CAMPFIRE: Children's and Young Adult Master Protocol for Innovative Pediatric Research
Phase: PHASE2
Conditions: Neoplasms, Child, Adolescent
Sponsor: Eli Lilly and Company

 
 
Master protocol: J1S-MC-JAAA (b) 
 
 
CAMPFIRE: Children's and Young Adult Master Protocol for Innovative 
Pediatric Research   
 
 
Approval Date: 26-Sep-2019 
 

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Protocol J1S-MC-JAAA(b)
CAMPFIRE: Children’s and 
Young Adult Master Protocol for Innovative 
Pediatric Research
Confidential Information
The information contained in this protocol is confidential and is intended for the use of clinical investigators.  It 
is the property of Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to 
persons not involved in the clinical investigation of LY900023, unless such persons are bound by a 
confidentiality agreement with Eli Lilly and Company or its subsidiaries. 
Note to Regulatory Authorities:  This document may contain protected personal data and/or commercially 
confidential information exempt from public disclosure.  Eli Lilly and Company requests consultation 
regarding release/redaction prior to any public release.  In the United States, this document is subject to 
Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or otherwise disseminated 
without the written approval of Eli Lilly and Company or its subsidiaries.
LY900023
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 7 Dec 2018
Amendment (a) Electronically Signed and Approved by Lilly:  2 Aug 2019
Amendment (b) Electronically Signed and Approved on date provided below.
Approval Date: 26-Sep-2019 GMT

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Table of Contents
Section
Page
Protocol J1S-MC-JAAA(a) CAMPFIRE:  Children’s and 
Young Adult Master Protocol for Innovative Pediatric Research.........................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .........................................................................................................9
3.
Introduction ......................................................................................................................10
3.1.
Study Rationale............................................................................................................10
3.2.
Background..................................................................................................................10
3.3.
Benefit/Risk Assessment..............................................................................................11
4.
Objectives and Endpoints..................................................................................................12
5.
Study Design.....................................................................................................................13
5.1.
Overall Design .............................................................................................................13
5.2.
Number of Patients.......................................................................................................13
5.3.
End of Study Definition ...............................................................................................14
5.4.
Scientific Rationale for Study Design...........................................................................14
5.5.
Justification for Dose ...................................................................................................14
6.
Study Population...............................................................................................................15
6.1.
Inclusion Criteria..........................................................................................................15
6.2.
Exclusion Criteria ........................................................................................................19
6.3.
Lifestyle Restrictions....................................................................................................19
6.4.
Screen Failures.............................................................................................................20
7.
Treatments........................................................................................................................21
7.1.
Treatments Administered .............................................................................................21
7.1.1.
Packaging and Labelling ......................................................................................21
7.2.
Method of Treatment Assignment ................................................................................21
7.3.
Blinding .......................................................................................................................22
7.4.
Dose Modification........................................................................................................22
7.5.
Preparation/Handling/Storage/Accountability...............................................................22
7.6.
Treatment Compliance .................................................................................................22
7.7.
Concomitant Therapy...................................................................................................23
7.8.
Treatment after the End of the Study............................................................................23
7.8.1.
Treatment after Completion of Investigation ........................................................24
7.8.1.1.
Continued Access...........................................................................................24
8.
Discontinuation Criteria ....................................................................................................26

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8.1.
Discontinuation from Study Treatment.........................................................................26
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................27
8.2.
Discontinuation from the Study....................................................................................27
8.3.
Lost to Follow-Up........................................................................................................27
9.
Study Assessments and Procedures ...................................................................................28
9.1.
Efficacy Assessments...................................................................................................28
9.1.1.
Appropriateness of Assessments ..........................................................................28
9.1.2.
Definitions of Efficacy Measures .........................................................................28
9.2.
Adverse Events ............................................................................................................29
9.2.1.
Serious Adverse Events........................................................................................30
9.2.2.
Suspected Unexpected Serious Adverse Reactions ...............................................31
9.2.3.
Complaint Handling.............................................................................................31
9.3.
Treatment of Overdose.................................................................................................31
9.4.
Safety...........................................................................................................................31
9.4.1.
Safety Measures...................................................................................................31
9.4.2.
Safety Monitoring ................................................................................................32
9.5.
Pharmacokinetics .........................................................................................................32
9.6.
Pharmacodynamics ......................................................................................................32
9.7.
Pharmacogenomics ......................................................................................................33
9.7.1.
Whole Blood Sample for Pharmacogenetic Research ...........................................33
9.8.
Biomarkers...................................................................................................................33
9.8.1.
Tissue Samples for Biomarker Research...............................................................34
9.8.2.
Other Samples for Biomarker Research................................................................34
9.9.
Health Economics ........................................................................................................35
10.
Statistical Considerations ..................................................................................................36
10.1. Sample Size Determination ..........................................................................................36
10.2. Populations for Analyses..............................................................................................36
10.3. Statistical Analyses ......................................................................................................36
10.3.1.
Safety Analyses....................................................................................................36
10.3.2.
Other Analyses.....................................................................................................37
10.3.2.1.
Patient Disposition..........................................................................................37
10.3.2.2.
Patient Characteristics ....................................................................................37
10.3.2.3.
Treatment Compliance....................................................................................37
10.3.2.4.
Extent of Exposure .........................................................................................37
10.3.2.5.
Concomitant Therapy .....................................................................................38
10.3.2.6.
Post-Study-Treatment Therapy.......................................................................38
10.3.2.7.
Pharmacokinetic/Pharmacodynamic Analyses ................................................38
10.3.2.8.
Biomarker Analysis ........................................................................................38

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10.3.2.9.
Healthcare Resource Utilization......................................................................38
10.3.3.
Subgroup Analyses ..............................................................................................38
10.3.4.
Interim Analyses..................................................................................................38
11.
References ........................................................................................................................39

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List of Tables
Table
Page
Table 2.1.
Summary of Content of the CAMPFIRE Master Protocol and 
Protocol Addenda.....................................................................................9

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List of Figures
Figure
Page
Figure 7.1.
Continued-access diagram for each investigation....................................24

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................40
Appendix 2.
Clinical Laboratory Tests........................................................................44
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................45
Appendix 4.
Creatinine Clearance Formula.................................................................49
Appendix 5.
Protocol Amendment J1S-MC-JAAA(a) Summary CAMPFIRE:  
Children’s and Young Adult Master Protocol for Innovative 
Pediatric Research ..................................................................................50

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1.
Synopsis
Protocol Title:
CAMPFIRE: Children’s and Young Adult Master Protocol for Innovative Pediatric Research
Rationale:
Study J1S-MC-JAAA (JAAA; hereinafter referred to as the CAMPFIRE Master Protocol) is a 
platform to accelerate the development of novel treatments for pediatric and young adult patients 
with cancer.  This platform uses innovative designs and an overarching infrastructure to harness 
the benefits of shared data and operational efficiencies.  
Objectives and Endpoints:
The main purpose of the platform is to create a framework to evaluate the efficacy and safety of 
Eli Lilly and Company (Lilly) investigational drugs alone or in combination with various 
available treatments or other investigational agents in specified populations of pediatric and 
young adult patients as hypotheses emerge.  The clinical research objectives and endpoints for 
specific investigations are detailed in each individual addendum. 
Overall Design:
Each investigation consists of the:
1. master document, which defines the platform concept and overall structure, as well as 
the common elements across all investigations and
2. individual addenda, which define drug/disease-specific hypotheses and 
investigational requirements.
Each addendum will describe the:

study population, 

rationale for evaluating the proposed treatment, and 

endpoints and analyses specific to each investigation.  
Findings will be reported in addendum-specific study report(s).  Once all patients for a particular 
investigation have met study completion (as defined in that addendum), that addendum will be 
closed. The master protocol end of study will occur when all addenda have individually 
completed and no new investigations are planned.  
Number of Patients:
Planned enrollment is provided in each specific protocol addendum.
Treatment Arms and Duration:
Administration of the agent(s) being evaluated is described in the specific protocol addendum.

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2.
Schedule of Activities
This master document defines the platform concept and overall structure, as well as common 
elements across all investigations.  Individual addenda will define study-specific hypotheses and
requirements for the study treatment/diseases being evaluated in the investigation.  Table 2.1
describes the elements found in the master protocol and addenda.
Table 2.1.
Summary of Content of the CAMPFIRE Master Protocol and 
Protocol Addenda
CAMPFIRE Master Protocol
Addenda

Synopsis

Introduction, including the master protocol
rationale, and background information about unmet 
need in pediatric oncology

General inclusion and exclusion criteria

General Discontinuation criteria

Reporting of AEs, SAEs, and SUSARs

General assessment of efficacy, PK, genetics, and 
biomarkers

Data management methods

Study governance, regulatory requirements, and 
ethics, including informed consent/assent

List of references cited in the master protocol

List of abbreviations and definitions used in the 
master protocol

Investigation-specific synopsis

Background information about the investigation 
treatment(s) under evaluation, including the 
rationale for selection of tumor type(s) under 
investigation, the unmet medical need, and any 
accompanying investigation treatment(s)

Investigation-specific objectives, endpoints, study 
design, and statistical plan

Investigation-specific inclusion and exclusion 
criteria

Study drug administration and dosage modifications 
for agents under evaluation

Safety lead-in criteria and associated terms (if 
applicable)

Investigation-specific discontinuation criteria 

AEs of special interest

Safety information specific to investigation 
treatment(s) and/or indication(s) under 
evaluation (if applicable)

Schedule of activities and schedule for collection of 
samples for PK, genetics, and biomarker research

Investigation-specific data management methods

List of restricted and prohibited concomitant 
therapy

List of references cited in the addendum

List of abbreviations and definitions used in the 
addendum
Abbreviations:  AE = adverse event; PK = pharmacokinetics; SAE = serious adverse event; SUSAR = suspected, 
unexpected serious adverse reaction.

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3.
Introduction
3.1.
Study Rationale
Study J1S-MC-JAAA (JAAA; hereafter referred to as the CAMPFIRE Master Protocol) is a 
platform to accelerate the development of novel treatments for pediatric and young adult patients 
with cancer through the use of innovative designs and an overarching infrastructure to harness 
the benefits of operational efficiencies and shared data.  It is designed to be a framework that 
enables the seamless evaluation of efficacy and safety of Eli Lilly and Company (Lilly)
investigational drugs, alone or in combination with various treatments as hypotheses emerge.
3.2.
Background
Pediatric cancer drug development can be difficult due to scientific, ethical, and operational 
challenges.  However, there is a critical unmet need for more effective, tolerable, and safe new 
treatments in order to improve the cure rate, diminish the acute toxic effects associated with 
existing treatments, and minimize the long-term risks for survivors (Vassal et al. 2013).  
A master protocol is an overarching platform that enables concurrent investigation of unique 
study drug(s) in indication-specific mechanism-of-action driven hypotheses with distinct 
endpoints through individual addenda, while standardizing structure and operational components
under one master construct.  This standardization helps facilitate review, ease the burdens of site 
participation and study execution, speed access, and optimize resources through elimination of 
redundancy. The flexibility of the standard overarching structure with individual addenda allows 
for rapid implementation or closing of individual addenda without jeopardizing the other 
ongoing addenda being investigated.  Furthermore, by utilizing innovative designs and adaptive 
analytics, there is an opportunity to maximize learnings via integration of relevant evidence in 
specified related addenda.  This allows enrollment of a reduced number of patients, while 
randomizing a greater portion of patients to a novel treatment by conserving control arms and 
historical data.
Further advantages of using master protocols include, but are not limited to: 

a central governance/review structure to streamline oversite and ensure safety and 
consistency across the entire platform,

standardized systems and processes for operational efficiencies and to speed 
implementation,

the potential standardization of study template/language across addenda and informed 
consent forms (ICFs) to ensure consistency and familiarity for ease of review and 
execution, and for improved compliance,

a streamlined enrollment procedure that uses the same sites for patient enrollment for 
increased screening success rates and enhanced study participation, 

a centralized database and informatics infrastructure to facilitate data collection and 
sharing, enable dynamic decision making, and support additional research,

the use of Bayesian decision rules and adaptive techniques for randomization and/or 
analysis,

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
the ability to leverage a common control arm across investigations for a specific disease, 
and the capacity to update the control over time as standards of care evolve,  

the flexibility to add or remove investigations based on early evidence of efficacy and 
safety, and 

the faster and more reliable acquisition of early-stage data for informing 
pivotal/confirmatory studies.  
Given the high unmet medical need for children and young adults with cancer, Lilly anticipates 
that a master protocol will provide a more efficient model for assessment of efficacy and safety 
of novel therapies, whether monotherapy or in combination, for pediatric and young adult 
patients with cancer.  In addition, working with a consistent set of sites across investigations and 
over time allows for acquired experience to help ensure the safety of patients and improve the 
quality of study data collected.  Together, these attributes of a pediatric master protocol are 
anticipated to advance research, help speed decision making and accelerate development of the 
most promising agents and combinations.
3.3.
Benefit/Risk Assessment
The direct benefit and risk of experimental treatment regimens are inherent to the compounds 
making up those regimens.  As a result, this component of the benefit risk profile will be 
particular to each investigation and will be described in the addendum covering it.
Elements of benefit and risk to individual patients that are exclusive to the Master Protocol itself 
are limited to design and operational aspects of a platform trial.  By using shared control cohorts 
where possible and appropriately incorporating additional information across cohorts, platform 
trials reduce the number of patients needed to have adequate power to perform multiple 
investigations and potentially decreases the duration of the investigations.  In particular, the 
number of patients exposed to control arms of potentially less effective therapies is reduced.
On the other hand, the platform trial can introduce complexity for investigators and create the 
risk of reduced adherence to protocol procedures if consistency between investigations is not 
maintained.  Common schedules of activities, safety assessments and inclusion/exclusion criteria 
across investigations are specified in the Master Protocol to minimize this risk along with 
training and appropriate safety monitoring for each investigation.   
In conclusion, by providing a clinical trial design that maximizes the available information 
across multiple investigations and by outlining consistent patient specifications and trial 
elements across these investigations, this platform trial has a positive benefit risk assessment.
More information about the known and expected benefits, risks, serious adverse events (SAEs), 
and reasonably anticipated adverse events (AEs) of the investigational study drug(s) used in the 
individual addendum are to be found in their respective Investigator’s Brochures (IBs).
More detailed information about the known and expected benefits and risks of the combination 
agents may be found in the following:  Patient Information Leaflet, Patient Package Insert, or 
Summary of Product Characteristics.

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4.
Objectives and Endpoints
The main purpose of the CAMPFIRE Master Protocol is to create a framework to seamlessly 
evaluate the efficacy and safety of each investigational agent or study drug regimen eligible for 
development in specified populations of pediatric and young adult patients. Refer to each 
addendum for specific investigation objectives and endpoints.

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5.
Study Design
5.1.
Overall Design
Each investigation consists of:
1. master document, which defines the platform concept and overall structure, as well as the 
common elements across all investigations, 
2. individual addenda, which define drug/disease-specific hypotheses and investigational 
requirements.
Each addendum will describe the:

study population, 

rationale for evaluating the proposed treatment, and 

endpoints and analyses specific to each investigation.  
Findings will be reported in investigation-specific study report(s).  Once all patients for a 
particular investigation have met study completion (as defined in that addendum), that 
investigation will be closed and the end of study declared for that specific investigation once all 
patients are off study for the particular investigation, including the continued-access 
phase (Section 7.8). An investigation-specific study report will be produced within one year of 
the end of study declared for that specific investigation. The CAMPFIRE Master Protocol end of 
study will occur when all addenda have individually been completed and no new investigations 
are planned.  
Investigations of common scientific interest may leverage information across addenda to 
maximize learning and minimize redundancy.  Examples of this include comparator control arms
of common interest. When this involves concurrent investigations within the same patient 
population, patients will be randomized among the treatment arms within corresponding
addenda (see Section 7.2).
Statistical analyses relevant to the specific hypothesis will be found in the relevant addendum 
and the more detailed addendum statistical analysis plans (SAPs).  See Sections 7.2 and 10 for 
more information. 
New addenda will be implemented as hypotheses emerge and new agents become available, 
compelling new investigations.  At any given time, multiple investigations may be open.  Once 
all patients for a particular addendum have met the end of study for that addendum, it will be 
closed and an appropriate clinical study report will be created for the investigation (Section 5.3). 
5.2.
Number of Patients
Planned enrollment will be limited to those needed for the addendum-specified analysis and is
provided in Section 3.5.2 of each addendum.
CCI

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5.3.
End of Study Definition
The CAMPFIRE Master Protocol will reach the end of study when all addenda have individually 
completed and no new addenda are planned.  
The end of the study for each investigation is the date of the last visit or last scheduled procedure 
shown in the Schedule of Activities (Section 3.2 in each addendum) for the last patient.
Refer to Section 3.5.3 in each addendum for the investigation-specific end of study definition.
5.4.
Scientific Rationale for Study Design
The scientific rationale regarding the investigation-specific study design is provided in each 
protocol addendum.
5.5.
Justification for Dose
Refer to each investigation-specific addendum for information about the dose(s) selected for 
each study arm in that addendum.

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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria of 
the CAMPFIRE Master Protocol and the additional criteria for enrollment provided in the 
protocol addendum to which they are enrolling.  Any investigation-specific exceptions to the 
following criteria in a specific investigation will be described in that addendum; Sections 3.5.1.1 
and 3.5.2.1.
[1]
have either measurable or evaluable disease using standard techniques by the 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) 
(Eisenhauer et al. 2009). 
[2]
The patient, or patient’s parent/guardian, has given written informed 
consent (and assent, as applicable) and authorization for release of 
health/information for research prior to any study-specific procedures being 
performed (refer to Appendix 2, Study Governance, Regulatory, and Ethical 
Considerations).
[3]
The patient has a Lansky (<16 years of age; Lansky et al. 1987) or 
Karnofsky (≥16 years of age; Karnofsky et al. 1948) performance score of at 
least 50.
[4]
Patients must have discontinued all previous treatments for cancer or 
investigational agents ≥7 days after the last dose or as shown below, and must 
have recovered from the acute effects to ≤Grade 2 for alopecia and decreased 
tendon reflex and to ≤Grade 1 for all other effects at the time of enrollment, 
unless otherwise noted.  For agents with known AEs occurring beyond the 
required wait period outlined in the table, this period must be extended until 
after the time during which the AE is known to occur. Consult with the Lilly 
CRS/CRP for the appropriate length of time prior to the first dose of study 
treatment on additional therapies not mentioned.
Previous Treatment
Length of Time Prior to First Dose of Study 
Treatment
Cytotoxic and myelosuppressive chemotherapy
≥14 days after the last dose of cytotoxic or 
myelosuppressive chemotherapy (or ≥42 days if 
prior nitrosourea)
Hematopoietic growth factors
≥14 days after the last dose of a long-acting 
growth factor (for example, pegfilgrastim) or
≥48 hours for short-acting growth factor
Cellular therapy
≥42 days after the completion of any type of 
cellular therapy (eg modified T cells, NK cells, 
dendritic cells, etc.) agent
Interleukins, interferons, and cytokines (other than 
≥21 days after the completion of interleukins, 

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Previous Treatment
Length of Time Prior to First Dose of Study 
Treatment
hematopoietic growth factors)
interferon, or cytokines (other than hematopoietic 
growth factors)
Antibody therapy
≥21 days after the last infusion of antibody 
therapy
Radiotherapy
≥ 14 days since local palliative radiation therapy 
(RT) (small port); craniospinal XRT, or 50% or 
greater pelvic radiation; ≥ 42 days for other 
substantial radiation (such as 
metaiodobenzylguanidine therapy)
Radiopharmaceutical therapy (eg, radiolabeled 
antibody, 131I-MIBG)
≥42 days after systemically administered 
radiopharmaceutical therapy
Stem cell infusion without TBI
≥84 days must have elapsed after auto-transplant 
or stem cell infusion
Corticosteroids
≥14 days for patients who have received a course 
of systemic corticosteroids (≥5 days) to modify 
immune AEs related to prior therapy. 
Note: Patients who are on chronic replacement 
dose for endocrine disorders or are on a stable 
or decreasing dose for indications other than 
treating the underlying cancer, may still be 
eligible (consult Lilly CRP/CRS)
Live vaccines
≥28 days after last live vaccine
[5]
The patient has adequate hematologic and organ function ≤1 week (7 days) 
prior to first dose of study drug:

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System
Laboratory Value
Hematologic
ANC
1000/µL
G-CSF permitted up to 48 hours prior.
Patients with documented history of benign ethnic 
neutropenia or other conditions could be considered with a
lower ANC after discussion with and approval from the 
Lilly CRP/CRS
Platelets
75,000/mm3
Platelet transfusion permitted up to 72 hours prior.
Hemoglobin
8 g/dL (≥80 g/L)
Transfusions to increase the patient’s hemoglobin level to at 
least 8 g/dL are permitted; however, study treatment must 
not begin until 7 days after the transfusion. and CBC criteria 
for eligibility are confirmed within 24 hr of C1D1
Hepatic
Total bilirubin
1.5×ULN
Except patients with document history of Gilbert Syndrome 
who must have a total bilirubin level of <3.0×ULN
ALT and AST
2.5×ULN OR
5.0×ULN if the liver has tumor involvement
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; CBC = complete blood count; ULN = upper limit of normal.

Creatinine clearance or radioscope glomerular filtration rate (GFR)
≥60 mL/min/m2 (Appendix 4) OR

Serum creatinine meeting the following parameters: 
o
for patients ≥18 years of age serum creatinine ≤1.5×upper limit of 
normal (ULN);
o
for patients <18 years of age, serum creatinine based on age/gender 
as follows:
Age
Maximum Serum
Creatinine (mg/dL)
Male
Female
1 to <2 years
0.6
0.6
2 to <6 years
0.8
0.8
6 to <10 years
1.0
1.0
10 to <13 years
1.2
1.2
13 to <16 years
1.5
1.4
16 to <18 years
1.7
1.4
The threshold creatinine values in this table were derived from the Schwartz formula for 
estimating glomerular filtration rate (Appendix 4).

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[6]
Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 7 days prior to Cycle 1 Day 1.
[7]
Both female and male patients of childbearing potential must agree to use 
highly effective contraceptive precautions during the trial and for at least
3 months following the last dose of study drug, or longer, if appropriate for 
other study drugs according to their label in order to prevent pregnancy.  
Females of childbearing potential (FOCBP) and males who are abstinent (if 
this is complete abstinence, as their preferred and usual lifestyle) or in a 
same-sex relationship (as part of their preferred and usual lifestyle) must agree 
to either remain abstinent or stay in a same-sex relationship without sexual 
relationships with someone of the opposite sex. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods), declaration of 
abstinence just for the duration of a trial, and withdrawal are not acceptable 
methods of contraception.
Females: FOCBP participating must test negative for pregnancy prior to 
initiation of treatment as indicated by a negative urine or serum pregnancy test 
at the screening visit.  Two forms of effective contraception, where at least 
one form is highly effective (less than 1% failure rate; includes combination 
oral contraceptives, implanted contraceptives, or intrauterine devices) must be 
used. Effective contraception (such as male or female condoms with 
spermicide, diaphragms with spermicide, or cervical sponges) may be used as 
the second therapy. Barrier protection methods without concomitant use of a 
spermicide are not a reliable or acceptable method. Thus, each barrier method 
must include use of a spermicide (i.e., condom with spermicide, diaphragm 
with spermicide, or female condom with spermicide). It should be noted that 
the use of male and female condoms as a double barrier method is not 
considered acceptable due to the high failure rate when these methods are 
combined.
Males: Males, regardless of their fertility status, with nonpregnant FOCBP
partners must agree to use condoms as well as one additional highly effective 
method of contraception (less than 1% failure rate; includes combination oral 
contraceptives, implanted contraceptives, or intrauterine devices) for the 
duration of the study and up to 3 months following the last dose of study drug, 
or longer, if appropriate for other study drugs according to their label in order 
to prevent pregnancy.
Barrier protection methods without concomitant use of a spermicide are not an 
effective or acceptable method of contraception. Thus, each barrier method 
must include use of a spermicide. It should be noted, however, that the use of 
male and female condoms as a double barrier method is not considered 
acceptable due to the high failure rate when these barrier methods are 
combined.  Males with pregnant partners should use condoms during 
intercourse for the duration of the study and for at least 3 months after the last 

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dose of study drug, or longer, if appropriate for any study drug according to 
the label.
[34] Pediatric and young adult patients will be enrolled, where the specific age 
requirement for each indication will be specified in the protocol addenda
6.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria.  Additional 
exclusion criteria for each study arm are provided in the applicable study arm-specific protocol 
addendum.  Exceptions, where applicable, to the following criteria will be defined in each 
specific addendum.
[8]
Patients with severe and/or uncontrolled concurrent medical disease or 
psychiatric illness/social situation that in the opinion of the investigator could 
cause unacceptable safety risks or compromise compliance with the protocol. 
[9]
Patients who have active infections requiring therapy.

Patients with an active fungal, bacterial, and/or known severe viral infection 
including, but not limited to, human immunodeficiency virus (HIV) or 
viral (A, B, or C) hepatitis (screening is not required).
[10] Patients who have had allogeneic bone marrow or solid organ transplant are 
excluded.
[11] Surgery: Patients who have had, or are planning to have, the following invasive 
procedures are not eligible:

Major surgical procedure, laparoscopic procedure, or significant traumatic injury 
within 28 days prior to enrollment. 
o
Central line placement or subcutaneous port placement is not considered 
major surgery. 
o
Core biopsy, fine needle aspirate, and bone marrow biopsy/aspirate are not 
considered major surgeries.  Refer to the specific addenda to determine if 
results are required prior to enrollment. 

Surgical or other wounds must be adequately healed prior to enrollment.
[12] Female patients who are pregnant or breastfeeding are excluded.
[13] Patients who are currently enrolled in a clinical study involving an 
investigational product, or any other type of medical research judged not to be 
scientifically or medically compatible with this study.
6.3.
Lifestyle Restrictions
This section is not applicable unless otherwise stated in the specific protocol addendum.

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6.4.
Screen Failures
Individuals who do not meet the criteria for participation in the individual investigation (screen 
failure) may be re-screened only after discussion with and with permission from the Lilly 
CRP/CRS or designee.  Individuals who do not meet criteria for participation in an individual 
investigation may be considered for another investigation within the CAMPFIRE Master 
Protocol. 
Screening laboratory tests may not be repeated more than twice in order to meet eligibility 
during the screening period.
Repeating laboratory tests during the screening period, after a patient has not met requisite 
criteria, does not constitute re-screening.

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7.
Treatments
7.1.
Treatments Administered
Administration of the study drug(s) is described in the applicable protocol addendum.
A delay of a dose due to holiday, weekend, bad weather, or other unforeseen circumstances will 
be permitted as specified in each addendum and not counted as a protocol deviation.  However, 
clinical assessment time frames relative to drug administration, as shown in the addendum
schedule of activities, must be maintained.  
Patients may continue to receive study treatment until a criterion for discontinuation is met.  See 
Section 7.8.1 for information about continued access to study treatment after the primary 
analysis for a given study arm.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the drug(s) and planned duration of each individual’s 
treatment to the patient/study site personnel/legal representative

verifying that instructions are followed properly

maintaining accurate records of study treatment dispensing and collection

at the end of the study returning all unused medication to Lilly, or its designee, 
unless Lilly and sites have agreed all unused medication is to be destroyed by the 
site, as allowed by local law.
7.1.1. Packaging and Labelling
Typically, study drugs will be provided by Lilly, but commercially available supply may be 
site-sourced where local regulations permit or for cases of regional restrictions or supply 
limitations.
Clinical study materials will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
The CAMPFIRE Master Protocol and its addenda may consist of both single and multi-arm 
investigations.  Assignment to treatment arms in an investigation will be determined by a 
computer-generated random sequence using an interactive web response system (IWRS).  
Randomization ratios will be described within addenda when they contain multiple arms.  When 
patients are eligible for more than one investigation (ie, more than one investigation is ongoing 
for a given patient population) they will be randomly assigned across investigations to one of the 
open treatment arms.  If there is a common treatment arm among addenda, the randomization 
ratios between that common arm and other treatments within each addenda will determine the 
overall ratios across addenda.  For example, Addendum 1 has a randomization ratio of 2:1 
experimental regimen A to control and Addendum 2 has a randomization ratio of 3:1 
experimental regimen B to control; the overall randomization is 2:3:1 for experimental regimen 
A to experimental regimen B to control.  When arms are not shared across addenda, each new 

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addendum will specify the relative weighting between its arms and those of the previously 
opened addenda.
Some addenda may incorporate adaptive treatment randomization methodology, in which case 
the adaptation rules will be described in the addendum.  Allocation to treatment across addenda 
will follow the rules described above for fixed randomization designs. 
Participating in one investigation does not preclude the patient from enrolling in another 
investigation within the CAMPFIRE Master Protocol at a subsequent time as long as eligibility 
criteria are met. Individuals who do not meet criteria for participation in an individual 
investigation may be considered for another addendum within the CAMPFIRE Master Protocol
for which they are eligible (see Section 6.4).
7.3.
Blinding
Blinding will be determined for the specific investigation in each addendum. 
7.4.
Dose Modification
Refer to each addendum for specific dose modification instructions.
7.5.
Preparation/Handling/Storage/Accountability
Investigators should consult the study drug information provided in the Pharmacy Manual or 
label for the specific addendum for administration information (including warnings, precautions, 
contraindications, adverse reactions, and dose modifications).
7.6.
Treatment Compliance
For an addendum in which study drug is administered by site personnel:
Study medication that is administered intravenously will be administered only at the 
investigational sites by the authorized study site personnel.  As a result, treatment compliance is 
ensured.
For an addendum in which study drug is not administered by site personnel:
Patient compliance with study medication that is not administered by site personnel will be 
assessed as described in the specific addendum.  Deviations from the prescribed dosage regimen 
should be recorded in the patient’s record.
A patient will be considered significantly noncompliant if he or she is judged by the investigator 
to have intentionally or repeatedly taken more or less than the prescribed amount of medication.  
The threshold required to maintain status as compliant will be at least 80% unless otherwise 
specified in in Section 3.6.5 of the specifically enrolled addendum.
Potential discontinuation of a patient due to study drug noncompliance will be discussed between 
the investigator and the Lilly CRP/CRS before the final determination is made to discontinue the 
patient from the study.

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7.7.
Concomitant Therapy
All concomitant medications should be recorded throughout the patient’s participation in the 
study.
Concomitant medications and supportive care therapies must also be documented at the time of 
discontinuation and at the short-term follow-up visit.
Appropriate documentation for all forms of premedications, concomitant medications, and
supportive care (for example, medications such as sedatives, antibiotics, analgesics, 
antihistamines, corticosteroids, erythropoietin; procedures such as paracentesis, thoracentesis; or 
blood products such as blood cells, platelets, or fresh frozen plasma transfusions) must be 
captured on the electronic case report form (eCRF).
No other chemotherapy, investigational medications, other anticancer therapy, immunotherapy, 
hormonal cancer therapy, palliative radiation, or palliative surgery for cancer will be permitted 
while patients are on study treatment.  Radiation and surgery for cancer (other than palliative) 
may be allowed after discussion with the Lilly CRP.  Exceptions will be defined in each 
addendum.
A list of restricted and prohibited concomitant therapy is provided in the applicable specific 
addendum, Section 3.7.6.
7.8.
Treatment after the End of the Study
The CAMPFIRE Master Protocol will reach the end of study when all addenda have been 
individually completed and no new addenda are planned.  The end of the study for each 
investigation is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 3.2 in each addendum) for the last patient. Investigators will continue to 
follow the Schedule of Activities provided in the applicable protocol addendum until notified by 
Lilly that end of study for that investigation has occurred.
Refer to Figure 7.1 for a depiction of these concepts per investigation:  investigation completion, 
the continued-access period, and end of study.

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Figure 7.1.
Continued-access diagram for each investigation.
7.8.1. Treatment after Completion of Investigation
The completion of the investigation occurs following the final analysis, as defined in the 
applicable addenda and when determined by Lilly.  Investigators will continue to follow the 
investigation-specific Schedule of Activities related to the study treatment period as outlined in 
the addenda for all patients until notified by Lilly that the completion of investigation has 
occurred. After that notification from Lilly, the investigation will enter the continued access 
period.
Several investigations (e.g. up to a total of approximately 10 investigations) will be added to the 
master protocol construct over approximately the next 5 years of the entire master protocol 
duration. These sub-protocols will be submitted and reviewed as independent clinical trial 
applications and will each include an estimation of the study duration.
7.8.1.1.
Continued Access
Follow-up will be done as long as the patient is on treatment and participates in the trial.
After the final analysis of a given investigation-specific addendum has been conducted and Lilly 
has declared that the continued access period has begun, patients on that addendum who are still 
on study treatment may continue to receive study treatment if they are experiencing clinical 
benefit and no undue risks.  Investigators will continue to follow the continued access Schedule 

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of Activities provided in the applicable protocol addendum for patients who remain on study 
treatment or in short-term follow-up during the continued access period.
The patient’s continued access to study treatment will end when a criterion for discontinuation is 
met (Section 8).  Continued access follow-up will begin when the patient and the investigator 
agree to discontinue study treatment, and lasts approximately 30 (±7) days.  Follow-up 
procedures will be performed as in the continued access Schedule of Activities shown in the 
applicable protocol addendum.
For patients who are in short-term follow-up during the study treatment period (as defined in the 
investigation-specific addendum) when the continued-access period begins, they will continue in 
short-term follow-up until the 30-day short-term follow-up visit is completed.  Long-term 
follow-up during the study treatment period (as defined in the investigation-specific addendum)
does not apply during the continued access period.  Patients who are in long-term follow-up 
when the continued access period begins will be discontinued from long-term follow-up.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Patients will be discontinued from study treatment in the following circumstances:

The patient is enrolled in any other clinical study involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study.

The patient becomes pregnant during the study.

Investigator/Physician decision
o
the investigator/physician decides that the patient should be discontinued from the 
study or study drug(s)
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study drug(s) occurs prior to introduction of the other 
agent

Patient, parent, or legal guardian decision
o
the patient or the patient’s designee (for example, parents or legal guardian) 
requests to be discontinued from the study or study drug

Sponsor decision
o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and GCP

The patient has radiographic progressive disease or significant symptomatic disease 
deterioration characterized as progression of disease, in the opinion of investigator, in the 
absence of radiographic evidence of PD.  In the event a patient is discontinued from 
treatment due to symptomatic deterioration, every effort should be made to document 
disease progression, unless it is not medically appropriate.

The patient experiences unacceptable toxicity (for example, a persistent moderate toxicity 
that is intolerable to the patient).

The patient is noncompliant with study procedures and/or treatment (Section 7.6).

The patient has had maximum dose reductions allowed per protocol and experiences an 
AE that would cause an additional dose reduction.

Additional investigation-specific discontinuation criteria as shown in Section 3.8 of the 
addenda.
The reason and date of discontinuation will be collected for all patients.  Patients who are 
discontinued from study treatment will have follow-up procedures performed as shown in the 
addendum-specific Schedule of Activities (Section 3.2).

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8.1.1. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly. If Lilly or the investigator identifies a 
patient who did not meet enrollment criteria and was inadvertently enrolled, a discussion must 
occur between the Lilly CRP/CRS and the investigator to determine if the patient may continue 
in the study, where local laws allow.  If both agree, it is medically appropriate to continue, the 
investigator must obtain documented approval from the Lilly CRP/CRS to allow the 
inadvertently enrolled patient to continue in the study with or without study treatment.  Patients 
who are discontinued from study treatment will have follow-up procedures performed as shown 
in the addendum-specific Schedule of Activities (Section 3.2).
8.2.
Discontinuation from the Study
Patients will be discontinued from the specific addendum in the following circumstances:

participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP

the patient becomes pregnant during the specific addendum.  See Section 9.2.1
regarding regulatory reporting requirements on fetal outcome

the investigator decides that the patient should be discontinued from the study

the patient requests to be discontinued from the specific addendum

the patient’s designee (legal representative) requests that the patient be 
discontinued from the specific addendum.
Patients who are discontinued from the specific addendum will have follow-up procedures 
performed as shown in the addendum-specific Schedule of Activities (Section 3.2).
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Study site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow-up.

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9.
Study Assessments and Procedures
Refer to the applicable protocol addendum for the schedule of activities, the schedule for 
collection of samples, and the list of laboratory tests.
Unless otherwise stated in the following subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days after receipt of confirmed test results.  Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards.
9.1.
Efficacy Assessments
Tumor assessments will be performed for each patient at the times shown in the schedule of 
activities and methods provided in the applicable protocol addendum.  
Since radiographic imaging scans may be needed for an independent review or future regulatory 
purposes, copies of all scans will be collected throughout the study and stored centrally by a 
coordinating vendor designated by Lilly.
9.1.1. Appropriateness of Assessments
The measures used to assess efficacy and safety in this study are consistent with those most 
commonly used for the disease entities and therapeutic classes under investigation.  See addenda 
for more detail.
9.1.2. Definitions of Efficacy Measures
Evaluation of efficacy measures may be primary, secondary, or exploratory endpoints of the
CAMPFIRE Master Protocol’s addenda.  Included here are a list of common efficacy measures 
with standard definitions and general guidance for their use if adopted by an addendum.
Overall survival (OS) is defined as the time from enrollment until death from any cause.  If the 
patient is alive or lost to follow-up at the time of data analysis, OS data will be censored on the 
last date the patient is known to be alive.  Where applicable, the comparison of OS between 
treatment arms, as well as the corresponding hazard ratio (HR) estimator, will be described in 
each addendum.  Overall survival curves, the median and survival rates at various time points 
with 95% CI, for each treatment arm will be estimated using the Kaplan-Meier method (Kaplan 
and Meier 1958).  Sensitivity analyses for OS will be described in the addendum’s SAP.
Progression-free survival (PFS) is defined as the time from enrollment until the first occurrence 
of documented disease progression per addenda-specified criteria, or death from any cause in the 
absence of PD. Patients known to be alive and without disease progression will be censored at 
the time of the last adequate tumor assessment.
Progression-free survival 2 (PFS2) is defined as the time from enrollment to disease 
progression (objective radiological or symptomatic progression) on the next line of treatment, or 
death from any cause in the absence of observed disease progression.  If the patient is alive at the 

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cutoff for analysis, and disease progression after the first post-study treatment regimen has not 
been observed, PFS2 data will be censored on the last date the patient was known to be alive.
Objective response rate (ORR) is defined as the number of patients who achieve a best overall 
response of complete response (CR) or partial response (PR) divided by the total number of 
patients randomized to the corresponding treatment arm (intent-to-treat [ITT] population). 
Duration of response (DoR) is defined as the time from the date that measurement criteria for 
CR or PR (whichever is first recorded) are first met until the first date that disease is recurrent or 
documented disease progression is observed, per addenda-specified criteria, or the date of death 
from any cause in the absence of documented disease progression or recurrence.
Disease control rate (DCR) is defined as the proportion of treated patients achieving a best 
overall response of PR or CR or stable disease (SD).
Clinical benefit rate (CBR): The proportion of patients with CR, PR, or SD ≥6 months 
according to RECIST v1.1.
9.2.
Adverse Events
The investigator will use Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5.0 (NCI 2017) to assign AE severity grades.
Investigators are responsible for:

monitoring the safety of patients in this study and for alerting Lilly or its designee 
to any event that seems unusual, even if this event may be considered an 
unanticipated benefit to the patient

the appropriate medical care of patients during the study

documenting their review of each laboratory safety report

following, through an appropriate health care option, AEs that are serious or 
otherwise medically important, considered related to study treatment or the study, 
or that caused the patient to discontinue study treatment before completing the 
study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  Frequency of 
follow-up evaluation is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed and assent obtained, as applicable, study site personnel will record via 
case report form (CRF) the occurrence and nature of each patient’s preexisting conditions, 
including clinically significant signs and symptoms of the disease under treatment in the study.  
In addition, study site personnel will record via CRF any change in the preexisting conditions 
and any new conditions as AEs.  Investigators should record their assessment of the potential 
relatedness of each AE to study procedure or study treatment via CRF.

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The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatments, or pathologies.  A “reasonable possibility” means that there is a 
cause-and-effect relationship between the study treatment and/or study procedure and the AE.
Adverse event grading of toxicities related to estimated GFR should be evaluated based on the 
Cockcroft-Gault method or measured GFR (Appendix 4).
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
Study site personnel must report any dose modifications or treatment discontinuations that result 
from AEs to Lilly or its designee via CRF/electronic data entry/designated data transmission 
methods, clarifying, if possible, the circumstances leading to the dose modification or 
discontinuation of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above.
All AEs occurring after signing the ICF are recorded by the site in the CRF/electronic data 
entry/designated data transmission methods. SAE reporting to Lilly/the sponsor begins after the 
patient has signed the ICF and has received study treatment.  However, if an SAE occurs after 
signing the ICF, but prior to receiving study treatment, it needs to be reported ONLY if it is 
considered reasonably possibly related to study procedure.
Study site personnel must notify Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a Lilly/sponsor-approved method.  If alerts are issued via telephone, 
they are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE but should be reported.  However, to fulfill regulatory requirements any pregnancy 
should be reported following the SAE process to collect data on the outcome for both mother and 
fetus.

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Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
Planned hospitalizations or procedures for preexisting conditions that were recorded in the 
patient’s medical history at the time of enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.
Serious adverse events, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to study treatment.
9.2.2. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to study treatment or study procedure.  
United States 21 CFR 312.32 and Regulation (EU) No 536/2014 and the associated detailed 
guidances or national regulatory requirements in participating countries require the reporting of 
SUSARs.  Lilly has procedures that will be followed for the recording and expedited reporting of 
SUSARs that are consistent with global regulations and associated detailed guidances.
9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, to monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
In case of overdose of study drug or comparator, refer to the IB and/or product label for the 
specific agent.
9.4.
Safety
9.4.1. Safety Measures
For each patient, safety measures (such as electrocardiograms [ECGs], vital signs, laboratory 
tests, or other tests) should be collected as shown in the Schedule of Activities contained in the 
specific protocol addendum.
Results from any clinical laboratory test analyzed by a central laboratory (refer to Addendum 
Attachment 2) will be provided to investigative sites by Lilly or its designee.

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Refer to Section 9.2 for details on the recording of AEs.
9.4.2. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
For addenda with eligibility criteria of a baseline alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) <2.5× ULN or total bilirubin <1.5× ULN:
In patients enrolled with normal or near normal ALT or AST (ALT or AST<1.5x ULN), initiate 
close monitoring and evaluation if:

ALT or AST >3x ULN and TBL >2x ULN or 

ALT or AST >5x ULN 
In patients enrolled with elevated baseline ALT or AST (≥1.5x ULN), initiate close monitoring 
and evaluation if:

ALT or AST >3x baseline or

ALT or AST >2x baseline and TBL >2x ULN
Close monitoring and evaluation involves liver tests, including ALT, AST, total bilirubin, direct 
bilirubin, gamma-glutamyl transferase (GGT), and creatine phosphokinase (CPK), which should 
be measured and repeated within 3 to 5 days to confirm the abnormality and to determine if it is 
increasing or decreasing.
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator based on the 
hepatic monitoring tests as outlined in each addendum and in consultation with the Lilly 
CRP/CRS.  Monitoring of ALT, AST, and total bilirubin should continue until levels normalize 
or return to approximate baseline levels.
Refer to Section 3.9.3.1.1 of the addendum for details regarding hepatic safety data collection in 
the event of particular circumstances.
9.5.
Pharmacokinetics
When applicable, pharmacokinetic samples will be collected as shown in the relevant protocol 
addendum.
Blood samples will be used to determine the serum/plasma concentration of the study drug and 
other agents.  Corresponding metabolites of the study drug may be monitored as appropriate.
Bioanalytical samples collected to measure study drug concentration will be retained for a 
maximum of 1 year following the last patient visit for the study.
9.6.
Pharmacodynamics
Pharmacodynamic samples will be collected as shown in the applicable protocol addendum.

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9.7.
Pharmacogenomics
9.7.1. Whole Blood Sample for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
applicable protocol addendum, Attachment 3, where local regulations allow.
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable responses to study treatment 
and to investigate genetic variants thought to play a role in the addenda-specified tumor type.  
Assessment of variable response may include evaluation of AEs or differences in efficacy.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.  Samples will be retained at a 
facility selected by Lilly for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ethical review boards (ERBs)/institutional review 
boards (IRBs) impose shorter time limits.  This retention period enables use of new technologies, 
response to questions from regulatory agencies, and investigation of variable responses that may 
not be observed until later in the development of the study drug(s) or after study drug(s) become
commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing technologies include whole genome and exome 
sequencing, genome-wide association studies, multiplex assays, and candidate gene studies.  
Regardless of the technology utilized, data generated will be used only for the specific research 
scope described in this section.
Lilly may disclose the results of clinically relevant findings to the investigator. Because Lilly 
does not have a direct relationship with research participants, it is the investigator’s 
responsibility to provide the finding to the research participant and/or their parent/guardian and 
discuss its relevance for their healthcare. If the research participant/parent/guardian does not 
want to be provided with the finding, he or she needs to communicate that decision to the 
investigator.
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, variability of patient response (including 
safety), and clinical outcome.  These samples may also be used to develop related research 
methods or to validate diagnostic tools or assays. Sample collection is incorporated into clinical 
studies to enable examination of these questions through measurement of biomolecules including 
deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, lipids, and other cellular 
elements.  
Details will be provided in Section 3.9.6 of the applicable protocol addendum. Samples for 
biomarker research will be collected as specified in Addendum Attachment 3, where local 
regulations allow.

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It is possible that biomarker data for patients in the study have already been generated from 
samples that were collected and analyzed prior to enrolling in this study.  This may include data 
generated from genetic analyses.  If available, these data may be requested from medical records 
for use in the research described in Sections 9.7 (Pharmacogenomics) and 9.8 (Biomarkers) of 
the CAMPFIRE Master Protocol and Section 3.9.6 of the addendum.
Lilly may disclose the results of clinically relevant findings to the investigator. Because Lilly 
does not have a direct relationship with research participants, it is the investigator’s 
responsibility to provide the finding to the research participant and/or their parent/guardian and 
discuss its relevance for their healthcare. If the research participant/parent/guardian does not 
want to be provided with the finding, he or she needs to communicate that decision to the 
investigator.
9.8.1. Tissue Samples for Biomarker Research
Tissue samples for biomarker research will be collected for the purposes described in Section 9.8
of the CAMPFIRE Master Protocol and Section 3.9.6 of the addenda.  Samples for biomarker 
research will be collected according to the sampling schedule in Attachment 3 of the addenda, 
where local regulations allow.
The pathology report accompanying archival tissue may also be requested.  The pathology report 
must be coded with the patient number.  Personal identifiers, including the patient’s name and 
initials, must be removed from the institutional pathology report prior to submission.
Archival blocks will be sectioned and returned to the study site.  Slides and tissue samples 
collected on-study will not be returned.
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last patient visit for the study, or for a shorter period if local regulations and/or 
ERBs/IRBs impose shorter time limits.  This retention period enables the use of new 
technologies, response to questions from regulatory agencies, and investigation of variable 
response that may not be observed until later in the development of the study drugs or after the 
study drugs become commercially available.
Technologies are expected to improve during the 15-year storage period and, therefore, cannot 
be specifically named.  Existing approaches, including mutation profiling, copy number 
variability analysis, gene expression assays, immunohistochemistry, and/or multiplex assays may 
be performed on these tissue samples to assess potential associations between these biomarkers 
and clinical outcomes.
9.8.2. Other Samples for Biomarker Research
The following samples for biomarker research may be collected according to the sampling 
schedule in Attachment 3 of the addenda, where local regulations allow:

whole blood for pharmacogenomic research (as described in Section 9.7)

serum

plasma

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All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last patient visit for the study, or for a shorter period if local regulations and/or 
ERBs/IRBs impose shorter time limits.  This retention period enables use of new technologies, 
response to questions from regulatory agencies, and investigation of variable response that may 
not be observed until later in the development of the study drugs or after the study drugs become 
commercially available.
Technologies are expected to improve during the 15-year storage period and, therefore, cannot 
be specifically named.  Existing approaches, including mutation profiling, copy number 
variability analysis, gene expression assays, immunoassays, and/or multiplex assays may be 
performed on these samples to assess potential associations between these biomarkers and 
clinical outcomes.
9.9.
Health Economics
The self-reported questionnaires (if applicable) will be administered as shown in the Schedule of 
Activities (Section 3.2) of each addendum in countries where the questionnaires have been 
translated into the native language of the region and linguistically validated.

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10. Statistical Considerations
10.1. Sample Size Determination
Each addendum will provide justification for total sample size and the randomization ratio 
between arms needed to address the objectives of the associated investigation. For event-driven 
endpoints, the addendum will also provide the requisite number of events for the associated 
analyses. Any multiple comparison and sequential testing procedures will be described in the 
addenda.
10.2. Populations for Analyses
Each addendum will describe the specific analysis populations.
10.3. Statistical Analyses
Statistical analysis of this CAMPFIRE Master Protocol and its addenda will be the responsibility 
of Lilly or its designee.
Statistical analyses for each investigation will be specified within the associated addendum. The 
description of the analyses will include the statistical model(s) and success criteria for primary 
and secondary efficacy endpoints, analyses of safety, and other analyses (eg patient disposition, 
treatment compliance, etc.). Statistical operating characteristics associated with the analysis of 
the primary endpoint (or other endpoints serving as basis for justifying sample size) will be 
provided and may be obtained via trial simulation where appropriate.
The statistical modeling approach for primary/secondary efficacy endpoints will be carefully 
developed and prespecified to address the custom scientific objective(s) of each investigation. 
The analyses may involve the use of Bayesian methods (eg Bayesian augmented control), rules 
governing any adaptive design elements (eg arm-dropping), and borrowing of information across 
addenda where scientifically/statistically justified. In the case of Bayesian analyses, methods for 
constructing prior distributions will be fully prespecified, with detailed rules provided in the 
SAP.
By design, the inclusion of new addenda will not affect statistical inferences of other ongoing 
addenda, unless those ongoing addenda jointly prespecified adaptive design/analysis elements 
that make appropriate statistical accommodations. Adaptation rules and associated statistical 
operating characteristics of prespecified adaptive designs will be provided in any such 
addendum. 
10.3.1. Safety Analyses
The safety analyses are described below.  Any additional safety analyses will be described in the 
addendum.  In general, all patients who receive at least 1 dose of any study therapy will be 
evaluated for safety and toxicity.
The Medical Dictionary for Regulatory Activities (MedDRA®) Version 21 (or higher) will be 
used when reporting AEs.  The MedDRA Lower Level Term (LLT) will be used in the 

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treatment-emergent computation.  Treatment-emergent adverse events will be summarized by 
System Organ Class (SOC) and by decreasing frequency of Preferred Term (PT) within SOC.
Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drug

SAEs, including possible relationship to study drug

AEs leading to dose adjustments

discontinuations from study treatment due to AEs or death

treatment-emergent abnormal changes in laboratory values

treatment-emergent abnormal changes in vital signs.
10.3.2. Other Analyses
10.3.2.1. Patient Disposition
A detailed description of patient disposition will be provided, including a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated, as 
well as number and percentage of patients completing the study, as defined in the addendum’s 
SAP, or discontinuing (overall and by reason for discontinuation).  A summary of all important 
protocol deviations will be provided.
10.3.2.2. Patient Characteristics
Demographic data are collected and reported to demonstrate that the study population represents 
the intended target patient population.
A summary of baseline patient and disease characteristics, historical diagnoses, preexisting 
conditions, and prior therapies (if applicable) will be reported using descriptive statistics. 
10.3.2.3. Treatment Compliance
For study treatments administered at the investigator site, treatment compliance is assured and 
will not be further evaluated.
Study treatment compliance for patient or caregiver administered treatments will be assessed as 
the proportion of treatment that is actually taken, relative to what is expected, after accounting 
for protocol-defined dose adjustments.  The study treatment taken will be derived from the 
difference between the total number of pills dispensed and returned over the course of the 
patient’s treatment.
10.3.2.4. Extent of Exposure
The number of cycles received, dose omissions, dose reductions, dose delays, and dose intensity 
will be summarized for all treated patients by treatment arm.

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10.3.2.5. Concomitant Therapy
All concomitant medications should be recorded throughout the patient’s participation in the 
study. A summary of prior and concomitant medications will be reported for each addendum.
10.3.2.6. Post-Study-Treatment Therapy
Post-study-treatment therapy data collection will be described in the addenda as applicable. 
Except when an addendum specifies that patients will be discontinued from the study 
immediately after the post-study treatment follow-up visit, the numbers and percentages of 
patients receiving post-study-treatment anticancer therapies will be provided by type of 
therapy (surgery, radiotherapy, or systemic therapy) and by drug class and/or name, overall and 
by line of therapy.
10.3.2.7. Pharmacokinetic/Pharmacodynamic Analyses
A summary of the planned pharmacokinetic/pharmacodynamic analyses will be described in 
each addendum. 
10.3.2.8. Biomarker Analysis
A summary of the planned biomarker analysis will be described in each addendum.
10.3.2.9. Healthcare Resource Utilization
Healthcare resource utilization will be described in each addendum, if applicable.
10.3.3. Subgroup Analyses
A prespecified list of subgroups will be identified in the SAP for each addendum.  The treatment 
effect within each subgroup will be summarized. 
10.3.4. Interim Analyses
Any planned interim analyses for an addendum will be described and justified within that 
addendum. If an unplanned interim analysis is deemed necessary for reasons other than a safety 
concern, the applicable addenda will be amended.

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11. References
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-247.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
1958;53:457-481.
Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The use of nitrogen mustards in the 
palliative treatment of carcinoma with particular reference to bronchogenic carcinoma. 
Cancer. 1948;1(4):634-669.
Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR. The measurement of performance in 
childhood cancer patients. Cancer. 1987;60(7):1651-1656.
[NCI] National Cancer Institute. Cancer Therapy Evaluation Program, Common Terminology 
Criteria for Adverse Events, Version 5.0, DCTD, NCI, NIH, DHHS. 2009. Publish date: 
27 Nov 2017.
Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A. A simple estimate of glomerular 
filtration rate in children derived from body length and plasma creatinine. Pediatrics. 
1976;58(2):259-263.
Schwartz GJ, Gauthier B. A simple estimate of glomerular filtration rate in adolescent boys. 
J Pediatr. 1985;106(3):522-526.
Vassal G1, Zwaan CM, Ashley D, Le Deley MC, Hargrave D, Blanc P, Adamson PC. New drugs 
for children and adolescents with cancer: the need for novel development pathways. Lancet 
Oncol. 2013;14(3):e117-24.

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Appendix 1. Abbreviations and Definitions
Term
Definition
AE
Adverse event:  any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and that does not necessarily have a 
causal relationship with this treatment.  An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
blinding/masking
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment.  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment, but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment, but the investigator and/his staff and the patient are not.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received.
CBC
complete blood count
CBR
clinical benefit rate
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
COA
clinical outcome assessment
collection database
a computer database in which clinical study data are entered and validated
CPK
creatine phosphokinase
CR
complete response
CRF
case report form
CRP
Clinical research physician:  Individual responsible for the medical conduct of the 
study.  Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician, or other medical officer.

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CRS
clinical research scientist
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DNA
deoxyribonucleic acid
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture system
end of study
Date of the last visit or last scheduled procedure shown in the Schedule of Activities 
(Section 2) for the last patient
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
FOCBP
Females of child bearing potential
GCP
good clinical practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation (formerly the International Conference on 
Harmonisation)
interim analysis
An analysis of clinical study data conducted before the final reporting database is 
created/locked
investigation
CAMPFIRE Master Protocol combined with an addendum

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investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical study, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IRB
institutional review board
ITT
Intention-to-treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IWRS
interactive Web-response system
LLT
MedDRA Lower Level Term
MedDRA
Medical Dictionary for Regulatory Activities
NK
natural killer
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PFS2
progression-free survival 2
PK
pharmacokinetic(s)
PR
partial response
PT
MedDRA Preferred Term
randomize
The process of assigning patients to an experimental group on a random basis.
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
re-screen
To screen a patient who was previously declared a screen failure for the same study.
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan

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screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.
screen failure
A patient who does not meet 1 or more criteria required for participation in a study.
SD
stable disease
SOC
MedDRA System Organ Class
study completion
Will occur in the applicable addenda, as determined by Lilly.
SUSAR
suspected unexpected serious adverse reaction
TBI
total body irradiation
ULN
upper limit of normal

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Appendix 2. Clinical Laboratory Tests
Clinical laboratory tests will be specified in each addendum.

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Appendix 3. Study Governance, Regulatory, and 
Ethical Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient/patient’s legal representative understands the nature of 
the study, the potential risks and benefits of participating in the study, and that the 
patient’s participation is voluntary.

ensuring that informed consent is given by each patient/patient’s legal 
representative.  This includes obtaining the appropriate signatures and dates on 
the ICF prior to the performance of any study procedures and prior to the 
administration of study treatment.

providing a copy of the signed ICF(s) to the patient/patient’s legal representative 
and retaining a copy of the signed ICF in the site file.

answering any questions the patient/patient’s legal representative may have 
throughout the study and sharing in a timely manner any new information that 
may be relevant to the patient’s/patient’s legal representative’s willingness to 
continue the patient’s participation in the study.
A legal representative must give informed consent for a child to participate in this study.  In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if capable.
Ethical Review
Documentation of ERBs/IRBs approval of the protocol and the ICF and assent form (if available)
must be provided to Lilly before the study may begin at the investigative site(s).  Lilly or its 
representatives must approve the ICF, including any changes made by the ERBs/IRBs, before it 
is used at the investigative site(s).  All ICFs must be compliant with the International Council for 
Harmonisation (ICH) guideline on GCP.
The ERB/IRB should include or consult with experts who are knowledgeable in pediatric ethical, 
clinical, and psychosocial issues.
The study site’s ERBs/IRBs should be provided with the following:

the protocol, protocol amendments, and relevant protocol addenda, and the 
current IB or package labeling, Patient Information Leaflet, Package Insert, or 
Summary of Product Characteristics and updates during the course of the study

ICF

assent form (if available)

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
other relevant documents (for example, curricula vitae advertisements)
Regulatory Considerations
This study will be conducted in accordance with the protocol and with:

consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 

applicable ICH GCP Guidelines

applicable laws and regulations
Some obligations of Lilly may be assigned to a third-party organization.
Investigator Information
Physicians with a specialty in pediatric oncology will participate as investigators in this clinical 
study.
Protocol Signatures
Lilly’s responsible medical officer will approve the protocol, confirming that, to the best of his 
or her knowledge, the protocol accurately describes the planned design and conduct of the study.
After reading the protocol and addendum, each principal investigator will sign the protocol 
and/or addendum signature page and send a copy of the signed page to a Lilly representative.
Final Report Signature
For single-site study addenda:
The investigator will sign the final clinical study report of each addendum, indicating agreement, 
to the best of his or her knowledge, with the analyses, results, and conclusions of the report.
For multi-center study addenda:
The clinical study report coordinating investigator for each addendum will sign the final clinical 
study report for each study, indicating agreement that, to the best of his or her knowledge, the 
report accurately describes the conduct and results of the study.
The investigator with the most qualified/analyzable/enrolled patients will serve as the clinical 
study report coordinating investigator for an individual addendum.  If this investigator is unable 
to fulfill this function, another investigator will be chosen by Lilly to serve as the clinical study 
report coordinating investigator.
The Lilly responsible medical officer and statistician will approve the final clinical study report 
for the CAMPFIRE Master Protocol and each addendum, confirming that, to the best of his or 
her knowledge, the report accurately describes the conduct and results of the study.

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Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

provide sponsor start-up training to instruct the investigators and study 
coordinators.  This session will give instruction on the protocol, the completion of 
the CRFs, and study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and verify data reported to detect potential errors.
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs/IRBs with direct access to original source 
documents.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered as source and for the confirmation that data reported 
are accurate and complete by signing the CRF.
Additionally, clinical outcome assessment (COA) data (questionnaires, scales, etc.) will be 
collected by the subject/caregiver/investigator site personnel via a paper source document and 
will be transcribed by the investigator site personnel into the EDC system.
Data collected via the sponsor-provided data capture system will be stored at a third-party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system.  Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and results will be provided to the investigator for review 
and retention.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.

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Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB/IRB of the 
study site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.

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Appendix 4. Creatinine Clearance Formula
Note:  This formula is to be used for calculating creatinine clearance (CrCl) from local 
laboratory results only.
Patients ≥18 years old
Cockcroft-Gault prediction of creatinine clearance from serum creatinine (1976)
For serum creatinine concentration in mg/dL:
CrCl=
(mL/min)
(140 – agea) (wt) 0.85 (if female), or 1.0 (if male)
72 serum creatinine (mg/dL)
For serum creatinine concentration in µmol/L:
CrCl=
(mL/min)
(140 – agea) (wt) 0.85 (if female), or 1.0 (if male)
0.81 serum creatinine (mol/L)
a
Age in years, weight (wt) in kilograms.
Source:  Cockcroft and Gault 1976.
-OR-
Patients <18 years old will use the Schwartz formula for the determination of creatinine 
clearance.
All Females and Pre-adolescent Males:
Ccr (mL/min/1.73 m2) = 0.55 × Height (cm)/Scr (mg/dL)
Adolescent Males:
Ccr (mL/min/1.73 m2) = 0.70 × Height (cm)/Scr (mg/dL)
Note:  Ccr = creatinine clearance and Scr = serum creatinine.
Source:  Schwartz et al. 1976; Schwartz and Gauthier 1985.

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Appendix 5. Protocol Amendment J1S-MC-JAAA(b) 
Summary CAMPFIRE:  Children’s and Young Adult 
Master Protocol for Innovative Pediatric Research
Overview
Protocol J1S-MC-JAAA CAMPFIRE:  Children’s and Young Adult Master Protocol for 
Innovative Pediatric Research has been amended.  The new protocol is indicated by amendment 
(b) and will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

An inclusion criterion was added to clarify that age requirements will be specified in the 
protocol addenda

Additional detail was added to the Benefit/Risk Assessment

A current estimate of investigations to be added to the master protocol construct was 
added to Section 7.8.1

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Section 3.3 Benefit/Risk Assessment
The direct benefit and risk of experimental treatment regimens are inherent to the compounds 
making up those regimens.  As a result, this component of the benefit risk profile will be 
particular to each investigation and will be described in the addendum covering it.
Elements of benefit and risk to individual patients that are exclusive to the Master Protocol itself 
are limited to design and operational aspects of a platform trial.  By using shared control cohorts 
where possible and appropriately incorporating additional information across cohorts, platform 
trials reduce the number of patients needed to have adequate power to perform multiple 
investigations and potentially decreases the duration of the investigations.  In particular, the 
number of patients exposed to control arms of potentially less effective therapies is reduced.
On the other hand, the platform trial can introduce complexity for investigators and create the 
risk of reduced adherence to protocol procedures if consistency between investigations is not 
maintained.  Common schedules of activities, safety assessments and inclusion/exclusion criteria 
across investigations are specified in the Master Protocol to minimize this risk along with 
training and appropriate safety monitoring for each investigation.   
In conclusion, by providing a clinical trial design that maximizes the available information 
across multiple investigations and by outlining consistent patient specifications and trial 
elements across these investigations, this platform trial has a positive benefit risk assessment.
Section 6.1 Inclusion Criteria
[34] Pediatric and young adult patients will be enrolled, where the specific age requirement for 
each indication will be specified in the protocol addenda
Section 7.8.1 Treatment after completion of investigation
Several investigations (e.g. up to a total of approximately 10 investigations) will be added to the 
master protocol construct over approximately the next 5 years of the entire master protocol 
duration. These sub-protocols will be submitted and reviewed as independent clinical trial
applications and will each include an estimation of the study duration.

Leo Document ID = c2d7eb8a-41f0-4448-b3af-50a8e66f1ace
Approver: 
Approval Date & Time: 26-Sep-2019 11:57:55 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 26-Sep-2019 17:13:40 GMT
Signature meaning: Approved
PPD
PPD