository participant's death or loss of 
competence, the participant's samples and data will continue to be used as part of the 
RBR and MAGIC research. 
4.5.13.6 
Withdrawal from the Research Biosample Repository and 
Mount Sinai Acute GVHD International Consortium 
Biorepository 
Patients who give consent to provide RBR and MAGIC biorepository samples have the 
right to withdraw their consent at any time for any reason.  After withdrawal of consent, 
any remaining samples will be destroyed.  However, if RBR and MAGIC biorepository 
samples have been tested prior to withdrawal of consent, results from those tests will 
remain as part of the overall research data.  If a patient wishes to withdraw consent to 
the testing of his or her RBR and MAGIC biorepository samples during the study, the 
investigator must inform the Medical Monitor or the MAGIC Principal Investigator (as 
applicable) in writing of the patient's wishes through use of the appropriate Subject 
Withdrawal Form and must enter the date of withdrawal on the appropriate eCRF.  If a 
patient wishes to withdraw consent to the testing of his or her RBR and MAGIC 
biorepository samples after closure of the site, the investigator must inform the Sponsor 
by emailing the study number and patient number to the following email address: 
global.rcr-withdrawal@roche.com 
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR and MAGIC biorepository samples.  Likewise, a patient's withdrawal of 
consent for testing of RBR and MAGIC biorepository samples does not constitute 
withdrawal from this study. 
4.5.13.7 
Monitoring and Oversight 
RBR and MAGIC biorepository samples will be tracked in a manner consistent with 
Good Clinical Practice by a quality-controlled, auditable, and appropriately validated 
laboratory information management system, to ensure compliance with data 
confidentiality as well as adherence to authorized use of samples as specified in this 
protocol and in the Informed Consent Form.  Sponsor monitors and auditors will have 
direct access to appropriate parts of records relating to patient participation in the RBR 
and the MAGIC biorepository for the purposes of verifying the data provided to the 
Sponsor.  The site will permit monitoring, audits, IRB/EC review, and health authority 
inspections by providing direct access to source data and documents related to the RBR 
and MAGIC biorepository samples. 








 
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Zhang et al. 2020).  Similarly, infection with murine gamma herpes virus MHV68 showed 
no significant differences in levels of MHV68 in lungs or spleens or changes in leukocyte 
populations between RIP1 KD and WT mice (Webster et al. 2020).  In addition, RIP1 
inactivation does not affect cellular nuclear envelope rupture (a critical step for viral 
replication) or proinflammatory cytokine production during influenza A−virus infection 
(Kuriakose et al. 2016).  However, considering the uncertainty of the translatability of 
some of these reported findings to humans, the Sponsor cannot exclude the potential 
risk that inhibition of RIP1 with GDC-8264 could increase the risk of serious infections.  
RIP1 KD mice may demonstrate a blunted systemic inflammatory response to certain 
inflammatory stimuli.  For example, in WT mice, TNF causes hypothermia (a 
manifestation of severe systemic inflammation) and shock; however, hypothermia and 
shock do not occur after TNF administration to RIP1 KD mice (Newton et al. 2014).  
Also, it has been reported that RIP1 KD mice may be impaired in their inflammatory 
response to lipopolysaccharide, although other published data have not replicated this 
finding (Newton et al. 2016, Saleh et al. 2017).  Nevertheless, if this result translates to 
humans, it is possible that patients exposed to GDC-8264 who have active infections 
may exhibit a blunted clinical response.  As such, patients with uncontrolled active 
infections are excluded from this study (see Section 4.1.2). 
Although data are limited regarding human experience following pharmacologic inhibition 
of RIP1, no indication of serious infection risk has been reported for several different 
RIP1 inhibitors dosed up to 12 weeks in healthy subjects or patients, including patients 
taking concomitant immunomodulatory drugs such as methotrexate.  GSK2982772, a 
potent orally administered RIP1 inhibitor, has been tested in healthy human subjects in a 
SAD/MAD trial (Weisel et al. 2017), patients with active plaque-type psoriasis (Weisel 
et al. 2020), patients with moderate to severe rheumatoid arthritis (Weisel et al. 2021a), 
and patients with active ulcerative colitis (Weisel et al. 2021b).  One non-serious adverse 
event of herpes zoster (moderate in severity) in the GSK2982772 psoriasis study in a 
patient in the high-dose group (60 mg twice a day) led to the patient’s discontinuation 
from study treatment, but no serious infections were reported (Weisel et al. 2020).  
Similarly, no indication of a risk of serious infections was reported for DNL104, another 
RIP1 inhibitor, when administered to healthy subjects in a SAD/MAD study (Grievink 
et al. 2020).  To date, no serious infection has been reported in any participant from the 
studies of GDC-8264.  For additional information, refer to the GDC-8264 Investigator’s 
Brochure. 




 
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GDC-8264 treatment will be withheld (see Table 7), and a PK sample should be 
obtained as soon as possible.  Patients on concomitant medications known to increase 
the risk of seizure may continue taking those medications, provided they have not 
previously experienced a seizure at or below the dose level being administered prior to 
initiation of GDC-8264. 
5.1.2 
Management of Patients Who Experience Adverse Events 
5.1.2.1 
Dose Modifications 
Dose modification is not permitted in this study for any patient. 
5.1.2.2 
Treatment Interruption 
GDC-8264 treatment may be temporarily suspended in patients who experience 
toxicity considered to be related to GDC-8264.  If GDC-8264 has been withheld for 
> 14 days because of toxicity, the patient should be discontinued from GDC-8264, unless 
resumption of treatment is recommended by the investigator after discussion with the 
MAGIC Principal Investigator and the Medical Monitor.   
GDC-8264 treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures) in consultation with the MAGIC Principal Investigator and the Medical 
Monitor.  The investigator should consult with the MAGIC Principal Investigator and the 
Medical Monitor to determine an acceptable length of treatment interruption. 
5.1.2.3 
Management Guidelines 
Guidelines for management of specific adverse events are outlined in Table 7.  These 
guidelines are intended to inform rather than supersede an investigator's clinical 
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Table 7 
Guidelines for Management of Patients Who Experience Adverse 
Events 
Event 
Action to Be Taken 
Hematologic toxicity 
ANC ≤ 500/µL (0.5 × 109/L) 
for 3 days 
• Continue GDC-8264 and monitor ANC.  
• If ANC remains ≤ 500/µL (0.5 × 109/L) after 3 days, withhold 
GDC-8264. 
• Monitor ANC and resume GDC-8264 when ANC > 500/µL 
(0.5 × 109/L). 
• If not resolved in ≤ 14 days while withholding GDC-8264, 
permanently discontinue GDC-8264. 
Note that growth factor use is permitted. 
Platelet count < 10,000/µL 
(100 × 109/L)   
for 7 days 
• Continue GDC-8264 and monitor platelet count.  
• If platelet count remains < 10,000/µL (100 × 109/L) after 7 days, 
withhold GDC-8264.  
• If platelet count sustainable at > 10,000/µL (100 × 109/L) (with 
transfusions, if necessary), resume GDC-8264. 
• If not resolved in ≤ 14 days while withholding GDC-8264, 
permanently discontinue GDC-8264.  
Note that transfusions are permitted. 
Hepatic events 
 
Total bilirubin, ALT, or AST 
increased, and cause is not 
clearly attributable to 
aGVHD or other 
transplant-related 
complication (e.g., 
veno-occlusive disease) 
For patients with normal bilirubin, ALT, and AST values at 
screening: 
• Withhold GDC-8264 for any Grade ≥ 3 increase. 
• If not resolved in ≤ 14 days, permanently discontinue 
GDC-8264. 
For patients with elevated bilirubin, ALT, and AST values at 
screening: 
• If any values > 3 × baseline, withhold GDC-8264 until values 
resolve to baseline. 
• If not resolved in ≤ 14 days, permanently discontinue 
GDC-8264. 
aGVHD = acute graft-versus-host disease; PK = pharmacokinetic; QTcF = QT interval corrected 
through use of Fridericia's formula; ULN = upper limit of normal. 


 
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Table 7 
Guidelines for Management of Patients Who Experience Adverse 
Events (cont.) 
Event 
Action to Be Taken 
Seizure 
Any grade 
• 
Immediately withhold GDC-8264 and report event as an adverse 
event of special interest (see Section 5.2.3). 
• 
Obtain PK sample as soon as possible. 
• 
Evaluate event and if not confirmed as seizure, resume 
GDC-8264. 
• 
If event confirmed as seizure, permanently discontinue 
GDC-8264. 
ECG abnormalities 
Any one of the following: 
• Torsades de pointes 
• Sustained (at least two 
ECG measurements 
> 30 minutes apart) 
QTcF that is > 500 ms 
and > 60 ms longer than 
the baseline value (i.e., 
last value prior to 
initiation of study 
treatment) 
• Sustained absolute 
QTcF that is > 515 ms 
(at least two ECG 
measurements 
> 30 minutes apart) 
• New ECG finding of 
clinical concern 
 
• Withhold GDC-8264.  For torsades de pointes, permanently 
discontinue GDC-8264.  For sustained QTcF events or all other 
ECG findings of clinical concern, permanently discontinue GDC-
8264 when there is no clear alternative cause.  If there is a clear 
alternative cause, GDC-8264 may be resumed at investigator's 
discretion following consultation with the MAGIC Principal 
Investigator and the Medical Monitor, provided abnormalities 
have resolved and patient is appropriately monitored. 
• Contact the MAGIC Principal Investigator and the Medical 
Monitor as soon as possible. 
• Obtain PK sample if not already scheduled for that timepoint. 
• Initiate standard-of-care treatment at investigator's discretion.  
Management of sustained QTcF prolongation should include 
close monitoring, with ECGs repeated at least hourly until two 
successive ECGs show resolution of the findings, correction of 
any electrolyte abnormalities, and possible discontinuation of 
other concomitant medications that are known to prolong the QT 
interval. 
• Evaluate patient for potential concurrent risk factors 
(e.g., electrolyte abnormalities, concomitant medications known 
to prolong the QT interval, severe bradycardia). 
• Consult with cardiologist or electrophysiologist to confirm ECG 
changes and ascertain the likelihood of drug-induced arrhythmia 
versus background occurrence of arrhythmias, as it is not 
uncommon to record arrhythmias such as non-sustained 
ventricular tachycardia, supraventricular tachycardia, pauses, or 
atrial fibrillation in healthy volunteers receiving placebo during 
periods of extended ECG monitoring.   
aGVHD = acute graft-versus-host disease; PK = pharmacokinetic; QTcF = QT interval corrected 
through use of Fridericia's formula; ULN = upper limit of normal. 
 
 


 
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Table 7 
Guidelines for Management of Patients Who Experience Adverse 
Events (cont.) 
GDC-8264-related toxicity not described above 
Grade 3 laboratory or 
non-laboratory abnormality 
attributable to GDC-8624  
• 
Withhold GDC-8264.  Resume GDC-8264 only after the toxicity 
has resolved to Grade 1 or better. 
• 
If no improvement to Grade 2 or better in ≤ 14 days while 
withholding GDC-8264, permanently discontinue GDC-8264. 
Grade 4 laboratory or 
non-laboratory abnormality 
attributable to GDC-8624 
that is not clearly 
attributable to aGVHD or 
other transplant-related 
complication 
• 
Immediately withhold GDC-8264. 
• 
If improvement to Grade 2 or better, resume GDC-8264. 
• 
If no improvement to Grade 2 or better in ≤ 14 days while 
withholding GDC-8264, permanently discontinue GDC-8264. 
aGVHD = acute graft-versus-host disease; PK = pharmacokinetic; QTcF = QT interval corrected 
through use of Fridericia's formula; ULN = upper limit of normal. 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.8 
and 5.3.5.9 for more information) 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
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• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from GDC-8264 (see Section 5.3.5.4 for more 
information) 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
GDC-8264 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity 
of an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
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5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of nondirective 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The investigator will use the NCI CTCAE (v5.0) grading scale for assessing the severity 
of each adverse event reported during the study.  The investigator will use the grading 
scale in Table 8 for assessing the severity of adverse events that are not specifically 
listed in NCI CTCAE. 
For infection adverse events, the investigator will also use the Blood and Marrow 
Transplant Clinical Trial Network (BMT CTN) infection severity grading system 
(see Appendix 7) for assessing the severity of infection adverse events (i.e., in addition 
to using the NCI CTCAE grading scale). 
Table 8 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 


 
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5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether 
an adverse event is considered to be related to the GDC-8264, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 9): 
• 
Temporal relationship of event onset to the initiation of GDC-8264 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of GDC-8264, or reintroduction of GDC-8264 (as applicable) 
• 
Known association of the event with GDC-8264 or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non−GDC-8264−related factors that are known to be associated with 
the occurrence of the event (e.g., adverse events associated with standard-of-care 
treatment with systemic corticosteroids or medications commonly used in the 
management of aGVHD) 
 
Table 9 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon rechallenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the adverse event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the adverse event 
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5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the adverse event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the adverse event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the adverse event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the adverse event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
adverse event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the adverse event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The adverse event eCRF should be updated by 
changing the event from "non-serious" to "serious," providing the date that the event 
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A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the adverse event eCRF.  Investigators should use clinical judgment 
to assess each event as recurrent or intermittent.  An intermittent adverse event should 
be recorded as a single event. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention  or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the adverse event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the adverse event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated creatinine," as opposed to "abnormal creatinine").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, low albumin level 
of 2.0 g/dL should be recorded as "hypoalbuminemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the adverse event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
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• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (e.g., hypertension) should be recorded 
on the adverse event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the adverse event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the adverse event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator to progression of aGVHD should be recorded as a clinical event.  All 
other deaths that occur during the adverse event reporting period, regardless of 
relationship to GDC-8264, must be recorded on the adverse event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).  An independent DSMB will 
monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the adverse event eCRF.  Generally, only one such event should be 


 
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reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the adverse event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the adverse event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.9 
Lack of Efficacy or Worsening of Acute Graft-Versus-Host 
Disease 
Events that are clearly consistent with worsening of aGVHD should not be recorded as 
adverse events.  These data will be captured as efficacy assessment data only.  In most 
cases, worsening will be based on aGVHD grading scale but may be based on 
symptomatic deterioration.  Every effort should be made to document aGVHD worsening 
through use of objective criteria.  If there is any uncertainty as to whether an event is due 
to disease aGVHD worsening, it should be reported as an adverse event. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization for patients who are not otherwise hospitalized at the 
initiation of the study should be documented and reported as a serious adverse event 
(per the definition of serious adverse event in Section 5.2.2), except as outlined below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
• 
Hospitalization due to worsening of aGVHD (see Section 5.3.5.9 
 


 
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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.11 
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse} 
(hereafter collectively referred to as "special situations"), are defined as follows: 
• 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
• 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
• 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
• 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 
 
Special situations and adverse events associated with special situations are to be 
reported separately on the adverse event eCRF, as outlined in the sections below. 
Reporting Special Situations 
All special situations associated with GDC-8264, regardless of whether they result in an 
adverse event, should be recorded on the adverse event eCRF as described below: 
• 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
• 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
• 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 


 
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• 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
• 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
• 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
• 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
• 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
• 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
Reporting Adverse Events Associated with Special Situations 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the adverse event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For GDC-8264, adverse events associated with special 
situations should be recorded as described below for each situation: 
• 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
• 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
• 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
• 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
• 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
• 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 


 
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• 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
• 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the adverse event eCRF, one entry to report the accidental overdose (special 
situation) and one entry to report the headache (adverse event).  The "Accidental 
overdose" and "Medication error" boxes would need to be checked for both entries. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor and the MAGIC DCC immediately; under no circumstances 
should reporting take place more than 24 hours after the investigator learns of the event.  
The following is a list of events that the investigator must report to the Sponsor and the 
MAGIC DCC within 24 hours after learning of the event, regardless of relationship to 
GDC-8264: 
• 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
• 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
• 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor and the MAGIC DCC 
immediately (i.e., no more than 24 hours after becoming aware of the information).  New 
significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event's outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours per day, 7 days per week.  Details will be provided separately. 






 
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5.4.3.3 
Abortions 
A spontaneous abortion in a female patient exposed to study drug or the female partner 
of a male patient exposed to study drug should be classified as a serious adverse event 
(as the Sponsor considers abortions to be medically significant), recorded on the 
adverse event eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the adverse event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to 
GDC-8264 or the female partner of a male patient exposed to GDC-8264 should be 
classified as a serious adverse event, recorded on the adverse event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported. 
During the adverse event reporting period (defined in Section 5.3.1), resolution of adverse 
events (with dates) should be documented on the adverse event eCRF and in the patient's 
medical record to facilitate source data verification. 
All pregnancies reported during the study should be followed until pregnancy outcome, 
with follow-up information on the infant collected according to procedures outlined in 
Section 5.4.3. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 










 
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6.7 
BIOMARKER ANALYSES 
The PD biomarker analyses will include all patients with one pretreatment and at least 
one post-treatment biomarker assessment.  PD biomarkers will be assessed as an 
absolute increase over time, and/or as a percent change relative to original baseline for 
each patient.  Results will be summarized through use of summary statistics and or other 
graphs as required.  Descriptive statistics will be listed by clinical response status.  
Additional PD biomarker analyses will be conducted as appropriate. 
Additional PD biomarker analyses will include all patients with one pretreatment 
biomarker assessment, provided there are sufficient data in each biomarker group to 
facilitate a meaningful analysis.  Baseline values will be used to evaluate predictive 
biomarkers in the context of activity (clinical and/or pharmacologic), drug levels, and/or 
safety endpoints.  Results will be summarized descriptively.   
The MAGIC biomarkers will be utilized to retrospectively conduct exploratory safety and 
efficacy analyses on a predefined cohort of patients who have an Ann Arbor score of 2 
or 3 at screening. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor, in collaboration with MAGIC, will supply eCRF specifications for this study.  
A contract research organization (CRO) in collaboration with the MAGIC DCC will be 
responsible for data management of this study, including quality checking of the data.  
Data entered manually will be collected via EDC through use of eCRFs.  Sites will be 
responsible for data entry into the EDC system.  In the event of discrepant data, the 
CRO and/or the MAGIC DCC will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
MAGIC will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Central laboratory data will be sent directly to the Sponsor, and 
ST2 and REG3α data from MAGIC laboratory via EDC system, using the Sponsor's and 
MAGIC standard procedures to handle and process the electronic transfer of these data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of MAGIC's data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor's 
standard procedures will be used to handle and process the electronic transfer of these 
data.   
eCRFs and any data updates will be maintained in the EDC system's audit trail.  System 
backups for data stored at on MAGIC's server(s) and records retention for the study data 
will be consistent with the MAGIC's standard procedures.  


 
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7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor or its designee direct access to applicable source documents and 
reports for trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site 
must also allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 


 
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as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, medication 
inventory records, and images, must be retained by the investigator for 15 years after 
completion or discontinuation of the study or for the length of time required by relevant 
national or local health authorities, whichever is longer.  After that period of time, the 
documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trials Directive 
(2001/20/EC) or Clinical Trials Regulation (536/2014) and applicable local, regional, 
and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
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forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC−approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) to 
communicate information that might affect a patient's willingness to continue in the 
study, the patient or a legally authorized representative must re-consent by signing the 
most current version of the Consent Forms or the addendum, in accordance with 
applicable laws and IRB/EC policy.  For any updated or revised Consent Forms, the 
case history or clinical records for each patient shall document the informed consent 
process and that written informed consent was obtained using the updated/revised 
Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S. Health Insurance Portability 
and Accountability Act (HIPAA) of 1996.  If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies. 


 
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8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the investigator 
and reviewed and approved by the IRB/EC before the study is initiated.  In addition, any 
patient recruitment materials must be approved by the IRB/EC.  
The investigator is responsible for providing written summaries of the status of the study 
to the IRB/EC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC.  Investigators are also responsible for 
promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or access.  
In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5). 


 
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Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.5). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 


 
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9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by Genentech, Inc.  The Sponsor will provide 
clinical operations management, data management, pharmacovigilance oversight, site 
monitoring, and medical monitoring in collaboration with the MAGIC Consortium and the 
CRO.  Verification of the source data at each site will be performed by the contracted 
CRO monitors. 
Approximately 20 sites in the United States and Canada will participate to enroll 
approximately 40 patients.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected from each participating site.  Biopsies collected for the diagnosis and 
management of aGVHD will be provided to the Sponsor on an as-available basis from 
each institution’s pathology laboratory after the samples are no longer needed for clinical 
care.  ECGs will be performed and read locally at each site.   
A DSMB will be employed to monitor and evaluate patient safety throughout the study. 
9.5 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and/or other summaries of clinical study results may be 
available in health authority databases for public access, as required by local regulation, 
and will be made available upon request.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/  
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 


 
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the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
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2018;128:4970−79. 


















 
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115/Protocol GA43861, Version 4 
Appendix 3  
Ann Arbor Scoring 
The Mount Sinai Acute GVHD International Consortium (MAGIC), a group of 
25 hematopoietic cellular transplantation centers conducting graft-versus-host 
disease(GVHD) research, has validated an algorithm that combines two gastrointestinal 
biomarkers (interleukin [IL]-33 receptor suppressor of tumorigenesis 2 [ST2]) and 
regenerating islet-derived 3-alpha [REG3α]) into a single value that estimates the 
probability of 6-month non-relapse mortality (NRM) for individual patients, known as the 
MAGIC algorithm probability (MAP).  The MAP also predicts response to treatment, 
maximum aGVHD severity, and overall survival.  The MAP is able to separate patients 
into three distinct risk strata (Ann Arbor scores 1, 2, and 3).  The concentration of ST2 
and REG3α are determined by validated ELISA.  The MAP is calculated using the 
following formula: 
MAP = 1‐EXP(‐EXP(0.577*LOG(REG3α,10)+1.844*LOG(ST2,10)‐11.263)) 
 
Ann Arbor aGVHD score cut-offs are as follows: 
• 
Ann Arbor Score 1:  MAP < 0.141 
• 
Ann Arbor Score 2:  0.141 ≤ MAP ≤ 0.290 
• 
Ann Arbor Score 3:  MAP > 0.290 
 
References 
Hartwell MJ, Özbek U, Holler E, et al. An early biomarker algorithm predicts lethal graft-
versus-host disease and survival. JCI Insight 2017; 2:e89798. 
Srinagesh HK, Özbek U, Kapoor U, et al. The MAGIC algorithm probability is a validated 
response biomarker of treatment of acute graft-versus-host disease. Blood Adv 
2019;3:4034−42. 
 


 
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Appendix 4  
Mount Sinai Acute GVHD International Consortium (MAGIC) 
Acute GVHD Target Organ Staging 
 
Reference 
Harris AC, Young R, Devine S, et al. International, multi-center standardization of acute 
graft-versus-host disease clinical data collection: a report from the Mount Sinai 
Acute GVHD International Consortium.  Biol Blood Marrow Transplant 
2016;22:4−10. 


Appendix 4: Mount Sinai Acute GVHD International Consortium (MAGIC) Acute GVHD Target 
Organ Staging  
  
GDC-8264—Genentech, Inc. 
117/Protocol GA43861, Version 4 
Percent Body Surface Area Calculation (Rule of Nines) 
The percent body surface area (%BSA) of skin involvement is estimated assigning 
percentages to different body areas using the Rule of Nines (Moore et al. 2021) as 
shown in the figure below.  The entire head is estimated as 9% (4.5% each for the 
anterior and posterior aspects).  The entire trunk is estimated at 36% and can be divided 
into 18% for anterior components and 18% for the back.  The anterior aspect of the trunk 
can further be divided into chest (9%) and abdomen (9%).  The upper extremities total 
18% and thus 9% for each upper extremity.  Each upper extremity can further be divided 
into anterior (4.5%) and posterior (4.5%).  The lower extremities are estimated at 36%, 
with18% for each lower extremity.  Again, each lower extremity can be further divided 
into 9% each for the anterior and posterior aspects.  The groin is estimated at 1%. 
 
References 
Moore RA, Waheed A, Burns B. Rule of Nines. [Updated 9 July 2021]. In: StatPearls 
[resource on the Internet]. Treasure Island: StatPearls Publishing, January 2022. 
Available from: https://www.ncbi.nlm.nih.gov/books/NBK513287/. 
Wallace Rule of Nines for determining percent of burned body surface area. Contributed 
by OpenStax College, (Public Domain). In: StatPearls [resource on the Internet]. 
Treasure Island: StatPearls Publishing, January 2022.. Available from: 
https://www.ncbi.nlm.nih.gov/books/NBK537190/figure/article-38400.image.f1/.  
 


 
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Appendix 5  
National Institutes of Health Chronic GVHD 
Diagnosis and Staging 
 
 
 


Appendix 5: National Institutes of Health Chronic GVHD Diagnosis and Staging 
  
GDC-8264—Genentech, Inc. 
119/Protocol GA43861, Version 4 
 
 
 


Appendix 5: National Institutes of Health Chronic GVHD Diagnosis and Staging 
  
GDC-8264—Genentech, Inc. 
120/Protocol GA43861, Version 4 
 
Reference 
Jagasia MH, Grenix HT, Arora M, et al. National Institutes of Health consensus 
development project on criteria for clinical trials in chronic graft-versus-host 
disease: I. The 2014 diagnosis and staging working group report.  Biol Blood 
Marrow Transplant 2015;21:389−401.


 
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121/Protocol GA43861, Version 4 
Appendix 6  
Primary Disease Relapse or Progression Guidance 
Primary disease relapse or progression is defined in Section 3.1.4.7.  Additional 
guidance on assessment of relapse or progression is provided below.   
For acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome (MDS), 
relapse is defined as meeting any of the following criteria: 
• 
Reappearance of leukemia blast cells in the peripheral blood 
• 
Greater than 5% blasts in the bone marrow not attributable to another cause 
(e.g., bone-marrow regeneration) 
• 
For patients with MDS:  appearance of previous or new dysplastic changes within 
the bone marrow, with or without falling donor chimerism 
• 
Development of extramedullary leukemia or leukemic cells in the cerebral spinal 
fluid 
 
For lymphoproliferative diseases, relapse or progression is defined as meeting all of the 
following criteria: 
• 
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size 
Increased fluoro-deoxyglucose (FDG) uptake in a previously unaffected site will 
be considered relapsed or progressive disease (PD) only after confirmation with 
other modalities.  In patients with no prior history of pulmonary lymphoma, new 
lung nodules identified by computed tomography (CT) scan are mostly benign.  
Thus, a therapeutic decision should not be made solely on the basis of the 
positron emission tomography (PET) without histologic confirmation. 
At least a 50% increase from nadir in the sum of the product diameters of any 
previously involved nodes, or in a single involved node, or the size of other 
lesions (e.g., splenic or hepatic nodules).   
To be considered PD, a lymph node with a diameter of the short axis of less 
than 1.0 cm must increase by ≥ 50% and to a size of 1.5 × 1.5 cm or more than 
1.5 cm in the long axis. 
• 
Lesion that is PET-positive if observed in a typical FDG-avid lymphoma or 
PET-positive before therapy, unless the lesion is too small to be detected with 
current PET systems (less than 1.5 cm in its long axis by CT) 
• 
For patients with chronic lymphocytic leukemia (CLL) who present in complete 
remission prior to transplantation:  in addition to the criteria above, reappearance of 
circulating malignant cells that are phenotypically characteristic of CLL 
 


Appendix 6: Primary Disease Relapse or Progression Guidance 
  
 
GDC-8264—Genentech, Inc. 
122/Protocol GA43861, Version 4 
For multiple myeloma, relapse or progression is defined as meeting any one or more of 
the following criteria: 
• 
Direct indicators of increasing disease and/or end-organ dysfunction 
(i.e., hypercalcemia, renal failure, anemia, and bone disease) related to the 
underlying clonal plasma-cell proliferative disorder 
This criterion is not used in calculation of time to progression or 
progression-free survival but can be reported optionally or for use in clinical 
practice 
• 
Development of new soft tissue plasmacytomas or bone lesions (osteoporotic 
fractures do not constitute progression) 
Definite increase in the size of existing plasmacytomas or bone lesions, defined 
as a 50% (and ≥ to 1 cm) increase as measured serially by the sum of the 
product diameters of the measurable lesion. 
• 
Hypercalcemia (>  11 mg/dL) 
• 
Decrease in hemoglobin of ≥ 2 g/dL not related to therapy or other 
non-myeloma-related conditions 
• 
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and 
attributable to myeloma 
• 
Hyperviscosity related to serum paraprotein 
  
For the purposes of assessing relapse free survival, if patient is in complete response 
(CR; as defined in Section 3.1.4.1), relapse is defined as meeting any one or more of the 
following criteria: 
• 
Reappearance of serum or urine M-protein by immunofixation or electrophoresis 
• 
Development of ≥ 5% plasma cells in the bone marrow 
• 
Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone 
lesion, or hypercalcemia; see above). 
 
For myeloproliferative neoplasms, relapse from CR is defined as meeting one or more of 
the following criteria: 
• 
Reappearance of bone-marrow disease, including blasts, monocytic blast 
equivalents, or fibrosis 
• 
New extramedullary disease, including new or reappearance of splenomegaly, 
hepatomegaly, skin lesions, etc. 
 
Institution of any therapy to treat persistent, progressive or relapsed malignancy, 
including the withdrawal of immunosuppressive therapy or treatment of relapse with 
donor lymphocyte infusion, will be considered evidence of relapse/progression 
regardless of whether the criteria described above were met.  The use of preemptive 


Appendix 6: Primary Disease Relapse or Progression Guidance 
  
 
GDC-8264—Genentech, Inc. 
123/Protocol GA43861, Version 4 
donor lymphocyte infusion is not considered as relapse.  Relapse will also be considered 
to have occurred if the criteria described above were not met but the cause of death was 
attributed to relapse. 
The date of relapse is the earlier of one of the following:  
• 
Relapse criteria met 
• 
Malignant disease that did not meet the specified relapse criteria was detected and 
treatment was initiated 
• 
Death occurred and cause was reported as relapse 
 
Non-malignant diseases will be considered to have a transplant status of persistent or 
active disease.  Graft failures will be considered recurrence. 
 








Appendix 7: Bone and Marrow Transplant Clinical Trials Network Severity Grading Table 
and Recurrence Interval Definitions 
  
GDC-8264—Genentech, Inc. 
127/Protocol GA43861, Version 4 
Multiple Organ Dysfunction Syndrome 
-2 or more of the following: Renal failure requiring dialysis, respiratory failure requiring bipap or 
intubation, heart failure requiring pressors, liver failure 
Pediatrics: 
-Pediatric SIRS definition and suspected or proven infection and cardiovascular dysfunction or 
ARDS or TWO or MORE other organ dysfunctions 
 
Pediatric SIRS definition: 
Two or more of the following, one of which must be abnormal temperature or leukocyte count 
1) Core temperature >38.5C or < 36C 
2) Tachycardia, otherwise unexplained persistent in absence of external stimulus, chronic 
drugs or painful stimuli. or bradycardia, in < 1 year old, otherwise unexplained persistent. 
3) Tachypnea or mechanical ventilation for an acute process not related to underlying 
neuromuscular disease or general anesthesia 
4) Leukocytosis or leukopenia for age (not secondary to chemotherapy) or >10% bands 
 
Pediatric organ dysfunction criteria: 
 
Cardiovavascular: despite administration of fluid bolus >40 ml/kg in 1 hour: 
• 
Hypotension <5th percentile for age (or per Table 1)  
• 
Pressors at any dose  
• 
Two of the following:  
o Capillary refill > 5 secs  
o Core to peripheral temperature gap > 3oC  
o Urine output < 0.5 mL/kg/hr  
o Unexplained metabolic acidosis (Base deficit > 5.0 mEq/L)  
o Blood lactate > 2 x ULN  
 
Respiratory: 
• 
ARDS or  
• 
Intubated or  
• 
>50% FiO2 to maintain SaO2 > 92%  
 
Neurologic: 
• 
Glasgow Coma Score < 11 or  
• 
Acute change in mental status with a decrease in GSC >3 pts from abnormal baseline  
 
Renal: 
• 
Serum creatinine > 2 x ULN for age or 2-fold increase in baseline creatinine  
 
Hepatic: 
• 
Total bilirubin >4 mg/dL or  
• 
ALT >2 x ULN for age  
 
 


Appendix 7: Bone and Marrow Transplant Clinical Trials Network Severity Grading Table 
and Recurrence Interval Definitions 
  
GDC-8264—Genentech, Inc. 
128/Protocol GA43861, Version 4 
TABLE 1: FOUR AGE GROUPS RELEVANT TO HCT: 
Age 
Tachycardia 
(bpm) 
Bradycardia 
(bpm) 
Tachypnea 
(breaths/min) 
Leukocytosis / 
Leukopenia 
(WBC) 
Hypotension 
Systolic BP 
mmHg 
1 mo to 1 yr 
>180 
<90 
>34 
>17.5 to <5.0 
<100 
2 yr to 5 yr 
>140 
NA 
>22 
>15.5 to <6.0 
<94 
6 yr to 12 yr 
>130 
NA 
>18 
>13.5 to <4.5 
<105 
13 yr to < 18 yr 
>110 
NA 
>14 
>11 to <4.5 
<117 
 
Disseminated Infections:  
1. Two or more non-contiguous sites with the SAME organism 
2. A disseminated infection can occur at any level of severity, but most will be grade 2 or 3. 
 
Recurrence Intervals to Determine Whether an Infection is the Same or New: 
1. CMV, HSV, EBV, HHV6: 2 months (< 60 days) 
2. VZV, HZV: 2 weeks (< 14 days) 
3. Bacterial, non-C. difficile: 1 week (< 7 days) 
4. Bacterial, C. difficile: 1 month (< 30 days) 
5. Yeast: 2 weeks (< 14 days) 
6. Molds: 3 months (< 90 days) 
7. Helicobacter: 1 year (< 365 days) 
8. Adenovirus, Enterovirus, Influenza, RSV, Parainfluenza, Rhinovirus: 2 weeks (< 14 days) 
9. Polyomavirus (BK virus): 2 months (< 60 days) 
 
For infections coded as “Disseminated” per the Infection Form, any previous infection with the 
same organism but different site within the recurrence interval for that organism will be counted 
as part of the disseminated infection. 
 
Reference 
[BMT CTN] Bone and Marrow Transplant Clinical Trials Network. Severity grading table and 
recurrence interval definitions Version 3, 19 March 2013 [resource on the Internet] 2021 [cited 
17 December 2021]. Available from: 
https://web.emmes.com/study/bmt2/public/Definition/Severity%20Grading_Recurrence%20Inter
val.pdf.  
 
 



ICF_001.pdf: 
Official Title: 
A Phase Ib, Open-Label, Randomized, Dose-Finding, Multicenter 
Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of 
GDC-8264 in Combination with Standard of Care in the Treatment of 
Acute Graft-Versus-Host Disease in Patients who have Undergone 
Allogeneic Hematopoietic Stem Cell Transplantation 
NCT Number: 
NCT05673876 
Document Date: 
ICF Version 4: 14 June 2023 


GDC-8264—Genentech, Inc. 
Master ICF for Study GA43861, Version 4, 14 June 2023 
Page 1 of 20 
SECTION 1: STUDY OVERVIEW 
 
{Table of contents may be deleted to reduce length of consent form} 
1.1 
Introduction 
1.2 
What is the purpose of this study? 
1.3 
What will happen if I participate? 
1.4 
Are there any benefits? 
1.5 
Are there any risks? 
1.6 
Are there any special requirements? 
1.7 
Will I be paid to participate? 
1.8 
Will it cost me anything? 
1.9 
What happens if I am injured? 
1.10 Can I stop being in the study? 
MASTER INFORMED CONSENT FORM 
TITLE: 
A PHASE Ib, OPEN-LABEL, RANDOMIZED, 
DOSE-FINDING, MULTICENTER STUDY TO 
EVALUATE THE SAFETY, 
PHARMACOKINETICS, AND EFFICACY OF 
GDC-8264 IN COMBINATION WITH 
STANDARD OF CARE IN THE TREATMENT OF 
ACUTE GRAFT-VERSUS-HOST DISEASE IN 
PATIENTS WHO HAVE UNDERGONE 
ALLOGENEIC HEMATOPOIETIC STEM CELL 
TRANSPLANTATION 
PROTOCOL NUMBER: 
GA43861 
SPONSOR: 
Genentech, Inc. 
STUDY DOCTOR: 
{Name} 
{Phone number} 
NAME OF INSTITUTION: 
{Name} 
INSTITUTION ADDRESS: 
{Address} 
NAME OF IRB/EC: 
{Name} 
IRB/EC APPROVAL DATE: _______________________________________ 


GDC-8264—Genentech, Inc. 
 
Master ICF for Study GA43861, Version 4, 14 June 2023 
Page 2 of 20 
 
1.1  
INTRODUCTION 
 
You are being asked to take part in this research study (also known as a clinical 
trial) because you have undergone an allogeneic hematopoietic stem cell 
transplantation (HSCT) and have been diagnosed with acute graft-versus-host 
disease (acute GVHD).  “Graft” represents the cells that you received from the 
donor.  “Host” represents the person (in this case, you) receiving the cells.  Acute 
GVHD is when the donor graft attacks and damages some of your tissues.  Acute 
GVHD can cause skin rash and stomach or intestinal problems such as nausea, 
vomiting, or diarrhea.  It may also damage your liver and cause hepatitis or jaundice 
(yellowing of the skin).  Acute GVHD may also increase your risk of developing an 
infection. 
 
Some people who have acute GVHD are at increased risk of non-relapse mortality, 
that is, dying from acute GVHD or other causes not related to their primary cancer.  
Based on your symptoms, you may be at higher risk of a poor outcome.   
 
This study is testing an experimental drug called GDC-8264, which is being 
developed to treat acute GVHD.  GDC-8264 will be given to you in addition to 
prednisone or methylprednisolone, which are standard medications used to treat 
acute GVHD after HSCT.  This is the first study of GDC-8264 in patients with 
acute GVHD after HSCT.   
 
All individuals will be considered for this clinical trial, regardless of race, 
ethnicity, sex, sexual orientation, gender identity, veteran status, or disability status. 
 
Genentech, Inc. (a member of the Roche Group) is the sponsor of this study and is 
paying {Name of Study Site} to cover the costs of this study. 
 
This consent form tells you what will happen if you take part.  It also tells you about 
the possible benefits and risks of being in the study. 
 
Taking part in this study is your choice.  Please read the information carefully and 
feel free to ask questions.  It may be helpful for you to discuss this information with 
your family and friends. 
 
Instead of participating in this study, you may choose to 
– 
Get treatment with standard medications prescribed by your doctor to treat acute 
GVHD without being in this study 
– 
Join a different study 
 
 
Talk to your doctor about all of your choices, and the risks and benefits of each 
choice.  If you choose not to take part, you will not lose the regular care you receive 
from your doctors. 
 
If you decide to take part, you will be asked to sign this consent form.  You will be 
given a copy of your signed consent form. 
 






GDC-8264—Genentech, Inc. 
 
Master ICF for Study GA43861, Version 4, 14 June 2023 
Page 5 of 20 
 
 
Certain medications should not be used during this study.  Your study doctor will talk 
to you about these medications.  You should talk to your study doctor before starting 
any medications, vitamins, or other supplements (including vaccines, topical 
medications, or herbal remedies), even if they don't need a prescription. 
 
1.7  
WILL I BE PAID TO PARTICIPATE? 
{If participants will not be paid, include the following:} 
You will not be paid for taking part in this study. 
{If participants will be paid the same amount per visit, include the following:} 
You will be paid {per visit amount} for each visit that you complete, {including} [or] {not 
including} the screening visit. 
{If participants will be paid a varying amount per visit, include the following text 
and a payment schedule (see sample schedule):} 
You will be paid for each visit you complete, according to the following schedule: 
{Sample payment schedule:} 
{Visits (e.g. Screening visit and Days XX, XX, and XX)} 
${amount} per visit 
{Visits (e.g. Days XX, XX, and XX)} 
${amount} per visit 
 
{If reimbursement for travel expenses is allowed, include the following:} 
You will be reimbursed for your reasonable costs (for example, transportation, parking) 
to travel from your home to the study site. 
Information from this study, including information from research on your samples, may 
lead to discoveries, inventions, or development of commercial products.  You and your 
family will not receive any benefits or payment if this happens. 
1.8  
WILL IT COST ME ANYTHING? 
While participating in this study, you will not have to pay for drugs or procedures that are 
required only for this study and are not part of your regular medical care.  {Responsible 
party [e.g., "You or your health plan"]} will have to pay for medicines and clinic, hospital, 
and doctors’ services that are part of your regular medical care.{Delete the following 
for sites not requiring this language:}  Some health plans will not pay for medications 
or procedures for people participating in research studies.  Your study doctor can find 
out what your health plan will pay for. 
1.9  
WHAT HAPPENS IF I AM INJURED? 
If you get injured because you took part in this study, contact your study doctor as soon 
as possible at {telephone number}.  Your study doctor will explain your options and tell 
you where to get treatment. 


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Genentech will pay for reasonable costs of immediate care for any physical injury that 
results from the study drug but only if all of the following are true: 

Genentech and the study doctor agree that your injury resulted from the study drug
and not from a preexisting medical condition

The costs are not paid for by your medical insurance

Your injury was not because you or the study team did not follow instructions
You will not receive any other kind of payment. 
If you get injured in this study, you will not lose any of your legal rights to seek payment 
by signing this form. 
1.10 
CAN I STOP BEING IN THE STUDY? 
You can leave this study at any time.  Tell your study doctor if you are thinking about 
stopping, and your study doctor will tell you how to stop safely.  If you leave this study, 
you will not lose access to any of your regular care. 
If there are important new findings or changes in this study that may affect your health or 
willingness to continue, your study doctor will let you or your legally authorized 
representative know as soon as possible. 
You may be required to stop participating in the study, even if you wish to continue. 
Below are some of the reasons why you may be asked to stop: 

Your safety would be at risk if you continued

You were unable to or did not follow study instructions or procedures

You need medical care that is not allowed by this study

This study has been stopped by Genentech or a health authority
When your participation ends, no new information will be collected about you with three
exceptions:  1) if you experience a side effect after the study that is believed to be related 
to GDC-8264, the study doctor may report the side effect to Genentech, 2) information 
may be obtained from records available to the public to help track the course of your 
disease, and 3) any laboratory samples collected prior to stopping may still be tested, 
unless you specifically ask for your samples to be destroyed.  However, Genentech will 
still be able to use information that was collected prior to stopping, including information 
from samples that were tested prior to stopping. 


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SECTION 2: STUDY DETAILS 
 
{Table of contents may be deleted to reduce length of consent form} 
2.1 
Study treatment risks 
2.2 
Study procedures and potential risks 
2.3 
Access to study drug after completing the study 
2.4 
Use and handling of laboratory samples 
2.5 
Protection, use, and sharing of information 
2.6 
Handling of genetic information 
2.7 
Study results 
2.8 
Contact information 
2.9 
Other research studies 
  
2.1  
STUDY TREATMENT RISKS 
Risks Associated with GDC-8264 
GDC-8264 has had limited testing in humans.  In the first study in healthy volunteers, 
55 people received GDC-8264 and the most common side effects observed (reported by 
5 people or more) were, headache, dizziness, rash or skin reactions, sleepiness, 
abdominal pain, diarrhea, nausea, and catheter-site bruising.  Of these, the most 
common side effect was headache, which was reported by 20% of the healthy 
volunteers (11 out of 55 people) who received GDC-8264.  All side effects were mild to 
moderate in severity.  Potential side effects, based on human and animal studies or 
knowledge of similar drugs, are convulsion and increased risk of bacterial or viral 
infection.  There may be side effects that are not known at this time.  You will be closely 
monitored for potential side effects while participating in this study. 
2.2  
STUDY PROCEDURES AND POTENTIAL RISKS 
 
Procedures with associated risks are listed below.  The study doctor will provide more 
detailed information about the risks and their frequency. 
Procedures with Associated Risks 
Procedure 
Approximate Timing 
Potential Risks 
Blood sample (about 
13 tablespoons at each visit) 
 Screening 
 Multiple times on two 
days 
 Once a week while you 
are receiving GDC-8264 
 Twice during follow-up 
Drawing blood can cause pain, 
bruising, or infection where the 
needle is inserted.  Some people 
experience dizziness, fainting, or 
upset stomach when their blood is 
drawn. 
Mouth swab 
 Day 1 
A mouth swab could be painful if 
your mouth is inflamed due to your 
acute GVHD.  Your study doctor 
may wait to take the mouth swab 
once your mouth has begun to heal.  




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2.4  
USE AND HANDLING OF LABORATORY SAMPLES 
Sample Use 
Blood and tissue samples will be collected for reasons such as the following: 
 Check your health through standard 
laboratory tests 
 Find out if you are pregnant 
 Check how quickly your blood clots 
 Find out how GDC-8264 is processed by 
your body 
 Perform additional analyses related to 
processing of GDC-8264  
 Find out how variations in biomarkers (such 
as proteins or genes) affect your disease or 
your response to GDC-8264 
 
{Include the following if the site allows screening samples from individuals who 
do not enroll in the study to be used for additional research related to the disease 
and the development of disease-related tests or tools:}  blood samples collected at 
screening may be used for research related to your disease and the development of 
tests or tools that help with detecting or understanding your disease, even if you are not 
eligible for or decide not to take part in this study, unless you specifically ask for your 
samples to be destroyed. 
Tissue samples may be collected during routine clinical procedures, such as skin biopsy 
or intestine biopsy (done by endoscopy or colonoscopy), for diagnosis and management 
of your acute GVHD (in other words, not only for this study).  If these tissue samples are 
collected, and only when they are no longer needed for your clinical care, they will be 
shared with Genentech.  These leftover (unused) tissue samples may include any that 
were collected from up to 2 weeks before the study or obtained during the study.  The 
tissue samples will be used to learn more about your disease or your response to 
GDC-8264. 
Genome Testing 
{If IRB/EC has not granted approval for collection of buccal scraping samples for 
whole genome sequencing (WGS) or whole exome sequencing (WES) (as 
described in Section 4.5.11} of the protocol), delete the entire "Genome Testing" 
section.  If IRB/EC has granted approval for collection of buccal scraping samples 
for WGS or WES, include the following:}Biomarker testing may involve analysis of 
your genome (DNA), an "instruction book" for the cells in your body.  Tissue samples 
from your mouth (taken with a mouth swab) may be tested for inherited genome 
variations associated with acute GVHD.  Testing may include analysis of all of your DNA 
(whole genome sequencing) or analysis of all of your DNA that codes for proteins (whole 
exome sequencing).  Analyses of samples from a large number of people may help 
researchers learn more about GDC-8264 and similar drugs, acute GVHD and other 
diseases, possible links among diseases, genome variations and how they might affect a 
disease or a person's response to treatment, and new avenues for drug development 
and personalized therapies. 


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Sample Storage 
Samples will be securely stored for a defined period (as described below) and will then 
be destroyed, with one exception:  Leftover tissue samples from a previous biopsy or 
biopsy during the study and subsequently shared with Genentech will be returned to 
your doctor upon request or no later than 5 years after the final study results have been 
reported. 
{If IRB/EC has granted approval for collection of buccal scraping samples for 
WGS or WES, include the following:} 
Samples will be stored for up to 5 years after the final study results have been reported, 
with the following exceptions: 
 
{If the site does not require a defined storage period for WGS or WES 
samples, include the following:} Samples for whole genome sequencing or whole 
exome sequencing will be stored until they are no longer needed or until they are 
used up. 
 
{If the site requires a defined storage period for WGS or WES samples, 
include the following:} Samples for whole genome sequencing or whole exome 
sequencing will be stored for up to 15 years after the final study results have been 
reported. 
 
Samples for biomarker testing will be stored for 10 years after the final study results 
have been reported. 
 
{If IRB/EC has not granted approval for collection of buccal scraping samples for 
WGS or WES, include the following:} 
Samples will be stored for up to 5 years after the final study results have been reported, 
with the following exception: 
 
Samples for biomarker testing will be stored for 10 years after the final study results 
have been reported. 
 
2.5  
PROTECTION, USE, AND SHARING OF INFORMATION 
During this study, health and personal information ("information") about you will be 
collected.  This section describes the protection, use, and sharing of your information, 
which consists of the following: 
 
Information in your medical record, which is held by {Study Site} ("study site") 
 
Information (including imaging data) that is collected or produced during this study 
("study data"), which is held by the study site, Genentech, other Roche affiliates, 
Genentech's collaborators, and Genentech's representatives (people and 
companies who work for Genentech) 
 
Your privacy is very important, and Genentech uses many safeguards to protect your 
privacy, in accordance with applicable data privacy laws and laws related to the conduct 
of clinical trials.   


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Your study data and samples will be labeled with a participant identification (ID) number 
that is unique to you and not related to or derived from information that identifies you 
(such as your name or any other personally identifying information).  Genentech, other 
Roche affiliates, Genentech's collaborators, and Genentech's representatives will only 
have access to study data and samples labeled with a participant ID number, except 
when accessing your medical record under certain circumstances, as described below: 
Your information (including your medical record, which contains personal 
information that can identify you) may need to be reviewed to make sure the study 
is being done properly or to check the quality of the information.  This information 
will be kept private.  The following people and groups of people may review {If 
copying of information is not allowed, delete "and/or copy":}and/or copy this 
information: 
 
Authorized individuals (such as study monitors and auditors) representing 
Genentech and Genentech's collaborators and licensees (people and 
companies who partner with Genentech) 
 
The Institutional Review Board or Ethics Committee (people responsible for 
protecting the rights and safety of people who take part in research studies) 
 
Regulatory authorities (government agencies involved in keeping research safe 
for people) 
 
Genentech, other Roche affiliates, and Genentech's collaborators and licensees may 
use study data labeled with your participant ID number.  Your study data may also be 
shared with independent researchers or government agencies, but only after personal 
information that can identify you has been removed.  Your study data may be combined 
with other people's data and/or linked to other data collected from you.  Your study data 
may be used to help better understand why people get diseases and how to best 
prevent, diagnose, and treat diseases, and to develop and provide access to new 
medicines, medical devices, and health care solutions. 
Your information will not be given to your insurance company or employer, unless 
required by law.  If the results from this study are published in a medical journal or 
presented at a scientific meeting, you will not be identified. 
Information from this study will be retained by the study site for 15 years after the end of 
the study or for the length of time required by applicable laws, whichever is longer.  In 
addition, Genentech will retain the study data for 25 years after the final study results 
have been reported or for the length of time required by applicable laws, whichever is 
longer. 
If a participant is eligible for Medicare, federal law requires Genentech to inform the 
Centers for Medicare & Medicaid Services (the agency responsible for the Medicare 
program) when Genentech is going to pay for a participant injury.  Genentech may need 


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to share information, such as your name, date of birth, sex, and Medicare ID number (if 
you have one), with the Centers for Medicare & Medicaid Services. 
{For U.S. sites providing a separate HIPAA authorization, ensure that the 
authorization includes the following:} 
Your health information (including imaging data) may be used or shared for the purposes 
of this research study and for research related to acute GVHD, common pathways (links) 
among diseases, the use of experimental drugs in disease therapy, and/or the 
development of tests or tools that help with detecting or understanding acute GVHD.  
Your health information may be used by and/or shared with Genentech, other Roche 
affiliates, Genentech’s collaborators and licensees, the Institutional Review Board or 
Ethics Committee, and regulatory authorities. 
{For U.S. sites NOT providing a separate HIPAA authorization, include the 
following:} 
If you sign this consent form, you give permission to the study site to use and/or share 
your "health information," which includes all information about you that has been and will 
be collected by the study site (including imaging data) and information in your study site 
medical record.  Your health information may be used or shared for the purposes of this 
research study and for research related to acute GVHD, common pathways (links) 
among diseases, the use of experimental drugs in disease therapy, and/or the 
development of tests or tools that help with detecting or understanding acute GVHD.  
You do not have to sign this consent form, but if you do not, you cannot take part in this 
research study. 
Your health information may be used by and/or shared with Genentech, other Roche 
affiliates, Genentech’s collaborators and licensees, the Institutional Review Board or 
Ethics Committee, and regulatory authorities.  Your health information and samples may 
be analyzed in any country worldwide.  Those persons who receive your health 
information may not be required by federal privacy laws to protect it and may share your 
health information with others without your permission, if permitted by laws that apply to 
them. 
You have the right to see and get a copy of your medical records kept by the study site 
that are related to the study.  However, by signing this consent form, you agree that you 
generally will not be able to review or receive some of your records related to the study 
until after the entire study has been completed.  This is to protect the scientific integrity 
of the study. 
Your permission to use and share your health information does not have an expiration 
date. 


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You may change your mind and take back your consent at any time.  If you take back 
your consent, no new health information will be collected about you.  However, 
Genentech will still be able to use and share any health information about you that has 
already been collected during this study.  To take back your consent, you must do so in 
writing by contacting your study doctor (see Section 2.8). 
2.6  
HANDLING OF GENETIC INFORMATION  
{If IRB/EC has not granted approval for collection of buccal scraping samples for 
WGS or WES, delete Section 2.6.  If IRB/EC has granted approval for collection of 
buccal scraping samples for WGS or WES, include the following:} 
Testing of your samples may provide information related to your genome ("genetic 
information"), including information about inherited characteristics.  Your samples and 
genetic information will not be labeled with your name, your picture, or any other 
personally identifying information.  Genentech uses many safeguards to protect your 
privacy. 
{For U.S. sites that have granted approval for collection of buccal scraping 
samples for WGS or WES, include the following:} 
The Genetic Information Nondiscrimination Act generally makes it illegal for health 
insurance companies, group health plans, and most employers to discriminate against 
you on the basis of your genetic information.  This act generally will protect you in the 
following ways:  
 
Health insurance companies and group health plans cannot request your genetic 
information from this research 
 
Health insurance companies and group health plans cannot use your genetic 
information when making decisions regarding your eligibility or premiums 
 
Employers with 15 or more employees cannot use your genetic information from this 
research when setting the terms of your employment 
 
This federal law does not protect you against genetic discrimination by companies that 
sell life insurance, disability insurance, or long-term care insurance. 
2.7  
STUDY RESULTS 
{If IRB/EC has granted approval for collection of buccal scraping samples for 
WGS or WES, include the following:}  You may request access to the genome 
sequencing data obtained from your blood sample (as described in Section 2.4), if 
permitted by local law.  You must submit any request for access to such sequencing 
data to your study doctor.  This information shared with you and your study doctor may 
be available in the form of a file of raw genomic sequencing data.  This file will not 
contain any interpretation of your data, and no clinical report will be available.  The data 
will not be included in your medical record.  Your blood sample may be tested many 
years after the study has ended, or may never be tested.  This means your genomic 
sequencing data may not be available at the time of your request, or may never be 


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available.  Genentech will do its best to forward available data, but there is no guarantee 
that data will be forwarded in response to every request. 
{If IRB/EC has granted approval for collection of buccal scraping samples for 
WGS or WES, include the following:} 
Results from exploratory biomarker tests will not be shared with you or your doctor, 
unless required by law, and will not be part of your medical record, except as described 
above. 
{If IRB/EC has not granted approval for collection of buccal scraping samples for 
WGS or WES, include the following:} 
Results from exploratory biomarker tests will not be shared with you or your doctor, 
unless required by law, and will not be part of your medical record. 
A clinical study report containing the results of this trial will be made available to anyone 
who requests a copy.  Before this report is provided, additional steps will be taken to 
protect your information from being linked to you. 
An easy-to-understand summary of the results of this study will be made available to 
you.  Your study doctor may inform you about the availability of the summary for this 
study.  The summary will not include any information that could be used to identify you or 
any other study participants.  Once available, you can obtain the summary from your 
study doctor or you may be able to view the summary by entering the study number 
(GA43861) in the search bar at the following site: 
https://forpatients.roche.com/ 
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, as 
required by U.S. law.  This website will not include information that can identify you.  At 
most, the website will include a summary of the results.  You can search this website at 
any time. 
2.8  
CONTACT INFORMATION 
If you have any questions, contact your study team, listed below: 
 
Study Doctor 
Study Coordinator 
Name: 
 
 
Address: 
 
 
Telephone number:  
 
Email address: 
 
 
 


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If you have any questions about your rights while taking part in this study, call {Study 
Site}’s Institutional Review Board or Ethics Committee (a group of people who review the 
research to protect your rights) at {telephone number}: 
2.9  
OTHER RESEARCH STUDIES 
Genentech may inform your study doctor about other Genentech or Roche research 
studies that might be of interest to you, taking into consideration your medical records 
and/or information collected as part of this study.  If allowed by local laws, your study 
doctor may contact you in the future to see if you would like to learn more about taking 
part in a new research study.  Taking part in a new research study would be entirely 
voluntary. 


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Signature 
I confirm that I have read this consent form, or it has been read to me.  I 
understand the information presented and have had my questions answered.  I 
understand that I will be given a copy of all {total number of pages} pages of this 
form after it has been signed and dated.  I agree to take part in this research study 
as described above and authorize {Study Site} to use and share my information as 
described in this form. 
 
Participant name (print) 
 
 
 
If applicable – Name of participant’s legally authorized 
representative (print) 
 
Relationship to participant 
 
Participant signature or signature of participant’s legally 
authorized representative 
 
Date 
I, the undersigned, have fully explained this informed consent to the participant 
named above and/or the participant’s legally authorized representative. 
 
Name of person conducting informed consent discussion (print) 
 
 
 
Signature of person conducting informed consent discussion 
 
Date 
 
Witness name a (print) 
 
 
 
Witness signature a 
 
Date 
 
 
a If the investigator or Institutional Review Board or Ethics Committee deems a witness signature is 
necessary (as per ICH Guidelines, Good Clinical Practice [E6], 4.8.9, or local regulations). 


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SECTION 3: 
CONSENT FOR OPTIONAL COLLECTION AND/OR 
STORAGE OF SAMPLES FOR THE RESEARCH 
BIOSAMPLE REPOSITORY AND THE MOUNT SINAI ACUTE 
GVHD INTERNATIONAL CONSORTIUM BIOREPOSITORY 
   
INTRODUCTION 
The Research Biosample Repository (RBR) is a collection of samples that will be tested 
by researchers during Study GA43861 and for future research.  Reasons for testing may 
include: 
 
Finding out why certain people are more likely to respond to treatments than others 
 
Finding out how and why diseases act differently in different people 
 
Developing new treatments for diseases or medical conditions 
 
Finding out why certain people are more likely to have side effects than others 
 
Finding out how treatments are processed in the body 
 
Finding out how treatments affect the body 
 
Developing better ways for preventing diseases or treating diseases earlier 
 
Developing or improving tests or tools that help with detecting or understanding 
diseases and identifying the right medicine for the right patient 
 
The Mount Sinai Acute GVHD International Consortium (MAGIC) biorepository is a 
collection of samples that will be tested by researchers during Study GA43861 and for 
future research on graft-versus-host disease (GVHD). 
You are being asked to donate leftover (unused) blood and tissue samples to the RBR 
and the MAGIC biorepository.  MAGIC may share some leftover blood samples and 
related medical information with independent researchers outside of the consortium, but 
only for research that MAGIC has approved and after personal information that can 
identify you has been removed. 
Donating your samples to the RBR and the MAGIC biorepository is your choice.  No 
matter what you choose, it will not affect your participation in the main study or the 
regular care you receive from your doctors.  
WHAT WILL HAPPEN IF I PARTICIPATE? 
Listed below are the procedures for donating samples, along with any potential risks. 
Procedure 
Potential Risks 
Leftover (unused) blood and tissue samples 
that were collected during the study 
(including any additional tissue samples your 
doctor decided to collect) will be donated to 
the RBR. 
There are no additional risks associated with 
donating your leftover samples to the RBR. 


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Leftover (unused) blood samples collected to 
measure biomarkers for tests used in 
estimating risk of non-relapse mortality during 
the study will be donated to the MAGIC 
biorepository. 
There are no additional risks associated with 
donating your leftover samples to the MAGIC 
biorepository. 
 
{If the site does not require a defined storage period, include the 
following:}Samples will be securely stored in the RBR and the MAGIC biorepository 
until they are no longer needed or until they are used up, and will then be destroyed. 
{If the site requires a defined storage period, include the following:}Samples will be 
securely stored in the RBR and the MAGIC biorepository for up to 15 years after the final 
study results have been reported, and will then be destroyed. 
Testing of RBR samples may involve analysis of your genome (DNA), the "instruction 
book" for the cells in your body.  Your samples may be tested for inherited or non-
inherited genome variations, to allow for exploration of broad health research questions 
across disease areas.  Testing may include analysis of all of your DNA (whole genome 
sequencing) or analysis of part of your DNA.  Analyses of samples from a large number 
of people may help researchers learn more about GDC-8264 and similar drugs, acute 
GVHD and other diseases, possible links among diseases, mutations and how they 
might affect a disease or a person's response to treatment, and new avenues for drug 
development and personalized therapies. 
ARE THERE ANY BENEFITS TO DONATING SAMPLES? 
You will not receive any direct benefit from donating your samples.  However, research 
performed on these samples may benefit patients with acute GVHD or a similar 
condition in the future. 
WILL I BE PAID IF I DONATE SAMPLES? 
You will not be paid for donating samples to the RBR and the MAGIC biorepository. 
Information from research on your RBR and MAGIC biorepository samples may lead to 
discoveries, inventions, or development of commercial products.  You and your family 
will not receive any benefits or payment if this happens. 
HOW WILL MY PRIVACY BE PROTECTED? 
Your samples and information will be labeled with your participant ID number; they will 
not be labeled with your name, your picture, or any other personally identifying 
information.  Your samples and information will be kept under the same level of privacy 
used for the main study.  Genentech uses many safeguards to protect your privacy. 
Information from the analyses will not be given to your insurance company or employer, 
unless required by law.  If the research results are published in a medical journal or 


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presented at a scientific meeting, you will not be identified.  Information from the sample 
analyses will not be part of your medical record. 
Genentech, other Roche affiliates, Genentech's collaborators and licensees, and MAGIC 
and MAGIC collaborators may study the RBR and MAGIC biorepository samples and 
information in any country worldwide. 
Data from analysis of RBR and MAGIC biorepository samples may be shared with 
researchers or government agencies, but only after personal information that can identify 
you has been removed.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, testing, and commercialization of products that treat or diagnose disease, 
or improve patient care.  These data will not include information that identifies you.   
WILL I HAVE ACCESS TO MY TEST RESULTS? 
Information from the sample analyses will not be shared with you or your doctor, unless 
required by law, except as described below. 
You may request access to the genome sequencing data obtained from your RBR blood 
sample, if permitted by local law.  You must submit any request for access to such 
sequencing data to your study doctor.  This information shared with you and your study 
doctor may be available in the form of a file of raw genomic sequencing data.  This file 
will not contain any interpretation of your data, and no clinical report will be available.  
The data will not be included in your medical record.  Your blood sample may be tested 
many years after the study has ended, or may never be tested.  This means your 
genomic sequencing data may not be available at the time of your request, or may never 
be available.  Genentech will do its best to forward available data, but there is no 
guarantee that data will be forwarded in response to every request. 
CAN I CHANGE MY MIND ABOUT STORING MY SAMPLES IN THE RBR? 
You can change your mind at any time.  If you want to withdraw your consent for the 
RBR and the MAGIC biorepository, tell your study doctor that you no longer want your 
samples stored or used for research.  After you withdraw consent, any samples that 
remain will be destroyed.  If you change your mind and your samples have already been 
tested, Genentech and MAGIC will still be able to use the results from those tests.  If you 
withdraw or discontinue from the main study, your RBR and MAGIC biorepository 
samples will continue to be stored and used for research unless you specifically ask that 
they be destroyed.   


GDC-8264—Genentech, Inc. 
 
Master ICF for Study GA43861, Version 4, 14 June 2023 
Page 20 of 20 
 
Signature 
I willingly consent to allow my samples to be stored in the RBR and the MAGIC 
biorepository and used for the research described above. 
 
Participant name (print) 
 
 
 
If applicable – Name of participant’s legally authorized 
representative (print) 
 
Relationship to participant 
 
Participant signature or signature of participant’s legally 
authorized representative 
 
Date 
I, the undersigned, have fully explained this informed consent to the participant 
named above and/or the participant’s legally authorized representative. 
 
Name of person conducting informed consent discussion (print) 
 
 
 
Signature of person conducting informed consent discussion 
 
Date 
 
Witness name a (print) 
 
 
 
Witness signature a 
 
Date 
 
 
a If the investigator or Institutional Review Board or Ethics Committee deems a witness signature is 
necessary (as per ICH Guidelines, Good Clinical Practice [E6], 4.8.9, or local regulations).