A Randomized, Open-Label, Phase 2 Study Evaluating Abemaciclib in Combination With Irinotecan and Temozolomide in Participants With Relapsed or Refractory Ewing's Sarcoma
Phase: PHASE2
Conditions: Sarcoma, Ewing, Neoplasm Metastasis
Sponsor: Eli Lilly and Company



J1S-MC-JP04(b) Clinical Protocol Addendum
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1.
Protocol Addendum J1S-MC-JP04(b)
A Randomized, Open-Label, Phase 2 Study Evaluating 
Abemaciclib in Combination with Irinotecan and 
Temozolomide in Participants with Relapsed or Refractory 
  
Confidential Information 
The information contained in this protocol addendum 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 abemaciclib (LY2835219), unless such persons are bound by a 
confidentiality agreement with Eli Lilly and Company or its subsidiaries. This document and 
its associated attachments are subject to United States Freedom of Information Act (FOIA) 
Exemption 4. 
LY900023 (JAAA CAMPFIRE Protocol); Abemaciclib (LY2835219) 
This addendum is to be performed in addition to all procedures required by 
Protocol J1S-MC-JAAA or any subsequent amendments to that protocol. 
Eli Lilly and Company 
Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s): 
EudraCT: 2021-004734-11 
EU CT number: 2023-506772-28-00 
Document ID: VV-CLIN-122379 
Revised Protocol Addendum JP04 (b) Electronically Signed and Approved by Lilly on 
date provided below. 

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Protocol Addendum Substantiality  
This addendum is considered to be nonsubstantial.  
Protocol Addendum Summary of Changes Table  
DOCUMENT HISTORY
Document
Date
Protocol Addendum a
25-Aug-2022
Original Protocol Addendum
20-Jan-2022 
Addendum [b] 
Overall Rationale for the Revision: 
This addendum is being updated to incorporate tumor assessments during follow-up in 
participants discontinuing treatment without disease progression. 
Other changes and clarifications were made based on recent feedback from sites and are 
provided in the table below. 
Section # and Name 
Description of Change 
Brief Rationale 
3.1. Synopsis 
Added regulatory agency 
identifier number(s), brief 
summary, study population, 
intervention groups and 
duration, ethical 
considerations of benefit/risk, 
and data monitoring 
committee 
To align with EU CTR (536/2014) 
requirement 
3.2. Schedule of Activities 
Added text to clarify that 
tumor assessments should be 
continued during follow-up in 
participants discontinuing 
treatment without disease 
progression 
Added to ensure proper assessment of 
study endpoints 
3.2. Schedule of Activities 
Deleted 12-lead ECG testing 
at baseline and poststudy- 
treatment follow-up 
Deleted since none of the drugs are 
cardiotoxic in nature 
3.2. Schedule of Activities 
 
Alignment 
3.2. Schedule of Activities 
Updated Table JP04.2 to 
remove requirement of 
 
Reduce trial burden for participants 
randomized to Arm A 
 

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Section # and Name 
Description of Change 
Brief Rationale 
Updated Table JP04.2 to 
remove requirement of 
for 
participants randomized to 
Arm B 
Reduce trial burden for participants 
randomized to Arm B 
 
 Revised age to 10-17 years 
for Arm A 
 Updated language for 
C1D1 treatment 
 Added text in Table 
JP04.2 to initiate 
 
during treatment
Clarification 
3.2. Schedule of Activities 
Added guidance in Table 
JP04.2 to reduce Hematology 
frequency when deemed 
appropriate. 
Added to reduce trial burden for study 
participants. Alignment with product 
labels 
3.2. Schedule of Activities 
Added guidance in Table 
JP04.2to eliminate Clinical 
chemistry frequency when 
deemed appropriate. 
Added to reduce trial burden for study 
participants. Alignment with product 
labels 
3.2. Schedule of Activities 
Added instruction in Table 
JP04.3 to perform tumor 
imaging 
Added to ensure proper assessment of 
study endpoints 
3.5.3. End of Study Definition 
Revised language on study 
completion 
Correction to ensure satisfactory 
assessment of secondary endpoints 
before study completion 
3.6.1. Inclusion Criteria 
Revised language of criterion 
39 to provide clarity on 
eligibility of participants who 
are currently on systemic 
steroids 
Clarification 
3.6.1.1. Exceptions to the 
CAMPFIRE Master Protocol 
Inclusion Criteria 
Updated additional therapies 
that the study participants 
must discuss with the Lilly 
CRP/CRS for appropriate 
length of time prior to first 
dose of study treatment 
Feedback from sites 
3.6.1.1. Exceptions to the 
CAMPFIRE Master Protocol 
Corrected laboratory value of 
hemoglobin to 
 g/L 
Correction 

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Section # and Name 
Description of Change 
Brief Rationale 
Inclusion Criteria 
 
3.7.1. Treatments 
Administered 
Updated authorization of 
treatments administered as 
defined by EU Clinical Trial 
Regulation and whether used 
in accordance with the EU 
authorization in Table JP04.6 
To align with EU CTR (536/2014) 
requirement 
Added language for 
packaging and labeling 
3.7.4.1. General Dosing 
Instructions: Abemaciclib 
Added dosing instructions for 
participants who vomit 
abemaciclib tablets after 
ingestion 
Clarification 
 
3.7.4.3. General Dosing 
Instructions: Temozolomide 
Added dosing instructions for 
participants who vomit 
temozolomide after ingestion 
3.7.4.6.3. Management of 
Diarrhea 
Updated language on anti-
diarrhea therapy 
Updated 
3.7.6. Concomitant Therapy 
Added provision for palliative 
radiation and surgery after 
discussing with Lilly CRP 
Added for flexibility and to ensure 
optimal participant care 
3.7.8.2. Discontinuation of 
One Study Treatment 
Added to specify abemaciclib 
can be continued beyond 
Cycle 12 until discontinuation 
criteria is met  
Clarification 
3.7.8.3.2. Dose Modification 
for Non-Hematologic 
Toxicities 
 
Specified study definition of 
footnote 
Clarification 
Added an exception that dose 
modification for non-
hematologic toxicities is not 
required if deemed clinically 
insignificant by the 
investigator  
Medical judgement 
3.9.6. Biomarkers 
 Revised language on 
biomarker data 
 Revised timeframe for 
retention or storage of 
biomarker samples from 
15 years to 7 years 
Updated 
3.9.6.1. Tissue Samples for 
Deleted language on non- 
Medical judgment 

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Section # and Name 
Description of Change 
Brief Rationale 
Biomarker Research
genetic biomarkers and their 
retrospective assessment 
3.9.6.2. Plasma Samples for 
Biomarker Research 
Deleted language on 
assessment methods of 
plasma samples 
Medical judgment 
3.10.3. Statistical Analysis 
Added required language on 
handling of missing, unused, 
and spurious data. Also, 
deleted redundant details 
To align with EU CTR (536/2014) 
requirement 
3.10.3.5.2. Futility Interim 
Analysis 
Specified assessment details 
for futility analysis 
To be consistent with SAP and 
regulatory agreements 
Attachment 1. Protocol JP04 
Addendum Abbreviations and 
Definitions 
Updated list of abbreviations 
Updated 
Attachment 5 Protocol JP04 
Addendum Restricted and 
Prohibited Concomitant 
Therapy 
Updated guidance table for 
modulators of CYP3A  
Updated guidance 
Attachment 9 Country-specific 
Requirements 
Added appendix for Germany 
and Spain 
To align with EU CTR (536/2014) 
requirement 
Revised age for 
 
Clarification 
 
 
 
 
 
 
 
 
Attachment 10 Supporting 
Documentation and 
Operational Considerations 
 
 
 
Added new section on 
Supporting Documentation 
and Operational 
Considerations 
To align with EU CTR (536/2014) 
requirement 
sponsor or designee 
significant issues related to 
participant safety, participant 
 

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Section # and Name 
Description of Change 
Brief Rationale 
Updated required language on 
data protection 
Updated time frame for 
posting of summary of results 
as specified by local law or 
regulation 
Updated events meeting the 
AE definition 
Updated required language on 
regulatory reporting of SAEs 
Attachment 11 
Amendment J1S-MCJP04(a) 
A Randomized, Open-Label, 
Phase 2 Study Evaluating 
Abemaciclib in Combination 
with Irinotecan and 
Temozolomide in Participants 
with Relapsed or Refractory 
 
To update addendum history 
Throughout  
 Minor editorial changes 
have been made 
throughout 
 
alignment 
These are minor, therefore they have 
not been individually summarized 
 
 

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2. 
Table of Contents  
Protocol Addendum J1S-MC-JP04 
A Randomized, Open-Label, Phase 2 Study Evaluating 
Abemaciclib in Combination with Irinotecan and 
Temozolomide in Participants with Relapsed or Refractory 
 
Section 
Page  
1. 
Protocol Addendum J1S-MC-JP04(b) A Randomized, Open-Label, 
Phase 2 Study Evaluating Abemaciclib in Combination with 
Irinotecan and Temozolomide in Participants with Relapsed or 
 ...................................................................................................1 
Protocol Addendum Substantiality ................................................................................................2 
Protocol Addendum Summary of Changes Table .........................................................................2 
2. 
Table of Contents ....................................................................................................................7 
3. 
Study J1S-MC-JP04 Addendum ............................................................................................14 
3.1. 
Synopsis ............................................................................................................................14 
3.2. 
Schedule of Activities.......................................................................................................18 
3.3. 
Introduction ......................................................................................................................29 
3.3.1. 
Study Rationale ........................................................................................................29 
3.3.2. 
Background ..............................................................................................................29 
3.3.2.1. 
 ................................................................................................29 
3.3.2.2. 
Abemaciclib .......................................................................................................30 
3.3.2.3. 
Irinotecan ............................................................................................................31 
3.3.2.4. 
Temozolomide ....................................................................................................31 
3.3.2.5. 
Irinotecan and Temozolomide Combination ......................................................32 
3.3.3. 
Benefit/Risk Assessment ..........................................................................................32 
3.3.3.1. 
Benefit/Risk Assessment of COVID-19 ............................................................33 
3.4. 
Objectives and Endpoints .................................................................................................35 
3.5. 
Study Design ....................................................................................................................36 
3.5.1. 
Overall Design .........................................................................................................36 
3.5.1.1. 
Criteria to Begin Day 1 of Subsequent Cycles (C2 and 
beyond) ...............................................................................................................36 
3.5.2. 
Number of Participants ............................................................................................37 
3.5.3. 
End of Study Definition ...........................................................................................37 
3.5.4. 
Scientific Rationale for Study Design ......................................................................37 
3.5.5. 
Justification for Dose ...............................................................................................37 
3.6. 
Study Population ..............................................................................................................39 

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3.6.1. 
Inclusion Criteria ......................................................................................................39 
3.6.1.1. 
Exceptions to the CAMPFIRE Master Protocol Inclusion 
Criteria ................................................................................................................39 
3.6.2. 
Exclusion Criteria ....................................................................................................41 
3.6.2.1. 
Exceptions to the CAMPFIRE Master Protocol 
Exclusion Criteria ...............................................................................................42 
3.6.3. 
Lifestyle Restrictions ...............................................................................................42 
3.6.4. 
Screen Failures .........................................................................................................42 
3.7. 
Treatments ........................................................................................................................43 
3.7.1. 
Treatments Administered .........................................................................................43 
3.7.2. 
Method of Treatment Assignment ...........................................................................44 
3.7.3. 
Blinding ....................................................................................................................44 
3.7.4. 
General Dosing Instructions .....................................................................................45 
3.7.4.1. 
Abemaciclib .......................................................................................................45 
3.7.4.2. 
Irinotecan ............................................................................................................45 
3.7.4.3. 
Temozolomide ....................................................................................................46 
3.7.4.4. 
Supportive Care ..................................................................................................46 
3.7.4.5. 
Premedication .....................................................................................................46 
3.7.4.6. 
Supportive Management for Diarrhea ................................................................46 
3.7.4.6.1. 
Diarrhea suspected due to irinotecan ...........................................................46 
3.7.4.6.2. 
Diarrhea suspected due to abemaciclib ........................................................47 
3.7.4.6.3. 
Management of Diarrhea ..............................................................................47 
3.7.5. 
Pneumocystis prophylaxis ........................................................................................47 
3.7.6. 
Concomitant Therapy ...............................................................................................48 
3.7.7. 
Participants with Difficulty Swallowing ..................................................................48 
3.7.8. 
Dose Modification ....................................................................................................48 
3.7.8.1. 
Planned or anticipated logistical delays .............................................................48 
3.7.8.1.1. 
Additional Guidance for Surgeries ...............................................................49 
3.7.8.2. 
Discontinuation of One Study Treatment ...........................................................49 
3.7.8.3. 
Dose-Modification Guidance due to Toxicity ....................................................50 
3.7.8.3.1. 
Dose Modification for Hematologic Toxicities ...........................................50 
3.7.8.3.2. 
Dose Modification for Non-Hematologic Toxicities ...................................53 
3.7.9. 
Treatment Compliance .............................................................................................56 
3.8. 
Discontinuation Criteria ...................................................................................................56 
3.9. 
Study Assessments and Procedures ..................................................................................56 
3.9.1. 
Efficacy Assessments ...............................................................................................56 
3.9.1.1. 
Product Acceptability and Palatability Assessments .........................................57 
3.9.2. 
Adverse Events ........................................................................................................57 
3.9.2.1. 
Adverse Events of Special Interest .....................................................................57 

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3.9.3. 
Safety .......................................................................................................................58 
3.9.3.1. 
Safety Monitoring ..............................................................................................58 
3.9.3.1.1. 
Special Hepatic Safety Data Collection .......................................................58 
3.9.3.1.2. 
Guidance for Monitoring Renal Function ....................................................59 
3.9.3.1.3. 
Guidance for Venous Thromboembolic Events ...........................................59 
3.9.3.1.4. 
Guidance for Interstitial Lung Disease/Pneumonitis ...................................60 
3.9.4. 
Pharmacokinetics .....................................................................................................60 
3.9.5. 
Pharmacodynamics ..................................................................................................61 
3.9.6. 
Biomarkers ...............................................................................................................61 
3.9.6.1. 
Tissue Samples for Biomarker Research ...........................................................62 
3.9.6.2. 
Plasma Samples for Biomarker Research ..........................................................63 
3.9.6.3. 
Whole-blood sample for biomarker research .....................................................63 
3.9.7. 
Genetics ....................................................................................................................63 
3.9.8. 
Health Economics ....................................................................................................64 
3.10. Statistical Considerations .................................................................................................64 
3.10.1. 
Sample Size Determination ......................................................................................64 
3.10.2. 
Populations for Analysis ..........................................................................................64 
3.10.3. 
Statistical Analysis ...................................................................................................64 
3.10.3.1. 
Efficacy Analysis ...............................................................................................65 
3.10.3.1.1. 
Progression-free Survival .............................................................................65 
3.10.3.1.2. 
Overall Survival ...........................................................................................66 
3.10.3.1.3. 
Objective Response Rate ..............................................................................66 
3.10.3.1.4. 
Duration of Response ...................................................................................66 
3.10.3.1.5. 
Disease Control Rate ....................................................................................66 
3.10.3.2. 
Safety Analysis ...................................................................................................66 
3.10.3.3. 
Other Analysis ....................................................................................................66 
3.10.3.3.1. 
Pharmacokinetic Analyses ...........................................................................66 
3.10.3.3.2. 
Exploratory Biomarker Analyses .................................................................67 
3.10.3.3.3. 
Product Acceptability and Palatability .........................................................67 
3.10.3.4. 
Subgroup Analysis .............................................................................................67 
3.10.3.5. 
Interim Analysis .................................................................................................67 
3.10.3.5.1. 
Safety Interim Analysis ................................................................................67 
3.10.3.5.2. 
Futility Interim Analysis ..............................................................................68 
4. 
References .............................................................................................................................69 
 

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List of Tables 
Table 
Page 
Table JP04.1. 
Baseline Schedule of Activities .........................................................................19 
Table JP04.2. 
On-Study-Treatment Schedule of Activities .....................................................21 
Table JP04.3. 
Poststudy-Treatment Follow-Up Schedule of Activities ...................................26 
Table JP04.4. 
Continued-Access Schedule of Activities .........................................................28 
Table JP04.5. 
Objectives and Endpoints ..................................................................................35 
Table JP04.6. 
Treatment Regimens ..........................................................................................43 
Table JP04.7. 
PFS Event/Censoring Scheme ...........................................................................65 
 
 

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List of Figures 
Figure 
Page 
Figure JP04.1. 
Illustration of study design. ...............................................................................36 
 
 

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List of Attachments 
Attachment 
Page 
Attachment 1. 
Protocol JP04 Addendum Abbreviations and Definitions ................................73 
Attachment 2. 
Protocol JP04 Addendum Clinical Laboratory Tests ........................................78 
Attachment 3. 
Protocol JP04 Addendum Sampling Schedule for Biomarkers and 
Pharmacokinetics...............................................................................................80 
Attachment 4. 
Protocol JP04 Addendum Hepatic Monitoring Tests for Treatment-
Emergent Abnormality ......................................................................................82 
Attachment 5. 
Protocol JP04 Addendum Restricted and Prohibited Concomitant 
Therapy ..............................................................................................................84 
Attachment 6. 
Protocol JP04 Addendum Abemaciclib Dosing Chart ......................................87 
Attachment 7. 
Protocol JP04 Addendum Contraceptive Guidance and Collection of 
Pregnancy Information ......................................................................................88 
Attachment 8. 
Protocol JP04 Addendum Provisions for Changes in Study Conduct 
During Exceptional Circumstances ...................................................................91 
Attachment 9. 
Protocol JP04 Addendum Country-specific Requirements ...............................94 
Germany 
 ...........................................................................................................................94 
Spain 
 ...........................................................................................................................96 
Attachment 10. Supporting Documentation and Operational Considerations ............................98 
Regulatory, Ethical, and Study Oversight Considerations.............................................................98 
Regulatory and Ethical Considerations ..........................................................................................98 
Financial Disclosure.......................................................................................................................99 
Informed Consent Process .............................................................................................................99 
Data Protection  ...........................................................................................................................99 
Committees Structure...................................................................................................................100 
Dissemination of Clinical Study Data..........................................................................................100 
Adverse Events and Serious Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ...........................................................101 
Definition of AE  .........................................................................................................................101 
Definition of SAE ........................................................................................................................102 
Definition of Product Complaints ................................................................................................103 

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Recording and Follow-Up of AE and/or SAE and Product Complaints .....................................103 
Reporting of SAEs .......................................................................................................................105 
Regulatory Reporting Requirements ............................................................................................105 
Attachment 11. Protocol Addendum Amendment History .......................................................107 
 

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3. 
Study J1S-MC-JP04 Addendum  
3.1. Synopsis  
Protocol Title: 
A Randomized, Open-Label, Phase 2 Study Evaluating Abemaciclib in Combination with 
 
Regulatory Agency Identifier Number(s):  
EudraCT: 2021-004734-11 
EU CT number: 2023-506772-28-00 
Rationale: 
Study J1S-MC-JP04 (JP04) is designed to investigate the efficacy of abemaciclib in combination 
with irinotecan and temozolomide for the treatment of participants with relapsed or refractory 
-like tumors. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
To characterize the efficacy of abemaciclib 
in combination with irinotecan + 
temozolomide
 
PFS as determined by BIRC using RECIST 
1.1 
Secondary 
 
To evaluate the safety profile of 
abemaciclib, irinotecan, and temozolomide 
combination 
Safety (including but not limited to): 
TEAEs, SAEs, deaths, laboratory 
abnormalities, vital signs, and physical 
examinations
 
To characterize the clinical activity of the 
abemaciclib, irinotecan, and temozolomide 
combination 
OS
 
ORR 
 
DoR 
 
DCR 
 
PFS as determined by investigator 
assessment using RECIST 1.1
To characterize the PK of the abemaciclib 
in combination with irinotecan + 
temozolomide
 
Concentrations of abemaciclib 
To assess the acceptability and palatability 
of the age-appropriate tablet and/or granule 
drug product, including dispersed tablets 
and/or granules 
Assessment of tablet, granule, or dispersed
drug product presentation, including 
acceptability and palatability 

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Abbreviations: BIRC = blinded independent review committee; DCR = disease control rate; DoR = duration of 
response; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PK = 
pharmacokinetics; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1 (Eisenhauer et al. 
2009); SAE = serious adverse event; TEAE = treatment-emergent adverse event. 
Brief Summary: 
This study evaluates the benefits of adding abemaciclib to irinotecan and temozolomide in 
partic
-like tumors. 
Study details: 
 Treatment will continue until disease progression, unacceptable treatment-related toxicity, 
or participant or physician decision to discontinue. 
 Participants discontinuing study intervention will return for a short-term follow-up visit 
(Visit 801) 30 days (±14 days) after discontinuation of all study treatments. 
 Long-term follow-up begins the day after the short-term follow-up visit and continues 
until 
or study completion. Long-term follow-
up visits should occur approximately every 2-3 months (Q60-90D). For participants 
without disease progression at treatment discontinuation, tumor assessments should occur 
approximately every 3 months. 
Study Population:  
Participants have 
-like tumor that has not responded to 
previous treatment or has returned, are 1 to <40 years 
 kg, and have a life expectancy 
of at least 8 weeks. Participants must be able to swallow and/or have a gastric/nasogastric tube. If 
on systemic steroids at study entry, the dose must be stable or decreasing during the 7 days prior 
to Cycle 1 Day 1. 
Intervention Groups and Duration: 
All participants will come to the investigative site on Day 1 to 5 of each 21-day cycle to receive: 
 Irinotecan IV infusion  
 Temozolomide capsules 
Arm A participants will also take abemaciclib orally twice daily during each 21-day cycle.  
Additional evaluations on Day 8 and Day 15 of each cycle will be conducted either at the study 
site, remotely (that is, by telephone, IT-assisted virtual visit, mobile healthcare, or a combination 
thereof) at the direction of the sponsor, according to local laws and regulations. 
Ethical Considerations of Benefit/Risk:  
The safety and efficacy profile for combination of abemaciclib, irinotecan, and temozolomide 
supports the overall benefit/risk profile. This combination was tolerable in Part A of Study JPCS 
in pediatric participants with relapsed or refractory solid tumors. Considering the measures to 
minimize risk, including frequent assessments by the medical team including monitoring of 

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hematologic and hepatic laboratory values, and the potential benefit of disease control, the 
benefit/risk profile is considered favorable for this patient population.  
Data Monitoring Committee: Yes (Independent DMC). 
 
 

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Overall Design:
Study JP04 is a multicenter, randomized, open-label, Phase 2 study in participants with relapsed 
sarcoma-like tumors.
Abbreviation: n = number of participants; PFS = progression-free survival.
a
One futility analysis will occur after approximately 
 events have been observed. See Section 3.10.3.5.2.
Number of Participants:
At least 45 participants will be enrolled. 
Treatment Arms and Duration:
Participants will receive treatment until evidence of disease progression or other discontinuation 
criteria have been fulfilled.
Starting Doses
Cycle = 21 days
Abemaciclib PO
Irinotecan IV
(Days 1-5 each cycle)
Temozolomide PO
(Days 1-5 each cycle)
<18 years
Arm A
55 mg/m2 BID (max 
dose 100 mg BID)
100 mg BID
50 mg/m2/day × 5
100 mg/m2/day × 5
Arm B
None
50 mg/m2/day × 5
100 mg/m2/day × 5
Abbreviations: BID = twice daily; IV = intravenous; PO = orally.

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3.2. Schedule of Activities  
This section includes the following SoA: 
 Screening, Treatment, and Post-Discontinuation Follow-Up SoA for all participants 
 Continued-Access SoA for participants on abemaciclib (See Section 7.8.1 of the 
CAMPFIRE Master Protocol for additional details) 
Overview 
The windows for the SoA and administration of first dose are based on calendar days. 
At any time in the study, laboratory and pregnancy tests may be collected at a local clinic in 
accordance with local laws and regulations if deemed appropriate by the investigator. All results 
should be reviewed and recorded in the eCRF. A virtual visit with the study investigator is not 
required for a local lab draw or pregnancy test. 
Screening and Baseline 
The screening period allows up to 28 days for confirmation of eligibility and completion of 
baseline assessments. 
Treatment Period 
Cycles are 21 days. During the on-study treatment period, participants will return to clinic on 
Days 1-5 for IV infusions. Additional evaluations on Day 8 and Day 15 of each cycle will be 
conducted on-site, remotely (that is, by telephone, IT-assisted virtual visit, mobile healthcare, or 
a combination thereof) or a combination of remote and on-site at the direction of the sponsor, 
according to local laws and regulations. 
Treatment will continue until disease progression, unacceptable treatment-related toxicity, or 
participant or physician decision to discontinue. 
Tumor Response 
Tumor response per RECIST 1.1 should be assessed approximately every 2 cycles (at Cycles 3 
and 5) and then every 3 cycles (beginning Cycle 8) until the participant has objective disease 
progression, death, or study completion. 
Short- and Long-Term Follow-Up 
Participants discontinuing study intervention will return for a short-term follow-up visit (Visit 
801). The short-term follow-up visit will take place 30 days (±14 days) after the decision is made 
to discontinue all study treatment. 
After the short-term follow-up visit, all participants will enter the long-term follow-up period 
(Visit 802-8XX). Long-term follow-up begins the day after the short-term follow-up visit is 
completed and continues until 
 withdrawal from study, or study completion. 
Long-term follow-up visits should occur approximately every 2-3 months (Q60-90D). Tumor 
assessments should continue approximately every 3 months during follow-up for participants 
without evidence of disease progression at the time of treatment discontinuation. 
 
 

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Table JP04.1. 
Baseline Schedule of Activities  
Day relative to C1D1
Procedure
28
14
Instructions
Informed consent 
X 
 
Must be signed prior to conducting any 
protocol-specific tests/procedures 
 
Minor participants must be re-consented if they 
reach the age of majority during the course of 
the study.
Inclusion/exclusion criteria
X
Confirm prior to randomization  
Randomization
X
Demographics 
X 
 
Include race, gender, ethnicity, and birth date 
per local regulations.
Preexisting conditions and 
medical history, including 
relevant surgical history
X 
 
sarcoma-
like fusion genes, if known
Prior and current treatments for 
X 
 
Record prior anticancer therapy
Substance use (alcohol and 
tobacco) 
X 
 
Concomitant medications 
X 
Record all premedication, supportive care, and 
concomitant medication  
See Section 3.7.6
Adverse events 
X
CTCAE Version 5.0
Height, weight, and body 
surface area
X 
 
Vital signs 
X 
Temperature, blood pressure, pulse rate, and 
respiratory rate 
Physical examination 
X 
 Includes respiratory auscultation 
X
Performance status 
X 
Lansky for age <16 years
Tumor imaging  
X 
 According to RECIST 1.1 
 Radiologic assessments obtained previously as 
part of routine clinical care may be used as the 
baseline assessment if they were done no more 
than 28 days before C1D1.  
 Perform CT scans of the chest, abdomen, pelvis, 
and the site of the known lesion(s) if located 
elsewhere. Same modality will be used 
throughout study 
 Scans will be performed and reviewed locally, 
and must be submitted to the sponsor designated 
facility. 
 See Section 3.9.1 
Hematology 
 
X 
Labs drawn within 7 days of C1D1 can be used 
for both screening/baseline and C1D1 
 See Attachment 2 for guidance on sample 
collection

J1S-MC-JP04(b) Clinical Protocol Addendum
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Day relative to C1D1
Procedure
28
14
Instructions
Clinical chemistry 
 
X 
Labs drawn within 7 days of C1D1 can be used 
for both screening/baseline and C1D1  
 See Attachment 2 for guidance on sample 
collection
Serum or urine pregnancy test 
 
X 
 Only females of childbearing potential 
 See Attachment 2 for guidance on sample 
collection  
 A negative serum pregnancy test, or a negative 
urine pregnancy test within 7 days prior to first 
study treatment on C1D1 is required.  
 For France, serum pregnancy test must be 
performed.  
Local practice and guidelines are applicable
Exploratory biomarkers (tumor 
tissue collection) 
X 
 Archival or fresh tumor sample will be collected, 
where available. The most recent sample is 
desired. Relapse or metastatic sample where 
available is preferred 
See Attachment 3
Abbreviations: C1D1 = Cycle 1 Day 1; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events (NCI 2017); RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1 
(Eisenhauer et al. 2009). 

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Table JP04.2. 
On-Study-Treatment Schedule of Activities  
Procedure 
All Treatment Periods (Cycle = 21 Days) 
Notes 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5-n 
Relative Day 
within Dosing 
Cycle 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
 
Concomitant 
medicationsa 
X  
 Collected continuously throughout study 
 Record all premedication, supportive care, and 
concomitant medication  
 See Section 3.7.6 
Adverse eventsa 
X  
 Collected continuously throughout study 
 CTCAE Version 5.0 
Height, weight, 
and BSA 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 -7 days is acceptable 
 BSA must be calculated with Mosteller 
formula (see also Attachment 6) 
Vital signsa 
See Notes 
 Temperature, blood pressure, pulse rate, and 
respiratory rate 
 Perform D1-5 of every cycle 
o Perform before irinotecan infusion and 
within 1 hour after each irinotecan infusion 
o Note: If not administering irinotecan (i.e., 
due to a dose hold), only Day 1 vitals are 
required 
Physical 
examination  
X 
 
 
X 
 
 
Xa 
 
 
Xa 
 
 
Xa 
 
 
 Complete before treatment administration 
 Include respiratory auscultation 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 

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Procedure 
All Treatment Periods (Cycle = 21 Days) 
Notes 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5-n 
Relative Day 
within Dosing 
Cycle 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
 
 
See Notes 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Performance 
status 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 Lansky for age < 16 years 
 
 
 Complete before treatment 
 Perform every other Cycle (1, 3, 5, etc.) 
Tumor imaging  
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 RECIST 1.1 
 Day 1 of C3, C5, C8, C11, C14 and every 3 
cycles thereafter 
 Up to 7 days before planned D1 is allowed 
 Same modality used at baseline  
 CT scans of the chest, abdomen, pelvis, and 
the site of the known lesion if located 
elsewhere 
 See Section 3.9.1 for additional guidance 

J1S-MC-JP04(b) Clinical Protocol Addendum 
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Procedure 
All Treatment Periods (Cycle = 21 Days) 
Notes 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5-n 
Relative Day 
within Dosing 
Cycle 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
 
Participant 
abemaciclib 
dosing diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 Provide to participants on C1D1, C2D1 and 
C3D1  
 Participants/caregiver should complete daily 
through Cycle 3 Day 21  
 Review diary at each study visit through 
C4D1 for the date and time of each dose (±3 
days is acceptable for review) 
Hematologyb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 See Attachment 2 for sample collection 
guidance 
 D1, D8, and D15 of all cycles 
 
before starting a new cycle of 
therapy (i.e., Day 1). If not starting a new 
therapy (i.e., Days 8 and 15), a window ±3 
days is acceptable.  
 May collect more frequently if indicated.  
 After Cycle 3, Days 8 and/or 15 CBCs may be 
eliminated if irinotecan has been discontinued 
 
Clinical 
chemistryb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 See Attachment 2 for sample collection 
guidance 
 D1, D8, and D15 for all cycles 
 
before starting a new cycle of 
therapy (i.e., Day 1). If not starting a new 
therapy (i.e., Days 8 and 15), a window ±3 
days is acceptable. May collect more 
frequently if indicated.  
 After Cycle 3, Days 8 and/or 15 clinical 
chemistry may be eliminated at investig
discretion. 

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Procedure 
All Treatment Periods (Cycle = 21 Days) 
Notes 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5-n 
Relative Day 
within Dosing 
Cycle 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
 
Urine and serum 
pregnancy testb 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 Only females of childbearing potential 
 See Attachment 2 for sample collection 
guidance 
 
required per local regulations and/or 
institutional guidelines 
 Serum confirmation only needed if urine test 
is positive 
Drug product 
acceptability and 
palatability 
questionnaire 
X 
 
 
X 
 
 
X 
See Notes 
 For Arm A participants only 
 For Day 1 of Cycles 1-3 (+3 days acceptable 
as long as participant is on-site), perform 
within approximately 30 minutes after dose 
 If the method of abemaciclib administration 
changes at any point during the trial, the 
questionnaire corresponding to the new 
administration method should be completed at 
the next clinic visit  
 See Section 3.9.1.1 
PK samples 
See Attachment 3 for sampling schedule 
See Section 3.9.4 and Attachment 2 for sample 
collection guidance 
Exploratory 
biomarkers 
(plasma, whole 
blood) 
See Attachment 3 for sampling schedule 
 Predose (C1D1) and at disease progression or 
time of study treatment discontinuation 
 See Attachment 2 for sample collection 
guidance 
Administer 
irinotecan 
See Notes 
Administer on Days 1-5 of each cycle 
Administer 
temozolomide 
See Notes 
 Administer on-site prior to irinotecan infusion 
on Days 1-5 of each cycle 
 If irinotecan is omitted, on-site visit is not 
required on Days 2-5 
Dispense 
See Notes 
Arm A only: PO BID per Section 3.7.1 

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Procedure 
All Treatment Periods (Cycle = 21 Days) 
Notes 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5-n 
Relative Day 
within Dosing 
Cycle 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
 
abemaciclib 
Participant returns 
study drugs 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Return at Day 1 of each cycle to assess 
compliance (± 5 days) 
Abbreviations: BID = twice daily; BSA = body surface area; C = cycle; CBC = complete blood count; CTCAE = Common Terminology Criteria for Adverse 
Events (NCI 2017); D = day; 
; IV = intravenous; 
; 
; PO = 
orally; PK = pharmacokinetics; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1 (Eisenhauer et al. 2009). 
a Virtual or remote visits, potentially partnered with a Home Health Service may be leveraged for participants when deemed appropriate by the investigator and 
allowed by local laws and regulations. 
b Home health service may be leveraged to collect and process laboratory samples prior to or during a 
 visit (on-site or virtual/remote). Must be 
allowed by local laws and regulations.  

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Table JP04.3. 
Poststudy-Treatment Follow-Up Schedule of Activities  
 
Short-Term Follow-Upa 
Long-
Term 
Follow-
Upd 
 
Visit
801 
802-8XX
 
Visit Interval 
Tolerance (Days)
 
 
Procedure 
Instructions
Concomitant 
medication 
Xb 
 
 
AE collection 
Xb 
X 
 CTCAE Version 5.0
 After Visit 801, only study treatment-related 
serious events are reported
Survival 
information
X 
X 
Poststudy treatment 
and anticancer 
therapy information 
Xb 
X 
 Telephone assessment is acceptable. For all 
participants, details on subsequent anticancer 
treatment (start/stop dates and treatments 
administered)
Height, weight
Xb
 
Vital signs 
Xb 
 
 Measure temperature, blood pressure, pulse rate, 
and respiratory rate
Physical 
examination 
Xb 
 
 Include respiratory auscultation 
Xb
 
 
X 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Performance status 
Xb 
 
 Lansky for age <16 years
 

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Short-Term Follow-Upa 
Long-
Term 
Follow-
Upd 
 
Visit
801 
802-8XX
 
Visit Interval 
Tolerance (Days)
 
 
Procedure 
Instructions
Tumor imaging  
X 
X 
 According to RECIST 1.1 
 No longer required after objective PD 
 Obtain within 4-6 weeks of treatment 
discontinuation due to clinical (not objectively 
confirmed) PD 
 V801 scan is not required if treatment 
discontinuation was not due to PD and the most 
recent scan prior to discontinuation was <90 
days. LTFU scan interval should remain every 
60-90 days until objective PD 
 CT scans of the chest, abdomen, pelvis, and the 
site of the known lesion if located elsewhere 
 Same modality used at baseline should be used 
throughout study 
 See Section 3.9.1 for additional guidance 
Hematology 
Xc
See Attachment 2 for sample collection guidance
Clinical chemistry 
Xc
See Attachment 2 for sample collection guidance
Exploratory 
biomarkers (plasma 
sample)
See Attachment 2 and Attachment 3 for 
sample collection guidance 
Only for participants who did not have a sample 
collected at the time of disease progression or at 
the time when study treatment was discontinued
Abbreviations: AE = adverse event; BSA = body surface area; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events (NCI 2017); 
; 
 
; LTFU = long-term follow-up; 
; PD = progressive disease; RECIST 
1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1.
a Short-term follow-up begins the day after the participant and the investigator agree that the participant will no 
longer continue study treatment and lasts approximately 30 days. In all cases, no follow-up procedures will be 
performed for a participant who withdraws informed consent unless he or she has explicitly provided permission 
and consent. 
b Virtual or remote visits, assumes partnered with a Home Health Service may be leveraged for participants when 
deemed appropriate by the investigator and allowed by local laws and regulations. 
c Site-provided home health service may be leveraged to collect and process laboratory samples prior to or during 
a 
 visit (on-site or virtual/remote). Must be allowed by local laws and regulations. 
d Long-term follow-up begins the day after the short-term follow-up visit is completed and continues until 
or study completion. Long-term follow-up visits should occur 
approximately every 2-3 months (Q60-90D).  
 
 

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Table JP04.4. 
Continued-Access Schedule of Activities  
 
Study 
Treatment
Follow-Up
a
 
Visit 
501-5XX
901
Procedure
 
 
Instructions
AE collection
X 
X
CTCAE Version 5.0
Administer abemaciclib 
X 
 
Administer irinotecan
X 
 
Administer temozolomide
X 
 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2017). 
a Continued-access follow-up begins 1 day after the participant and the investigator agree that the participant will 
no longer continue treatment in the continued-access period and lasts approximately 30 days. In all cases, no 
follow-up procedures will be performed for a participant who withdraws informed consent unless he or she has 
explicitly provided permission and consent. 
 

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3.3. Introduction  
Study JP04 is a Phase 2, global, multicenter, randomized, open-label study for pediatric and adult 
participants with relapsed or refractory 
-like tumors. The 
study will evaluate the benefits of adding abemaciclib to irinotecan and temozolomide.  
3.3.1. Study Rationale  
aggressive sarcoma of the bone and/or soft tissue, with a peak incidence 
in adolescents but can occur from infancy to adulthood. A multidisciplinary approach of 
neoadjuvant chemotherapy, surgery, or radiation (reserved for unresectable tumors) has 
improved 5-year EFS and OS to 69% and 72%, respectively, in the pediatric population (Leavy 
et al. 2008). However, 30% to 40% of those who present initially with localized or metastatic 
disease will ultimately suffer a disease recurrence (Leavey et al. 2008). Time to relapse is 
typically short: a median of only 1.4 years for patients with initial localized disease, and 12 
months for those initially metastatic (Leavey et al. 2008). The prognosis for patients after disease 
relapse is dismal with 5-year OS rate of only 13% and mOS of only 7 months following 
progression (Stahl et al. 2011; Diaz-Beveridge et al. 2015). Long-term survivors of relapsed 
 are rare. There is an urgent unmet need for new therapeutic strategies to 
improve this dismal prognosis. 
To date, salvage therapies remain inadequate and there is no single standard treatment for 
relapsed or refractory 
. Among the accepted regimens, although irinotecan and 
temozolomide have demonstrated some of the highest response rates of up to 63% and a 2-year 
OS rate of 36% in 
 patients (Casey et al. 2009; Raciborska et al. 2013; Ju et al. 
2021), these dismal outcomes highlight the need for continued improvements. Despite large 
multinational studies of novel combinations, treatment of 
 relies 
entirely on chemotherapeutic agents that have been largely unchanged for decades. This 
highlights a need for rationale-targeted therapies beyond conventional cytotoxic chemotherapy. 
Based on the role of CDKs in the activation of DNA-damage signaling and repair, along with the 
evidence of CDK pathway aberrations 
it is hypothesized that the addition of 
abemaciclib to irinotecan plus temozolomide may be of potential benefit for treatment of 
E
 
Study JP04 is designed to investigate the efficacy of abemaciclib in combination with irinotecan 
-like tumors. 
3.3.2. Background  
3.3.2.1. 
  
 is an aggressive sarcoma of the bone and/or soft tissue, most common in 
adolescence but reported from young children to adults. With the current multimodal therapies 
including dose intensified and interval compressed systemic chemotherapy with surgery and/or 
radiation, survival has improved for those with localized disease. Unfortunately, patients 
presenting with metastatic disease at initial diagnosis or those with relapsed disease have little 

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chance for cure. Even if relapse is limited and localized, the long-term survival is 22% to 24% 
and even less for patients with distant relapse (Rodríguez-Galindo et al. 2008). 
The t(11;22) chromosomal 
Delattre et al. over 20 years ago, and further research demonstrated that the resulting fusion 
protein EWSR1-FLI1 is expres
sarcoma-
-like tumors are undifferentiated round cell tumors that 
features are alternative rearrangements, such as CIC-rearrangements, BCOR-rearrangements, and 
EWSR1-non-ETS rearrangements, among others (Renzi et al. 2019). The response to standard 
-like subtypes (Renzi et al. 2019). Thus, additional 
research is needed to understand how to tailor treatment for tumors with unique rearrangements. 
the EWSR1-FLI1 fusion 
sarcoma phenotype and, therefore, was initially considered an ideal target. However, thus far, no 
EWSR1-FLI1-directed therapies have delivered a meaningful clinical benefit (Grohar et al. 
2017). This lack of efficacy may result from a lack of EWSR1-FLI1 enzymatic activity (Riggi et 
approaches relying on alternative mechanisms, such as cell-cycle inhibition. 
In 
oma, the cell cycle is deregulated by multiple mechanisms and Cyclin D1 has 
been shown to be a direct target of EWSR1-FLI1 (Matsumoto et al. 2001; Kowalewski et al. 
2011). 
 tumors frequently carry mutations in cell-cycle regulators, including 
overexpression of cyclin D1 (CCND1), amplification of CDK4, losses or low expression of CDK 
inhibitors (Kennedy et al. 2015) making CDK4/6 inhibition a logical target. Further research 
supporting exploration of CDK4 and 6 inhibition in 
rcoma was provided by 
demonstration of 
 cell line sensitivity to CDK4/6 inhibition and slowed growth 
in xenograft models after treatment with CDK4/6 inhibitors (Kennedy et al. 2015). 
3.3.2.2. 
Abemaciclib  
Abemaciclib is an orally administered, potent, and selective inhibitor of CDK4 and 6 currently 
approved for the treatment of hormone receptor-positive, human epidermal growth factor 
receptor 2-negative, advanced breast cancer as monotherapy and in combination with endocrine 
therapies (Dickler et al. 2017; Goetz et al. 2017; Sledge et al. 2017; Johnston et al. 2019). 
A goal of inhibiting CDK4 and 6 is to prevent cell-cycle progression through the G1 restriction 
point, thus arresting tumor growth. Cyclin-dependent kinases 4 and 6 participate in a complex 
with D-type cyclins to initiate the transition through the G1 restriction point, which controls 
entry into S phase and is essential for maintaining control of cell division (Sherr 1996; Ortega et 
al. 2002). 
The proposed investigation of abemaciclib in the treatment of 
 is based on both 
the mechanism of action and nonclinical data supporting critical involvement of the CDK4 
pathway in 
 tumors. Additionally, preclinical models demonstrate that cancers 
such as 
 with D-type cyclin-activating features, genomic aberrations known to 

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elevate D-cyclin levels, are sensitive to abemaciclib (Gong et al. 2017; Dowless et al. 2018). In 
the cell-deriv
-year-old patient), of 
the 6 animals treated with the triplet combination of abemaciclib, irinotecan, and temozolomide, 
1 had a partial regression and 5 had SD, while the 6 animals treated with temozolomide and 
irinotecan experienced progressive disease (Dowless et al. 2018). The combination was well 
tolerated based on evaluation of body weight. In addition, durable responses with abemaciclib in 
combination with irinotecan and temozolomide have been 
models (Dowless et al. 2018).
A673
for 28 
days), temozolomide and irinotecan (daily for 5 days, rest for 16 days, then daily for 5 
days), or abemaciclib, temozolomide, and irinotecan (same schedules for each drug as 
above). Treatment started on approximately Day 15. (A) Tumor volume over time; (B) 
tumor response assessment at Day 31 (Modified from Dowless et al. [2018]).
Abbreviations: CDX = cell-derived xenograft; PD = progressive disease; PR = partial response; SD = stable disease; 
T/C = treated tumor size divided by control tumor size; TMZ = temozolomide.
3.3.2.3. Irinotecan
Irinotecan is a topoisomerase I inhibitor frequently used in combination with temozolomide for 
treatment of relapsed or refractory 
(Casey et al. 
2009). The irinotecan AE profile is well documented and predictable. Notably, irinotecan can 
cause myelosuppression and early and late forms of diarrhea; early diarrhea may be accompanied 
by cholinergic symptoms (Irinotecan US Package Insert 2020).
3.3.2.4.
Temozolomide
Temozolomide is a DNA-alkylating agent widely used in combination with irinotecan in 
pediatric solid tumors (Casey et al. 2009). The safety profile of temozolomide is well established 
and predictable and is known to cause myelosuppression and hepatotoxicity (Temozolomide US 
Package Insert 2019). Per the SmPC, temozolomide is indicated for children from the age of 3 
years, adolescents and adult patients; however, temozolomide is globally also used in children 

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several publications (Wagner et al. 2004; Casey et al. 2009; Grill et al. 2013; Di Giannatale et al. 
2014; Kurucu et al. 2015; Moreno et al. 2017; Le Teuff et al. 2020; Defachelles et al. 2021). See 
also Section 3.5.5 for dose justification. 
3.3.2.5. 
Irinotecan and Temozolomide Combination  
irinotecan and temozolomide demonstrated schedule-dependent synergy and antineoplastic 
activity in pediatric 
al. 2000; Wagner et al. 2004, 2007). The combination delivered objective response rates of 29% 
with some CRs and a mean duration of response of 30 weeks in patients with relapsed or 
(Wagner et al. 2007) . Casey et al. reported a time to progression of 16.2 months in pediatric and 
2009). 
The combination of irinotecan and temozolomide is tolerated with manageable toxicities, 
including diarrhea, colitis, neutropenia, and thrombocytopenia (Casey et al. 2009). 
3.3.3. Benefit/Risk Assessment  
here is an urgent need 
for new strategic combinations incorporating targeted therapies into already accepted 
chemotherapy regimens. The irinotecan and temozolomide combination is a preferred regimen 
Thus, all participants will receive a known active 
therapy 
abemaciclib. The addition of abemaciclib may result in improved clinical benefit compared to 
irinotecan and temozolomide without abemaciclib. 
The combination of abemaciclib, irinotecan, and temozolomide was preliminarily characterized 
in the pediatric I3Y-MC-JPCS (JPCS) Phase 1b study. This combination exhibited a manageable 
safety profile. Treatment with the combination of abemaciclib, irinotecan, and temozolomide is 
expected to be tolerated and may delay disease progression. Prolonged disease control may also 
delay the need for further cytotoxic chemotherapy. 
Based on the overlapping toxicities of abemaciclib, irinotecan, and temozolomide, these are 
considered the most significant risks on JP04: 
 
 
 Grade 3-4 neutropenia 
 Grade 3-4 thrombocytopenia 
 febrile neutropenia 
 hepatotoxicity 
 ILD/pneumonitis, and 
 VTE. 

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Signs and symptoms of deep vein thrombosis and pulmonary embolism are closely monitored 
throughout the study and guidance for venous thromboembolic events is provided in Section 
3.9.3.1.3 and dose modifications are provided in Section 3.7.8.3.2. 
Hematology, hepatic, and renal function tests are regularly monitored throughout the study. 
Increased susceptibility to infection will be mitigated through regular hematology laboratory 
testing and monitoring of vital signs. These activities enable appropriate investigator oversight, 
including the identification and management of AEs. 
This combination of abemaciclib, irinotecan, and temozolomide was found to be tolerable in 
Study JPCS, a Phase 1b dose escalation trial in pediatric participants with relapsed or refractory 
solid tumors. In Study JPCS, hematological toxicities, such as neutropenia and 
thrombocytopenia, along with gastrointestinal toxicities, such as diarrhea and vomiting, were 
common AE events at the RP2D. The RP2D combination was abemaciclib 55 mg/m2 BID, 
irinotecan 50 mg/m2/day for 5 days along with temozolomide 100 mg/m2/day for 5 days.  
Appropriate safety assessments, on-study monitoring, and AE management are detailed in 
Section 3.9.3 and Section 9.2 of the CAMPFIRE Master Protocol. Risks are minimized with 
deliberate inclusion and exclusion criteria to ensure the safety of eligible participants selection. 
Additionally, participants will have vital sign monitoring, hematology and hepatic monitoring, 
and assessment of participant-reported symptoms monitored according to the SoA (Section 3.2). 
To begin each cycle of therapy, participants will be required to meet minimum laboratory criteria 
prior to the start of each cycle. When necessary, doses will be modified and/or omitted if 
required per Section 3.7.8.  
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of abemaciclib are to be found in the IB. 
More detailed information about the known and expected benefits and risks of irinotecan and 
temozolomide may be found in the Patient Information Leaflet, Package Insert, and/or Summary 
of Product Characteristics. 
Overall, the potential risks of the abemaciclib in combination with irinotecan and temozolomide 
are justified in consideration of the measures to minimize these risks and the potential benefit of 
improved disease control in participants with 
 a disease 
with a terrible prognosis and need for effective therapeutic options. 
3.3.3.1. 
Benefit/Risk Assessment of COVID-19  
Ensuring the health and safety of research participants, reducing the burden on the healthcare 
system, and upholding the integrity of clinical trial data are of the utmost importance. Based on 
sarcoma, the potential benefits study participants may receive outweigh the risks they may 
encounter by being on-site at the facility to receive treatment during the COVID-19 pandemic. 
Whether these patients seek treatment in a clinical trial setting or in a standard healthcare setting, 
the risk of COVID-19 infection will be present. Activities in this trial were designed to reflect 
the standard of care activities for this patient population. However, there are some additional 

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visits to ensure patient safety and to meet the trial objectives. These additional visits are not 
considered to pose a significant increase in risk, since standard local hospital/clinic procedures to 
prevent the spread of COVID-19 will be in place. 
 

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3.4. Objectives and Endpoints  
 
Table JP04.5 shows the objectives and endpoints of the study. 
Table JP04.5. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 To characterize the efficacy of abemaciclib in 
combination with irinotecan + temozolomide 
PFS as determined by BIRC using RECIST 
1.1 
Secondary 
 To evaluate the safety profile of abemaciclib, 
irinotecan, and temozolomide combination 
Safety (including but not limited to): 
TEAEs, SAEs, deaths, laboratory 
abnormalities, vital signs, and physical 
examinations 
 To characterize the clinical activity of 
abemaciclib, irinotecan, and temozolomide 
combination 
OS
 ORR 
 DoR 
 DCR 
 PFS as determined by investigator 
assessment using RECIST 1.1 
 To characterize the PK of abemaciclib in 
combination with irinotecan + temozolomide 
 Concentrations of abemaciclib 
 To assess the acceptability and palatability of 
the age-appropriate tablet and/or granule drug 
product, including dispersed tablets and/or 
granules 
 Assessment of tablet, granule, or dispersed 
drug product presentation, including 
acceptability and palatability 
Exploratory
 To explore the relationship between 
abemaciclib concentrations and clinical 
outcomes
 Outcomes such as clinical efficacy and 
safety 
 To explore correlation of biomarkers to 
clinical outcomes 
 Outcomes such as clinical efficacy and/or 
exposure parameters 
Abbreviations: BIRC = blinded independent review committee; DCR = disease control rate; DoR = duration of 
response; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; 
PK = pharmacokinetics; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1 (Eisenhauer 
et al. 2009); SAEs = serious adverse events; TEAE = treatment-emergent adverse event. 
 
 

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3.5.
Study Design
3.5.1.Overall Design
Study JP04, combined with Protocol J1S-MC-JAAA (hereinafter referred to as the CAMPFIRE 
Master Protocol), is a multicenter, randomized, open-label, Phase 2 study in participants with
.
Participants will be randomized 2:1 between 2 treatment arms and will be treated until disease 
progression or having met other discontinuation criteria.
Figure JP04.1 illustrates the study design.
Figure JP04.1.
Illustration of study design.
Abbreviations: n = number of participants; PFS = progression-free survival.
a
One futility analysis will occur after approximately 
 events have been observed. See Section 3.10.3.5.2.
3.5.1.1.
Criteria to Begin Day 1 of Subsequent Cycles (C2 and beyond)

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Treatment may be suspended for a maximum of 21 days to allow a participant sufficient time for 
recovery from study treatment-related toxicity. In exceptional circumstances, a delay >21 days is 
permitted upon agreement by Lilly CRP/CRS. 
3.5.2. Number of Participants  
At least 45 participants will be enrolled. 
 
 
3.5.3. End of Study Definition  
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 3.2) for the last participant. 
Study completion is the date of the last visit or last scheduled procedure associated with the final 
evaluation of all primary and secondary objectives. Investigators will continue to follow the SoA 
(Section 3.2) for all participants until notified by Lilly that study completion has occurred. 
 
3.5.4. Scientific Rationale for Study Design  
The overall rationale for the study design is described in Study Rationale (Section 3.3.1) and in 
the Statistical Considerations (Section 3.10) sections. Dose selection details can be found in 
Section 3.5.5. 
A randomized, controlled design is being used in this study. Randomization minimizes 
systematic bias in the selection and assignment of participants to study therapy and provides 
justification for inferential statistical methods to be used on data from this study. All randomized 
participants will receive irinotecan plus temozolomide, a standard of care in the treatment of 
articipants assigned to Arm A will also receive 
abemaciclib. However, participants in the control arm will not receive matching placebo. 
Therefore, participants and investigators will not be blinded to treatment assignment. This 
minimizes the burden placed on pediatric participants, and is additionally supported by the 
potentially unblinding adverse event profile of abemaciclib. A combination of randomization, a 
primary endpoint derived from a blinded, independent review committee, and a blinding plan to 
f the 
study and provide reliable evidence on the effectiveness of the study interventions. 
Additionally, the primary analysis will utilize a Bayesian-augmented control arm to incorporate 
historical data, minimizing the number of participants required to be randomized.  
In this study, collection of demographic information includes race and ethnicity. The scientific 
rationale is based on the need to assess variable response in safety and/or efficacy based on race 
or ethnicity. 
3.5.5. Justification for Dose  
Irinotecan and Temozolomide 

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The combination of irinotecan and temozolomide has been reported with a range of doses for 
 sarcoma trials, temozolomide 80-
150 mg/m2/day ×5 days with irinotecan 10-20 mg/m2/day ×5 days (sometimes repeated 2 
consecutive weeks) has demonstrated tolerability and efficacy (Wagner et al. 2007; Casey et al. 
2009; McNall-Knapp et al. 2010; Wagner et al. 2010; Bagatell et al. 2011; Hernández-Marqués 
et al. 2013; Palmerini et al. 2018). Importantly, different schedules of irinotecan administration 
in children with relapsed rhabdomyosarcoma showed that a shorter course of 50 mg/m2/day ×5 
days is equivalent to the longer, more protracted schedule of 20 mg/m2/day for 10 days thus 
reducing participant and caregiver burden of frequent clinic visits for IV infusions (Mascarenhas 
et al. 2010). Therefore, in this study, temozolomide 100 mg/m2/day and irinotecan 50 mg/m2/day 
will be administered on Days 1 through 5 of a 21-day cycle. These doses, in combination with 
abemaciclib, were tolerated in the Phase 1b JPCS study. 
Abemaciclib 
In Study JPCS, abemaciclib was administered at 2 dose levels in combination with 
temozolomide and irinotecan: 55 and 70 mg/m2 BID. These doses were originally selected for 
exploration based on the BSA-adjusted adult dose used in abemaciclib combination studies. 
Abemaciclib is predominantly cleared by CYP3A4, which is expected to have matured after the 
first year of life (Bartelink et al. 2006). Therefore, between the age of 1 to 18 years, CYP-
mediated metabolism is largely dependent on liver volume, which is better correlated with BSA 
rather than body weight (Bartelink et al. 2006). 
 
 
  
Based on the safety, tolerability, and PK of the drug combination in Study JPCS, the abemaciclib 
dose of 55 mg/m2 was declared to be the RP2D when given together with irinotecan 
50 mg/m2/day ×5 days and temozolomide 100 mg/m2/day ×5 days in 21-day cycles. 
Study JP04 includes both adults and pediatric participants. 
 
 
  
 
 
 
 
 

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3.6. Study Population  
3.6.1. Inclusion Criteria  
Participants are eligible to be included in the Study JP04 only if they meet all of the inclusion 
criteria in Section 6.1 of the CAMPFIRE Master Protocol and the following criteria: 
Age and Weight 
[35] 
Participants aged 1 to <40 years  
[36] 
Body 
 kg  
Disease and Participant Characteristics 
[37] 
-like 
tumor by institutional pathologist at time of original diagnosis. The original pathological 
report is required. Repeat biopsy at progression is not required 
[38] 
Must be able to swallow and/or have a gastric/nasogastric tube  
a) Participants in the European Union must be able to swallow intact capsules 
[39] 
If on systemic steroids at study entry, the dose must be stable or decreasing during the 7 
days prior to C1D1 
[40] 
Life expectancy of at least 8 weeks and able to complete at least 1 cycle of treatment 
[41] 
Participants/caregivers are able and willing to make themselves available for the duration 
of the study and are willing to follow study procedures, including adherence to the PK 
sampling schedule 
3.6.1.1. 
Exceptions to the CAMPFIRE Master Protocol Inclusion Criteria  
For Study JP04, the below inclusion criteria should be used in place of the CAMPFIRE Master 
Protocol inclusion criteria of the corresponding number. 
[1] 
Refractory disease or confirmed radiological progression or recurrence following first or 
-like tumor.  
a. Must have one measurable or evaluable lesion per RECIST 1.1 (Eisenhauer et al. 
2009) 
[3] 
Adequate performance status based on age 
a) 
 
b) 
 
Note: Participants who are unable to walk because of paralysis, but are up in a 
wheelchair, will be considered ambulatory for the purpose of assessing the 
performance score 
[4] 
Participants must have discontinued all previous treatments for cancer or investigational 

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enrollment, unless 
peripheral sensory neuropathy are acceptable) or as specified in Inclusion Criterion 5. 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. For additional therapies 
not mentioned in the table, including targeted therapies, consult with the Lilly CRP/CRS for the 
appropriate length of time prior to the first dose of study treatment. 
Previous Treatment 
Length of Time Prior to First Dose of Study Treatment 
Cytotoxic and myelosuppressive 
chemotherapy 
 
Hematopoietic growth factors 
-acting growth factor (e.g., pegfilgrastim)  
-acting growth factor
Cellular therapy
., modified T or NK cells) 
Interleukins, interferons, and cytokines 
leukins or interferon and cytokines (other than 
hematopoietic growth factors)
Radiotherapy 
., local palliative) 
-
 
Autologous stem cell infusion  
84 days  
Corticosteroids 
14 days after 
 to modify immune AEs.  
Note: Participants on chronic replacement or a stable/decreasing dose for 
at least 7 days may be eligible (consult Lilly CRP/CRS)
Live vaccines 
live virus are permitted)
Abbreviations: AE = adverse event; CRP/CRS = clinical research physician/clinical research scientist; NK = natural 
killer; TBI = total body irradiation. 
[5] 
Cycle 1: 

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System
Laboratory Value
Hematologic
Absolute neutrophil count 
1000/µL 
G-
to C1D1 not allowed 
Platelets 
75,000/mm3  
Hemoglobin
8 g/Dl
g/L) 
 
Hepatic
Total bilirubin 
1.5× ULN  
Exception: <3.0× ULN for participants with Gilbert Syndrome
ALT and AST 
3× ULN 
Exception: 5.0× ULN if the liver has tumor involvement
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; C1D1 = Cycle 1 Day 1; G-
CSF = granulocyte-colony stimulating factor; PRBC = packed red blood cell; ULN = upper limit of normal. 
 
 mL/min/m2 or serum creatinine based on 
age/gender (see Appendix 5 of the CAMPFIRE Master Protocol) 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 
 
1.7 
1.5 
[6] 
Female participants of childbearing potential must have a negative urine or serum 
pregnancy test within 7 days prior to Cycle 1 Day 1. For France, serum pregnancy 
test must be performed. 
[7] 
Women of reproductive potential must agree to use highly effective contraceptive 
precautions (and avoid sperm donation for males) during the trial. For 
abemaciclib, females should use contraception for at least 3 weeks following the 
last abemaciclib dose. After the last dose of irinotecan and temozolomide, females 
should use contraception for at least 6 months, and male participants with a 
WOCBP partner should use contraception for at least 3 months. Following last 
dose of temozolomide treatment, men must refrain from sperm donation per 
product label.  
See Attachment 7 for additional details on contraceptive guidance and the 
collection of pregnancy information. 
3.6.2. Exclusion Criteria  
Participants will be excluded from Study JP04 if they meet any of the exclusion criteria in 
Section 6.2 of the CAMPFIRE Master Protocol or the following criteria: 

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[42] 
Have received any prior CDK4 and 6 inhibitor 
[43] 
Progression during prior treatment with irinotecan and/or temozolomide 
[44] 
Have a known intolerability or hypersensitivity, such as urticaria, allergic reaction 
including anaphylaxis, toxic necrolysis, and Stevens-Johnson syndrome, to any of the 
study treatments or dacarbazine 
[45] 
Diagnosed and/or treated additional malignancy within 3 years prior to enrollment that, in 
the judgment of the investigator and Lilly, may affect the interpretation of results, with 
the exception of curatively treated basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, and/or curatively resected in situ cervical and/or breast cancers 
[46] 
A serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of 
the investigator, would preclude participation in this study (such as severe 
myelosuppression, interstitial lung disease, severe dyspnea at rest or requiring oxygen 
therapy, current bowel obstruction, history of major surgical resection involving the 
preexisting chronic condition resulting in clinically significant diarrhea). 
3.6.2.1. 
Exceptions to the CAMPFIRE Master Protocol Exclusion Criteria  
There are no exceptions to the CAMPFIRE Master Protocol exclusion criteria.  
3.6.3. Lifestyle Restrictions  
Participants should refrain from consuming grapefruit, grapefruit juice, and grapefruit-containing 
products while on study due to the effect on CYP3A4. 
3.6.4. Screen Failures  
This section should be used in place of Section 6.4 of the CAMPFIRE Master Protocol. 
Screen failures are defined as participants who consent/assent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Individuals may be rescreened 1 time. 
weeks. 
acceptable representative, parent(s), or legal guardian (when applicable) must sign a new 
informed consent form (ICF) and assent (if applicable) and will be assigned a new identification 
number. Repeating of laboratory tests during the screening period or repeating screening tests to 
comply with the protocol-designated screening period does not constitute rescreening.  
Screening must occur within 28 days of Cycle 1 Day 1, but a 7-day window beyond 28 days is 
acceptable without being considered as a protocol deviation or screen fail. 

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3.7. Treatments  
3.7.1. Treatments Administered  
Table JP04.6 shows the treatment regimens. 
Table JP04.6. 
Treatment Regimens 
Starting Doses 
Cycle = 21 days 
 
Abemaciclib PO 
Irinotecan IV 
(Days 1-5 each cycle) 
Temozolomide 
PO 
(Days 1-5 each 
cycle) 
<18 years 
 
Arm A 
55 mg/m2 BID  
(max dose 100 mg BID)
100 mg BID 
50 mg/m2/day × 5 
100 mg/m2/day × 5
Arm B 
None 
50 mg/m2/day × 5 
100 mg/m2/day × 5
Authorized 
as defined 
by EU 
Clinical 
Trial 
Regulation 
Authorized and not used according to EU 
authorization 
 
Authorized and not 
used according to EU 
authorization 
 
Authorized and 
not used according 
to EU 
authorization 
 
Abbreviations: BID = twice daily; IV = intravenous; PO = orally. 
Participants will begin dosing-assigned treatment on Cycle 1 Day 1. A cycle is defined as an 
interval of 21 days timed to irinotecan and temozolomide. The 21-day cycle, anchored to 
irinotecan and temozolomide, should be maintained throughout the treatment phase. Cycles may 
not be less than 21 days. 
When delays are required, doses should be resumed at the earliest medically appropriate 
opportunity based on investigator judgment and dose adjustment guidelines (Section 3.7.8).  
Treatment will continue until progression, unacceptable toxicity, or other discontinuation criteria 
are met (Section 3.8). 
A delay to the start of a cycle of a dose due to holiday, weekend, weather, or other unforeseen 
circumstances will be permitted for a maximum of 7 days and not counted as a protocol 
deviation. In exceptional circumstances, a delay of >7 days is permitted upon agreement between 
the investigator and the Lilly CRP/CRS. Abemaciclib treatment may continue during the delay if 
there is sufficient drug supply and if there are no toxicities that would prevent treatment. 
Irinotecan and temozolomide must be administered on 5 consecutive days. 

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Packaging and labeling 
Treatments administered in the study will be supplied by the sponsor in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements.  
3.7.2. Method of Treatment Assignment  
ducted by the 
investigational site. Upon confirmation of eligibility, the site will register the participant by 
assigning the participant a unique study identification number via the IWRS, which is accessible 
24 hours a day. Study treatment will be allocated to participants using the IWRS. Participants 
who meet all enrollment criteria will be randomly assigned to receive study treatment.  
Participants will be stratified by 
 time 
8), 
 isolated pulmonary metastases vs other metastases (Leavey et al. 2008), and 
 age 
). 
3.7.3. Blinding  
This is an open-label study. The participant, caregiver, and all staff involved in treating and 
caring for study participants will have full knowledge of treatment assignments. 
To maintain the scientific integrity of this trial, 
access to aggregate safety and 
efficacy data will be strictly controlled prior to the interim and final analyses. Access to the 
electronic data capture (eDC) system will be limited to those who require this information for 
their role, and all access will be documented. 
For the accumulated aggregate database, that is, the database to which Lilly statisticians (or those 
of its designee) have access, treatment assignment and other parameters that can disclose 
treatment assignment will be scrambled or masked. Therefore, the sponsor and all investigative 
sites will remain blinded to treatment group assignments for the aggregate database until the 
database lock for the final analysis. Scrambled treatment assignments will be used in the 
reporting database until the study reaches its final analysis or the study is determined to be 
positive by the DMC. During this time, analyses using unblinded treatment codes will be 
performed only at the interim analysis points specified in the protocol/SAP.  
For those safety and efficacy analyses assigned to the DMC, only the designated SAC, which is 
independent of the sponsor, will perform analyses on unblinded data, that is, an aggregate 
database with correct treatment assignments. 
Further details are included in the study blinding plan. 

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3.7.4. General Dosing Instructions  
Obesity: For participants 
 kg/m2, the American Society of Clinical Oncology 
Guidelines recommends calculation of dose using the actual body weight for calculation of body 
surface area- or weight-based dosing (ASCO [Griggs et al. 2012]). 
For each cycle, the actual dose administered for study drugs must be within 10% of the planned 
dose; any total cycle dose that is not within 10% (either > 110% or < 90%) of the planned dose 
will result in a protocol deviation. Please contact the Lilly CRP/CRS to discuss any questions for 
individual situations. 
3.7.4.1. 
Abemaciclib  
For participants in Arm A, abemaciclib will be administered at a starting dose of 55 mg/m2 PO 
BID continuously throughout the study unless interrupted for toxicity. Doses will be 
administered at approximately the same times on each day. Please see Attachment 6 
(abemaciclib dosing chart) to determine if a change in BSA necessitates a change in abemaciclib 
dosing. 
Abemaciclib is provided as either 25 mg tablets, 50 mg tablets, or 2.5 mg granules.
 
Abemaciclib should be taken BID (with at least approximately 6 hours separating doses) at the 
same time each day.  
Participants taking abemaciclib tablets should be instructed to swallow tablets whole and not 
chew or crush them. If the participant is unable to swallow the abemaciclib tablets or oral 
granules, please refer to Section 3.7.7. Participants taking oral granules should follow the 
provided instructions for using the measuring device and administering the drug. 
 
 
 
 
3.7.4.2. 
Irinotecan  
Irinotecan will be administered at a starting dose of 50 mg/m2/day as an IV infusion over 90 
minutes (unless approved otherwise by the Lilly CRP/CRS) on Days 1-5 of each cycle unless 
interrupted for toxicity. It is recommended to allow a minimum of 20 hours between sequential 
days of irinotecan dosing. 
Participants with prior abdominal/pelvic radiotherapy, or total body irradiation for bone marrow 
transplantation should have irinotecan dose reduced to 37.5 mg/m2/day at start of therapy. 
Impaired glucuronidation: Participants known to have reduced UGT1A1 activity, such as an 
UGT1A1*28 or UGT1A1*6 allele, may have increased risk of hematological toxicity and/or 

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diarrhea. An irinotecan dose reduction at the start of therapy should be considered for these 
participants. Additionally, participants with reduced UGT1A1 activity should be carefully 
monitored for hematologic toxicities and diarrhea. UGT1A1 testing is not required. 
3.7.4.3. 
Temozolomide  
Temozolomide will be administered at a starting dose of 100 mg/m2/day PO daily on Days 1-5 of 
each cycle unless interrupted for toxicity. Except for C2D1 and C4D1 when PK collection is 
required and temozolomide must be administered at the study site, temozolomide may be 
administered either at home or on-site. Doses may be rounded per local clinical practice. 
Temozolomide should be administered on an empty stomach approximately 1 hour prior to 
irinotecan infusion and can be administered with abemaciclib. If a participant spits out or vomits 
temozolomide within 15 minutes of ingestion, the dose should be repeated. If vomiting occurs a 
second time, the dose should not be repeated. IV temozolomide is not allowed. 
3.7.4.4. 
Supportive Care  
Participants should receive full supportive care to maximize quality of life. All supportive care 
should be recorded on the eCRF. 
 The use of G-CSF is permitted for all cycles, including first cycle, based on ASCO 
(Smith et al. 2015) and European Society for Medical Oncology (Crawford et al. 2010) 
guidelines. Administration of G-CSF is encouraged for all participants, regardless of 
treatment arm, at high risk of 
. 
 If clinically indicated, erythropoietin, packed red blood cell transfusions, and other blood 
products may be used according to the ASCO guidelines (Rizzo et al. 2008). 
 Prophylactic antibiotic treatment should be consistent with ASCO guidelines 
Lehrnbecher et al. 2017). 
3.7.4.5. 
Premedication  
Nausea and vomiting have been frequently reported with irinotecan and temozolomide. 
Prophylactic anti-emetics(s) are recommended before each daily treatment with irinotecan and 
temozolomide. 
Consider atropine IV or subcutaneous in participants with cholinergic symptoms (e.g., increased 
salivation, rhinitis, miosis, diaphoresis, and abdominal cramping) or early-onset diarrhea-
associated with irinotecan. 
3.7.4.6. 
Supportive Management for Diarrhea  
Both abemaciclib and irinotecan frequently cause diarrhea. Importantly, participants should 
receive instructions on the management of diarrhea at the start of each cycle. Along with 
standard fluid and electrolyte management, loperamide is recommended. Though it may be 
difficult, investigators should determine the most likely cause of diarrhea as therapeutic 
interventions differ according to the offending agent.  
3.7.4.6.1. 
Diarrhea suspected due to irinotecan  
Early diarrhea occurs during or shortly after irinotecan infusion. It is usually transient and 
infrequently severe. It may be accompanied by cholinergic symptoms of rhinitis, increased 
salivation, miosis, lacrimation, diaphoresis, flushing, and abdominal cramping.  

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Prophylactic or concomitant use of antibiotics, such as cefixime and cephalosporin, can be used 
for irinotecan-
 
prescribing information for additional management of diarrhea attributed to irinotecan. 
Early diarrhea and the associated cholinergic symptoms may be prevented. Consider 
prophylactic or therapeutic administration of atropine (according to label or institutional 
practice) unless clinically contraindicated. 
Late diarrhea 
24 hours after irinotecan infusion, can be prolonged, and may 
lead to dehydration, electrolyte imbalance, or sepsis. Late irinotecan-induced diarrhea can 
be complicated by colitis, ulceration, bleeding, ileus, obstruction, infection. It can be life-
threatening. 
3.7.4.6.2. Diarrhea suspected due to abemaciclib  
Diarrhea was the most frequently reported TEAE with abemaciclib in the adult Phase 3 
registration studies (MONARCH 2 [Sledge et al. 2017]; MONARCH 3 [Goetz et al. 2017; 
Johnston et al. 2019]; monarchE [Johnston et al. 2020]). Diarrhea was generally manageable 
with standard anti-diarrheal agents and dose adjustment. 
3.7.4.6.3. 
Management of Diarrhea  
It is important for all participants to receive education about diarrhea potential with irinotecan 
and abemaciclib before beginning therapy. Diarrhea related to abemaciclib is most frequent in 
the early cycles and is manageable with supportive measures. These should be discussed before 
symptoms arise so that participant and caregivers are prepared. 
anti-diarrhea therapy (e.g., loperamide or 
. Participants should be encouraged to drink at least maintenance volumes 
of fluids based on their age and body size. 
Participants and caregivers should be in communication with the investigative site for 
recommendations to monitor and replace fluid and electrolytes. Site personnel should assess 
participant by phone or at the site within 24 hours of diarrhea onset to monitor hydration status 
and diarrhea severity. 
If associated with severe nausea and/or vomiting such that the participant is unable to maintain 
hydration with enteral fluids, then the participant should be admitted for IV hydration, electrolyte 
replacement, and close monitoring. 
If diarrhea is associated with fever or severe neutropenia, broad-spectrum antibiotics should be 
prescribed per institutional guidelines. 
Follow dose-modification guidance in Section 3.7.8.3.2, including dose suspension and/or 
reduction as appropriate.
3.7.5. Pneumocystis prophylaxis  
Pneumocystis jirovecii pneumonia may occur in participants receiving irinotecan and 
temozolomide. This risk is increased in those receiving corticosteroids or with longer treatment 
regimens. PCP prophylaxis is encouraged.  

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3.7.6. Concomitant Therapy  
No other chemotherapy, investigational medications, immunotherapy, hormonal cancer therapy, 
herbal supplements and/or herbal drugs intended to treat cancer will be permitted while 
participants are on study treatment.  
Palliative radiation and surgery for cancer may be allowed after discussion with the Lilly CRP. 
A list of restricted and excluded concomitant therapies and exceptions is provided in Attachment 
5. All premedication, supportive care, and concomitant medication must be reported on the CRF 
at each visit. 
3.7.7. Participants with Difficulty Swallowing  
If, after initiating study treatment, a participant develops difficulty swallowing, the following 
should be considered.  
 
Abemaciclib: 
 
 
 
 
 
 
 
 
 
 
 
 
Temozolomide: 
o follow standard of care for alternative administration (Trissel et al. 2006; CCLG 
2016).  
o IV administration of temozolomide is not allowed.  
o 
 
 
3.7.8. Dose Modification  
3.7.8.1. 
Planned or anticipated logistical delays  
For planned logistical delays (including but not limited to vacation or holidays), additional 
abemaciclib may be dispensed and continued until next scheduled site visit. In the event that the 
participant has met criteria to begin the next cycle, but the start (i.e., Day 1) is delayed due to 
logistical reasons, so long as the participant has adequate abemaciclib supply, they should 
continue until next Day 1 visit. If a treatment is interrupted due to inadequate abemaciclib supply, 
the cycle will continue and next irinotecan and temozolomide administrations should remain on 
previous schedule; in other words, the missed abemaciclib doses will not be made up. 

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For participants undergoing surgery, refer to the following guidelines for abemaciclib dose 
modifications: 
 Minor surgeries and procedures: investigators should treat as clinically indicated and 
closely monitor any signs of infection or healing complications. 
 Major surgeries: suspend abemaciclib for 7 days before surgery and resume as clinically 
indicated. 
 Both absolute neutrophil and platelet counts should be adequate before resuming 
abemaciclib. Surgical wounds should be without infection and healing well. 
 
 
3.7.8.1.1. 
Additional Guidance for Surgeries  
If a tumor becomes operable while on study treatment, the participant may undergo surgical 
resection to remove the lesion. A participant who undergoes surgery is not considered 
noncompliant and does not incur a protocol deviation. 
3.7.8.2. 
Discontinuation of One Study Treatment  
Participants may discontinue irinotecan and/or temozolomide (due to chemotherapy-associated 
toxicities) while continuing abemaciclib upon discussion with the Lilly CRP/CRS. If abemaciclib 
must be discontinued, participants may continue to receive irinotecan and/or temozolomide. For 
all study drugs, if dose reductions are required beyond the lowest dose, the drug should be 
discontinued. 
discretion and the individual 
 situation. Prior to continuing the participant on 
chemotherapy beyond Cycle 12, the investigator should discuss with the Lilly CRP/CRS. 
Abemaciclib may continue beyond Cycle 12 until discontinuation criteria is met.  
 
 

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3.7.8.3. 
Dose-Modification Guidance due to Toxicity  
Dose reductions of abemaciclib, irinotecan, and temozolomide should follow the guidance 
outlined in the following tables. The investigator may use his/her discretion if more conservative 
dose modifications are necessary beyond what is outlined in Sections 3.7.8.3.1 and 3.7.8.3.2. If 
the investigator considers specific modifications are necessary for an individual participant, this 
can be discussed and approved by the Lilly CRP/CRS. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
3.7.8.3.1. Dose Modification for Hematologic Toxicities  
Hematological toxicities of abemaciclib overlap with those caused by irinotecan and 
temozolomide. Neutropenia is common with all 3 study treatments and was frequent in Study 
JPCS with this combination. Empiric use of G-CSF is encouraged. The tables below offer 
guidance for dose modifications for neutropenia, febrile neutropenia, and thrombocytopenia. No 
dose modifications are required for anemia, leukopenia, or lymphopenia. 
When reduced, abemaciclib should still be taken twice daily; in other words, reduce each dose of 
each administration rather than eliminate either the morning or evening dose. 
 
 

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Dose Modification for Neutropenia 
Note: For hematologic toxicities, dose holds, and reductions - apply simultaneously to all drugs as indicated  
 
Abemaciclib 
Irinotecan 
Temozolomide 
Severity and 
Duration
Dose 
Hold
Dose 
Reduction
Dose 
Hold 
Dose Reduction 
Dose Hold 
Dose Reduction 
Grade 3  
Recommend G-CSF in subsequent cycle 
Grade 4 
Initial incident 
Hold until 
ANC 
Consider 1 
dose level 
reduction.  
 
If already 
taking G-
CSF, reduce 
1 dose level.
Hold until 
ANC 
Reduce 1 dose level 
 
Recommend G-CSF 
in subsequent cycle 
Hold until 
ANC 
 
No reduction 
 
Recommend G-CSF 
in subsequent cycle 
Grade 4
>7 days duration 
or 
>14-day cycle 
delay 
Reduce 1 
dose level 
 
Recommend 
G-CSF in 
subsequent 
cycle 
Reduce 1 dose level 
 
Recommend G-CSF 
in subsequent cycle 
Grade 4 
Recurrenta 
Reduce 1 dose level
 
Recommend G-CSF 
in subsequent cycle
Dose Modification for Febrile Neutropenia
Note: For hematologic toxicities, dose holds, and reductions - apply simultaneously to all drugs as indicated
Grade 3 
Initial incident 
Hold until 
resolution 
Consider 1 
dose level 
reduction 
 
Recommend 
G-CSF in 
subsequent 
cycle
 
Hold until 
resolution 
Consider 1 dose 
level reduction 
 
Recommend G-CSF 
in subsequent cycle 
No change 
Grade 3 
Recurrenta 
Reduce 1 
dose level 
 
Recommend 
G-CSF in 
subsequent 
cycle 
Reduce 1 dose level
Recommend G-CSF 
in subsequent cycle
Grade 4 
Reduce 1 dose level 
if not previously on 
G-CSF 
 
Reduce 2 dose 
levels if G-CSF was 
used 
 
Recommend G-CSF 
in subsequent cycle
Hold until 
resolution 
Reduce 1 dose level 
 
Recommend G-CSF 
in subsequent cycle 
Abbreviations: ANC = absolute neutrophil count; G-CSF = granulocyte-colony stimulating factor. 
Grade 3: ANC < 1000/mm3; Grade 4: ANC < 500/mm3. 
a Recurrent toxicity refers to the same event occurring within the next 8 weeks (as measured from the stop date of 
the preceding event). 
 

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Dose Modification for Thrombocytopenia 
Note: For hematologic toxicities, dose holds, and reductions - apply simultaneously to all drugs as indicated 
 
Abemaciclib 
Irinotecan 
Temozolomide 
Severity and 
Duration 
Dose Hold 
Dose 
Reduction
Dose Hold 
Dose 
Reduction
Dose Hold 
Dose Reduction 
Grade 2 that 
causes >7-day 
cycle delay 
Hold until 
 
No change 
No change 
Hold until 
 
 
No change 
Grade 3
that causes >7-
day cycle delay 
Reduce 1 dose level 
Grade 4  
Initial incident 
Consider 1 
dose level 
reduction 
Hold until 
platelets
 
 
No change 
Reduce 1 dose level 
 
If platelet count ever 
drops below 
10.000/mm3, 
discontinue 
Grade 4
>7 days duration 
or 
>14-day cycle 
delay 
Reduce 1 
dose level 
 
 
Reduce 1 dose 
level 
Grade 4 
Recurrent 
Discontinue 
Grade 2: platelets < 75,000/mm3; Grade 3: platelets < 50,000/mm3; Grade 4: platelets < 25,000/mm3. 
 
 

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3.7.8.3.2. Dose Modification for Non-Hematologic Toxicities  
Dose Modification for Hepatic Toxicity 
Note: For hepatic toxicities, dose holds, and reductions - apply simultaneously to all drugs as indicated 
Toxicity 
Severity 
Abemaciclib 
Irinotecan 
Temozolomide
Dose Hold 
Dose 
Reduction
Dose 
Hold
Dose 
Reduction
Dose Hold 
Dose 
Reduction
ALT/AST 
Increased 
with 
normal 
bilirubin 
Persistent or 
recurrenta 
Grade 2
Hold until 
 
Reduce 1 
dose level 
No change 
No change 
Grade 3b 
Hold until 
Grade 1 
Reduce 1 
dose level 
Hold until 
 
Reduce 1 dose 
level 
Grade 4 
Discontinue 
Discontinue 
Discontinue 
ALT/AST 
Increased 
with 
increased 
bilirubin 
in the 
absence of 
cholestasis
ALT/AST 
and total 
bilirubin 
>2× ULN 
Discontinue 
Discontinue 
Discontinue 
Elevated 
Bilirubin 
with 
normal 
AST/ALT 
1.5-2× ULN 
No change 
Hold until
 
Reduce 1 
dose level 
No change 
>2× ULN 
Discontinue 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal. 
a Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event). 
b Grade 3 AST/ALT increase (>5× ULN or 5× baseline) is a trigger for additional assessments and hepatic 
monitoring. See Section 3.9.3.1.1 for additional guidance for hepatic monitoring. 
 
 

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Dose Modification for Diarrhea 
Note: Abemaciclib-associated diarrhea is common in the initial cycles and is less frequent in later cycles. Per 
discretion, dose reductions may be implemented sequentially 
 
Abemaciclib 
Irinotecan 
Severity and 
Duration
Dose Hold 
Dose Reduction 
Dose Hold 
Dose Reduction 
Grade 2
that does not 
resolve within 24 
Hold until Grade 1 
May reduce 1 
level 
Hold until Grade 1 
May reduce 1 level 
Grade 2
that persists or 
recursa after 
resuming the same 
dose despite 
maximal 
supportive 
measures 
Hold until Grade 1 
Reduce 1 dose 
level 
Reduce 1 dose level 
Grade 3 
Grade 4 
Hold until Grade 1  
Reduce 2 dose levels 
Any grade that 
requires 
hospitalization 
Hold until Grade 1 
Reduce 2 dose levels 
a Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the same 
event occurring within the next 8 weeks (as measured from the stop date of the preceding event). 
 
Dose Modification for ILD/Pneumonitis 
Note: For ILD/pneumonitis, dose holds, and reductions - apply simultaneously to all drugs as indicated 
Severity 
Abemaciclib 
Irinotecan 
Dose Hold 
Dose 
Reduction 
Dose Hold 
Dose Reduction 
Grade 2 that persists or recurs despite 
maximal supportive measures and does not 
return to baseline or Grade 1 within 7 days 
Hold until 
Grade 1 
Reduce 1 dose 
level 
Hold until 
Grade 1 
Reduce 1 dose 
level 
Grade 3  
Discontinue 
Grade 4
Abbreviation: ILD = interstitial lung disease. 
 
 

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Dose Modification for Venous Thromboembolic Events
Note: For VTE, dose holds, and reductions - apply simultaneously to all drugs as indicated
Severity 
Abemaciclib
Irinotecan
 
Dose Hold 
Dose 
Reduction
Dose Hold 
Dose Reduction 
Grade 1 or 2 
Hold dose and 
treat as clinically 
indicated. 
Abemaciclib 
may be resumed 
when the 
participant is 
clinically stable.
No change 
Hold dose and treat 
as clinically 
indicated. 
Irinotecan may be 
resumed when the 
participant is 
clinically stable. 
No change 
Grade 2 
Persistent or 
recurrenta,b 
 
Hold until 
resolved 
Reduce 1 
dose level 
Hold until resolved 
Reduce 1 dose level 
Grade 3 
Grade 4 
a Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event). 
b that does not resolve with maximal supportive measures within 7 days. 
 
Dose Modification for Non-Hematologic Toxicities 
(Except nausea, diarrhea, ALT/AST increased, VTE, ILD/pneumonitis, or deemed clinically insignificant by the 
investigator) 
 then initial dose hold and 
reductions may be made for individual, 2, or all 3 drugs as deemed appropriate by the investigator.  
Severity 
Abemaciclib 
Irinotecan 
Temozolomide 
Dose Hold 
Dose 
Reduction
Dose Hold 
Dose 
Reduction 
Dose Hold 
Dose 
Reduction
Grade 2
Persistent 
or 
recurrenta,b
Hold until 
Grade 1 
Reduce 1 dose 
level 
No change 
 Hold until 
Grade 1 
No change 
Grade 3 
Hold until  
 
Reduce 1 dose 
level 
Hold until 
Grade 1 
Reduce 1 
dose level 
Grade 4
Discontinue
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ILD = interstitial lung disease. 
a Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event). 
b that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1. 
 
 

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3.7.9. Treatment Compliance  
This section should be used in place of the requirements specified in Section 7.6 of the 
CAMPFIRE Master Protocol. 
The participant 
compliant unless dose holds are necessitated by AE. Dose suspensions or cycle delays will not 
result in a participant being considered as noncompliant. A participant may be considered 
noncompliant if he/she is judged by the investigator to have intentionally or repeatedly taken 
s of study treatment in a cycle. Potential discontinuation of a 
participant due to noncompliance will be discussed between the investigator and the Lilly 
CRP/CRS before any determination is made.  
3.8. Discontinuation Criteria  
Refer to the CAMPFIRE Master Protocol for discontinuation criteria.  
3.9. Study Assessments and Procedures  
Section 3.2 provides the Schedule of Activities for this study. 
Attachment 2 provides a list of the laboratory tests that will be performed for this study. 
Attachment 3 provides the schedule for collection of samples in this study. 
3.9.1. Efficacy Assessments  
Tumor assessments will be performed for each participant at the times shown in the SoA 
(Section 3.2). 
Computed tomography scans, including spiral CT, are the preferred methods of measurement 
( 5 mm scan thickness recommended); however, MRI is also acceptable in certain situations, 
such as when body scans are indicated or if there is a concern about radiation exposure 
associated with CT. Contrast agent (intravenous or oral) is required unless medically 
contraindicated. 
The CT portion of a PET-CT scan may be used for response assessment if the CT is of equal 
diagnostic quality to a diagnostic CT (with intravenous and oral contrast). A PET scan alone or 
as part of a PET-CT cannot be used for response assessment according to RECIST 1.1 
(Eisenhauer et al. 2009). 
The method of tumor assessment used at baseline must be used consistently throughout the 
study. Radiologic scan of the chest, abdomen, and pelvis is required. 
For participant with evaluable disease only, response assessments should be made according to 
RECIST 1.1 for non-target disease only. 
Scans will be performed and reviewed locally for treatment-based decisions. Because evaluation 
of tumor assessments for the primary objective will occur by a blinded independent review 
committee, scans will also be collected and stored centrally. 

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See Section 3.10.3.1 for definitions of the efficacy endpoints. 
3.9.1.1. 
Product Acceptability and Palatability Assessments  
The participant and/or caregiver will be asked to provide responses to questions designed to 
assess the acceptability and palatability of the abemaciclib tablet swallowed whole, dispersed in 
food or liquid, or dispersed and administered through a nasogastric or gastrostomy tube 
(Kozarewicz 2014). If the participant is using abemaciclib oral granules, the participant and/or 
caregiver will be asked to provide responses to questions designed to assess the acceptability and 
palatability of the oral granules swallowed whole, placed in food or liquid, or dispersed and 
administered through a nasogastric or gastrostomy tube. The questionnaire for tablet or oral 
granule acceptability will assess the participant
 swallow the drug product as designed. 
The questionnaire for acceptability and palatability of the tablet or oral granules dispersed in 
food or liquid will assess the participant
 
 taste 
 appearance 
 smell 
 mouthfeel 
 aftertaste of the dispersion, and 
 ease of preparing and taking the dispersion.  
The questionnaire for acceptability of the tablet or oral granules dispersed and administered 
through a nasogastric or gastrostomy tube will assess the ease of preparation and administration 
of the dispersion. The appropriate questionnaire will be administered within approximately 30 
minutes after dosing at Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1. If a participant 
changes the method of abemaciclib administration at any point during the trial, the appropriate 
questionnaire corresponding to the new administration method should be completed at the next 
clinic visit following the method change. The questionnaire will be completed by caregivers 
(proxy) for participant
participant
participant and caregiver will complete the questionnaires. For participant
questionnaire will be self-completed. In the event a participant 
complete the questionnaire (i.e., limited physical capability), the caregiver can complete the 
questionnaire for the participant (only one questionnaire would need to be submitted for 
participant
 
3.9.2. Adverse Events  
Refer to the CAMPFIRE Master Protocol for Adverse Event general definitions, responsibilities, 
and reporting information. 
3.9.2.1. 
Adverse Events of Special Interest  
Adverse events of special interest for abemaciclib include 
 neutropenia 
 infections 
 diarrhea 
 hepatic events, including increases in AST/ALT 

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VTEs, and
ILD/pneumonitis
No AEs need to be adjudicated.
Section 3.7.4.4 describes supportive care measures. Section 3.7.8.3.1 presents the dose-
modification guidelines for abemaciclib. 
Contact the Lilly CRP/CRS if questions arise concerning AESIs.
3.9.3.Safety
3.9.3.1.
Safety Monitoring
The Lilly CRP/CRS will monitor safety data throughout the course of the study. Additionally, 
the DMC will provide external oversight of participant safety independently of the Lilly study 
team and Lilly Global Patient Safety (see Section 3.10.3.5.1). If excessive toxicity is observed, 
the study may be amended, or combination treatment halted to address the safety concern, as 
appropriate. 
3.9.3.1.1.
Special Hepatic Safety Data Collection
Close Hepatic Monitoring and Evaluation
Liver testing (Attachment 4), including ALT, AST, ALP, TBL, D. Bil, GGT, and CK, should be 
repeated within 2 to 4 days to confirm the abnormality and to determine if it is increasing or 
decreasing, if 1 or more of these conditions occur:
If a participant with baseline 
results of ...
develops the following elevations:
ALT or AST <1.5× ULN
× ULN or
×
× ULN
× ULN
× baseline or
×
× ULN
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for 
possible causes of abnormal liver tests should be initiated in consultation with the Lilly
CRP/CRS. At a minimum, evaluation should include physical examination, a thorough medical 
history that includes symptoms, recent illnesses (for example, heart failure, systemic infection, 
hypotension, or seizures), history of concomitant medications (including over-the-counter, 
herbal, and dietary supplements), and history of alcohol drinking and/or other substance abuse. 
In addition, the evaluation should include a blood test for PT-INR; serological tests for viral 
hepatitis A, B, C, E, autoimmune hepatitis; and an abdominal imaging study (for example, 
ultrasound or CT scan).
Based on the 
history and initial evaluation results, further testing should be 
considered, including tests for hepatitis D virus, cytomegalovirus, Epstein-Barr virus, 
blood alcohol levels, urinary ethyl glucuronide, and blood phosphatidylethanol. Based on the 

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investigator should consider referring the participant for a hepatologist or gastroenterologist 
consultation, magnetic resonance cholangiopancreatography, endoscopic retrograde 
cholangiopancreatography, cardiac echocardiogram, and/or a liver biopsy.  
Additional Hepatic Safety Data Collection 
Additional safety data should be collected via the CRF if any of the following conditions occur:  
In participants enrolled with baseline ALT or AST <1.5× ULN 
 
× ULN on 2 or more consecutive tests 
 
× ULN and elevated TBL 
× ULN 
× ULN 
 
× baseline on 2 or more consecutive tests 
 
× 
× 
ULN 
In all study participants  
 Discontinuation from study treatment due to a hepatic event or abnormality of 
liver tests 
 Occurrence of a hepatic event considered to be an SAE. 
 
3.9.3.1.2. 
Guidance for Monitoring Renal Function  
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
transporters without affecting glomerular function (as measured by iohexol clearance). In clinical 
studies, increases in serum creatinine occurred within the first month of abemaciclib, remained 
elevated but stable through the treatment period, were reversible upon treatment discontinuation, 
and were not accompanied by changes in markers of renal function, such as blood urea nitrogen, 
cystatin C, or calculated GFR based on cystatin C. 
Dose adjustment (omission, reduction, or discontinuation) should not be based solely on serum 
creatinine values because these may not reflect renal function. If renal impairment is suspected, 
measurement of cystatin C on a central chemistry laboratory sample may be performed to 
confirm renal function. 
3.9.3.1.3. 
Guidance for Venous Thromboembolic Events  
In breast cancer, VTE has been identified as an ADR for abemaciclib in combination with 
endocrine therapy (ET). In the randomized Phase 3 breast cancer studies a greater number of 
participants experienced VTEs in abemaciclib plus ET arms than in the placebo plus ET arms or 
ET alone arm. Most participants who experienced VTEs were treated with anticoagulants. In 
studies of single-agent abemaciclib in the metastatic breast cancer population or other tumor 
types, including non-small cell lung cancer, no increased rates of VTEs were observed as 
compared to the incidence of VTEs for these patient populations who were treated with other 
anticancer agents. At this time, the mechanism underlying the association between abemaciclib 
and the occurrence of VTEs is not known. 

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Monitor participants for signs and symptoms of deep vein thrombosis and pulmonary embolism 
and treat as medically appropriate. Refer to Section 3.7.8.3.2 for guidance on dose adjustments 
or discontinuation of abemaciclib.  
3.9.3.1.4. 
Guidance for Interstitial Lung Disease/Pneumonitis  
Interstitial lung disease/pneumonitis has been identified as an ADR for abemaciclib and 
irinotecan. The majority of events observed in abemaciclib clinical trials were Grade 1 or 2 with 
serious cases and fatal events reported. Additional information is available in the IB. 
Ask participants to report any new or worsening pulmonary symptoms, such as dyspnea, cough, 
and fever. Investigate and treat ILD/pneumonitis as per local clinical practice (including 
corticosteroids as appropriate). If ILD/pneumonitis is suspected, evaluation may include high-
resolution CT, bronchoalveolar lavage, and biopsy as clinically indicated. Refer to Section 
3.7.8.3.2 for guidance on dose adjustments or discontinuation of abemaciclib and irinotecan for 
participants with ILD/pneumonitis. Consultation with lung experts is recommended for 
differential diagnosis and further treatment. If abemaciclib is resumed, close monitoring, 
including additional clinic visit for physical examination and imaging study as indicated, is 
recommended. 
3.9.4. Pharmacokinetics  
PK samples will be collected as shown in Attachment 3 Abemaciclib PK samples will be 
collected only for Arm A participants whereas temozolomide and irinotecan PK samples will be 
collected for Arm A and Arm B participants. 
Two methods of PK sampling will be employed: 
1) 
 will be used to collect a blood sample by 
capillary puncture, and
2) blood samples will also be collected by venous puncture into a vacutainer. These samples 
should then be processed into plasma. 
Samples collected using microsampling will be analyzed for concentrations of abemaciclib and 
its active metabolites, M2 and M20. Samples collected using vacutainers will be analyzed for 
concentrations of abemaciclib, M2 and M20, and temozolomide and irinotecan.  
The time and date of each PK sample collection should be recorded on the laboratory requisition 
form. 
It is important to collect the time and date of doses of study drugs (Cycle 1 Day 1 to Cycle 4 Day 
1).  
 For temozolomide and irinotecan doses, the time and date of each drug administration on 
Day 1 of Cycles 1 to 4 should be recorded by the study site and entered into the eCRF.  
 For abemaciclib, participants will complete a paper Participant Dosing Diary to record 
the dosing times and dates during the first 3 treatment cycles. The information in this 
diary should be collected through Cycle 3 Day 21 and reviewed at each visit through 

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Cycle 4 Day 1 for each prior cycle. The date and time of abemaciclib doses taken 3 days 
prior to and on the day of each PK sample should be documented in the eCRF. 
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon by the investigator and Lilly. Instructions for the collection and 
handling of blood samples will be provided by Lilly. The actual date and time (24-hour clock 
time) of each sample will be recorded.  
Bioanalytical samples collected to measure drug concentrations will be retained for a maximum 
of 1 year following the last participant visit for the study. 
3.9.5. Pharmacodynamics  
Pharmacodynamics will not be assessed in this addendum. 
3.9.6. Biomarkers  
Biomarker research will address questions as described in Sections 9.7 and 9.8 of the 
CAMPFIRE Master Protocol. 
This study will analyze biomarkers relevant to study intervention, mechanism of action, the 
variable response to study drug(s) (including evaluation of AEs or differences in efficacy), cell 
cycle, immune function, or pathways associated with 
enable examination of these questions through the measurement of biomolecules, including 
DNA, RNA, proteins, lipids, and other circulating or cellular elements. 
 
 can also be used to identify biomarkers of participant response or 
resistance. Except for the cases detailed in Section 3.9.6.1 (tumor DNA sequencing without 
patient-matched germline subtraction) and Section 3.9.6.2 (ctDNA sequencing without patient-
matched germline subtraction), biomarker analyses will not produce interpretable results on 
germline DNA and therefore will not lead to the identification of genetic findings. Biomarker 
analyses using DNA as a substrate will generate interpretable information on tumor somatic 
variants, tumor somatic copy number changes, and tumor somatic rearrangements. Biomarker 
analyses using RNA as substrate will avoid the identification of genetic variants and will focus 
on quantifying 
 
 Biomarker analysis results may occur after the clinical study report is 
written and therefore a separate biomarker Data Analysis Plan will be developed.  
Samples for biomarker research will be collected as specified in Attachment 2 and Attachment 3, 
where local regulations allow. It is possible that biomarker data for participants in the study have 
already been generated from samples that were collected and analyzed prior to enrolling in this 
trial. 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 3.9.6.1 and 3.9.6.2; 
for instance, to understand the role of various co-occurring alterations. 
Samples may be used to develop related research methods or to validate diagnostic tools or 
assays, but only within the specific research scope described in this protocol. The samples may 
be analyzed as part of a multi-study assessment of non-genetic factors involved in the response 

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to study intervention or study interventions of this class, and/or to understand study disease or 
related conditions, within the scope described in this protocol. 
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the study site personnel. Samples will be retained 
for a maximum of 7 years after the last participant visit for the study, or for a shorter period if 
local regulations and/or ERBs/IRBs impose shorter time limits, at a facility selected by the 
sponsor or its designee. 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 study treatment or after study treatment becomes 
commercially available. Technologies are expected to improve during the 7-year storage period, 
and therefore, cannot be specifically named. Regardless of the technology utilized, data 
generated will be used only for the specific biomarker research scope described in this section, 
and within the limits of this protocol. 
3.9.6.1. 
Tissue Samples for Biomarker Research  
Tissue samples for biomarker research will be collected for the purposes described in 
Section 3.9.6. The following samples for biomarker research will be collected according to the 
sampling schedules in Attachment 2 and Attachment 3, where local regulations allow. 
Submission of tumor sample, archival or fresh, obtained prior to initiation of study treatment, 
will be collected, where available. The most recent sample is desired. Relapse or metastatic 
sample where available is preferred. The tumor samples will preferably be in the form of a 
formalin fixed paraffin-embedded block. If this is not possible, 
 
. Samples are not required for 
study eligibility and can be submitted any time during the study, if not submitted at screening 
(preferred). Due diligence should be used to make sure that tumor sample (not a normal adjacent 
or a tumor margin sample) is provided.  
Pathology report accompanying tumor tissue will be requested. Pathology reports must be coded 
must be removed from the institutional pathology report prior to submission. Archival blocks 
will be sectioned. Sponsor has a right to retain a portion of the submitted tissue, and archival 
blocks may be returned to the study site, upon request. Tissue blocks from biopsies collected at 
baseline/disease progression may be returned to sites if there is available tissue left over, upon 
request. 
Tumor DNA analysis (whole exome or panel DNA sequencing) may be performed with patient-
matched germline DNA subtraction. Germline DNA for each participant will originate from 
DNA extracted from whole blood as described in Section 3.9.6.3. Review of germline DNA 
sequencing results may be conducted, but only for data quality control purposes. At no point in 
this process will germline DNA variants be analyzed and interpreted by the research personnel. 
As such, tumor DNA analysis with germline DNA subtraction will not produce interpretable 
results on germline DNA, is not considered genetic research, and therefore, will not lead to the 

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identification of genetic incidental findings. Genetic incidental findings are variations present in 
germline DNA that are discovered unintentionally. 
Tumor DNA analysis (whole exome or panel DNA sequencing) may be performed without 
germline DNA subtraction. When analyzed this way, it may be considered genetic research and 
the identification of genetic incidental findings is possible. However, the methods used in this 
study for biomarker analyses are not clinically validated to detect germline variants, and 
therefore, no clinical conclusions can be derived from them. As such, no genetic findings will be 
reported to the participants participating in biomarker research, subject to local regulations. 
Tumor RNA sequencing analyses quantitate tissue mRNA expression levels, report gene fusions, 
splice variants, and other somatic rearrangements and do not detect germline variants. Therefore, 
these analyses are not considered genetic research, and no genetic findings will be identified. 
3.9.6.2. 
Plasma Samples for Biomarker Research  
Plasma samples for biomarker research will be collected from all participants as specified in the 
sampling schedules in Attachment 2 and Attachment 3, where local regulations allow. 
Plasma samples may also be used for ctDNA analyses. ctDNA analysis may be performed with 
participant-matched germline DNA subtraction. Germline DNA for each participant will 
originate from DNA extracted from whole blood as described in Section 3.9.6.3. Review of 
germline DNA sequencing results may be conducted, but only for data quality control purposes. 
At no point in this process will germline DNA variants be analyzed and interpreted by the 
research personnel. As such, ctDNA analysis with germline DNA subtraction will not produce 
interpretable results on germline DNA, is not considered genetic research, and therefore, will not 
lead to the identification of genetic incidental findings. 
ctDNA analysis may be performed without germline DNA subtraction. In this case, it may be 
considered genetic research and the identification of genetic incidental findings is possible. 
Regardless of whether participant-matched germline DNA subtraction is used or not during the 
ctDNA analysis, the methods used in this study for biomarker analyses are not clinically 
validated to detect germline variants, and therefore, no clinical conclusions can be derived from 
them. As such, no genetics findings will be reported to the participants participating in biomarker 
research, subject to local regulations. 
3.9.6.3. 
Whole-blood sample for biomarker research  
A whole-blood sample for biomarker research will be collected from all participants as specified 
in sample scheduling in Attachment 3, where local regulations allow. This sample may be used 
for the extraction of DNA that allows p participant-matched germline DNA subtraction during 
tumor DNA analysis from tissue (Section 3.9.6.1) and ctDNA (Section 3.9.6.2). 
3.9.7. Genetics  
Genetic research will not be performed in this addendum 

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3.9.8. Health Economics  
Health economics and medical resource utilization parameters will not be evaluated in this study. 
3.10. Statistical Considerations  
3.10.1. 
Sample Size Determination  
At least 45 participants will be enrolled in the study using a 2:1 randomization ratio. The primary 
objective of this study is to compare the efficacy of abemaciclib in combination with irinotecan 
and temozolomide (Arm A) to irinotecan and temozolomide (Arm B), in terms of PFS by blinded 
 
Participants who are randomized but not administered treatment may be replaced to ensure that 
enough participants may complete the study. 
Under a frequentist analysis, the study will be powered to approximately 
 assuming a PFS 
HR of 
 at a 1-sided alpha of 
 This requires approximately 
 events from all randomized 
participants and accounts for the futility analysis described in Section 3.10.3.5.2. However, as 
described in Section 3.10.3.1.1 and in the SAP, the primary analysis will incorporate a Bayesian 
Augmented Control and Bayesian decision rule, altering the exact operating characteristics 
above. Specifying the same one-sided Type I error rate of 
 the Bayesian Augmented Control 
may increase power as high as approximately 
 Refer to the SAP for more detail on the 
model used and simulations. 
3.10.2. 
Populations for Analysis  
The following analysis sets will be defined for this study: 
Intention-to-treat (ITT) analysis set: will include all randomized participants. The ITT analysis 
of efficacy data will consider allocation of participants to treatment groups as randomized and 
not by actual treatment received. This analysis set will be used for all baseline and efficacy 
analyses.  
Safety analysis set: will include all randomized participants who received any quantity of study 
treatment, regardless of their eligibility for the study. The safety evaluation will be performed 
based on the first doses of study treatment a participant actually received, regardless of the arm 
to which he or she was randomized. The safety analysis set will be used for all dosing/exposure, 
safety, and resource utilization analyses. 
Pharmacokinetic analysis set: will include all participants who received at least 1 dose of any 
study drug, have at least 1 evaluable PK sample, and sufficient dosing information. 
Biomarker analysis set: will include the subset of participants from the ITT population from 
whom a valid assay result has been obtained. 
3.10.3. 
Statistical Analysis  
Statistical analysis of this study will be the responsibility of Lilly or its designee. 

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All tests of treatment effects will be conducted at a 1-sided alpha level of 
 unless otherwise 
stated, and all confidence or credible intervals (CIs) will be given at a 2-sided 
 level. 
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Additional exploratory analyses of the data 
will be conducted as deemed appropriate. 
Handling of missing, unused, and spurious data is addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses will be described in the final CSR. 
3.10.3.1. 
Efficacy Analysis  
3.10.3.1.1. 
Progression-free Survival  
Progression-free survival is defined as the time from randomization until the first occurrence of 
documented disease progression per RECIST 1.1 criteria, or death from any cause in the absence 
of progressive disease, whichever comes first. The primary analysis will consider documented 
disease progression as determined by the blinded independent review committee. Participants 
known to be alive and without disease progression will be censored at the time of the last 
adequate tumor assessment (a detailed PFS event/censoring scheme is provided in Table JP04.7). 
A Bayesian analysis will be performed to compare progression-free survival between treatment 
arms. Details of the hierarchical model and all historical data used to augment the control arm 
are in the SAP. The primary analysis will be performed after approximately 
 events have 
been observed. The study will be declared positive if the posterior probability that the hazard 
ratio for PFS of Arm A (the abemaciclib arm) versus Arm B (the control) is 
 is greater 
than 
 and it will be concluded that the abemaciclib arm is superior.  
Additionally, the corresponding HR between treatment arms will be estimated using a stratified 
Cox regression model (Cox 1972), stratified by randomization strata. Progression-free survival 
curves, median PFS, and PFS rates at various time points with 
 CI for each treatment arm 
will be estimated using the Kaplan-Meier method (Kaplan and Meier 1958). These analyses will 
be repeated for the secondary endpoint of PFS as determined by investigator assessment. 
Sensitivity analyses for PFS will be described in the SAP. 
Table JP04.7. 
PFS Event/Censoring Scheme  
Situation
Event/Censor
Date of Event or Censor
Tumor progression or death
Event
Earliest date of PD or death 
No tumor progression and no death 
Censored 
Date of last adequate tumor assessment, per 
RECIST 1.1 criteria, or date of randomization 
(whichever is later)b
Unless 
No baseline radiologic tumor assessment 
available 
Censored 
Date of randomization 
No adequate postbaseline tumor assessment 
available and death reported after 2 scan 
intervals following randomizationb,
Censored 
Date of randomization 
Tumor progression or death documented 
immediately after 2 or more scan intervals 
Censored 
Date of last adequate tumor assessment, per 
RECIST 1.1 criteria, or date of randomization 

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following last adequate tumor assessment 
or randomization (whichever is later)a,b
(whichever is later)a  
Abbreviations: CR = complete response; PD = progressive disease; PFS = progression-free survival; PR = partial 
response; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1; SD = stable disease. 
a Adequate tumor assessment per RECIST 1.1 criteria refers to an assessment with 1 of the following responses 
CR, PR, SD, or PD. 
b Refer to the SAP for the definition of 2 scan intervals, including any adjustment for scan window. 
3.10.3.1.2. Overall Survival  
Overall survival is defined as the time from randomization until death from any cause. Details 
concerning OS analyses can be found in the SAP. 
3.10.3.1.3. 
Objective Response Rate  
Objective response rate is defined as the number of participants who achieve a best overall 
response of CR or PR divided by the total number of participants randomized to the 
corresponding treatment arm (ITT population). The ORR, with 
 CI, will be summarized for 
each treatment arm and compared between treatment arms using the Cochran-Mantel-Haenszel 
test adjusting for the randomization strata. 
3.10.3.1.4. 
Duration of Response  
Duration of response 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 RECIST 1.1 criteria, or the date of death from 
any cause in the absence of documented disease progression or recurrence. Details can be found 
in the SAP. 
3.10.3.1.5. 
Disease Control Rate  
Disease control rate is defined as the number of participants who achieve a best overall 
response of CR, PR, or SD, divided by the total number of participants randomized to the 
corresponding treatment arm (ITT population). Details can be found in the SAP. 
3.10.3.2. 
Safety Analysis  
All participants who receive at least 1 dose of any study therapy will be evaluated for safety and 
toxicity. Refer to the CAMPFIRE Master Protocol Section 10.3.1 and the SAP for details of the 
safety analysis.  
3.10.3.3. 
Other Analysis  
3.10.3.3.1. Pharmacokinetic Analyses  
All participants who have received at least 1 dose of study treatment and have at least 1 post 
baseline evaluable PK sample will be included in the PK analysis population. 
Plasma concentrations will be summarized for each drug (and metabolite) using descriptive 
statistics.  
  
 
 
 
.  

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. 
3.10.3.3.2. Exploratory Biomarker Analyses  
Correlative analyses of biomarkers and clinical outcome will be performed. Potential biomarkers 
are highlighted in Section 3.9.6. Biomarker analysis results may occur after the CSR is written 
and therefore a separate biomarker Data Analysis Plan will be developed. 
3.10.3.3.3. 
Product Acceptability and Palatability  
Responses from the drug product acceptability and palatability questionnaires for tablets and oral 
granules taken as designed (i.e., swallowed whole), dispersed in food or liquid, or dispersed and 
administered through a nasogastric or gastrostomy tube will be summarized categorically 
(frequency and percentage) by age group, for each visit separately and in aggregate. In addition, 
general trends in acceptability and palatability from Cycle 1 Day 1 (baseline), Cycle 2 Day 1, 
and Cycle 3 Day 1 will be analyzed. 
3.10.3.4. 
Subgroup Analysis  
A prespecified list of subgroups will be identified in the SAP. The treatment effect within each 
subgroup will be summarized. Other subgroup analyses not specified in the SAP may be 
performed as deemed appropriate. These subgroups will be based on important characteristics, 
for example, prognostic significance. 
3.10.3.5. 
Interim Analysis  
3.10.3.5.1. 
Safety Interim Analysis  
The DMC is responsible for providing external oversight of participant safety in Study JP04 
independently of the Lilly study team and Lilly Global Patient Safety.  
Safety interim analyses will be reviewed by the DMC at a frequency described in the DMC 
charter, but no less than approximately every 6 months while participants are still in the on-study 
treatment period. The safety interim analyses will be conducted to evaluate the overall safety 
profile of abemaciclib when given in combination with irinotecan and temozolomide.  
At each safety interim analysis, the DMC may recommend that the trial continue without 
modifications, continue with specific modifications, or be stopped for safety concerns. There will 
be no prespecified rules for stopping the trial due to safety concerns. The DMC members will 
review safety data at each safety interim analysis. If a significant safety signal is identified, the 
DMC may recommend a protocol amendment, termination of enrollment, and/or termination of 
study treatment. The recommendations of the DMC will be communicated to the Lilly Senior 
Management Designee and, if necessary, an Internal Review Committee. Further details on the 
members, activities, and responsibilities of the DMC can be found in the DMC charter. 

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A limited number of Lilly representatives external to the study team may have access to 
treatment assignments as required for evaluation of selected SAEs for determination of 
regulatory reporting. 
3.10.3.5.2. 
Futility Interim Analysis  
One futility analysis is planned after approximately 
 events have been observed. The 
futility analysis will utilize PFS by investigator assessment. If the observed HR of PFS by 
investigator assessment is 
, the DMC should recommend that the study be stopped 
for futility.  
Only the DMC is authorized to evaluate unblinded interim efficacy and safety analyses. Blinding 
and unblinding details are specified in a separate blinding and unblinding plan document.  

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545. 

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Attachment 1. Protocol JP04 Addendum Abbreviations and 
Definitions  
The list of abbreviations and definitions found in the Study JP04 Addendum are included below. 
Term 
Definition 
abuse 
use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ADR 
adverse drug reaction 
AE 
Adverse event: any untoward medical occurrence in a participant or clinical 
investigation participant 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. 
AESI 
adverse event of special interest 
ALP 
alkaline phosphate 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
BID 
twice daily 
BMI 
body mass index 
BIRC 
blinded independent review committee 
BSA 
body surface area 
CDK 
cyclin-dependent kinase 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK or CPK 
creatine phosphokinase 
CR 
complete response 
CRF 
case report form 

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CRP/CRS 
clinical research physician/clinical research scientist: Individual responsible for the 
medical conduct of the study. Responsibilities of the CRP/CRS may be performed by a 
physician, clinical research scientist, global safety physician, or other medical officer. 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
D. Bil 
direct bilirubin 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDC 
electronic data capture 
EFS 
event free survival 
end of study 
Date of the last visit or last scheduled procedure shown in the Schedule of Activities 
(Section 3.2) for the last participant 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
ERB 
ethical review board 
ET 
endocrine therapy 
EU 
European Union 
EWS 
 
G-CSF 
granulocyte-colony stimulating factor 
GDPR 
EU General Data Protection Regulation 
GCP 
good clinical practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
HR 
hazard ratio 
IB 
 

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ICF 
Informed Consent Form 
IEC 
Independent Ethics Committees 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IMP 
product, which is being tested or used as a reference, including as a placebo, in a 
clinical trial 
interim analysis 
an analysis of clinical study data conducted before the final reporting database is 
created/locked 
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 participant (that is, 
the planned treatment regimen) rather than the actual treatment given. It has the 
consequence that participants 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. 
IV 
intravenous 
IWRS 
interactive Web response system 
medication error 
errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involves a failure to uphold 1 or more 
of the 5 
right route, at the right time. 
In addition to the core 5 rights, the following may also represent medication errors:  
sion associated with an AE or a product complaint 
 
-use date 
 
chnique inconsistent with the 
medication s labeling (for example, Summary of Product Characteristics, IB, local 
label, protocol), or 
 
misuse 
use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 

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mOS 
median overall survival 
MRI 
magnetic resonance imaging 
ORR 
objective response rate 
OS 
overall survival 
PC 
product complaint 
PCP 
Pneumocystis jirovecii pneumonia 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PO 
orally 
PR 
partial response 
PS 
performance status 
randomize 
the process of assigning participants to an experimental group on a random basis 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rescreen 
To screen a participant who was previously declared a screen failure for the same 
study 
RP2D 
recommended phase 2 dose 
SAC 
statistical analysis center 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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 
participant who does not meet one or more criteria required for participation in a study 
SD 
stable disease 
SoA 
schedule of activities 
study completion 
the date of the last visit or last scheduled procedure associated with the primary 
outcome 

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SUSAR 
suspected unexpected serious adverse reactions 
Refers to an adverse event that occurs in a clinical trial participant, which is assessed by 
the sponsor and or study investigator as being unexpected, serious and as having a 
reasonable possibility of a causal relationship with the study intervention. 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event: an untoward medical occurrence that emerges 
during a defined treatment period, having been absent at baseline, or worsens relative 
to the baseline state, and does not necessarily have to have a causal relationship with 
this treatment. 
ULN 
upper limit of normal 
VTE 
venous thromboembolic event 
 

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Attachment 2. Protocol JP04 Addendum Clinical Laboratory 
Tests  
Laboratory Test Prioritization to Minimize Blood Sampling 
Care should be taken to safeguard study participants with regards to the amount of blood drawn 
for study procedures. 
Efforts have been made to minimize the blood sampling required by this protocol. However, the 
following guidance is provided to assist sites in further minimization when deemed necessary by 
investigator discretion or according to local requirements. Sites should follow local IRB 
guidelines, where applicable. 
1. Participants aged <10 years of age, for local collections, reduced blood volume should be 
collected. Care has been taken to reduce the central laboratory collection requirements. If 
there is concern for those participants with weight <15 kg, please consult the Lilly 
CRP/CRS for further guidance. 
2. 
during collection. If difficulties arise, please prioritize samples as follows: Chemistry and 
Hematology, Cystatin C, Pregnancy 
, PK followed by 
Exploratory Biomarkers. 
Please refer to the laboratory manual for reduced volumes of central laboratory samples. 

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Hematology Local laboratory
Hemoglobin (HGB) 
Platelets (PLT)
Leukocytes (WBC  White Blood Cells) 
Absolute Count of:
Neutrophilsa
Lymphocytes 
Clinical Chemistry
Local laboratory
Serum Concentrations of:
Alkaline phosphatase (ALP) 
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST) 
Bicarbonate
Bilirubin, total
Blood urea nitrogen (BUN) or blood urea
Chloride
Creatinine
Glucose, random 
Potassium 
Sodium
Calculations Local laboratory
Creatinine clearance 
Calculated glomerular filtration rate (GFR)
 Hormones (Women of childbearing potential) Local laboratory
Serum pregnancy test
Urine pregnancy test
Additional Testing  
Cystatin C  central laboratory 
Pharmacokinetic Samples Central Laboratory
LY2835219 concentration
LSN2839567
LSN3106726
Irinotecan 
Temozolomide
Exploratory Biomarker storage samples 
Plasma
Whole blood (dried blood spot) 
Whole blood
Tissue 
Abbreviation: CRF = case report form. 
a Neutrophils reported by automated differential hematology instruments include both segmented and band forms. 
When a manual differential is needed to report the neutrophils, the segmented and band forms should be added 
together and recorded on the CRF, unless the CRF specifically provides an entry field for bands. 

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Attachment 3. 
Protocol JP04 Addendum Sampling Schedule for Biomarkers and 
Pharmacokinetics  
Instructions for recording information for PK sample collection and dose information are described in Section 3.9.4. 
Sampling Schedule for Biomarkers 
Procedure 
Screening 
Cycle 1, Day 1 
Predose 
Disease progression/study treatment 
discontinuation 
 
Tumor tissuea 
Exploratory Biomarker  Plasmab 
Exploratory Biomarker - Whole 
blood 
a Archival or fresh tumor sample will be collected, where available. The most recent sample is desired. Relapse or metastatic sample where available is 
preferred. The tumor samples will preferably be in the form of a formalin-fixed, paraffin embedded block. If this is not possible, 
 
. Tumor tissue samples are not required for study eligibility and can be submitted any time 
during the study, if not submitted at screening (preferred). 
b 
 
c Collect at the visit when the participant has confirmed disease progression and/or discontinued study treatment. If there is no visit planned, the participant 
should have a sample collected at the short-term follow-up visit. 
d 
a whole-blood sample will be collected. For participants <10 years of age, a whole-blood dried blood spot will be collected. 
Samples are not required for study eligibility and can be submitted any time during the study, if not submitted at C1D1 (preferred). 
 
 

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Sampling Schedule for Pharmacokinetics  
 
Drug 
Arm(s) 
Matrix 
  
Cycle 1 
Day 15 
  
Cycle 2 Day 1 
  
Cycle 3 
Day 1 
  
Cycle 4 Day 1 
Predosea 
Predosea 
End of 
irinotecan 
infusionb 
Predosea 
  
Predosea 
End of 
irinotecan 
infusionb 
Abemaciclib 
A 
Microsample 
Y 
  
Y 
Yc 
  
Yc 
  
Y 
Yc 
Plasma 
N 
N 
Yc 
Yc 
 
N 
Yc 
Temozolomide 
A and B 
Plasma 
N 
N 
Y 
N 
 
N 
Y 
Irinotecan 
A and B 
Plasma 
N 
N 
Y 
N 
  
N 
Y 
Abbreviations: N=No collection; Y = Yes collection. 
a Prior to the morning dose of abemaciclib. 
b Within 30 minutes of the end of the irinotecan infusion. 
c The abemaciclib plasma sample should be collected within ±10 minutes of the abemaciclib microsample. 
 

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Attachment 4. Protocol JP04 Addendum Hepatic Monitoring 
Tests for Treatment-Emergent Abnormality  
See Section 3.9.3.1.1 for guidance on appropriate test selection. 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
 Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
 Lymphocytes 
Creatine kinase (CK) 
 Monocytes 
Other Chemistry 
 Basophils 
Acetaminophen 
 Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin IgA (quantitative) 
Hepatitis A virus (HAV) testing: 
Immunoglobulin IgG (quantitative) 
 HAV total antibody 
Immunoglobulin IgM (quantitative) 
 HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatis B virus (HBV) testing: 
Urine Chemistry 
 Hepatitis B surface antigen (HBsAg) 
Drug screen 
 Hepatitis B surface antibody (anti-HBs) 
Ethyl glucuronide (EtG) 
 Hepatitis B core total antibody (anti-HBc) 
Other Serology

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 Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA) 
 Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) a 
 HBV DNA b 
Anti-actin antibody c 
Hepatis C virus (HCV) testing: 
Epstein-Barr virus (EBV) testing: 
 HCV antibody 
 EBV antibody 
 HCV RNA b 
 EBV DNA b 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
 HDV antibody 
 CMV antibody 
Hepatitis E virus (HEV) testing: 
 CMV DNA b 
 HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
 HEV IgM antibody 
 HSV (Type 1 and 2) antibody 
 HEV RNA b 
 HSV (Type 1 and 2) DNA b 
Microbiology d 
Liver kidney microsomal type 1 (LKM-1) antibody 
Culture: 
 
 Blood 
 
 Urine 
a Not required if anti-actin antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody (ASMA) is tested. 
d Assayed ONLY by investigator-designated local laboratory; no central testing available. 
 
 

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Attachment 5. Protocol JP04 Addendum Restricted and 
Prohibited Concomitant Therapy  
This attachment describes medications, treatments, and drug classes restricted or prohibited, with 
exceptions and conditions for use during the study treatment period (there are no prohibited 
therapies during the follow- up period). Participants who, in the assessment by the investigator, 
require the use of any of the prohibited treatments for clinical management should be removed 
from the trial. Participants may receive other supportive therapy or vaccinations that the 
investigator deems to be medically necessary. 
Vaccine Guidance 
Live vaccines are not permitted while on treatment and for at least 3 months after the last dose of 
abemaciclib. 
Guidance for Modulators of CYP3A 
Abemaciclib is extensively metabolized through oxidation by CYP3A. In clinical drug 
interaction studies,  
 coadministration of clarithromycin, a strong CYP3A inhibitor, increased exposure (AUC) 
of abemaciclib by 3.4-fold (Study I3Y-MC-JPBE), and  
 coadministration of rifampin, a strong CYP3A inducer, decreased exposure of 
abemaciclib by 95% (Study I3Y-MC-JPBF).  
Strong inhibitors of CYP3A (given via non-topical routes of administration) should be 
substituted or avoided if possible (see list below). This includes grapefruit or grapefruit juice. In 
particular, avoid oral administration of the very strong CYP3A inhibitor, ketoconazole. 
If coadministration with a strong CYP3A inhibitor is unavoidable, investigators should reduce 
the dose of abemaciclib according to the dose reduction table in Section 3.7.8.3. For participants 
receiving the original starting dose, the dose should be reduced to the first dose reduction level. 
For participants who have already had a dose reduction for tolerability, reduce the dose further to 
the second dose reduction level. For subjects receiving doses which do not have an appropriate 
dose reduction option, or who have already been dose reduced to the lowest possible dose level, 
the investigator may consider suspending abemaciclib for the duration of the strong CYP3A 
1 days must be discussed with Lilly CRP/CRS. 
Upon discontinuation of the strong CYP3A inhibitor, the dose of abemaciclib may be re-
escalated to the dose that was used before starting the strong inhibitor after a sufficient washout 
period (3 to 5 half-lives of the strong inhibitor). Re-escalation of abemaciclib dose requires 
review and approval from the Lilly CRP/CRS. 
Inducers of CYP3A should be substituted or avoided if possible (see list below). 
Coadministration with a CYP3A inducer 21 days must be discussed with the Lilly CRP/CRS. 

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Note: The information in this table is provided for guidance to investigators and does not 
preclude the use of these medications if clinically indicated. This list is intended to be 
exhaustive, but with available information continually evolving, the status of every relevant drug 
cannot be guaranteed. Please consult with the medical monitor in case of any doubt about a 
potential drug-drug interaction. 
Strong Inducers of CYP3A
Special Status
Aminoglutethimide 
Apalutamide 
Carbamazepine (daily dose exceeding 600 mg) 
Enzalutamide
Very limited use. Possibly available in Egypt and Lithuania 
 
 
Fosphenytoin (see also phenytoin) 
Ivosidenib 
Lumacaftor 
Mitotane 
Phenobarbital
 
Phenytoin 
Rifabutin 
Rifampicin (rifampin) 
Rifapentine
 
 
Supplement or food/drink
 
Moderate Inducers of CYP3A
 
Bosentan 
Carbamazepine (daily dose 600 mg or lower) 
Cenobamate 
Dabrafenib 
Danshen (Salvia miltiorrhiza) 
Efavirenz 
Elagolix 
Encorafenib 
Etravirine 
Genistein 
Lopinavir (alone) 
Lorlatinib 
Modafinil 
Nafcillin (intravenous) 
Pentobarbital 
Primidone 
Sotorasib 
Thioridazine 
Tocilizumab (atlizumab) 
 
 
 
 
Supplement or food/drink 
 
 
Probable moderate inducer based on observed autoinduction 
 
Supplement or food/drink 
 
 
 
Very limited use; Available in US 
Very limited use 
 
 
Very limited use; available in US; importable into UK 
 
non-traditional mechanism: reverses the IL-6 mediated 
suppression of CYP3A activity in participants with rheumatoid 
arthritis
 
Strong Inhibitors of CYP3A
Atazanavir and cobicistat 
Boceprevir 
 

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Ceritinib 
Clarithromycin 
Cobicistat (see atazanavir and cobicistat) 
Conivaptan 
Danoprevir and ritonavir 
Elvitegravir and ritonavir 
Fosamprenavir and ritonavir 
Grapefruit juice 
Idelalisib 
Indinavir and ritonavir 
 
 
 
 
 
 
 
Supplement or food/drink 
 
Itraconazole 
Josamycin 
Ketoconazole
Outside US 
Very limited use
Lonafarnib 
Lopinavir and ritonavir 
Mifepristone 
Nefazodone 
Nelfinavir 
Nirmatrelvir and ritonavir 
Posaconazole 
Ribociclib 
Ritonavir 
Saquinavir and ritonavir 
Telithromycin 
Tipranavir and ritonavir 
Tucatinib 
Viekirax (paritaprevir and ritonavir and 
ombitasvir and/or dasabuvir) 
Voriconazole
 
 
 
Very limited use; Available in US 
 
 
 
 
 
 
 
 
 
Outside of US 
 
Guidance for Transporter Substrates 
Abemaciclib inhibits the transporters P-glycoprotein, breast cancer resistance protein, organic 
cation transporter 2, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. The 
observed serum creatinine increase in clinical studies with abemaciclib is likely due to inhibition 
of tubular secretion of creatinine via OCT2, MATE1, and MATE2-K. In vivo interactions of 
abemaciclib with narrow therapeutic index substrates of these transporters, such as digoxin and 
dabigatran may occur. 
Irinotecan and Temozolomide 
Refer to the product labels of irinotecan and temozolomide for information regarding 
concomitant medications. 
 

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Attachment 6. Protocol JP04 Addendum Abemaciclib Dosing 
Chart  
BSA (m2) for participants <18 yearsa 
Abemaciclib dose (mg) 
0.2 
 
0.21-0.24 
 
0.25-0.29 
 
0.3-0.34 
 
0.35-0.38 
 
0.39-0.43 
 
0.44-0.68 
 
0.69-1.13 
 
1.14-1.59 
 
1.60+ 
 
All participant
 
 
a BSA calculations are made using the Mosteller formula (Mosteller 1987) 

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Attachment 7. 
Protocol JP04 Addendum Contraceptive 
Guidance and Collection of Pregnancy Information  
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g. amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Female with 1 of the following: 
 
Documented hysterectomy 
 
Documented bilateral salpingectomy 
 
Documented bilateral oophorectomy 
 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (e.g. Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
 
Note: 
 
medical records, medical examination, or medical history interview. 
 
Fertile men 
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
 
 
 

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Contraception Guidance: 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency 
 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
 
Intrauterine device
 
Intrauterine hormone-releasing systemc
 
Bilateral tubal occlusion
 
Vasectomized partner 
 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 
90 days.) 
Highly Effective Methodsb That Are User Dependent 
 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
o 
oral 
o 
intravaginal 
o 
transdermal 
o 
injectable 
 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
o 
oral 
o 
injectable 
 
Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.) 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c) Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for 
this study. Male condom and female condom should not be used together (due to risk of failure with friction) 
 
 
 

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Collection of Pregnancy Information 
Male participants with partners who become pregnant 
 
The investigator will attempt to collect pregnancy information on any 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive abemaciclib. 
 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
 The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the sponsor. Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination 
of the pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Female Participants who become pregnant 
 The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the sponsor within 24 hours of learning of a participant's pregnancy.  
 The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy related SAE considered reasonably related to the study intervention by the 
investigator will be reported to the sponsor as described in Section 9.2.1 of the CAMPFIRE 
Master Protocol. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention and be withdrawn from the study. 

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Attachment 8. 
Protocol JP04 Addendum Provisions for 
Changes in Study Conduct During Exceptional 
Circumstances  
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
In Germany, the procedures outlined in this appendix are applicable only to the COVID-19 
pandemic. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
pproval, sites may 
implement changes if permitted by local regulations.  
After approval by local Ethical Review Boards, regulatory bodies and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required (for example, upon implementation and suspension of changes). All 
approvals and notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of the 
study.  
Informed consent 
Additional consent from the participant will be obtained, if required, for: 
 participation in remote visits, as defined in Section 
 
 dispensation of additional study intervention during an extended treatment period,  
 alternate delivery of study intervention and ancillary supplies, and 

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 provision of their personal or medical information required prior to implementation of 
these activities.  
 
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
Remote visits 
Types of remote visits 
Telemedicine: 
Telephone or technology-assisted virtual visits, or both, are acceptable to complete 
appropriate assessments.  
Mobile healthcare: 
Healthcare visits may be performed by a mobile healthcare provider at locations other 
than the study site 
when participants cannot travel to 
the site due to an exceptional circumstance if written approval is provided by the sponsor. 
Such visits will be performed by a mobile healthcare provider trained on the study. 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of adverse events (AEs), serious adverse events (SAEs), and product complaints 
remain unchanged.  
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions. These actions may 
include:  
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit,  
 asking the participant
designee to go to the site and receive study supplies on a 
half,  

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 arranging delivery of study supplies, and 
 working with the sponsor to determine how study intervention that is typically 
administered on site will be administered to the participant; for example, during a 
mobile healthcare visit or at an alternate location such as an infusion center. 
These requirements must be met before action is taken: 
 Alternate delivery of study intervention should be performed in a manner that ensures 
product integrity. The existing protocol requirements for product accountability 
remain unchanged
 
 When delivering supplies to a location other than the study site (for example, 
), the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt). 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
If study intervention will be administered to the participant during a mobile healthcare visit 
or at an alternate location, this additional requirement must be met:  
 Only authorized study personnel may supply, prepare or administer study 
intervention. 
 
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents at alternate locations 
Source documents generated at a location other than the study site should be part of the 
 source documentation and should be transferred to the site in a secure and timely 
manner. 
 

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Attachment 9. 
Protocol JP04 Addendum Country-
specific Requirements  
The country-specific addendum reflected in this appendix must be performed in the respective 
country, in addition to all procedures required by current version of Protocol J1S-MC-JP04 
(JP04) where applicable. The consolidation of this country-specific addendum into this appendix 
is to facilitate transition of this trial to the CTIS system under the new clinical trial regulation 
(CTR) in Europe. 
Germany  
This addendum is to address feedback from the Federal Institute for Drugs and Medical Devices 
(BfArM) in Germany. 
The revised text in the following sections shows the changes applicable only to participants in 
Germany. All deletions have been identified by strikethroughs; all additions have been identified 
by the use of underscore. 
Protocol Section 3.2. Schedule of Activities 
Investigators will provide age-appropriate explanations to all children prior to any assessment or 
procedure. Investigators should assess and monitor physical pain and distress at each visit. 
Protocol Section 3.6.1. Inclusion Criteria 
[35] 
Participants aged 1  to <40 years 
Attachment 2. Protocol JP04 Addendum Clinical Laboratory Tests 
Table JP04.8 below shows the estimated blood volumes per visit, specified per age group and 
sex. These blood volumes are within the ranges established in the Ethical considerations for 
clinical trials on medicinal products conducted with minors (EU 2017). 
Table JP04.8 
Study JP04 Estimated Blood Volume Per Visit (mL) 
Baselinea 
Cycle 1 
Day 1 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 2 
Day 1 
< 10 
years 
10 
years 
< 10 
years
 10 
years
< 10 
years
10 
years
< 10 
years
10 
years
< 10 
years
10 
years
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 
Day 8 
Cycle 2 
Day 15 
Cycle 3 
Day 1 
Cycle 3 
Day 8 
Cycle 3 
Day 15 
< 10 
years 
 10 
years 
< 10 
years 
 10 
years 
< 10 
years 
 10 
years 
< 10 
years 
 10 
years 
< 10 
years 
 10 
years 
 
 
 
 
 
 
 
 
Cycle 4 
Day 1 
Cycle 4 onward 
Day 8 
Cycle 4 onward 
Day 15 
Cycle 5 onward 
Day 1 
Visit 801 

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< 10 
years 
10 
years 
< 10 
years
 10 
years
< 10 
years
10 
years
< 10 
years
10 
years
< 10 
years
10 
years
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: C1D1 = Cycle 1 Day 1; f = female; m = male; mL = milliliter; PK = pharmacokinetics; 
WOCBP = women of childbearing potential. 
 
a Baseline collections are represented in Table JP04.8 as a single collection volume though tests may be collected 
separately on different days as shown in Protocol Table JP04.1 Baseline Schedule of Activities in J1S-MC-JP04 
Clinical Protocol Addendum.
 
C1D1 can be used for both baseline and C1D1. 
Serum pregnancy collection to 
 
Blood volumes for haematology, clinical chemistry, pregnancy, and 
 are estimates as these are 
performed locally. 
Treatment collections: 
Cycle X Day 1: Haematology and clinical chemistry collections to o
therapy. 
Cycle X Day 8 and 15: Haematology and clinical chemistry collections have visit interval tolerance of ±3 days. 
 
Serum pregnancy: Confirmation only needed if urine test is positive. 1 mL estimated and displayed in table, 
 
 
Visit 801: 
 
Has visit interval tolerance of ±14 days. 
 
Exploratory biomarker collected only for participants who did not have a sample collected at the time of disease 
progression or at the time when study treatment was discontinued, additional 10 
age. 
Potential triggered collections: 
 
Hepatic monitoring triggered for safety reasons with a range of 1.8 mL to 76.3 mL. 
 
Cystatin C triggered for safety reasons, additional 2.5 mL. 
 
Disease Progression: Exploratory biomarker collection, additional 10 
age. 
Retests, as needed, PK an additional 0.01 to 4 mL. 
 
Reference 
[EU] Ethical considerations for clinical trials on medicinal products conducted with minors. 
Recommendations of the expert group on clinical trials for the implementation of Regulation 
(EU) No 536/2014 on clinical trials on medicinal products for human use. Rev. 1. Published 
September 18, 2017. Accessed August 10, 2022. 
https://www.ejprarediseases.org/wp-content/uploads/2021/10/EC_ethical-consideration-on-
clinical-trials-with-minors_2017.pdf 
 
 
 

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Spain  
This addendum is to address feedback from the Agencia Española de Medicamentos y Productos 
Sanitarios (AEMPS) in Spain. 
The revised text in the following sections shows the changes applicable only to participants in 
Spain. All deletions have been identified by strikethroughs; all additions have been identified by 
the use of underscore. 
Attachment 2. Protocol JP04 Addendum Clinical Laboratory Tests 
Table JP04.8 below shows the estimated blood volumes per visit, specified per age group and 
sex. These blood volumes are within the ranges established in the Ethical considerations for 
clinical trials on medicinal products conducted with minors (EU 2017). 
Table JP04.8 
Study JP04 Estimated Blood Volume Per Visit (mL) 
Baselinea 
Cycle 1 
Day 1 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 2 
Day 1 
<10 
years 
10 
years
<10 
years
10 
years
<10 
years
10 
years
<10 years 
10 
years
<10 
years
10 
years
 
 
 
 
 
 
 
 
 
 
Cycle 2 
Day 8 
Cycle 2 
Day 15 
Cycle 3 
Day 1 
Cycle 3 
Day 8 
Cycle 3 
Day 15 
<10 
years 
10 
years
<10 
years
10 
years
<10 
years
10 
years 
<10 years
10 
years
<10 
years
10 
years
 
 
 
 
 
 
 
 
Cycle 4 
Day 1 
Cycle 4 Onward  
Day 8 
Cycle 4 Onward 
Day 15 
Cycle 5 Onward  
Day 1 
Visit 801 
<10 
years 
10 
years
<10 
years
10 
years
<10 
years
10 
years
<10 years 
10 
years
<10 
years
10 
years
 
 
 
 
 
 
 
 
 
 
Abbreviations: C1D1 = Cycle 1 Day 1; f = female; m = male; mL = millilitre; WOCBP = women of childbearing 
potential. 
a Baseline collections represented as a single collection volume though tests may be obtained separately on 
separate days.
 
 
days of C1D1 can be used for both baseline and C1D1. 
 
Serum pregnancy collection to oc
 
Blood volumes for hematology, clinical chemistry, pregnancy,
 are estimates as 
these are performed locally. 
Treatment collections: 
 
Cycle X Day 1: Hematology and clinical chemistry collections to occur 
of therapy. 
 
Cycle X Day 8 and 15: Hematology and clinical chemistry collections have visit interval tolerance of 
±3 days. 
 
Cycle 1 Day 1: Exploratory biomarker collection, 
 

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Serum pregnancy: Confirmation only needed if urine test is positive. In total, 1 mL estimated and displayed 
 
 
Visit 801:
 
Has visit interval tolerance of ±14 days. 
Exploratory biomarker collected only for participants who did not have a sample collected at the time of disease 
progression or at the time when study treatment was discontinued, additional 10 
age. 
Potential triggered collections: 
 
Hepatic monitoring triggered for safety reasons with a range of 1.8 to 76.3 mL. 
 
Cystatin C triggered for safety reasons, additional 2.5 mL. 
 
Disease Progression: Exploratory biomarker collection, additional 10 
 
 
Retests, as needed, an additional 0.01 to 4 mL. 
Reference 
[EU] European Union. Ethical considerations for clinical trials on medicinal products conducted 
with minors. Recommendations of the expert group on clinical trials for the implementation of 
Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use. Rev. 1. 
Published September 18, 2017. Accessed August 18, 2022. https://www.ejprarediseases.org/wp-
content/uploads/2021/10/EC_ethical-consideration-on-clinical-trials-with-minors_2017.pdf

J1S-MC-JP04(b) Clinical Protocol Addendum
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Attachment 10. Supporting Documentation and 
Operational Considerations  
Regulatory, Ethical, and Study Oversight Considerations  
Regulatory and Ethical Considerations  
 This study will be conducted in accordance with the protocol and with the 
following: 
 Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and CIOMS International Ethical Guidelines 
 Applicable ICH GCP Guidelines 
 Applicable laws and regulations 
 The protocol, protocol amendments, ICF, IB, and other relevant documents (for 
example, advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
 Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
 Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
 The investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
 Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
 Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
o Reporting to the sponsor or designee significant issues related to participant 
safety, participant rights, or data integrity. 
 Investigator sites are compensated for participation in the study as detailed in the 
Clinical Trial Agreement. 
 

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Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
Informed Consent Process  
 
the study, including the risks and benefits, to the participant and answer all 
questions regarding the study. 
 Potential participants must be informed that their participation is voluntary. 
Participants will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
privacy and data protection requirements, where applicable, and the IRB/IEC 
or study center. 
 The medical record must include a statement that written informed consent 
was obtained before the participant was entered in the study and the date the 
written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF.  
 Revised consents must be appropriately obtained using the correct approved 
ICFs for applicable study participants in accordance with sponsor and ERB 
consenting guidance. 
 A copy of the ICF(s) must be provided to the participant and is kept on file. 
Participants who are rescreened are required to sign a new ICF. 
Data Protection  
 Participants will be assigned a unique identifier by the sponsor to protect the 
. Any participant information, such as records, 
datasets, or tissue samples that are transferred to the sponsor will contain the 
identifier only. Participant names or any information which would make the 
participant identifiable will not be transferred. 
 
sonal study-related 
data will be used by the sponsor in accordance with local data protection law. 
The level of disclosure must also be explained to the participant who will be 
required to give consent for their data to be used as described in the informed 
consent. This is done by the site personnel through the informed consent 
process. 

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 The participant must be informed through the informed consent by the site 
personnel that their medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 The sponsor has processes in place to ensure information security, data 
integrity, and data protection. These processes address management of data 
transfer, and prevention and management of unauthorized access, disclosure, 
dissemination, alteration or loss of information or personal data. These 
processes include appropriate contingency plan(s) for appropriate and timely 
response in the event of a data security breach. 
 The transfer of personal data is subject to appropriate safeguards through contractual 
laws and relevant legislations including the General Data Protection Regulation 
(GDPR). 
Committees Structure  
Interim analyses for safety and efficacy will be conducted under the guidance of an 
independent DMC. The DMC will consist of at least 3 members, including a chair, a physician, 
and a statistician. The DMC will communicate any recommendations based on interim analysis 
to the Sponsor. Further details on the members, activities, and responsibilities of the DMC can 
be found in the DMC charter. 
 
Early Safety Data Review AND/OR Committee  
Case unblinding may be performed for above reviews, if necessary. 
Dissemination of Clinical Study Data  
Report Preparation 
An investigator will sign the final CSR for this study, indicating agreement that, to the best of his 
or her knowledge, the report accurately describes the conduct and results of the study. 
Public Access to Reports and Data 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete dataset 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
 

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Adverse Events and Serious Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting  
 The definitions and procedures detailed in this appendix are in accordance with ISO 
14155. 
 Both the investigator and the sponsor will comply with all local medical device 
reporting requirements. 
Definition of AE  
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the study 
intervention. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal (investigational) product, or investigational 
combination product, whether or not related to the medicinal (investigational) product. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, and vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae.  
 Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
 
The disease/disorder being studied or expected progression, signs, or symptoms of the 

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condition. 
 Medical or surgical procedure (for example, endoscopy and appendectomy): the 
condition that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.  
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or more 
of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in 
doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 
life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (for example, sprained ankle), which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered SAEs. 

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f. 
Other situations: 
 Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.  
 
Definition of Product Complaints  
Product Complaint 
 A PC is any written, electronic, or oral communication that alleges deficiencies related to 
the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
study intervention. When the ability to use the study intervention safely is impacted, the 
following are also PCs: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected to 
ensure the safety of participants, monitor quality, and to facilitate process and product 
improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a PC or problem with the study intervention so that the situation can be assessed. 
 An event may meet the definition of both a PC and an AE/SAE. In such cases, it should 
be reported as both a PC and as an AE/SAE. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and PC Recording 
 When an AE/SAE/PC occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
 The investigator will then record all relevant AE/SAE/PC information 
information is reported on the appropriate CRF page, and PC information is reported on 
the PC Form. 
Note: An event may meet the definition of both a PC and an AE/SAE. In such cases, it 

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should be reported as both a PC and as an AE/SAE. 
 It is not 
records to Sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the PC Form for PCs. 
 There may be instances when copies of medical records for certain cases are requested by 
Sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to Sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.  
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories: 
 Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
 Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as serious  when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB in their assessment. 
 The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.

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 There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor or designee. 
 The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-Up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor 
or designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
Reporting of SAEs  
SAE Reporting via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE will be the electronic data collection tool. 
 If the electronic system is unavailable, then the site will use the SAE paper form (see next 
section) to report the event within 24 hours. 
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on an SAE paper form (see next section) or 
to the SAE coordinator by telephone. 
 Contacts for SAE reporting can be found in study training materials.  
 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the SAE coordinator. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in study training materials.  
Regulatory Reporting Requirements  

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SAE Regulatory Reporting 
Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities toward the safety of participants 
and the safety of a study intervention under clinical investigation are met. 
 The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The sponsor will evaluate the reported SAEs, including 
confirmation of relatedness and assessment of expectedness. The sponsor has 
processes for safety reports for identification, recording, and expedited reporting 
of SUSARs according to local regulatory requirements. The sponsor will comply 
with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
 An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (for example, summary or listing of SAEs) from 
the sponsor will review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements.  
 
 

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Attachment 11. Protocol Addendum Amendment History  
Amendment (a)  
The amendment is considered to be substantial because it is likely to have a significant impact on 
the 
 safety or the rights of the study participants, and 
 reliability and robustness of the data generated in the clinical study. 
Overall Rationale for the Amendment: 
This amendment incorporates clarifications and corrections to provide better flexibility for 
participants and investigators. Additionally, changes were made to better align with more recent 
abemaciclib safety guidance, incorporate regulatory agency feedback, improve operational 
efficiency, and to improve alignment with the CAMPFIRE Master Protocol.  
 
Section # and Name 
Description of Change 
Brief Rationale 
3.2 Schedule of Activities
Moved note that laboratory and 
pregnancy tests may be collected at a 
local clinic if deemed appropriate by 
the investigator to top of section 
Clarification 
3.2 Schedule of Activities
Added statement that minor 
participants will need to re-consent 
upon reaching age of majority 
Clarification 
3.2 Schedule of Activities
Added Vital signs to baseline 
assessments 
Correction 
3.2 Schedule of 
Activities; 3.6.1.1 
Exceptions to the 
CAMPFIRE Master 
Protocol Inclusion 
Criteria 
Added flexibility for baseline 
pregnancy test; 
Specified that serum pregnancy test is 
required in France 
Added for flexibility 
 
Per regulatory feedback 
3.2 Schedule of Activities
Clarified that concomitant 
medications and adverse events are 
collected continuously throughout the 
study 
Clarification 
3.2 Schedule of Activities
Separated physical examination and 
 measurement into separate 
procedures 
Clarification 
3.2 Schedule of Activities
Specified that 
 
Clarification 

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Section # and Name 
Description of Change 
Brief Rationale 
can occur at any visit every fourth 
cycle 
3.2 Schedule of Activities
Specified BSA calculation formula 
Clarification 
3.2 Schedule of Activities
imaging and Participant returns study 
drugs 
Correction 
3.2 Schedule of Activities
Removed BSA collection from V801 
Not needed in short-term 
follow-up 
3.2 Schedule of 
Activities; 
3.9.4 Pharmacokinetics 
Clarified patient dosing diary 
collection timeframe 
Clarification 
3.2 Schedule of 
Activities; 
3.9.1.1 Product 
Acceptability and 
Palatability Assessments 
Removed statement that the 
questionnaire will be administered at 
the time of dosing 
Removed to provide 
flexibility 
3.2 Schedule of Activities
Removed visit window from Long-
Term Follow-Up and added footnote 
describing timing 
Clarification 
3.3.2.4 Temozolomide 
 
 
 
3.3.3 Benefit/Risk 
Assessment 
Added language for VTE risk 
Alignment with current 
abemaciclib safety language 
3.3.3.1 Benefit/Risk 
Assessment of COVID-
19 
assessments) 
Clarification 
3.6.1 Inclusion Criteria 
Inclusion 38: added exclusion for 
France 
Per regulatory agency 
feedback 
3.6.1 Inclusion Criteria; 
Attachment 7 Protocol 
JP04 Addendum 
Contraceptive Guidance 
and Collection of 
Pregnancy Information 
Added new attachment with detailed 
contraceptive guidance / pregnancy 
information collection 
Added to provide additional 
details for contraception and 
pregnancy information 
collection beyond what is 
detailed in the CAMPFIRE 
Master Protocol 
3.6.1.1 Exceptions to the 
CAMPFIRE Master 
Protocol Inclusion 
Criteria 
-like 
 
Per regulatory agency 
feedback 

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Section # and Name 
Description of Change 
Brief Rationale 
3.6.1.1 Exceptions to the 
CAMPFIRE Master 
Protocol Inclusion 
Criteria 
Inclusion 7: Provided additional 
contraceptive guidance following last 
dose of irinotecan and temozolomide 
Per regulatory agency 
feedback 
3.6.2 Exclusion Criteria 
clarification 
Clarification 
3.5.2 Exclusion Criteria 
Exclusion 46: added 
myelosuppression as example of 
condition that would preclude 
participation in study 
Per regulatory agency 
feedback. 
3.6.4 Screen Failures 
Added section 
Section to be used in place 
of the language present in 
the CAMPFIRE Master 
Protocol 
3.7.2 Method of 
Treatment Assignment 
Removed requirement for Lilly 
CRP/CRS to confirm eligibility 
Operational 
3.7.2 Method of 
Treatment Assignment 
first 
for first stratification factor 
Clarification 
3.7.4 General Dosing 
Instructions 
Added dose administration 
instructions 
Clarification 
3.7.4.3 Temozolomide 
Specified that temozolomide should 
be administered approximately 1 hour 
before irinotecan infusion 
provide flexibility 
3.7.6 Concomitant 
Therapy 
Moved section from 3.7.9 
Alignment with 
CAMPFIRE Master 
Protocol 
3.7.7 Participants with 
Difficulty Swallowing 
Added new guidance for abemaciclib 
administration 
Added to provide flexibility 
for participants with 
difficulty swallowing 
3.7.8.3 Dose-
Modification Guidance 
due to Toxicity 
Added provision for investigators to 
discuss specific modifications for an 
individual patient with the Lilly 
CRP/CRS 
Per regulatory agency 
feedback. 
3.7.8.3.1 Dose 
Modification for 
Hematologic Toxicities 
Modified dose modifications to be 
more conservative 
Medical judgment 
3.7.9 Treatment 
Compliance 
Added addendum-specific 
requirements for treatment 
compliance 
Operational 

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Section # and Name 
Description of Change 
Brief Rationale 
3.9.4 Pharmacokinetics 
Specified that abemaciclib PK 
samples will be collected for Arm A 
only and that temozolomide and 
irinotecan PK samples will be 
collected for Arm A and Arm B 
participants. 
Clarification 
3.9.4 Pharmacokinetics 
 PK sampling 
collecting time and date of doses of 
study drugs 
Clarification 
3.9.6.1 Tissue Samples 
for Biomarker Research; 
Attachment 3 Protocol 
JP04 Addendum 
Sampling Schedule for 
Biomarkers and 
Pharmacokinetics; 
Attachment 3 Protocol 
JP04 Addendum 
Sampling Schedule for 
Biomarkers and 
Pharmacokinetics 
Clarified wording about tumor 
sample and whole blood sample 
submission 
Clarification  
3.10.2 Populations for 
Analysis 
Removed per-protocol analysis set 
Operational 
Attachment 2 Protocol 
JP04 Addendum Clinical 
Laboratory Tests 
Added alkaline phosphate to clinical 
chemistry panel 
Correction 
Attachment 3 Protocol 
JP04 Addendum 
Sampling Schedule for 
Biomarkers and 
Pharmacokinetics 
Specified that PK sampling will 
occur for Arm A only 
Clarification 
Attachment 6 Protocol 
JP04 Addendum 
Abemaciclib Dosing 
Chart 
Revised table 
Alignment with BSA 
formula used in study 
Attachment 7 Protocol 
JP04 Addendum 
Contraceptive Guidance 
and Collection of 
Pregnancy Information 
Added attachment 
Added to provide additional 
details for contraception and 
pregnancy information 
collection beyond what is 
detailed in the CAMPFIRE 

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Section # and Name 
Description of Change 
Brief Rationale 
Master Protocol
Attachment 8 JP04 
Addendum Provisions for 
Changes in Study 
Conduct During 
Exceptional 
Circumstances 
Added attachment 
Added to provide flexibility 
to patients and sites during 
exceptional circumstances