Clinical trial NCT03752177
Conditions: Solid Tumor
Keywords: TIM-3 PD-L1
Sponsor: Eli Lilly and Company
Start date: 2018-11-22; Completion date: 2019-10-09
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this study is to evaluate the safety of LY3415244, a PD-L1/TIM-3 bispecific antibody, administered as monotherapy to participants with advanced solid tumors.

Detailed description:

Arms: arm 1: Participants received 3 milligrams (mg) LY3415244 (Cohort A1), 10 mg LY3415244 (Cohort A2), 30 mg LY3415244 (Cohort A3) and 70 mg LY3415244 (Cohort A4) as an intravenous (IV) infusion on day (D)1 and D15 of each 28-day cycle every 2 weeks (Q2W). arm 2: Phase 1b dose expansion was planned but not initiated as dose escalation ended at cohort A4. Study did not achieve its primary objective of establishing a recommended phase 2 dose (RP2D) due to early termination of the study by Cohort A4.
Interventions: intervention 1: LY3415244
Intervention descriptions: intervention 1: Administered IV

Protocol documents:
Prot_000.pdf: 
Protocol J1C-MC-JZDA (b) 
 
 
A Phase 1a/1b Study of LY3415244, a Bispecific Antibody in Patients with Advanced Solid 
Tumors 
 
NCT03752177 
 
Approval Date: 13-Dec-2018 
 
 


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Protocol J1C-MC-JZDA(b)
A Phase 1a/1b Study of LY3415244, a Bispecific Antibody in 
Patientswith Advanced Solid Tumors
Confidential Information
The information contained in this document 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 
LY3415244, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Approval Date: 13-Dec-2018 GMT
LY3415244
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly:  30 May 2018
Amendment (a)Electronically Signed and Approved by Lilly on date provided below.
Amendment (b)Electronically Signed and Approved by Lilly on date provided below.


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Table of Contents
Section
Page
Protocol J1C-MC-JZDA(b) A Phase 1a/1b Study of LY3415244, a 
Bispecific Antibody in Patients with Advanced Solid Tumors.............................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................20
3.1.
Study Rationale............................................................................................................20
3.2.
Background..................................................................................................................20
3.2.1.
LY3415244..........................................................................................................21
3.2.1.1.
Nonclinical Pharmacokinetics.........................................................................21
3.2.1.2.
Nonclinical Toxicology ..................................................................................22
3.3.
Benefit/Risk Assessment..............................................................................................24
4.
Objectives and Endpoints..................................................................................................26
5.
Study Design.....................................................................................................................28
5.1.
Overall Design .............................................................................................................28
5.1.1.
Dose Escalation Phase..........................................................................................30
5.1.2.
Dose Expansion Phase .........................................................................................30
5.2.
Number of Patients.......................................................................................................31
5.3.
End of Study Definition ...............................................................................................31
5.4.
Scientific Rationale for Study Design...........................................................................31
5.5.
Justification for Dose ...................................................................................................31
6.
Study Population...............................................................................................................36
6.1.
Inclusion Criteria..........................................................................................................36
6.2.
Exclusion Criteria ........................................................................................................39
6.3.
Lifestyle Restrictions....................................................................................................41
6.4.
Screen Failures.............................................................................................................41
7.
Treatment..........................................................................................................................42
7.1.
Treatment Administered...............................................................................................42
7.1.1.
Packaging and Labeling .......................................................................................42
7.2.
Method of Treatment Assignment ................................................................................43
7.2.1.
Selection and Timing of Doses.............................................................................43
7.2.2.
Dose Escalation:  Phase 1a...................................................................................43
7.2.2.1.
Dose Escalation Method.................................................................................43
7.2.2.2.
Dose-Limiting Toxicity Determination ...........................................................44


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7.2.2.2.1.
Events That Are Not Considered to Be DLTs............................................45
7.2.2.2.2.
DLT-Equivalent Toxicities .......................................................................46
7.2.2.3.
Recommended Phase 2 Dose Determination...................................................46
7.3.
Blinding .......................................................................................................................46
7.4.
Dose Modification........................................................................................................47
7.5.
Preparation/Handling/Storage/Accountability...............................................................54
7.6.
Treatment Compliance .................................................................................................54
7.6.1.
Evaluable Patients................................................................................................54
7.6.1.1.
DLT-Evaluable Patients in Phase 1a ...............................................................54
7.7.
Concomitant Therapy...................................................................................................55
7.8.
Treatment after Study Completion................................................................................57
7.8.1.
Continued Access.................................................................................................57
8.
Discontinuation Criteria ....................................................................................................59
8.1.
Discontinuation from Study Treatment.........................................................................59
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................60
8.2.
Discontinuation from the Study....................................................................................60
8.3.
Lost to Follow-Up........................................................................................................60
9.
Study Assessments and Procedures ...................................................................................61
9.1.
Efficacy Assessments...................................................................................................61
9.1.1.
RECIST 1.1 with Confirmatory Scan for Disease 
Progression ..........................................................................................................62
9.1.1.1.
Rationale for RECIST 1.1 with Confirmatory Scan for 
Disease Progression........................................................................................62
9.1.1.2.
Application of RECIST 1.1 with Confirmatory Scan for 
Disease Progression........................................................................................63
9.1.1.3.
Criteria Required to Receive Treatment during 
Confirmatory Scan Period...............................................................................64
9.2.
Adverse Events ............................................................................................................64
9.2.1.
Serious Adverse Events........................................................................................65
9.2.2.
Suspected Unexpected Serious Adverse Reactions ...............................................66
9.2.3.
Complaint Handling.............................................................................................66
9.3.
Treatment of Overdose.................................................................................................66
9.4.
Safety...........................................................................................................................67
9.4.1.
Other Safety Measures .........................................................................................67
9.4.2.
Safety Monitoring ................................................................................................68
9.4.2.1.
Special Hepatic Safety Data Collection...........................................................68
9.5.
Pharmacokinetics .........................................................................................................68
9.6.
Pharmacodynamics ......................................................................................................69
9.6.1.
Immunogenicity Assessments ..............................................................................69


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9.7.
Genetics .......................................................................................................................70
9.7.1.
Whole Blood Sample for Pharmacogenetic Research ...........................................70
9.8.
Biomarkers...................................................................................................................70
9.8.1.
Tissue Samples for Biomarker Research...............................................................71
9.8.2.
Other Samples for Biomarker Research................................................................72
9.9.
Health Economics ........................................................................................................73
10.
Statistical Considerations ..................................................................................................74
10.1. Sample Size Determination ..........................................................................................74
10.2. Populations for Analyses..............................................................................................74
10.3. Statistical Analyses ......................................................................................................75
10.3.1.
Safety Analyses....................................................................................................75
10.3.2.
Efficacy Analyses ................................................................................................75
10.3.3.
Other Analyses.....................................................................................................76
10.3.3.1.
Patient Disposition..........................................................................................76
10.3.3.2.
Patient Characteristics ....................................................................................77
10.3.3.3.
Concomitant Therapy .....................................................................................77
10.3.3.4.
Treatment Compliance....................................................................................77
10.3.3.5.
Pharmacokinetic/Pharmacodynamic Analyses ................................................77
10.3.3.6.
Biomarker Analyses .......................................................................................77
10.3.3.7.
Immunogenicity Analysis ...............................................................................78
10.3.4.
Interim Analyses..................................................................................................78
11.
References ........................................................................................................................79
12.
Appendices .......................................................................................................................85


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List of Tables
Table
Page
CCI
Table JZDA.2.1.Baseline and On-Study Treatment Schedule of Activities...............................11
Table JZDA.2.2.Poststudy Treatment Follow-Up Schedule of Activities.................................16
Table JZDA.2.3.Continued Access Schedule of Activities.......................................................18
 
Table JZDA.4.1.Objectives and Endpoints...............................................................................26
Table JZDA.7.1.Treatment Regimen.......................................................................................42
Table JZDA.7.2.Dose-Limiting Toxicity.................................................................................45
Table JZDA.7.3.Management of Infusion-Related Reactions...................................................48
TableJZDA.7.4.Dose Modification Guidelines and AE Management for Toxicities At 
Least Possibly Related to Study Drug............................................................49
Table JZDA.7.5.Concomitant Medication Guidelines..............................................................55
Table JZDA.9.1.Summary of Response Assessment by RECIST, RECIST with 
Confirmatory Scan for PD, and irRC.............................................................63
Table JZDA.10.1.
Estimated Incidence Rate
and 2-Sided 95% Confidence Interval............................................................74
CCI


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List of Figures
Figure
Page
CCI
Figure JZDA.5.1.Illustration of study design.............................................................................29
 
 
 
 
 
Figure JZDA.7.1.Continued access diagram..............................................................................58
CCI


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................86
Appendix 2.
Clinical Laboratory Tests...............................................................................91
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations ...........................93
Appendix 4.
Sampling Schedule ........................................................................................96
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality..................103
Appendix 6.
Creatinine Clearance Formula......................................................................104
Appendix 7.
Dose-Finding Spreadsheet of the Modified Toxicity Probability Interval 
Method Showing Number of Patients Treated..............................................105
Appendix 8.
Definition of Woman of Childbearing Potential ...........................................107
Appendix 9.
Protocol Amendment J1C-MC-JZDA(a) Summary......................................108
Appendix 10.
Protocol Amendment J1C-MC-JZDA(b) Summary......................................131


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1. Synopsis
Protocol Title:  A Phase 1a/1b Study of LY3415244, a Bispecific Antibody in Patients with 
Advanced Solid Tumors
Rationale:
While inhibitors of either programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1)
have shown clinical activity and manageable safety profiles as monotherapy in a variety of tumor
types, efficacy can be low in some tumor types (Wu et al. 2015). The possible benefit of other 
immunotherapy agents alone or in combination with PD-1 or PD-L1 inhibitor, which can further 
augment the response, is an important area of interest.
T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3), a co-inhibitory
molecule, is expressed on T cells during activation and has been identified as a cell surface 
marker for “exhausted” T cells following chronic exposure to antigen (Wherry 2011) and marks 
the most exhausted or dysfunctional populations of T cells in the tumor microenvironment and 
during chronic viral infection. TIM-3 is often co-expressed with PD-1 and cytotoxic T-
lymphocyte antigen 4 on tumor-antigen-specific T cells in cancer patients.  Blocking TIM-3 
provides the opportunity to enhance antitumor T-cell immunity, much like targeting the PD-1 
axis, and provides the opportunity to combine anti-TIM-3 therapy with clinically validated 
checkpoint inhibitor antibodies such as PD-1 or PD-L1.
Dual-targeting of the TIM-3 and PD-1/PD-L1 pathway has been pursued preclinically.  For 
example, in vitro treatment of tumor-infiltrating lymphocytes harvested from CT26 tumor 
bearing mice with anti-TIM-3 and anti-PD-L1 resulted in more robust interferon gamma
production than with either antibody alone.  In vivo, combined targeting of the TIM-3 and PD-
L1 is more effective in controlling tumor growth than targeting either pathway alone in a CT26 
model, in a B16F10 model, and in a 5T33 myeloma model with low dose irradiation (Sakuishi et 
al. 2010, Anderson 2015 [WWW], and Jing et.al. 2015, respectively).  Synergistic antitumor 
effects have been observed for combinations of anti-TIM-3 with anti-PD-1 in CT26, MC38, and 
established methylcholanthrene-induced sarcomas (Ngiow et al. 2011).  TIM-3 expression is 
upregulated in PD-1 refractory patients and there is survival advantage with the addition of a 
TIM-3 blocking antibody following failure of PD-1 blockade in EGFRT790M/L858R or KrasG12D
transgenic tumor model (Koyama et al. 2016).  Collectively, these data suggest that blockade of 
both TIM-3 and PD-1/PD-L1 immune checkpoints is a promising approach for improved 
efficacy of immunotherapy. 
LY3415244, a TIM-3/PD-L1 bispecific antibody, can block both PD-L1 and TIM-3, thereby 
overcoming immune checkpoints and T-cell exhaustion. In vitro experiments have demonstrated 
that LY3415244 can bridge cells engineered to express TIM-3 with those that express PD-L1. 
The clinical relevance of bridging is unknown at this time. The goal of this study is to evaluate
the safety of LY3415244 administered as monotherapy to patients with advanced solid tumors.














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Baseline and On-Study Treatment Schedule of Activities
Abbreviations:  AE = adverse event; C1D1 = Cycle 1 Day 1; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram;
ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; ESR = erythrocyte sedimentation rate; HCC = 
hepatocellular carcinoma; HIV = human immunodeficiency virus; ICF = informed consent form; IV = intravenous; MUGA = multiple-gated acquisition; Q = 
every; RECIST 1.1 = Response Criteria in Solid Tumors Version 1.1; W = weeks.




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Poststudy Treatment Follow-Up Schedule of Activities
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; D = day; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; PD = progressive disease; SAE = serious adverse event; Q = every; W = week.
a
Short-term follow-up begins when the patient and investigator agree that the patient will discontinue study treatment and ends on the day of the 90-day 
follow-up visit.  No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has explicitly provided permission 
and consent.
b
Long-term follow-up begins the day after the patient completes the 90-day follow-up visit and ends with the patient’s death, upon loss to follow-up, or upon 
overall study completion, whichever is earlier.  No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has 
explicitly provided permission and consent.




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Continued Access Schedule of Activities
Abbreviations:  ADAs = antidrug antibodies; AE = adverse event; D = day; IG = immunogenicity; IRR = infusion-related reaction; PK = pharmacokinetics; 
Q = every; W = week.
a
Continued access follow-up begins when the patient and the investigator agree that the patient will no longer continue treatment in the continued access 
period and lasts approximately 90 days. No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has 
explicitly provided permission and consent.


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3. Introduction
3.1.
Study Rationale
Targeted checkpoint inhibitors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), 
programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1) have shown great promise 
in the treatment of cancer and have resulted in durable responses across many tumor types,
demonstrating that the targeting of checkpoint inhibitors is a clinically validated approach
(Brahmer et al. 2012; Topalian et al. 2012; Hamid et al. 2013; Reck et al. 2016; Bellmunt et al.
2017). However, there remains a large proportion of patients who do not respond.
The PD-1 checkpoint is known to be upregulated after activation of T-cell receptor and 
subsequently during T-cell exhaustion (Zou et al. 2016). T-cell immunoglobulin and mucin-
domain-containing molecule-3 (TIM-3) is another co-inhibitory molecule that marks exhausted 
or dysfunctional populations of T cells in the tumor microenvironment and during chronic viral 
infection. In fact, it is often co-expressed with PD-1 and CTLA-4 on tumor-antigen-specific 
T cells in cancer patients and negatively regulates T-cell activity (Fourcade 2010, Baitsch et al. 
2011; Pauken and Wherry 2015). More importantly, TIM-3 expression is found to be
upregulated in PD-1-refractory patients. In addition, administration of a TIM-3-blocking 
antibody to epidermal growth factor receptor (EGFR)T790M/L858R or Kirsten rat sarcoma (Kras)G12D
transgenic mice with tumors that progress upon treatment with anti-PD-1 appears to confer a 
survival advantage (Koyama et al. 2016).
LY3415244, a TIM-3/PD-L1 bispecific antibody, has been demonstrated to block PD-L1 and 
TIM-3, in respective in vitro assays.  In line with the biology of PD-L1 and TIM-3, this blockade 
could result in overcoming immune checkpoints and T-cell exhaustion. In vitro experiments 
have demonstrated that LY3415244 can bridge cells engineered to express TIM-3 with those that 
express PD-L1. The clinical relevance of bridging is unknown at this time. 
The goal of this study is to evaluate the safety of LY3415244 administered as monotherapy to 
patients with advanced solid tumors.
3.2.
Background
While inhibitors of both PD-1 and PD-L1 have shown clinical activity and manageable safety 
profiles as monotherapy in a variety of tumor types, their efficacy in various tumor types could 
potentially be improved (Wu et al. 2015). The possible benefit of targeting the PD-1/PD-L1
pathway with another immune checkpoint inhibitor, which can further augment the response, is 
an important area of interest.
T-cell immunoglobulin and TIM-3 were first discovered as a negative regulators of interferon 
gamma (IFN-γ) secreting T cells (Monney et al. 2002).  TIM-3 is expressed on T cells during 
activation and has been identified as a cell surface marker for “exhausted” T cells following 
chronic exposure to antigen (Wherry 2011).  Multiple ligands have been described for TIM-3, 
including phosphatidylserine (PtdSer), galectin-9 (Gal-9), and carcinoembryonic antigen cell 
adhesion molecule-1 (Zhu et al. 2005; DeKruyff et al. 2010; Huang et al. 2015).  Binding of 
TIM-3 with TIM-3 ligand leads to T-cell dysfunction, but the precise signaling mechanism for 


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these receptors has not beenfully elucidated.  In the context of chronic viralinfection, TIM-3 
expression on virus-specific Tcells has been associated with T-cell dysfunction, and inhibition 
of TIM-3 signaling has been shown to restore T-cell functionality (Jin et al. 2010).  Recently, 
TIM-3 expression on T-lymphocytes has also been shown to mediate T-cell exhaustion during 
chronic mycobacterium tuberculosis infection (Jayararman et al. 2016).
Consistent with its inhibitory role in autoimmune and chronic viraland bacterial infections, TIM-
3 has been shown to mark the most exhausted or dysfunctional populations of CD8+ T cells in 
animal models of solid and hematologic malignancies (Sakuishi et al. 2010; Zhou et al. 2011). 
TIM-3 has also been implicated in modulating antitumor immunity in a number of preclinical 
models. The growth of 4T1 mammary tumors was inhibited in TIM-3-deficient mice and anti-
TIM-3-monoclonal antibody (mAb)inhibited the growth of established EL4 lymphoma, 
suggesting that TIM-3 is a potential target for cancer immunotherapy (Dardalhon et al. 2010). 
TIM-3 blockade in WT3, TRAMP-C1, and CT26 mouse models resulted in antitumor activities
similar to anti-CTLA-4/PD-1 antibody and a greater efficacy with combined use of TIM-3 and 
PD-1 antibodies (Ngiow et al. 2011). NY-ESO-1-specific CD8+ T cells from patients with 
melanoma showed dysfunctional phenotypes and TIM-3 blockade restored IFN-γ and tumor 
necrosis factor-production as well as cell proliferation (Fourcade et al. 2010).  TIM-3 has also 
been reported to promote myeloid-derived suppressor cells (Dardalhon et al. 2010) and suppress 
natural killer (NK) cell activity (da Silva et al. 2014).
Dual-targeting of the TIM-3 and PD-1/PD-L1 pathway has been evaluatedpreclinically.  For 
example, in vitro treatment of tumor-infiltrating lymphocytes(TILs)harvested from CT26 
tumor-bearing mice with anti-TIM-3 and anti-PD-L1 resulted in more robust IFNproduction 
than with either antibody alone.  In vivo,combined targeting of the TIM-3 and PD-L1 ismore 
effective in controlling tumor growth than targeting either pathway alone in a CT26 model, in a 
B16F10 model, and in a 5T33 myeloma model with low dose irradiation (Sakuishi et al. 2010, 
Anderson 2015[WWW], and Jing et.al. 2015, respectively).  Synergistic antitumor effects have 
been observed for combinationsof anti-TIM-3with anti-PD-1 in CT26, MC38,and established 
methylcholanthrene-induced sarcomas(Ngiow et al. 2011).  TIM-3 expression is upregulated in 
PD-1 refractory patients and there is survival advantage with the addition of a TIM-3 blocking 
antibody following failure of PD-1 blockade in EGFRT790M/L858Ror KrasG12Dtransgenic tumor 
model (Koyamaet al. 2016).  Collectively, these data suggest that blockade of both TIM-3 and 
PD-1/PD-L1 immune checkpoints is a promising approach for improved efficacy of 
immunotherapy. 
3.2.1. LY3415244
3.2.1.1. Nonclinical Pharmacokinetics
CCI
The pharmacokinetics (PK)of LY3415244 wereevaluated in male cynomolgus monkeys 
following a single bolus intravenous (IV)administration
 
 




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CCI
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
CCI
CCI
CCI
CCI


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3.3. Benefit/Risk Assessment
LY3415244targets TIM-3 and PD-L1 Tcell checkpoint inhibitors and ispredicted toshare a 
similar profile of potential immune-related adverse drug reactions. The constellation ofimmune-
related adverse events (irAEs)observed across the immune checkpoint inhibitor class (see 
Section 7.4
CCI
)is generallyconsidered to be clinically monitorable and manageable (Chow 2013). 
Currently, there is limited safety datapublishedfrom ongoing clinical trialsevaluating several 
anti-TIM-3.Clinical data from Phase 1 dose escalation of TSR-022, an anti-TIM-3mAb, 
reported TSR-022 as being well-tolerated across multiple dose levels with safety profiles 
consistent with those of other checkpoint inhibitors (Weiss et al.2017).  Data from nonclinical 
models predictsa similar immune-related toxicity profile, as TIM-3 pathway blockade has been 
shown to enhance immune-drivenpathology in murine autoimmunity models (Monney et al. 
2002; Sánchez-Fueyo et al. 2003).It is currently unknown whether a bispecific antibody like 
LY3415244 that targets both TIM-3 and PD-L1would have an effect on the severity, onset, 
and/or frequency of adverse drug reactions ascompared to monotherapy administration.
 
 
 
 
 
 
CCI


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CCI
 
 
 
 
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of LY3415244are to be found in the 
Investigator’s Brochure (IB).  
CCI






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5. Study Design
5.1.
Overall Design
Study JZDA is a multicenter, nonrandomized, open-label, Phase 1a/1b study of intravenous 
LY3415244 in patients with advanced solid tumors. Inclusion and exclusion criteria are 
provided in Sections 6.1 and 6.2, respectively.
Phase 1a (dose escalation) will assess the safety and tolerability of LY3415244, administered as 
monotherapy in patients with advanced solid tumors.  The RP2D to be tested in Phase 1b will be 
identified in Phase 1a, as described in Section 7.2.2. Late toxicities of available data up to 
90 days will be considered for RP2D determination. Dose escalation of LY3415244 will be 
driven by a mTPI-2 method (Guo et al. 2016 [WWW]; see Section 7.2.2.1).
Phase 1b (dose expansion) will assess the safety and tolerability of LY3415244, administered as 
monotherapy in 4 expansion cohorts of patients with selected advanced solid tumor types of non-
small cell lung cancer (NSCLC), urothelial cancer, mesothelioma, and melanoma.
Patients in both phases will receive study treatment for a maximum of 12 months (see 
Section 8.1).
The data from Phase1 a will determine the RP2D but the RP2D dose may be modified in 
Phase 1b if supported by additional safety and/or PK/PD data. For the primary objective of 
establishing safety, patients will be followed for at least 24 weeks after the last patient is 
enrolled.  For the secondary objective of progression-free survival (PFS) and the tertiary 
objective of overall survival (OS), patients will be followed until death or until study completion 
(defined in Section 5.3), whichever occurs first.
Figure JZDA.5.1 illustrates the study design.


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Abbreviations: D = day; Meso = mesothelioma; mg = milligrams; NSCLC = non-small-cell lung cancer; pts = patients; Q = every; 
TBD = to be determined; W = week.
Note:  Cohort A8 is optional and may be explored at a dose not exceeding 1500 mg of LY3415244. 
Figure JZDA.5.1.
Illustration of study design.


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5.1.1.Dose Escalation Phase
Patients inCohortsA1, A2, A3, A4, A5, A6, A7,and A8, respectively,will receive doses of 3
mg, 10mg, 30mg, 70mg, 200mg, 600mg, 1000 mg, and a dose not exceeding 1500 mg 
according to anevery-2-weeks (Q2W) dosing regimen, provided safety is established in the 
preceding cohorts (see Table JZDA.7.1).  
After the first patient in Cohort A1 receives the first dose of LY3415244, there will be a delay of 
1week to allow for safety observation before the secondand thirdpatientsreceive LY3415244. 
There will be no additional delays for subsequent patients.
 
 
 
 
 
 
 
 
 
Cohorts of patients will be treated with escalating doses of LY3415244 according to amTPI-2
method until the criteria for reaching the maximum-tolerated dose (MTD) are met (see 
Section7.2.2.1).  The RP2D ofLY3415244to be tested in the Phase 1bportion of the studywill 
be identified in Phase 1a.  The RP2D may be below the MTD, which may or may not be reached 
during Phase 1a.For some immuno-oncology compounds that have manageable safety profiles 
and do not reach a MTD, additional information such as pharmacodynamic markers may be 
helpful in determining the appropriate RP2D (Agrawal et al. 2016; Parchmentet al.2016).  Late 
toxicities of available data up to 90 days will be considered forRP2D determination.
A 1-cycle (28 days)dose-limiting toxicity (DLT)observation period will applyto all cohorts in 
Phase 1a.
5.1.2.Dose Expansion Phase
Phase1b will begin after Eli Lillyand Company (Lilly)reviewsthe Phase 1a data and 
communicates the LY3415244doses to the study investigators.  
In Phase 1b, patients will enroll concurrently to each of the 4 expansion cohorts.
Individual patient, delays and discontinuations may occur as outlined inSection 7.4
CCI
.No dose 
reductions will be allowed.
Phase 1b will provide additional safety, tolerability, PK, pharmacodynamics, and efficacy data 
for LY3415244given as monotherapy.


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5.2. Number of Patients
Enrollment in each cohort will be adjusted if needed to allow adequate assessment of safety and 
preliminary antitumor activity at the LY3415244RP2D.  
Phase 1a:  Total enrollment will be determined by the incidence of DLTs.
o Cohorts A1 through A8:  approximately 27patients (minimum of 3patients per cohort) 
will be enrolled.  During Phase 1a DLT assessmentperiod, a maximum of 10 patients, 
per dose level,maybe enrolled.  
Phase 1b:
o Expansion cohorts:  approximately 80 patients (20 patients with NSCLC, 20 patients with 
urothelial cancer, 20patients with mesothelioma,and 20 patients with melanoma)
Because ofthe advanced disease state of this patient population and the screening involved in 
defining eligibility, more than the planned number of patients may be enrolled in a particular 
cohort, if approved by Lilly.
5.3. End of Study Definition
End of the studyis the date of the last visit or last scheduled procedureshown in the Schedule of 
Activities (Section 2)for the last patient.
5.4. Scientific Rationale for Study Design
See Sections 3.1and3.3.
5.5. Justification for Dose
CCI
Plasma concentrations of LY3415244, total soluble sTIM-3,and sPD-L1plasma concentrations 
in cynomolgus monkeys followinga single IV dose of 
 LY3415244were 
used to build a population PK/PD modelthatsimultaneously describes the temporal profiles of 
PK ofboth soluble targets. The developed population PK/PD model was translated to humans 
based on allometric scaling (body weight) and similar affinitybetween species (Kd). The model 
was thenused for the prediction of soluble TE% 
in 
humans.  Concentrations needed for reaching 
TE 
 
were estimated. 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI






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CCI
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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6. Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
Have histological or cytological evidence of a diagnosis of cancer that is 
advanced and/or metastatic.  The patient must be, in the judgment of the 
investigator, an appropriate candidate for experimental therapy after available 
standard therapies (per available local guidelines) have failed to provide 
clinical benefit for their disease.
[2]
For patients enrolled to Phase 1a, prior anti-PD-1 or anti-PD-L1 therapy or other 
immunotherapy is allowed.  For Phase 1b, prior anti-PD-1 or anti-PD-L1 therapy is 
required for patients with NSCLC, urothelial cancer, and melanoma.  For Phase 1a 
and Phase 1b, the following criteria need to be met:
a.
did not experience a toxicity that led to permanent discontinuation of prior anti-
PD-1, anti-PD-L1, or other immunotherapy.
b. have completely recovered to at least his or her previous baseline level prior to 
screening from any clinically significant AEs that occurred during prior 
immunotherapy.
c.
did not experience any of the following irAEs during prior anti-PD-1, anti-PD-L1, 
or other immunotherapy:
i.
a Grade 3 irAE (Table JZDA.7.4)
ii. any grade neurologic or ocular irAE
iii. any grade immune-related pneumonitis or cardiomyopathy
Patients with an endocrine AE are permitted to enroll if they are stably maintained 
on appropriate replacement therapy and are asymptomatic
d. did not require immunosuppressive agents, other than corticosteroids for the 
management of an AE, did not experience recurrence of a Grade 3 AE if 
re-challenged, and does not currently require maintenance doses of >10 mg 
prednisone (or equivalent) per day
[3]
For patients enrolled to Phase 1b expansion cohorts, have a histologically or 
cytologically confirmed diagnosis of:
a.
disease that did not initially respond to prior anti-PD-1 or anti-PD-L1 therapy
OR


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b. disease that initially responded to anti-PD-1 or anti-PD-L1 therapy (considered to 
have partial response [PR] or complete response [CR] for any duration) and later 
progressed
AND one of the following:
c.
metastatic NSCLC (Stage IV, any histological type) with 1 prior line of therapy.
Patients with an EGFR-sensitizing mutation, an ALK gene rearrangement, ROS1 
rearrangements, or BRAF V600E mutations must also have progressed after 
treatment with an appropriate tyrosine kinase inhibitor.  
d. locally advanced, unresectable or metastatic transitional cell carcinoma of 
urothelium (bladder, urethra, or renal pelvis) (patients with tumors of mixed 
pathology are eligible if predominantly transitional cell tumor) with at least 1 
prior line of systemic therapy.
e.
metastatic cutaneous melanoma with advanced unresectable disease. Acral 
lentiginous melanoma, uveal, and mucosal melanoma are excluded. 
[4]
Patients with mesothelioma are not required to have received prior anti-PD-1 or anti-
PD-L1 therapy.  If the patient has received prior anti-PD-1 or anti-PD-L1 therapy, 
then inclusion criteria [2]a through [2]d and [3]a and [3]b would apply.  Additionally, 
patients must have: 
a.
confirmed unresectable or medically inoperable malignant mesothelioma and 
progressive disease (PD) after at least one prior systemic treatment with a 
platinum-based doublet (both cisplatin and carboplatin are allowed) for 
unresectable MPM. All prior cytotoxic toxicities must have resolved to 
Grade ≤2 prior to registration.
Note: Inclusion criteria [5] through [15] apply to patients enrolled to Phase 1a and Phase 
1b portions of the study.
[5]
are able and willing to provide required, newly obtained core or excisional 
biopsy of a tumor lesion prior to study enrollment and undergo a biopsy 
procedure during the study treatment period for collection of an additional 
tumor tissue sample (see Section 9.8.1 for additional details). (Note: An 
archived tumor sample will be requested, if not restricted by local 
regulations).
[6]
Have at least 1 measurable lesion as defined by the Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1) (Eisenhauer et al. 2009). Bone 
metastases are not considered measurable.
[7]
Be ≥18 years old at the time of screening, or of an acceptable age to provide 
informed consent according to local regulations, whichever is older.
[8]
Have given written informed consent prior to any study-specific procedures.
[9]
Have adequate organ function as defined in the table below:






J1C-MC-JZDA(b) Phase 1 Oncology Protocol
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e.
prior or second concurrent primary malignancies that, in the judgment of the 
investigator and the Lilly Clinical Research Physician (CRP)/Clinical Research 
Scientist (CRS), may affect the interpretation of results. Patients with carcinoma 
in situ of any origin and patients with prior malignancies who are in remission and 
whose likelihood of recurrence is very low (such as basal cell carcinoma), as 
judged by the Lilly CRP/CRS, are eligible for this study
f.
active known or suspected autoimmune disease or any illness that could 
compromise the immune system (for example, prior organ transplant) within the 
past 2 years or a syndrome that requires systemic corticosteroids or 
immunosuppressive agents
This criterion does not apply to patients with:  (i) vitiligo, alopecia, or type I 
diabetes mellitus; (ii) residual hypothyroidism due to an autoimmune condition 
requiring only hormone replacement; or (iii) psoriasis not requiring chronic 
systemic immunosuppressive treatment within the past 2 years, and not expected 
to recur in the absence of an external trigger.
g. use of escalating or chronic supraphysiologic doses of corticosteroids or 
immunosuppressive agents (such as, cyclosporine).  Use of topical, ophthalmic, 
inhaled, and intranasal corticosteroids permitted.
This criterion does not apply to patients with:  (i) resolved childhood 
asthma/atopy or who require intermittent use of bronchodilators or local 
corticosteroid injections; (ii) hypothyroidism that is stable on hormone 
replacement; (iii) Raynaud’s syndrome; or (iv) Sjogren’s syndrome.
h. bowel obstruction, history or presence of inflammatory enteropathy or extensive 
intestinal resection (hemicolectomy or extensive small intestine resection, either 
condition with chronic diarrhea), Crohn’s disease, ulcerative colitis, or chronic 
diarrhea
i.
evidence of (i) interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity (for 
example, interstitial lung disease or radiation pneumonitis); (ii) active, 
noninfectious pneumonitis; or (iii) history of noninfectious pneumonitis that 
required corticosteroid therapy
j.
moderate or severe cardiovascular disease, such as the following:
i.
presence of cardiac disease, including a myocardial infarction or any other 
arterial thrombotic event including cerebrovascular accident or transient 
ischemic attack within 6 months prior to enrollment; unstable angina pectoris; 
New York Heart Association Class III/IV congestive heart failure; aneurysm 
of major vessels or heart; left ventricular ejection fraction <50% (evaluation 
based on institutional lower limit of normal); or uncontrolled hypertension


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ii. severe, moderate, or clinically significant valvulopathy; documented major 
ECG abnormalities that, in the judgment of the investigator, are clinically 
significant (for example, arrhythmias requiring treatment; recent myocardial 
infarction within the last 3 months; or mean QTc 470 ms calculated using 
Fridericia’s correction and confirmed by triplicate ECG)
[18] Have symptomatic central nervous system (CNS) malignancy or metastasis 
(screening not required). Patients with treated CNS metastases are eligible for this 
study if they are not requiring concurrent treatment, including but not limited to 
surgery, radiation, corticosteroids and/or anticonvulsants to treat CNS metastases, and 
their disease is asymptomatic and radiographically stable for at least 30 days.
[19] Have received a live vaccine within 30 days before the first dose of study treatment.  
Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette–Guérin, and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (for example, 
FluMist®) are live attenuated vaccines and are not allowed.
[20] Are pregnant, or planning to become pregnant during the study or within 6 months 
following the last dose of LY3415244. Plan to be breastfeeding from C1D1 of study 
or within 6 months following the last dose of LY3415244.
[21] Have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the study, interfere with the patient’s 
participation for the full duration of the study, or is not in the best interest of the 
patient to participate, in the opinion of the treating investigator
[22] Have current or history of allergy or hypersensitivity to study drug components
6.3.
Lifestyle Restrictions
There are no specific lifestyle restrictions for this protocol.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) within the 
28-day baseline screening period may be rescreened.  Individuals may be re-screened up to 
2 times after initial screening.  The interval between rescreening should be at least 1 week. Each 
time rescreening is performed, the individual must sign a new informed consent form (ICF) and 
will be assigned a new identification number. All required tests (see Section 2) must be repeated 
for patients who are rescreened in a new 28-day baseline screening period.
Repeating laboratory tests (including ECGs) that did not meet eligibility criteria during the 
28-day baseline screening period does not constitute rescreening.  However, laboratory tests may 
not be repeated more than twice, and the repeated laboratory test must meet the eligibility 
criteria.




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7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be assigned to receive LY3415244 in this study. 
An interactive web-response system (IWRS) will be used to dispense study drugs and to ensure 
that the correct number of patients is assigned to each cohort.
No dose escalations (that is, to the next cohort) can occur without prior discussion of clinical 
data and agreement with the responsible Lilly CRP/CRS. 
If investigators have eligible patients who have consented concurrently, more than the assigned
patients may be entered at a particular dose level provided that accrual has not ceased due to 
excessive toxicity.  This enrollment procedure is allowed because of the advanced disease state 
of this patient population and the screening involved in defining eligibility.  This event should be 
approved by Lilly following discussions with the investigators.
7.2.1.Selection and Timing of Doses
The doses will be administered at approximately the same times on each day.  The actual time of 
all dose administrations will be recorded in the electronic case report form (eCRF).
A cycle is defined as an interval of 28 days (Q2W regimen) as shown in Table JZDA.7.1.  A 
delay of a cycle due to holiday, weekend, bad weather, or other unforeseen circumstances will be 
permitted for a maximum of 7 days and not counted as a protocol deviation. The reason for the 
delay should be documented on the eCRF.
The first study treatment will be administered within 7 days after the patient is assigned to a 
treatment cohort. There should be a minimum of 14 days between doses of study drug.
A patient may continue to receive LY3415244 until he or she meets one or more of the specified 
reasons for discontinuation (see Section 8).
7.2.2.Dose Escalation: Phase 1a
7.2.2.1.
Dose Escalation Method
Dose escalation of LY3415244 (at the levels shown in Figure JZDA.5.1) will be driven by a
mTPI-2 method (Guo et al. 2016 [WWW]), taking into consideration available PK and 
pharmacodynamic data from previous dose levels.  Each cohort in this study will contain a 
minimum of 3 patients.
Like the 3+3 design, the mTPI-2 method incorporates prespecified escalation rules.  In contrast, 
the mTPI-2 method is based on quantitative models that incorporate uncertainty into the decision 
rules, thereby allowing more precise RP2D selection.  If 3 or 6 patients are enrolled in a cohort, 
the escalation rule parallels a traditional 3+3 design. However, it allows flexible number of 
patients in a cohort. For example, with 2 DLTs per 6 patients enrolled, the mTPI-2 would 
recommend staying at the current dose, as analogy to 1 DLT per 3 patients enrolled in 3+3 
design; therefore, it allows more patients for a more precise estimate of the DLT rate at this dose 
level. 


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Appendix 7 provides the mTPI-2 escalation rules for any cohort size up to 20 patients.
Following a discussion between the Lilly CRP/CRS and the investigators, a more conservative 
dose selection may be applied to the next cohort (for instance, if PK/pharmacodynamic data 
suggest that further dose increase would not be expected to yield additional benefit).  For 
example, if the rule indicates “E” to escalate, the dose may stay at the current dose level, be de-
escalated to a lower level, or escalation may cease.  In the mTPI-2, the cohort size is not fixed.  
However, each cohort in this study will contain a minimum of 3 patients, unless the escalation 
rules dictate that the dose should be de-escalated (“D” or “DU”).  Doses can be escalated, de-
escalated, and re-escalated following the rules in Appendix 7.  If the dose decision was “DU,” 
the dose cannot be re-escalated to that level.
This study is designed to identify a dose level with a dose-limiting target toxicity rate of 30%.  
The mTPI-2 method considers an equivalence interval (EI) around the target toxicity rate.  For 
this study, the EI is elicited to be (25%, 35%), resulting in the rules in Appendix 7.  
Safety data, in particular DLTs, will be the primary criteria for the dose escalation.  In addition, 
if available at the time of dose escalation decision, PK (for example, Cmax, AUC, 
pharmacodynamics results) will be used as secondary/supporting data for dose escalation.  
Intermediate and/or higher dose as well as alternative schedules of administration will be 
explored if deemed necessary after discussion between Lilly and investigators and taking into 
account patient safety and PK/PD data.  If needed, additional patients may be enrolled to further 
assess PK/PD or tolerability.
7.2.2.2.
Dose-Limiting Toxicity Determination
A DLT is defined as any of the events listed in Table JZDA, if the event occurs during the DLT 
observation period (Cycle 1) in Phase 1a, and toxicity that is not clearly and directly related to 
the primary disease or another etiology. 
All AEs of Grade 3 or higher that occur during the DLT observation period will be included in 
the DLT definition except for toxicities with a clear, alternative explanation, including the 
exceptions listed in Section 7.2.2.2.1.
Patients who experience a DLT in Cycle 1 will be discontinued from study treatment.




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
the disorder is manageable with or without systemic corticosteroid therapy 
and/or hormone replacement therapy, and 

the patient is asymptomatic
o
Grade 3 inflammatory reaction attributed to a local antitumor response (such as, 
inflammatory reaction in the lymph nodes or at sites of metastatic disease)
o
Any grade vitiligo or alopecia
o
Grade 3 or 4 lymphopenia

First occurrence of Grade 3 infusion-related reaction (IRR) during infusion of 
LY3415244, if both of the following criteria are met:
o
the patient did not receive corticosteroid prophylaxis, and
o
the Grade 3 IRR resolves within 6 hours with appropriate clinical management
If symptoms reappear, the event would be considered a DLT.

Grade 3 or 4 neutropenia meeting both of the following criteria:
o
not associated with fever or systemic infection, and
o
improves by at least 1 grade within 7 days with treatment

In order to exclude potential detection of electrolyte abnormalities that cannot be 
associated with clinical signs of symptoms, or laboratory test error. Isolated Grade 3 
electrolyte abnormalities meeting both of the following criteria:
o
not associated with clinical signs or symptoms, and 
o
reversed with appropriate maximal medical intervention within 2 days
It should be recognized that for patients who have received prior immune therapy, including 
check point inhibitor therapy, there is the potential for delayed manifestation of serious irAEs 
such as colitis, hepatitis, pneumonitis, and endocrinopathies.  Patients manifesting potential 
delayed irAEs should receive prompt evaluation and treatment.  .
7.2.2.2.2.
DLT-Equivalent Toxicities
A DLT-equivalent toxicity is any event listed in Table JZDA.7.2 occurring after Cycle 1 in 
Phase 1a or in any cycle of Phase 1b that would have met criteria for DLT if it had occurred 
during the DLT observation period. For individual patients experiencing a DLT-equivalent 
toxicity, dose modifications will be made as outlined in Section 7.4.
7.2.2.3.
Recommended Phase 2 Dose Determination
The RP2D will be chosen following discussion between the Lilly CRP/CRS and the investigators 
based on consideration of the totality of the data, including but not limited to LY3415244 dose 
adjustments (delays, reductions, or omissions), AEs, chronic intolerance, PK and 
pharmacodynamic data, and irAEs.  The final RP2D to be carried forward into any future studies 
will be confirmed or changed based on the combined data from Phase 1a and Phase 1b.  
7.3.
Blinding
This is an open-label study.


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7.4.
Dose Modification
No dose modification is allowed during Phase 1a DLT observation period (Cycle 1).
After the Phase 1a DLT observation period (Cycle 1), doses of the study drug may be delayed or 
discontinued to manage specific AEs or other toxicities. Dose reductions are not permitted. All 
dose modifications should be documented, including the approach taken and a clear rationale for 
the need for modification.
The investigator must assess whether the toxicity is at least possibly due to study treatment and 
apply the dose-modification guidelines.  Investigators are encouraged to consult Lilly for 
additional guidance.
If a patient requires a dose delay, study treatment should be resumed within 1 cycle, if possible 
and appropriate.  If study treatment cannot be resumed within 1 cycle, every effort should be 
made to restart on the first day of the next cycle. In rare circumstances, a delay of >28 days may 
be permitted before permanent treatment discontinuation, as long as the patient demonstrates 
clinical benefit, does not have objective progression, and is recovering from the toxicity.  Such 
circumstances must be discussed with the Lilly CRP/CRS.
Adverse events of immune-related etiology are expected because of the study drug’s mechanism 
of action and may occur shortly after the first dose or several months after the last dose.  Study 
treatment must be withheld if the patient experiences a drug-related toxicity or a severe or life-
threatening AE.  Dose reductions are not permitted.
A 4-hour observation period is required after the administration of LY3415244 in Cycles 1 to 3.
During observation period, patients treated with LY3415244 should be closely monitored for 
signs and symptoms indicative of an infusion-related reaction by medical staff from the start of 
the infusion until 4 hours after the end of the infusion, in an area where emergency medical 
resuscitation equipment and other agents (epinephrine prednisolone equivalents, etc.) are 
available.  LY3415244 infusion-related reactions will be defined according to the Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0 definition of IRRs.
Table JZDA.7.3 presents instructions for management of infusion-related reactions associated 
with LY3415244.


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Table JZDA.7.3.
Management of Infusion-Related Reactions
Grade
Management
2
First occurrence  
Stop the infusion and proceed with following:
1.
If resolved to Grade 0 or 1 within 1 hour after stopping the infusion
a.
restart the infusion at 50% of the original rate (for example, reduce 
from 100  to 50 mL/hr)
2.
If NOT resolved to Grade 0 or 1 within 1 hour after stopping the infusion:
a.
delay study treatment until the symptoms resolve in ≤48 hours, and 
b.
premedicate prior to the next scheduled dose.  Premedication should be 
administered 1.5 hours (±30 minutes) prior to the LY3415244 infusion 
with diphenhydramine (or other antihistamine), acetaminophen (or 
other antipyretic), steroids etc., at the discretion of treating physician.
Second occurrence  
Immediately and permanently discontinue study treatment
3 or 4
Immediately and permanently discontinue study treatment.
Patients who experience a Grade 3 IRR that resolves within 6 hours may 
continue on study treatment. For subsequent infusions, the patient should be 
premedicated 1.5 hours (±30 minutes) prior to the LY3415244 infusion with 
diphenhydramine (or other antihistamine), acetaminophen (or other antipyretic), 
steroids etc., at the discretion of treating physician.
If symptoms reappear, immediately and permanently discontinue study 
treatment.
Table JZDA.7.4 presents guidance for irAE management (including use of corticosteroids) and 
criteria for dose delays and discontinuations if the patient experiences a potential irAE 
considered at least possibly related to LY3415244.
Because of the potential for rapid and serious sequelae associated with irAEs, early intervention 
with corticosteroids is encouraged, concurrent with further diagnostic medical evaluations for 
possible nonimmune-related causes of AEs.  The treatment plan should always include a 
thorough workup of the issue to rule out other potential etiologies such as infection.  Guidelines 
used by local standards such as, but not limited to Haanen and colleagues (2017), Puzanov and 
colleagues (2017), or Brahmer and colleagues (2018), supersede the guidelines provided in
Table JZDA.7.4 if deemed appropriate by the investigator.  If a patient experiences an irAE that 
is not listed in this table, consult the Lilly CRP/CRS to discuss appropriate management.
Other corticosteroid options can be given at equivalent doses.  Corticosteroids should be tapered 
over 1 month once symptoms improve to Grade 1, and study treatment should not be restarted 
until corticosteroid tapering is complete.  During corticosteroid use, use prophylactic antibiotics 
to prevent opportunistic infections.












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Dose Modification Guidelines and AE Management for Toxicities At Least Possibly Related to Study Drug
Abbreviations: ADL = activities of daily living; ALT = alanine aminotransferase; AST = aspartate aminotransferase;
BSA = body surface area; CRP = clinical research physician; CRS = Clinical Research Scientist; 
CTCAE = Common Terminology Criteria for Adverse Events, Version 4.0; irAE = immune-related adverse 
event; IV = intravenous; SOC = system organ class; TB = total bilirubin; ULN = upper limit of normal.
a
If symptoms of grade is not specified, use CTCAE Version 4 definitions; otherwise, use the definitions provided 
in this table.
b
Discontinuation of study treatment is permanent; resumption of study treatment is not allowed. If a toxicity does 
not resolve to Grade 0-1 or if the corticosteroid dose cannot be reduced to 10 mg/day of prednisone or 
equivalent within 12 weeks, consult with the Lilly CRP/CRS about discontinuing study treatment.
c
Immunosuppressive refers to infliximab or cyclophosphamide.
d
Patients who have asymptomatic or clinically non-significant Grade 3 or 4 lipase or amylase elevations (for 
example, not associated with clinical symptoms or radiological signs of pancreatitis) that are transient as 
demonstrated by a decrease of at least 1 CTCAE Grade within 7days (± 3 days) of onset will not require 
discontinuation of LY3415244. If the elevation does not decrease by at least 1 CTCAE Grade within this time 
window, LY3415244 treatment may continue only after consultation and discussion with the Lilly CRP/CRS. 
7.5.
Preparation/Handling/Storage/Accountability
LY3415244 should be stored under refrigerated conditions (2C to 8C).  
7.6.
Treatment Compliance
The study medication will be administered only at the investigational site by the authorized study 
site personnel.  As a result, treatment compliance is ensured.  
7.6.1.Evaluable Patients
7.6.1.1.
DLT-Evaluable Patients in Phase 1a
A patient will be DLT evaluable if he or she experiences a DLT during the DLT observation 
period and has received at least 1 dose of study drug.
If a patient does not experience a DLT during the DLT observation period, he or she will be DLT
evaluable if he or she receives all assigned doses of study drug(s) during the DLT observation 
period
Patients who receive all doses of study drug but discontinue from study treatment before the end 
of the DLT observation period will be considered DLT evaluable for the assessment of a dose 
level, provided it can be documented that the patient did or did not experience a DLT within the 
DLT observation period.
Patients who are not DLT evaluable may be replaced to ensure that enough patients complete the 
DLT observation period at each dose level, unless accrual to that cohort has stopped due to a
DLT.
A patient may be deemed non-evaluable for assessment of a dose level in the event the patient 
experiences an AE which would meet DLT criteria, and furthermore has been determined 
through discussion between investigator and Lilly CRP/CRS to most likely be related to a 


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concomitant medication or a prior line of immune therapy (in the case of irAEs) due to 
previously established linkage. Adverse events from DLT non-evaluable patients will also be 
reviewed throughout the dose escalation process in Phase 1a.
To ensure collection of adequate PK or biomarker data, patients who complete the DLT 
observation period but who do not have a valid PK or biomarker assay result may be replaced, 
upon consultation with the investigator(s) and the Lilly CRP/CRS, unless accrual to that cohort 
has stopped because of a DLT.  Patients who are replaced for purposes of the PK or biomarker 
analysis are still considered DLT evaluable.
7.7.
Concomitant Therapy
Table JZDA.7.5 describes medications, treatments, and drug classes that are restricted or 
prohibited for use during the study treatment period, including exceptions and conditions.  There 
are no prohibited therapies during the postdiscontinuation follow-up period.  Patients who, in the 
opinion of the investigator, require the use of any of the prohibited treatments for clinical 
management should be discontinued from the trial.  Patients may receive other supportive 
therapy that the investigator deems to be medically necessary.
In general, medications or live vaccinations specifically prohibited in the exclusion criteria are 
not allowed during the ongoing trial.
Table JZDA.7.5.
Concomitant Medication Guidelines
Therapy
As Needed
Chronic Use
Exceptions or Conditions for Use
Antiplatelet therapy
Yes
Yes, with 
restrictions
Chronic use of aspirin up to 325 mg/day is permitted
Anticoagulation 
therapy
No
Yes, with 
restrictions
Patients who are on full-dose anticoagulation must be on 
a stable dose (minimum duration 14 days) of oral 
anticoagulant or low-molecular-weight heparin or 
similar agent.  If on warfarin, the patient must have an 
INR of ≤ 3 and no active bleeding or pathological 
condition present that carries a high risk of bleeding (for 
example, tumor involving major vessels or known 
varices).
Colony-stimulating 
factors
Yes
No
Follow local guidelines.  No prophylactic use
Erythroid growth 
factors
Yes
No
Follow local guidelines
Experimental 
medicines or 
investigational agents
No
No


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Concomitant Medication Guidelines
Therapy
As Needed
Chronic Use
Exceptions or Conditions for Use
Glucocorticoids
Yes, with 
restrictions
Yes, with 
restrictions
Use of corticosteroids for the management of 
investigational product-related AEs or in patients with 
contrast allergies is acceptable.  A temporary course of 
corticosteroids will be allowed for other indications, at 
the discretion of the principal investigator (for example, 
chronic obstructive pulmonary disease, radiation, 
nausea).  Systemic corticosteroids doses should not 
exceed 10 mg/day of prednisone or equivalent (except as 
stated otherwise in this protocol).
The use of physiologic doses of corticosteroids may be 
approved after consultation with Lilly.
The use of topical, ophthalmic, inhaled, and intranasal 
corticosteroids is permitted.
Immunosuppressive 
medications other 
than glucocorticoids 
(including, but not 
limited to 
methotrexate, 
azathioprine, and 
TNF-α blockers)
No
No
Use of immunosuppressive medications for the 
management of AEs related to LY3415244 or in patients 
with contrast allergies is acceptable
NSAIDs
Yes
No
See guidance for aspirin on the “antiplatelet therapy” 
line above.
Chronic use of other NSAIDs is not permitted.  
However, in certain medical situations, NSAIDs may be 
the best treatment option (for example, for pain 
management) and are therefore permissible as needed. 
Abbreviations:  AE = adverse event; INR = international normalized ratio; NSAIDs = nonsteroidal 
anti-inflammatory drugs; TNF = tumor necrosis factor.
No other chemotherapy, systemic radiotherapy, immunotherapy, cancer-related hormone 
therapy, experimental drugs, or herbal supplements intended to treat cancer will be permitted 
while the patients are on this study.  
Palliative radiation therapy to small areas of painful metastases that cannot be adequately 
managed with systemic or local analgesics is permitted after discussion with and agreement of 
the Lilly CRP/CRS.
In addition, any disease progression requiring other forms of specific antitumor therapy will also 
necessitate early discontinuation from the study.  Appropriate documentation for all forms of 
premedication, supportive care, and concomitant medications must be captured on the eCRF.  
Replacement hormonal therapy initiated before study entry will be allowed.
Patients should receive full supportive care. The use of granulocyte-colony stimulating factor (G-
CSF) is permitted at the discretion of the investigator based on American Society of Clinical 


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Oncology (ASCO) (Smith et al. 2015) and European Society for Medical Oncology (Crawford et 
al. 2010) guidelines. 
If clinically indicated at any time during the study, erythropoietin and packed red blood cell 
transfusions may be used according to ASCO guidelines (Rizzo et al. 2008).  Prophylactic 
antibiotic treatment should be consistent with ASCO guidelines (Flowers et al. 2013).
All concomitant medications should be recorded throughout the patient’s participation in the 
study.
7.8.
Treatment after Study Completion
7.8.1.Continued Access
Patients who are still on study drug at the time of study completion may continue to receive 
study drug if they are experiencing clinical benefit and no undue risks.  
The continued access period will apply to this study only if at least 1 patient is still on study drug
when study completion occurs.  Lilly will notify investigators when the continued access period 
begins.
Lilly may allow patients to enroll in a “rollover” protocol to provide long-term continued access 
for patients enrolled in this study.  
Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 90-day short-term follow-up visit is completed.  Long-term 
follow-up does not apply.
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.


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Figure JZDA.7.1.
Continued access diagram.


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8. Discontinuation Criteria
The reasons for treatment and study discontinuation and the dates of discontinuation will be 
collected for all patients.
Patients who discontinue during the study treatment period, whether or not they received study 
treatment, will have follow-up procedures performed as shown in the Schedule of Activities 
(Section 2).
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
8.1.
Discontinuation from Study Treatment
Patients will be discontinued from study treatment in the following circumstances: 

the patient is enrolled in any other clinical study involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study.

the patient becomes pregnant during the study

the patient is significantly noncompliant with study procedures and/or treatment
as described in Section 7.6

The patient experiences a DLT (see Section 7.2.2.2) during Cycle 1, a DLT-
equivalent toxicity (see Section 7.2.2.2.2), or other unacceptable toxicity

the patient requires a dose delay of >28 days, except as described in Section 7.4

the patient, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication.
Discontinuation from study treatment will occur prior to introduction of the new 
agent

the investigator decides that the patient should be discontinued from study 
treatment

the patient requests to be discontinued from study treatment

the patient has received the maximum duration of 12 months of study treatment 
(longer duration may be considered for a patient receiving clinical benefit, in 
consultation with the Lilly CRP/CRS). If tumor imaging shows initial disease 
progression, at the discretion of treating physician, patients may remain on study
treatment with repeat imaging 4 to 6 weeks later to assess tumor response or 
confirm progression per RECIST 1.1 with confirmatory scan on disease 
progression
Patients who are discontinued from study treatment will have follow-up procedures performed as 
shown in the Schedule of Activities (Section 2).


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Discontinuation of study treatment may be considered for patients who meet all of the following 
criteria:

have a confirmed CR, and

have received study treatment for at least 24 weeks, and

have received at least 2 cycles of study treatment beyond the date when the initial CR 
was declared.
8.1.1.Discontinuation of Inadvertently Enrolled Patients
If Lilly or the investigator site identifies a patient who did not meet enrollment criteria and who 
was inadvertently enrolled, a discussion must occur between Lilly CRP/CRS and the investigator 
to determine if the patient may continue in the study.  If both agree that it is medically 
appropriate to continue, the investigator must obtain documented approval from Lilly CRP/CRS
to allow the inadvertently enrolled patient to continue in the study with or without study 
treatment.  Safety follow-up is as outlined in the Schedule of Activities (Section 2).
8.2.
Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:

participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP).

the patient becomes pregnant during the study.  See Section 9.2 regarding 
regulatory reporting requirements on fetal outcome and breast-feeding

the investigator decides that the patient should be discontinued from the study

the patient requests to be discontinued from the study

the patient’s legal representative requests that the patient be discontinued from 
the study
Patients who discontinue from the study early will have end-of-study procedures performed as 
shown in the Schedule of Activities (Section 2).
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Study site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow-up.


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9. Study Assessments and Procedures
Section 2 provides the Schedule of Activities for this study. 
Appendix 2 provides a list of the laboratory tests that will be performed for this study.
Appendix 4 provides the schedule for collection of samples in this study.
Unless otherwise stated in the following subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days of receipt of confirmed test results.  Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards.
9.1.
Efficacy Assessments
Tumor assessments will be performed for each patient at the times shown in the Schedule of 
Activities (Section 2).  A secondary objective of the study is to document efficacy.
RECIST 1.1 (Eisenhauer et al. 2009) will be applied as the primary criteria for assessment of 
tumor response and disease progression.  Local tumor imaging (investigator assessment with site 
radiological reading) will be used. Modified RECIST will be applied for patients with pleural 
mesothelioma whereby tumor thickness (perpendicular to chest wall or mediastinum) would be 
measured at 2 positions on 3 separate levels on transverse cuts of CT scan (Byrne 2004).
Computed tomography (CT) is the preferred imaging method for the majority of patients.  
Magnetic resonance imaging should only be used when CT is contraindicated or for imaging in 
the brain.  The same imaging technique should be used for a patient throughout the trial.  
Imaging should include the chest, abdomen, and pelvis.  Intravenous and oral contrast is required 
unless medically contraindicated.
At Study Baseline:

Must be performed within 28 days prior to the first dose of study drug.

Scans performed as part of routine clinical management are acceptable for use as initial 
tumor imaging if they are of diagnostic quality and performed within protocol-required 
time frame as described above.
During Study Treatment: 

Performed every 8 weeks (±7 days), by the investigator, with confirmatory assessment 
obtained at the next routine scheduled imaging time point.

Per RECIST v1.1, PR or CR should be confirmed by a repeat tumor imaging assessment, 
preferably at the next scheduled imaging visit, and not less than 4 weeks from the date 
the response was first documented.  Thus, for Study JZDA, tumor imaging for 
confirmation of response may be performed at the earliest 4 weeks after the first 
indication of response, or at the next scheduled scan, whichever is clinically indicated.

Continue to perform imaging until whichever of the following occurs first:
o
disease progression confirmed by the second radiographic examination


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o
the start of new anticancer treatment
o
withdrawal of consent
o
death
o
study completion
If radiologic imaging verifies an initial assessment of PD, apply RECIST 1.1 with 
confirmatory scan for disease progression (Section 9.1.1).
During the Poststudy Treatment Period: Tumor assessments may continue for patients who 
are withdrawn from the study treatment for reasons other than disease progression every 6 to 12 
weeks depending on standard of care.
See Section 10.3.2 for definitions of the efficacy endpoints.
9.1.1.RECIST 1.1 with Confirmatory Scan for Disease Progression
9.1.1.1.
Rationale for RECIST 1.1 with Confirmatory Scan for Disease 
Progression
Response to immunotherapy may differ from responses typically observed with cytotoxic 
chemotherapy, including the following (Wolchok et al. 2009; Nishino et al. 2013):

Response to immunotherapy may be delayed.

Response to immunotherapy may occur after PD by conventional criteria.

The appearance of new lesions may not represent PD with immunotherapy.

Stable disease while on immunotherapy may be durable and represent clinical benefit.
Therefore, to adequately characterize additional patterns of response and progression specific to 
patients treated with immunotherapy, which cannot be captured by conventional criteria such as 
RECIST 1.1, alternative measures of tumor assessment have been developed:  (i) RECIST 1.1 
with confirmatory scan for disease progression and (ii) immune-related response criteria (irRC, 
Wolchok et al. 2009).  For both measures (i) and (ii), clinically stable patients may continue 
treatment until disease progression (per standard RECIST 1.1) is confirmed. As the irRC are still 
being developed and validated for various tumor types, Study JZDA will use RECIST 1.1 with 
confirmatory scan for disease progression, which may discourage the early discontinuation of 
study treatment and provide a more complete evaluation of its efficacy than would be seen with 
conventional response criteria.




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In determining whether or not progression can be confirmed, the site study team should consider 
all target lesions, nontarget lesions, and new lesions.
9.1.1.3.
Criteria Required to Receive Treatment during Confirmatory Scan 
Period
In order for patients to continue receiving LY3415244, the following criteria apply:

absence of clinically significant deterioration (defined in Section 9.1.1.2) 

absence of clinical symptoms indicating clinically significant disease 
progression

no decline in performance status

no significant, unacceptable or irreversible toxicities related to study treatment

patient must sign the addendum consent prior to being treated during this time 
period
9.2.
Adverse Events
The investigator will use CTCAE, Version, 4.0 (NCI 2009) to assign AE terms and severity 
grades.
Investigators are responsible for:

monitoring the safety of patients who have entered into this study and for 
alerting Lilly or its designee to any event that seems unusual, even if this 
event may be considered an unanticipated benefit to the patient.  

providing appropriate medical care to the patient during the study.

documenting their review of each laboratory safety report.

following, through an appropriate health care option, AEs that are serious or 
otherwise medically important, considered related to study treatment or the 
study, or that caused the patient to discontinue study drug before completing 
the study.  The patient should be followed until the event resolves, stabilizes 
with appropriate diagnostic evaluation, or is reasonably explained.  Frequency 
of follow-up evaluation is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish safety and toxicity.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  Study site personnel will record via eCRF any change in 
preexisting conditions and any new conditions as AEs.  Investigators should record their 
assessment of the potential relatedness of each AE to study treatment or study procedure via 
eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 


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concomitant treatment or pathologies.  A “reasonable possibility” means that there is a cause and 
effect relationship between the study treatment and/or study procedure and the AE.
Adverse Event grading of toxicities related to estimated glomerular filtration rate (GFR) should 
be evaluated based on the Cockcroft-Gault method (Cockcroft and Gault 1976) or measured 
GFR.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
Study site personnel must report any dose modifications or treatment discontinuation that results 
from AEs to Lilly or its designee via eCRF, clarifying, if possible, the circumstances leading to 
dose modification or discontinuation of treatment.
9.2.1.Serious Adverse Events
An SAE is any AE during this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization 

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or require hospitalization, may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above.
Although all AEs after signing the ICF are recorded in the eCRF, SAE reporting to Lilly begins 
after the patient has signed the ICF and has received study treatment.  However, if an SAE 
occurs after signing the ICF, but prior to receiving study treatment, it needs to be reported ONLY 
if it is considered reasonably possibly related to study procedure.
Where permitted, study site personnel must notify Lilly or its designee of any SAE within 
24 hours of investigator awareness of the event via a Lilly-approved method.  If alerts are issued 
via telephone, they are to be immediately followed with official notification on study-specific 
SAE forms.  This 24-hour notification requirement refers to the initial SAE information and all 
follow-up SAE information.
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE but should be reported.  To fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued and/or completed the study (the patient summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 


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been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
Planned hospitalizations or procedures for preexisting conditions that were recorded in the 
patient’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.
Serious adverse events, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to study treatment.
9.2.2.Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to study treatment or study procedure.  The 
United States 21 CFR 312.32, the Regulation (European Union) No 536/2014 and the associated 
detailed guidance or national regulatory requirements in participating countries require the 
reporting of SUSARs.  Lilly has procedures that will be followed for the recording and expedited 
reporting of SUSARs that are consistent with global regulatory regulations and the associated 
detailed guidance.
Regular communication will occur between investigators and the sponsor via various channels 
(that is, email, regularly scheduled teleconference, Safety Reporting Notification System, etc.) to 
ensure that all parties are aware of how patients are tolerating LY3415244.  If in the event that 
sites need to be made aware of an emerging safety issue in a timely manner, Lilly will, upon 
confirmation of the event, communicate to site staff via email and/or direct telephone calls to 
ensure receipt of all of the information.  Lilly will follow-up with individual sites until receipt of 
the information is confirmed and that the site has taken the appropriate safety measures.  
9.2.3.Complaint Handling
Lilly collects complaints on study drugs and drug delivery systems used in clinical studies in 
order to ensure the safety of study participants, monitor quality, and facilitate process and 
product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
If a patient receives a higher dose of LY3415244 than that specified in the protocol, patients 
should receive appropriate supportive care measures for any AEs, as deemed necessary by the 
treating investigator.


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9.4.
Safety
9.4.1.Other Safety Measures
Refer to the Schedules of Activities (Section 2) regarding the timing of vital signs, laboratory 
tests, and other tests. 
Perform ECGs as shown in Appendix 4.  Triplicate ECGs will be collected in Study JZDA. 
ECGs should be recorded according to the study-specific recommendations included in the ECG
manual.
ECGs will be initially interpreted by a qualified physician at the site (the investigator or qualified 
designee) as soon after the time of ECG collection as possible (ideally while the patient is still 
present) to determine whether the patient meets entry criteria and for immediate patient 
management.
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the patient for symptoms (for example, palpitations, near-
syncope, or syncope) and to determine if the patient can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in patient management is 
needed and must document his/her review of the ECG printed at the time of evaluation.
Any clinically significant findings that result in a diagnosis and that occur after the patient 
receives the first dose of study treatment should be reported to Lilly or its designee as an AE via 
eCRF.
All digital ECGs will be electronically transmitted to a designated central ECG laboratory.  The 
central ECG laboratory will perform a basic quality control check (for example, demographics 
and study details) and store the ECGs in a database. At a future time, the stored ECG data may 
be overread at the central ECG laboratory for further evaluation of machine-read measurements 
or to meet regulatory requirements.
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless a central ECG laboratory cardiologist overread of the ECGs is conducted prior to 
completion of the final study report (in which case the overread data would be used).
For each set of replicates, the cardiologist will determine the R-R and QT intervals and heart rate 
on the ECGs.  These data are not routinely reported back to the investigative site.  However, any 
clinically significant finding that was not present on the fully overread ECG will be reported to 
the investigator and to Lilly.  All data from the overreads will be placed in the Lilly database for 
analytical and study report purposes.
The investigator’s (or qualified designee’s) ECG interpretation will be used for decisions about 
study entry and immediate patient management will be based on the investigator's or qualified 
designee's ECG interpretation.  


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9.4.2.Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods. 
For Phase 1a, safety data will be reviewed on a cohort by cohort basis.  For Phase 1b, a safety 
review will be performed when every 10 patients have been treated for approximately 1 cycle for 
the first 20 patients enrolled into Phase 1b across all expansion cohorts, then every 3 months 
after the last patient enters study treatment (LPET) for 1 year, and then at least once a year 
afterward.  The purpose of this Phase 1b safety review is to evaluate the safety and tolerability 
for each expansion cohort and determine if a dose-limiting equivalent toxicity (DLET) has been 
observed. For the first 20 patients enrolled into Phase 1b, based on mTPI-2 method, if 7 or more 
DLETs are observed, accrual will be temporarily paused, and the available data from Phase 1a 
and 1b will be analyzed to potentially modify the RP2D, or the study; considerations for stopping 
recruitment should be given after discussion with investigator and sponsor.
If a study patient experiences elevated alanine aminotransferase (ALT) >5X upper limit of 
normal (ULN) and elevated total bilirubin (TBL) >2X ULN, or ALT ≥8X ULN, liver 
tests (Appendix 5) should be repeated within 3 to 5 days including ALT, AST), TBL, direct 
bilirubin (D.TBL), gamma-glutamyl transferase, (GGT) and creatine phosphokinase (CPK) to 
confirm the abnormality and to determine if it is increasing or decreasing.  If the abnormality 
persists or worsens, clinical and laboratory monitoring should be initiated by the investigator 
based on the hepatic monitoring tests (Appendix 5) and in consultation with the Lilly CRP/CRS. 
Monitoring of ALT, AST, and TBL should continue until levels normalize or return to 
approximate baseline levels.
9.4.2.1.
Special Hepatic Safety Data Collection
Hepatic data, such as lab tests (see Appendix 5), liver related signs and symptoms, results from 
hepatic monitoring procedures, and liver biopsy assessment if available, should be collected in 
the event that a patient meets one of the following conditions during the course of the study: 

elevation of serum ALT to ≥10X ULN

patients without liver tumors or liver metastasis: ALT ≥5X ULN and 
TBL ≥ 2X ULN

patients with liver tumors or liver metastasis: ALT ≥8X ULN and TBL ≥ 
2X ULN

discontinuation from treatment due to a hepatic event or abnormality of 
liver tests

occurrence of a hepatic event considered to be a SAE
9.5.
Pharmacokinetics
Pharmacokinetic samples will be collected as shown in Appendix 4.
Blood samples will be used to determine the study drug concentrations of LY3415244 (also 
known as bioanalytical samples).  


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Bioanalytical samples collected to measure LY3415244 plasma concentration will be retained 
for a maximum of 1 year following last patient visit for the study.
Instructions for the collection and handling of bioanalytical blood samples will be provided by 
Lilly.  The actual start and end date and time of LY3415244 infusion must be recorded on the 
eCRF.  The actual date and time that each bioanalytical blood sample is drawn must be recorded 
on the laboratory requisition page after the sample is drawn.
All study drug concentrations in bioanalytical plasma samples will be measured using validated 
assay methodology in a laboratory designated by Lilly.
The remaining sample collected for PK testing may be pooled and used for exploratory 
metabolism or bioanalytical assay validation work as deemed appropriate.
9.6.
Pharmacodynamics
Pharmacodynamic samples will be collected as shown in Appendix 4 to assess target 
engagement and activity for LY3415244. Potential pharmacodynamic markers may include 
measuring soluble markers (sPD-L1 and sTIM-3) in serum and immune cell subsets 
characterization and distribution. Tumor tissue, plasma, serum, and whole blood may be used 
for additional exploratory PD work as deemed appropriate by Lilly (see also Section 9.8).
Samples collected to measure pharmacodynamic biomarkers will be identified by the patient 
number (coded) and retained at a facility selected by the Lilly for a maximum of 15 years 
following last patient visit for the study.
9.6.1.Immunogenicity Assessments
Blood samples for immunogenicity testing will be collected as shown in Appendix 4 to 
determine antibody production against LY3415244.  Immunogenicity will be assessed by a 
validated assay designed to detect ADAs in the presence of LY3415244.  Antibodies may be 
further characterized and/or evaluated for their ability to neutralize the activity of LY3415244.
In the event of a drug hypersensitivity event (immediate or non-immediate), additional samples
will be collected as close to the onset of the event as possible and at 4 and 12 to 16 weeks after 
the event. 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 sampling should be recorded. 
Samples will be retained at a facility selected by Lilly for a maximum of 15 years after last the 
patient visit for the study, or for a shorter period if regulations and ethical review boards 
(ERBs)/institutional review boards (IRBs) impose shorter time limits.  The duration allows Lilly 
to respond to future regulatory requests related to LY3415244. Any samples remaining after 
15 years will be destroyed.


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9.7.
Genetics
9.7.1.Whole Blood Sample for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in Appendix 
4, where local regulations allow.
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to LY3415244 and to 
investigate genetic variants thought to play a role in cancer.  Assessment of variable response 
may include evaluation of AEs or differences in efficacy.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.  Samples will be retained at a 
facility selected by Lilly for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ERBs/IRBs impose shorter time limits.  This 
retention period enables use of new technologies, response to questions from regulatory 
agencies, and investigation of variable response that may not be observed until later in the 
development of LY3415244 or after LY3415244 becomes commercially available.
Molecular technologies are expected to improve during the 15 year storage period and therefore 
cannot be specifically named.  However, existing technologies include whole genome and exome 
sequencing, genome-wide association studies, multiplex assays, and candidate gene studies.  
Regardless of the technology utilized, data generated will be used only for the specific research 
scope described in this section.
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, variability of patient response (including 
safety), and clinical outcome.  Sample collection is incorporated into clinical studies to enable 
examination of these questions through measurement of biomolecules including DNA, RNA, 
proteins, lipids, and other cellular elements.  
As part of Lilly’s ongoing efforts to understand the relationship between cancer, genetics, and 
response to therapy, this study will analyze systemic and tumor tissue-associated biomarkers 
relevant to LY3415244, mechanism of action of LY3415244, the variable response to study 
drug(s), immune function, and pathways associated with cancer, including solid tumors and 4
expansion cohorts (NSCLC, urothelial carcinoma, mesothelioma, and melanoma). These 
samples may also be used to develop related research methods or to validate diagnostic tools or 
assays.
Samples for biomarker research will be collected as specified in Appendix 4, where local 
regulations allow.  It is possible that biomarker data for patients in the study has already been 
generated from samples that were collected and analyzed prior to enrolling in this study.  This 
may include data generated from genetic analyses.  If available, these data may be requested 
from medical records for use in the research described in Sections 9.7.1, 9.8.1, and 9.8.2.


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9.8.1.Tissue Samples for Biomarker Research
Tissue samples for biomarker research will be collected for the purposes described in 
Section 9.8.  The following samples for biomarker research will be collected as specified in
Appendix 4, where local regulations allow.
Collection of the following tumor tissue sample(s) is required for all patients in order to 
participate in this study:
For patients participating in Phase 1a and Phase 1b (all cohorts):

a newly obtained core or excisional pre-treatment biopsy of a tumor lesion and

a tumor tissue sample from a newly obtained biopsy specimen collected during the study 
treatment period as shown in Appendix 4. 

an archival formalin-fixed paraffin-embedded tumor tissue obtained from the primary 
tumor site, if available and not restricted by local regulations. (Regardless of whether or 
not the archival tissue is submitted, patients are still required to undergo pretreatment and 
on-treatment biopsies).
An attempt to obtain 4 core-needle biopsies or a surgical biopsy is required, unless medically 
contraindicated and discussed with Lilly CRP/CRS. Optimally, biopsies should be taken from the 
same lesion and from areas not previously irradiated. Biopsies should not be taken from areas 
that have been previously irradiated, unless the previously irradiated area has progressed.  
Collection of the following tumor tissue sample(s) is optional for all patients participating in this 
study:
For patients participating in Phase 1a and 1b (all cohorts)

a tumor tissue sample from a newly obtained biopsy specimen collected after disease 
progression or at additional study time points, if warranted and agreed upon by the 
investigator and Lilly. Such additional biopsies are optional and should be performed 
only if clinically feasible. If these additional samples are requested, they will be used to 
further investigate biomarkers that may explain treatment response and resistance 
mechanisms.  If a biopsy is performed after the patient signs the ICF, Lilly may request a 
tissue sample from the biopsy for additional biomarker testing at any time during the 
study including post-progression.
Newly acquired tumor biopsies are requested because they provide the most current biomarker 
characteristics of the tumor compared with biopsies taken at the time of diagnosis (tumor 
characteristics may shift during subsequent lines of treatment).  Pre- and on-treatment 
assessments are critical for meaningful clinical data; paired biopsies are planned to be tested 
from baseline over time for changes in molecular markers to document any potential 
immunomodulatory activity of treatment with LY3415244 and should be performed if clinically 
feasible. A minimum paired sample size of 19 in total is expected to provide adequate precision 
to estimate the immune response. Samples will be examined for biomarkers as described in 
Section 9.8, including but not limited to, TIM-3 and PD-L1 expression by 
immunohistochemistry.


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The tissue samples should be obtained using an appropriate method. Tumor tissue should be 
submitted as a newly acquired excisional or core needle (minimum 18 gauge) or surgical biopsy 
in formalin. Cytological or fine-needle aspiration specimens are not acceptable. If additional 
tumor biopsies are collected as part of clinical care, they should be submitted, along with 
pathology reports, for further analysis. See the Laboratory Manual for details regarding sample 
handling. At the time of tissue collection process, due diligence should be used to make sure that 
the tumor sample (not a normal adjacent tissue sample or a tumor margin sample) is provided
and contains tumor cells prior to shipment to the central laboratory.  This will help ensure that a 
quality biopsy sample has been taken. The pathology report must be coded with the patient 
number. Personal identifiers, including the patient’s name and initials, must be removed from 
the institutional pathology report prior to submission.  Tissue samples collected on-study will not 
be returned.
Samples will be retained at a facility selected by Lilly for a maximum of 15 years after the last 
patient visit for the study, or for a shorter period if local regulations and/or ERBs/IRBs impose 
shorter time limits.  This retention period enables the use of new technologies, response to 
questions from regulatory agencies, and investigation of variable response that may not be 
observed until later in the development of LY3415244 or after LY3415244 becomes
commercially available.
Technologies are expected to improve during the 15-year storage period and therefore cannot be 
specifically named.  Existing approaches, including but not limited to mutation profiling, copy 
number variability analysis, gene expression assays, multiplex assays, and/or 
immunohistochemistry may be performed on these tissue samples to assess potential associations 
between these biomarkers and clinical outcomes.
9.8.2.Other Samples for Biomarker Research
The following samples for biomarker research will be collected for the purposes described in 
Section 9.8, and as specified in Appendix 4, where local regulations allow. 

Whole blood 

Serum

Plasma

A maximum of 5 samples may be collected at additional time points during the study 
if warranted and agreed upon by the investigator and Lilly. If these additional samples 
are requested, they will be used to further investigate biomarkers that may explain 
treatment response and resistance mechanisms.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.  
Samples will be retained at a facility selected by Lilly for a maximum of 15 years after the last 
patient visit for the study, or for a shorter period if local regulations and/or ERBs/IRBs impose 
shorter time limits.  This retention period enables use of new technologies, response to questions 


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from regulatory agencies, and investigation of variable response that may not be observed until 
later in the development of LY3415244 or after LY3415244 becomes commercially available.
Technologies are expected to improve during the 15-year storage period and therefore cannot be 
specifically named.  Existing approaches, including but not limited to flow cytometry, mutation 
profiling, copy number variability analysis, gene expression assays, multiplex assays may be 
performed on these samples to assess potential associations between these biomarkers and 
clinical outcomes.
9.9.
Health Economics
Health economics and medical resource utilization parameters will not be evaluated in this study.


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10.Statistical Considerations
10.1. Sample Size Determination
The primary objective of this study is to assess the safety and tolerability of LY3415244, thereby 
identifying and confirming the RP2D of LY3415244 to be administered as monotherapy to 
patients with solid tumors.  The secondary objective is to evaluate PK and any observed evidence 
of clinical efficacy.  
In Phase 1a, the total sample size will be determined by the incidence of DLTs.
With at least 3 patients treated at the RP2D in the dose-escalation phase and additional patients 
treated at the RP2D in Phase 1b, a total of at least 20 patients can provide adequate precision for 
the estimated incidence rate of the following quantities of interest: (1) patients having a specified 
AE or (2) patients showing a response (PR/CR) to treatment.  With a total sample size of 20, the 
95% confidence interval (CI) is approximately equal to the observed incidence rate ±12% to 
24%. Example point estimates of incidence rates and corresponding 2-sided 95% CIs are 
summarized in Table JZDA.10.1. The values are provided as a reference for estimation rather 
than a basis of any decision criteria. The RP2D may be revised based on the safety data obtained 
in the expansion phase (Iasonos and O’Quigley 2013).
Table JZDA.10.1.
Estimated Incidence Rate
and 2-Sided 95% Confidence Interval
N=20
Number 
of Cases
Estimated 
Rate
95% CIa
Lower Limit
Upper Limit
0
0.0
0.0
0.17
3
0.15
0.03
0.38
5
0.25
0.09
0.49
10
0.50
0.27
0.73
15
0.75
0.51
0.91
Abbreviations:  CI = confidence interval; N = number of patients.
a
95% Clopper-Pearson interval for binomial distribution.
10.2. Populations for Analyses
The following analysis sets will be defined for this study:
Enrolled/Safety population: will include all patients who received any quantity of study 
treatment, regardless of their eligibility for the study.  The safety and efficacy evaluation will be 
performed based on the first dose of study treatment a patient actually received.  This population 
will be used for all dosing/exposure, safety, and efficacy analyses.
Pharmacokinetic population: will include all enrolled patients from whom a valid assay result 
(according to laboratory guideline) has been obtained.


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Biomarker population: will include the subset of enrolled patients from whom a valid assay 
result has been obtained.  No imputation will be performed for missing data due to the limitation 
of small sample size.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee.
Unless otherwise stated, all CIs will be given at a 2-sided 95% 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.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the Statistical Analysis Plan (SAP) and clinical study report (CSR).  Additional exploratory 
analyses of the data will be conducted as deemed appropriate.
10.3.1.
Safety Analyses
All patients who receive any quantity of LY3415244 will be evaluated for safety and toxicity.  
AE terms and severity grades will be assigned by the investigator using CTCAE Version 4.0.
Safety analyses will include summaries of the following:

DLTs:  the number of patients who experience any DLTs during Cycle 1 will be 
summarized by cohort by treatment arm in Phase 1a

DLT-equivalent:  the number of patients who experience any AE that qualifies as a DLT 
during any period of study will be summarized by the first dose by treatment arm in 
Phase 1a and by tumor type and treatment regimen in Phase 1b

AEs, including severity and possible relationship to study drug

AEs by Medical Dictionary for Regulatory Activities system organ class (SOC) by 
decreasing frequency of Preferred Term within an SOC

laboratory and non-laboratory AEs by CTCAE Version 4.0 term, maximum CTCAE 
grade, and CTCAE Grade 3 and above (regardless of causality and at least possibly 
related to study treatment)

changes in vital signs and ECGs
10.3.2.
Efficacy Analyses
The study was not designed to make an efficacy assessment.  However, any tumor response data 
will be tabulated for all patients in the enrolled/safety analysis set.
The efficacy endpoints are listed and defined as follows:
Objective response rate (ORR) is the proportion of enrolled patients who have received any 
amount of either study drug, have at least 1 postbaseline tumor image, and achieved a best 
overall response (BOR) of confirmed CR or PR.
Duration of response (DoR) is defined only for responders (patients with a confirmed CR or 
PR).  It is measured from the date of first evidence of a confirmed CR or PR to the date of the 


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first observed radiographically documented PD, or the date of death due to any cause, whichever 
is earlier.  If a responder is not known to have died or have objective progression as of the data 
inclusion cutoff date, DoR will be censored at the date of the last complete objective 
progression-free disease assessment.
Time-to-response (TTR) is the time from the date of first study treatment until the first 
evidence of a confirmed CR or PR.
Disease control rate (DCR) is the proportion of enrolled patients who have a BOR of confirmed 
CR, confirmed PR, or stable disease (SD).
Progression-free survival is defined as the time from the date of first study treatment until the 
date of the first observed radiographically documented PD or death due to any cause, whichever 
is earlier.  The censoring is taken in the following order:

If a patient does not have a complete baseline disease assessment, then the PFS time will 
be censored at the enrollment date, regardless of whether or not objectively determined 
disease progression or death has been observed for the patient; otherwise,

if a patient is not known to have died or have objective progression as of the data 
inclusion cutoff date for the analysis, the PFS time will be censored at the last complete 
objective progression-free disease assessment date.
Overall survival, an exploratory objective, is determined from the date of first study treatment 
until death due to any cause.  If the patient is not known to have died at the data inclusion cutoff 
date for the analysis (or is lost to follow-up), OS will be censored on the last date the patient was 
known to be alive.  This endpoint will be followed up for 12 months after the last patient has 
entered treatment.
The objective response rate, TTR, DCR, DoR, and PFS will be assessed based on RECIST v1.1 
(Eisenhauer et al. 2009) and RECIST v1.1 with confirmatory scan for disease progression 
(Section 9.1.1).
The estimate of ORR and DCR, and the corresponding CI, will be provided by dose-escalation 
treatment arm and by expansion according to RECIST v1.1 and RECIST v1.1 with confirmatory 
scan for disease progression (Section 9.1.1).  Time-to-event variables, such as TTR, DoR, PFS,
and OS (as an exploratory objective), will be summarized by Kaplan and Meier (1958) method
by dose-escalation treatment arm and expansion. Presentations of antitumor activity may include 
patients enrolled in the dose-escalation phase with the same tumor type and dosing scheme. 
Individual changes in the tumor burden over time will be presented graphically within a tumor 
type. Subgroup analysis of interest will be further defined in the SAP.
10.3.3.
Other Analyses
10.3.3.1. Patient Disposition
A detailed description of patient disposition will be provided, including a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients completing the study, as defined in the SAP, or 


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discontinuing (overall and by reason for discontinuation).  A summary of all important protocol 
deviations will be provided.
10.3.3.2. Patient Characteristics
Demographic data are collected and reported to demonstrate that the study population represents 
the target patient population considered for regulatory approval.
A summary of baseline patient and disease characteristics, historical diagnoses, preexisting 
conditions, and prior therapies will be reported using descriptive statistics. 
Other patient characteristics at baseline will be summarized as deemed appropriate.
10.3.3.3. Concomitant Therapy
A summary of prior and concomitant medications will be reported.
10.3.3.4. Treatment Compliance
The number of cycles received, dose omissions, dose delays, and dose intensity will be 
summarized for the enrolled/safety population.
LY3415244 will be administered at the investigator site, therefore treatment compliance is 
assured.
10.3.3.5. Pharmacokinetic/Pharmacodynamic Analyses
PK parameter estimates for LY3415244 therapy will be calculated by population PK analysis 
methods using nonlinear mixed effects modeling. The version of any software used for the 
analysis will be documented, and the program will meet the Lilly requirements of software 
validation. It is possible that other validated, equivalent PK software programs may be used if 
appropriate, warranted, and approved by Lilly global PK/PD management. In addition, selected 
PK parameters (based on actual sampling times), including Cmax, time of Cmax , and AUC may 
be calculated by noncompartmental analysis methods and/or model simulations. As an 
exploratory analysis, PK parameter estimates for Cmin at steady state following repeated dose 
may be evaluated. 
Pharmacokinetic/pharmacodynamic analyses will be conducted to explore exposure-response 
relationships between LY3415244 concentrations in systemic circulation and various 
pharmacodynamic measures, such as selected safety outcomes, receptor occupancy, and 
biomarkers. 
10.3.3.6. Biomarker Analyses
Biomarkers related to treatment, immune functioning, mechanism of action of study drugs, 
and/or cancer will be collected and reported.  In addition, the relationship between biomarkers 
and clinical outcome will be assessed.  Biomarker relationships by tumor type, changes in 
biomarker levels at baseline and over time, and differences among dose levels or exposure will 
be explored as possible.  The pharmacodynamic effect from all patients undergoing 
pharmacodynamic assessments will be explored (Section 10.3.3.5).


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10.3.3.7. Immunogenicity Analysis
The frequency and percentage of patients with preexisting ADA, ADA at any time point 
postbaseline, and with treatment-emergent ADA positivity (TE ADA+) to LY3415244 will be 
tabulated. Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) greater 
than the minimum required dilution if no ADAs were detected at baseline (treatment-induced 
ADA) or those with a 4-fold (2 dilutions) increase in titer compared to baseline if ADAs were 
detected at baseline (treatment-boosted ADA).  For the TE ADA+ patients, the distribution of 
maximum titers will be described.  The frequency of neutralizing antibodies may also be
tabulated in TE ADA+ patients.
The relationship between the presence of antibodies and the PK parameters and PD response 
including safety and efficacy to LY3415244 may be assessed.
10.3.4. Interim Analyses
In the Phase 1a dose-finding portion of the study, safety, PK, and biomarker data (if available) 
will be reviewed on a cohort-by-cohort basis during the study, until the MTD and/or RP2D is
determined.  The purpose of these cohort-by-cohort data reviews is to evaluate the safety data at 
each dose level and determine if a DLT has been observed.  The decision whether to advance to 
the next dose level will be made following discussion between the investigators and Lilly and 
will be relayed to the sites prior to patients being treated on the subsequent cohort.
Safety and available PK data will be reviewed during the study to inform dose escalation,
modifications to the dose-escalation strategy, or other design elements.
An interim analysis will be performed after all patients in Phase 1a have completed the DLT 
evaluation period.  The Lilly study team will evaluate the data from the interim safety and 
PK/PD analyses before opening the dose expansion cohorts in Phase 1b.  In these interim 
analyses, early antitumor activity may also be explored.
An expansion-specific safety and efficacy interim analysis will be conducted approximately 
24 weeks (6 months) after the LPET for each of the expansion cohorts. These interim analyses 
may be combined if they are expected to occur within approximately a month of each other.  
Interim analyses may also be combined with any prespecified safety review or reporting (that is, 
Trial Level Safety Reviews, Development Safety Update Reviews, or IB update reviews).  The 
expansion-specific safety and efficacy primary analyses will be conducted approximately 
52 weeks (12 months) after LPET for each of the expansion(s).
The final overall analysis of Study JZDA will coincide with the safety and efficacy primary 
analysis of the last expansion.
If it is deemed that enough data have been obtained to assess the primary and secondary 
objectives, a CSR might be created before the last patient visit.  In this case, all data until the 
data-cutoff date will be used for the analysis of safety, efficacy, PK, and PD biomarkers.  All 
data defined in the protocol will continue to be collected from patients on treatment after data-
cutoff date and results will be listed.  However, summary tables including data after data-cutoff 
date will not be created.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibody
AE
Adverse event:  any untoward medical occurrence in a patient or clinical 
investigation patient administered a pharmaceutical product and 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 
medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALT
alanine aminotransferase
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC0-2wk
area under the concentration versus time profiles of a 2-week dosing interval
BOR
best overall response
Cavg
2-week average concentration
Cmax
maximum plasma concentration
Cmin
trough concentration
CI
confidence interval
CNS
central nervous system
collection database
A computer database where clinical study data are entered and validated.
CR
complete response
CrCl
creatinine clearance 
CRP
clinical research physician: individual responsible for the medical conduct of 
the study.  Responsibilities of the CRP may be performed by a physician,
clinical research scientist, global safety physician or other medical officer.
CRS
clinical research scientist
CSR
clinical study report


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CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
Ctrough
lowest concentration of drug just prior to the next dose
DCR
disease control rate:  the percentage of patients with a best response of CR, PR, 
or SD.
DLT
dose-limiting toxicity
DoR
duration of response: the time from the date measurement criteria for CR or PR 
(whichever is first recorded) are first met until the first date that disease is 
recurrent or objective progression is observed, per RECIST 1.1 criteria, or the 
date of death from any cause in the absence of objectively determined disease 
progression or recurrence.
ECG
electrocardiogram
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
EI
equivalence interval
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the 
study are those who have been assigned to a treatment and have received at least 
one dose of study treatment.
ERBs/IRBs
ethical review boards/institutional review boards
ELISA
enzyme-linked immunosorbent assay
Enter
Patients entered in the study are those who have signed the informed consent 
form directly or through their legally acceptable representatives.
Gal-9
galectin-9
GCP
good clinical practice
G-CSF
granulocyte colony stimulating factors
GFR
glomerular filtration rate


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highly effective methods
of contraception
Methods include:

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:
o
oral
o
intravaginal
o
transdermal

Progestogen-only hormonal contraception associated with inhibition of 
ovulation :
o
oral
o
injectable
o
implantable 

Intrauterine device (IUD) 

Intrauterine hormone-releasing system ( IUS) 

Bilateral tubal occlusion 

Vasectomized partner (vasectomized partner is a highly effective birth 
control method provided that partner is the sole sexual partner of the 
woman of childbearing potential who is the trial participant and that the 
vasectomized partner has received medical assessment of the surgical 
success.)

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 treatments. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.)
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
irAEs
immune-related adverse events
IRR
infusion-related reaction
ICF
informed consent form
ICH
International Conference on Harmonization
IFN-γ
interferon gamma
IgG
immunoglobulin G
interim analysis
An analysis of clinical study data that is conducted before the final reporting 
database is authorized for datalock.
irRC
immune-related response criteria


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Investigational product 
A pharmaceutical form of an active substance 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, marketed products used for an unauthorized indication or 
marketed products used to gain further information about the authorized form.
IV
intravenous
Kd
equilibrium dissociation constant
Kras
Kirsten rat sarcoma
LOQ
limit of quantification
LPET
last patient enters/starts study treatment
mAb
monoclonal antibody
MABEL
minimum anticipated biological effect level
MPM
malignant pleural mesothelioma
MTD
maximum tolerated dose
mTPI-2
modified toxicity probability interval-2
NK cells
natural killer cells
NOAEL
no-observed-adverse-effect-level
NSCLC
non-small cell lung cancer
open-label
A study in which there are no restrictions on knowledge of treatment allocation, 
therefore the investigator and the study participants are aware of the drug 
therapy received during the study.
ORR
objective response rate: the percentage of patients who achieve a best overall 
response (BOR) of CR or PR 
OS
overall survival
PAD
pharmacologically active dose
PD
progressive disease
PD-1
programmed death 1
PD-L1
programmed death ligand 1
PFS
progression-free survival: the time from randomization until the first 
radiographic documentation of progression or death from any cause in the 
absence in progressive disease.  
PK
pharmacokinetic
PK/PD
pharmacokinetic/pharmacodynamic


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PR
partial response
PtdSer
phosphatidylserine
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is 
used to produce the analyses and output reports for interim or final analyses of 
data.
Re-screen
to screen a patient who was previously declared a screen failure for the same 
study
RO%
receptor occupancy
RP2D
recommended Phase 2 dose
SAP
Statistical Analysis Plan
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become 
part of a pool of potential candidates for participation in a clinical study.
Screen failure
A patient who does not meet one or more criteria required for participation in a 
study
sPD-L1
soluble programmed death ligand 1
SOC
system organ class
sTIM-3
Soluble T-cell immunoglobulin and mucin-domain-containing molecule-3
SUSAR
suspected unexpected serious adverse reactions
T1/2
terminal half life
TBL
total bilirubin
TE%
target engagement
TEAE
Treatment-emergent adverse event:   an untoward medical occurrence that 
emerges during a defined treatment period, having been absent pretreatment, or 
worsens relative to the pretreatment state, and does not necessarily have to have 
a causal relationship with this treatment.
TILs
tumor-infiltrating lymphocytes
TTR
Time-to-response




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Clinical Laboratory Tests
Abbreviations:   DNA = deoxyribonucleic acid; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; hCG = 
human chorionic gonadotropin; HCV = hepatitis C virus; RBC = red blood cells; RNA = ribonucleic acid; T4 = 
thyroxine; TSH = thyroid-stimulating hormone; WBC = white blood cells.
Note:  Study eligibility and decisions about treatment will be based on local laboratory results.
a
Neutrophils reported by automated differential hematology instruments include both segmented and band forms.
b
Performed centrally only, unless local laboratory is clinically indicated.
c   Hepatitis C RNA will only be triggered when anti-HCV testing is positive.


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Appendix 3.
Study Governance, Regulatory, and Ethical 
Considerations
Informed Consent
The investigator is responsible for: 

ensuring that the patient understands the nature of the study, the potential risks 
and benefits of participating in the study, and that their participation is voluntary 

ensuring that informed consent is given by each patient. This includes obtaining 
the appropriate signatures and dates on the ICF prior to the performance of any 
study protocol procedures and prior to the administration of study treatment.

answering any questions the patient may have throughout the study and sharing in 
a timely manner any new information that may be relevant to the patient’s 
willingness to continue the patient’s participation in the study.

providing a copy of the ICF to the patient and retaining a copy of the signed ICF 
in the site file
Ethical Review
Documentation of ERB/IRB approval of the protocol and the ICF must be provided to Lilly 
before the study may begin at the investigative site(s).  Lilly or its representatives must approve 
all ICFs, including any changes made by the ERBs/IRBs, before it is used at the investigative 
site(s).  All ICFs must be compliant with the ICH guideline on GCP.
The study site’s ERB/IRB should be provided with the following:

the protocol, protocol amendments, and relevant protocol addenda, and the 
current IB and updates during the course of the study

ICF

other relevant documents (for example, curricula vitae, advertisements)
Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines 

the ICH GCP guidelines

applicable laws and regulations
The investigator or designee will promptly submit the protocol to applicable ERB(s).


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Some of the obligations of Lilly will be assigned to a third party organization.
Investigator Information
Licensed physicians with a specialty in oncology will participate as investigators in this clinical 
study
Protocol Signatures
Lilly’s responsible medical officer will approve the protocol, confirming that, to the best of his 
or her knowledge, the protocol accurately describes the planned design and conduct of the study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The CSR coordinating 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.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the CSR coordinating investigator.
Lilly’s responsible medical officer and statistician will approve the final CSR for this study, 
confirming that, to the best of his or her knowledge, the report accurately describes the conduct
and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the CRFs, and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and verify data reported to detect potential errors
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes. If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.


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Data Capture Systems
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Data collected via the sponsor-provided data capture system(s) will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system(s).  Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports/electronic transfers will be provided to the 
investigator for review and retention.  Data will subsequently be transferred from the central 
vendor to the Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Study and Site Closures
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the 
ERB/IRB of the study site judges it necessary for medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Sampling Schedule
It is essential that the exact infusion start and stop times (actual clock readings) are recorded. 
The exact time of collection of each venous blood sample will be based on the clock used to 
record infusion times. Preferred time windows for each sample collection are provided in the 
tables in this appendix.
While best efforts should be made to draw the blood samples within the time windows provided, 
it is more important to ensure that the predose sample is actually collected before the start of first 
infusion of the day and postdose samples are collected after the respective infusion has 
completed.
It is also equally important to record the ACTUAL date and time of blood sample collection on 
the Requisition Form AFTER drawing the sample (that is, do not record the planned time of 
collection) and to record the ACTUAL infusion start and end dates and times on the eCRF in 
order to facilitate the data analyses. Blood sample collection must be from the opposite arm to 
that used for study drug infusion. If drug was administered via a central venous catheter, the 
sample collection should be from a different site.












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Phase 1a and 1b:  Pharmacokinetic, Pharmacodynamic, Immunogenicity, Biomarker, Pharmacogenomic, and ECG Collection Time Points (All 
Cohorts)
Abbreviations:  ADA = antidrug antibody; C = Cycle; D = Day; DLT = dose-limiting toxicity; ECG = electrocardiogram; IG = immunogenicity; 
IRR = infusion-related reaction; PD = pharmacodynamics; PGx = pharmacogenomics; PK = pharmacokinetics; Q = every; sPD-L1 = soluble programmed 
death ligand 1; sTIM-3 = soluble T-cell immunoglobulin and mucin-domain-containing molecule-3; W = week. 
a
In the event of an IRR, blood samples will be collected for both PK, and IG analyses at the following time points, as close as possible to:  (i) the onset of the 
IRR, (ii) the resolution of the IRR, and (iii) 30 (±3 days) following the IRR. As part of the IG analysis following IRR, exploratory hypersensitivity samples 
may be analyzed for markers of basophil/mast cell activation (e.g., tryptase), immune complex formation (e.g., C3 levels) and cytokine release (e.g., IL-6) as 
appropriate for the clinical presentation. If treatment-emergent ADAs are identified in the follow-up period, the patient will continue to be followed until 
ADA levels return to 2-fold above baseline (60-day posttreatment sample, every 3 months over the first year and then yearly thereafter until return to 2-fold 
above baseline unless deemed clinically unnecessary after 1 year), provided the patient has not been lost to follow up or has withdrawn consent.  Since 
LY3415244 plasma concentration is expected to be below the detection limit of the PK assay, no PK sample will be collected beyond 6 months after the last 
dose of LY3415244.
b
The 2-, 4-, 24-, 72-, 120-, and 168-hour samples are relative to the START of the corresponding dosing event.  These samples must be collected after 
completion of the infusion.  Allowable sampling window for pre-dose C1D1 is -8 hours.  Allowable sampling windows for 2-, 4-, 24-, 72-, 120-, and 168-hour 
are ±30 minutes, ±60 minutes, ±8 hours, ±24 hours, ± 24 hours, and ± 48 hours, respectively.  If  LY3415244 infusion need to be increased up to 2 hours the 
allowable sampling windows for the 2-hour sample is increased to +60 minutes. Samples at 30, 60, and 90 days post last LY3415244 dose have allowable 
sampling windows of ±7 days. However, it is essential that the exact infusion start and stop times (actual clock readings) are recorded.
c
For exploratory research, including but not limited to immunophenotyping.
d
Triplicate ECGs should be conducted immediately before the PK sample and after the patient has been supine for 5 minutes; collect at a minimum of 1-minute 
intervals, with all 3 replicate ECGs completed within 5 to 15 minutes. 


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Appendix 5.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment emergent hepatic abnormality and may 
be required in follow up with patients in consultation with the Lilly CRP/CRS.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin (HGB)
Hematocrit (HCT)
Hepatic Coagulationa
Erythrocytes (RBC)
Prothrombin Time (PT)
Leukocytes (WBC)
Prothrombin Time, INR
Neutrophilsb
Lymphocytes
Hepatic Serologiesa,c
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets (PLT)
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine aminotransferase (ALT)
Recommended Autoimmune Serologya:
Aspartate aminotransferase (AST)
Anti-nuclear antibody
Gamma-glutamyl transferase (GGT)
Anti-smooth muscle antibody
Creatine phosphokinase (CPK)
Anti actin antibody
Abbreviations:  Ig = immunoglobulin; INR = International Normalized Ratio; RBC = red blood cells; WBC = white 
blood cells.
a
Assayed by Lilly-designated laboratory.
b
Neutrophils reported manually and by automated differential hematology instruments include both segmented 
and band forms.
c
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 6.
Creatinine Clearance Formula
Note:  This formula is to be used for calculating creatinine clearance (CrCl) from local 
laboratory results only.  
For serum creatinine concentration in mg/dL:
CrCl =
(mL/min) 
(140 – agea) (wt)    0.85 (if female), or 1.0 (if 
male)
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(mL/min)
(140 – agea) (wt)  0.85 (if female), or 1.0 (if 
male)
               0.81 x serum creatinine
(µmo/L)
a age in years, weight (wt) in kilograms.
Reference:  Cockcroft and Gault 1976.


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Appendix 7.
Dose-Finding Spreadsheet of the Modified 
Toxicity Probability Interval Method Showing Number of 
Patients Treated
Source:  Guo et al. 2016 [WWW].
The number of patients dosed at a given dose level is shown in the columns (X-axis), while the 
number of DLTs experienced is shown in the rows (Y-axis).  The rules in this figure will be used 
for each dose level evaluated; the patient numbers and DLTs do not carry over from cohort to 
cohort.  By locating the intersection of the number of patients dosed and the number of DLTs, 1 
of 4 predefined rules is used:

E:  Escalate the dose

S:  Stay at the same dose

D:  De-escalate the dose


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
DU:  De-escalate the dose due to unacceptable toxicity.  The dose cannot be re-escalated 
to this dose level at a future point in the escalation.
For example, within a cohort:

If 1 of 3 patients experiences a DLT, stay at the same dose (see “S” in column 3, row 1).  
The fourth patient must be treated at the same dose level.

If 1 of 6 patients experiences a DLT, escalate the dose (see “E” at column 6, row 1).

If 2 of 3 patients experience a DLT the dose to treat the next patient is de-escalated (see 
“D” at column 3, row 2).

If 5 of 7 patients experience a DLT, the dose is determined to be unacceptably toxic, and 
the previous dose is defined as the MTD.


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Appendix 8.
Definition of Woman of Childbearing Potential
Definitions:
Woman of Childbearing Potential (WOCBP)
A female is not considered to be of childbearing potential due to surgical sterilization confirmed 
by medical history (at least 6 weeks post-surgical bilateral oophorectomy with or without 
hysterectomy or tubal ligation) or menopause.
Menopausal women include women with either:
a.
spontaneous amenorrhea for at least 12 months, not induced by a medical condition such as 
anorexia nervosa, and not taking medications during the amenorrhea that induced the 
amenorrhea (for example, oral contraceptives, hormones, gonadotropin-releasing hormone, 
antiestrogens, selective estrogen receptor modulators, or chemotherapy), or
b. spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone level 
>40 mIU/mL.
For individuals with permanent infertility due to an alternate medical cause other than the above,
(for example, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
Exceptions to those listed above would be if female and of childbearing potential, has a negative 
serum or urine pregnancy test within 7 days prior to the first dose of study medication, agrees to 
use a highly effective method of birth control during the study and for 6 months following the 
last dose of the study drugs, and is not breastfeeding.  If the urine pregnancy test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.


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Appendix 9. Protocol Amendment J1C-MC-JZDA(a) 
Summary
Overview
Protocol J1C-MC-JZDA, A Phase 1a/1b Study of LY3415244, a Bispecific Antibody in Patients 
with Advanced Solid Tumorshas been amended.  The new protocol is indicated by Amendment 
(a) and will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
Section 1. –Updated number of patients; updated table to reflect additional dose levels; 
clarified how RP2D is determined and the circumstances under which it may be modified
Section 2. –Table JZDA.2.1. clarified that instructions apply only for cycle-related 
procedures; increased postinfusion observation to 4 hours, per FDA request; included 
modified RECIST guidelines to instructions for tumor imaging/assessmentof 
mesothelioma patients; Table JZDA.2.3. updated continued access follow-up to 90 days 
in footnote a
Section 3.3.–  “in vivo” to “in vitro”
Section 4. –Table JZDA.4.1. updated to include AUC and PK
Section 5.1. –Clarified how RP2D is determined and the circumstances under which it 
may be modified; Figure JZDA.5.1. updated to reflect additional dose levels
Section 5.1.1. –Clarified dose escalation phase for each cohor in the study design; 
corrected typo (“PLoQK” to “PK”); clarified the timing of full PK review; updated 
reference and clarified how RP2D is determined, per PMDA request
Section 5.2. –Updated cohorts and number of patients to reflect new study design

 
Section 6.1. –Updated hematologic tests toinclude aPTT in lieu of PT and PTTin 
criterion [9]; updated discontinuation period for biologic agents to at least 21 daysin 
criterion [11]; updated requirement for duration of effective contraceptive use during 
study treatmentin criterion [13]
Section6.2. –Added examples of pulmonary toxicity in criterion [17], per PMDA 
request; updated examples of clinically significant ECG abnormalitiesin criterion [17]; 
clarifiedbreastfeedingexclusion criteriain criterion [20],per PMDA request
Section 6.4. –Clarified when anadditional laboratory testis needed
Section 7.1. –Updated Table JZDA.7.1. to reflect additional dose levels
Section 7.2.2.2. –Updated definition of DLT, per FDA request; updated hematologic 
toxicity in Table JZDA.7.2. per PMDA request

CCI
Section 7.2.2.2.1. –Provided additional justification for Grade 3 or greater toxicities that 
are to not be considered DLT, per FDA request


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
Section 7.4. – Updated postinfusion observation period to 4 hours; corrected table 
referenced in this section; updated Table JZDA.7.3.; included additional examples of 
local guidelines

Section 7.6.1.1. – Included review of adverse events from non-evaluable patients, per 
PMDA request

Section 7.7. – Updated “Table JZDA.7.7.” to “Table JZDA.7.5.”

Section 9.1. – Elaborated on pleural measurement requirements

Section 9.1.1.2. – Provided examples of situations requiring urgent medical intervention, 
per FDA request

Section 9.1.1.3. – Additional section to outline criteria required to receive treatment 
during confirmatory scan, per FDA request

Section 9.4.1. – Clarified on ECG data analyses

Section 9.4.2. – Clarification on Phase 1b safety stopping rule

Section 9.4.2.1. – Clarified types of hepatic safety data to be collected

Section 9.8.1. – Included statistical justification for biomarker sample size

Section 10.3.4. – Addressed need for exploring antitumor activity in interim analyses

Section 11. – Updated references list

Appendix 2. – Removed PTT from coagulation tests; corrected footnote reference for 
lipase; updated “T4” to “free T4” for consistency

Appendix 4. – Removed infusion parameters from data to be recorded; updated table to 
clarify data to be collected on the respective study days; added footnote to ECG for “30 
days post last LY3415244 dose” to indicate need for triplicate

Appendix 8. – Addition to define woman of childbearing potential, per PMDA request

Minor editorial changes were incorporated that may not be included in this summary








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Table JZDA.2.3.
Continued Access Schedule of Activities
…
Abbreviations:  ADAs = antidrug antibodies; AE = adverse event; D = day; IG = immunogenicity; IRR = infusion-related reaction; PK = pharmacokinetics; 
Q = every; W = week.
a
Continued access follow-up begins when the patient and the investigator agree that the patient will no longer continue treatment in the continued access 
period and lasts approximately 3090 days.  No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has 
explicitly provided permission and consent.


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Table JZDA.4.1.
Objectives and Endpoints
…
Abbreviations: AUC = area under time-concentration curve;Cmax=maximum serum/plasma concentration; 
Cmin=minimum serum/plasma concentration; CTCAE = Common Terminology Criteria in Adverse Events; 
DCR = disease control rate; DLT = dose-limiting toxicity; DOR = duration of response; ORR = objective 
response rate; PFS = progression-free survival; PK = pharmacokinetics;RECIST = Response Evaluation Criteria 
in Solid Tumors; RP2D = recommended Phase 2 dose; SAE = serious adverse event; TEAE = treatment-
emergent adverse event; TEADA = Treatment-emergent anti-drug antibodies; TTR = time-to-response.
Section 5.1. Overall Design
…
Phase1a (dose escalation)will assess the safety and tolerability of LY3415244, administered as 
monotherapy in patients with advanced solid tumors.  The RP2D to be tested in Phase 1b will be 
identified in Phase 1a, as described in Section 7.2.2. Late toxicities of available data up to 
90days will be considered for RP2D determination.Dose escalation of LY3415244 will be 
driven by a mTPI-2 method (Guo et al. 2016 [WWW]; see Section 7.2.2.1).
Phase1b (dose expansion)will assess the safety and tolerability of LY3415244, administered as 
monotherapy in 4 expansion cohorts of patients with selected advanced solid tumor types of non-
small cell lung cancer (NSCLC), urothelial cancer, mesothelioma, and melanoma.
Patients in both phases will receive study treatment for a maximum of 12 months (see 
Section8.1).
The data from Phase1 a will determine the RP2D but the RP2D dose may be modified in 
Phase1b if supported by additional safety and/or PK/PD data.The combined data from Phase 1a 
and Phase 1b will be analyzed to confirm or modify the RP2D.For the primary objective of 
CCI
establishing safety, patients will be followed for at least 24 weeks after the last patient is 
enrolled.  For the secondary objective of progression-free survival (PFS) and the tertiary 
objective of overall survival (OS), patients will be followed until death or until study completion 
(defined in Section5.3), whichever occurs first.


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Figure JZDA.5.1 illustrates the study design.
Abbreviations: D = day; Meso = mesothelioma; mg = milligrams; NSCLC = non-small-
cell lung cancer; pts = patients; Q = every;  TBD = to be determined; W = week.
Note:  Cohort A6A8 is optional and may be explored at a dose not exceeding 1500 mg 
of LY3415244. 
Figure JZDA.5.1.
Illustration of study design.
Section 5.1.1. Dose Escalation Phase
The first patient will be enrolled in Patients in Cohorts A1, A2, A3, A4, A5, A6, A7, and A8, 
respectively, will receive doses of 3 mg, 10 mg, 70 mg, 200 mg, 600 mg, 1000 mg, and a dose 
not exceeding 1500 mg according to an every-2-weeks (Q2W) dosing regimen, provided safety 
is established in the preceding cohorts and treated according to an every 2 weeks (Q2W) dosing 
regimen (see Table JZDA 7.1).  Patients in Cohort A1 will receive a 3 mg dose on Cycle 1 Day 1 
(C1D1); the dose will increase to 10 mg beginning at Cycle 1 Day 15 (C1D15).  However, if any 


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of the 3 patients in Cohort A1 experiences a clinically significant Grade 2 AE that is possibly 
related to study drug, all patients enrolled to Cohort A1 will remain on the 3mg dose (unless 
they have already escalated to the 10mg dose).  If per the modified toxicity probability interval
2 (mTPI2) method, the 3mg dose level is cleared, a 10mg doselevel will be initiated and there 
will be no further intrapatient dosing (that is, the 30and 70mg dose levels will be explored in 
separate 30mg and 70mg cohorts, rather than an intrapatient dose escalation cohort).
After the first patient in CohortA1 receives the first dose of LY3415244, there will be a delay of 
1week to allow for safety observation before the second and third patients receive LY3415244. 
There will be no additional delays for subsequent patients. 
Patients in Cohort A2 will receive a 30mg dose on C1D1; the dose will increase to 70 mg 
beginning at C1D15.  However, if any of the patients in Cohort A2 experiences a clinically 
significant Grade ≥2 AE that is possibly related to study drug, patients enrolled to Cohort A2 
will remain onthe 30mg dose (unless they have already escalated to the 70mg dose).  If per the 
mTPI2 method, the 30mg dose level is cleared, the 70mg dose level would then be explored in 
a separate cohort.  
CCI
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A 1-cycle (28 days) dose-limiting toxicity (DLT) observation period will apply to all cohorts in 
Phase 1a.
CCI
CCI


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Section 5.2. Number of Patients
Enrollment in each cohort will be adjusted if needed to allow adequate assessment of safety and 
preliminary antitumor activity at the LY3415244 RP2D.  
Phase 1a:  Total enrollment will be determined by the incidence of DLTs.
o Cohorts A1 through A6A8:  approximately 2127patients (minimum of 3patients per 
CCI
cohort) will be enrolled.  
…
 
 
 
 
 
 
 
 
 
…
 
 
 
 
 
 
 
 
CCI
CCI




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i.
evidence of (i) interstitial lung disease that is symptomatic or may interfere with 
the detection or management of suspected drug-related pulmonary toxicity (for 
example, interstitial lung disease or radiation pneumonitis); (ii) active, 
noninfectious pneumonitis; or (iii) history of noninfectious pneumonitis that 
required corticosteroid therapy
j.
moderate or severe cardiovascular disease, such as the following:
i.
presence of cardiac disease, including a myocardial infarction or any other 
arterial thrombotic event including cerebrovascular accident or transient 
ischemic attack within 6 months prior to enrollment; unstable angina pectoris; 
New York Heart Association Class III/IV congestive heart failure; aneurysm 
of major vessels or heart; left ventricular ejection fraction <50% (evaluation 
based on institutional lower limit of normal); or uncontrolled hypertension
ii. severe, moderate, or clinically significant valvulopathy; documented major 
ECG abnormalities that, in the judgment of the investigator, are clinically 
significant (for example, symptomatic or sustained atrial or ventricular 
arrhythmias; second or third degree atrioventricular block; bundle branch 
blocks; ventricular hypertrophy arrthythmias requiring treatment; recent 
myocardial infarction within the last 3 months; or mean QTc 470 ms 
calculated using Fridericia’s correction and confirmed by triplicate ECG)
…
[20] Are pregnant, breastfeeding, or planning to become pregnant during the study or 
within 6 months after completing the studyfollowing the last dose of LY3415244.
Plan to be breastfeeding from C1D1 of study or within 6 months following the last 
dose of LY3415244.
Section 6.4. Screen Failures
…
Repeating laboratory tests (including ECGs) that did not meet eligibility criteria during the 28-
day baseline screening period does not constitute rescreening.  However, laboratory tests may 
not be repeated more than twice.  If the results of a repeated laboratory test meet the eligibility 
criteria, that an additional laboratory test must be repeated again to confirm eligibility.
Section 7.1. Treatment Administered
LY3415244 will be administered as an IV infusion over approximately 60 minutes, depending on 
dose level (doses ≤70 mg may require bolus IV infusion).  In Cycles 1 through 3, the
LY3415244 infusion will be followed by a 14-hour observation period.
Table JZDA 7.1 shows the treatment regimen.




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Section 7.2.2.2.1. Events That Are Not Considered to Be DLTs
The following events listed in this section will not be considered to be DLTs:

Toxicity Adverse event that is clearly and directly related to the primary disease or to another 
etiology

Known class effects that have been observed with immunotherapy:
o
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency), if both 
the following criteria are met:

the disorder is manageable with or without systemic corticosteroid therapy 
and/or hormone replacement therapy, and 

the patient is asymptomatic
o
Grade 3 inflammatory reaction attributed to a local antitumor response (such as, 
inflammatory reaction in the lymph nodes or at sites of metastatic disease)
o
Any grade vitiligo or alopecia
o
Grade 3 or 4 lymphopenia

First occurrence of Grade 3 infusion-related reaction (IRR) during infusion of LY3415244, if 
both of the following criteria are met:
o
the patient did not receive corticosteroid prophylaxis, and
o
the Grade 3 IRR resolves within 6 hours with appropriate clinical management
If symptoms reappear, the event would be considered a DLT.

Grade 3 or 4 neutropenia meeting both of the following criteria are met:
o
is not associated with fever or systemic infection, and
o
improves by at least 1 grade within 7 days with treatment
In order to exclude potential detection of electrolyte abnormalities that cannot be associated 
with clinical signs of symptoms, or laboratory test error.

Grade 3 or 4 lymphopenia

In order to exclude potential detection of electrolyte abnormalities that cannot be associated 
with clinical signs of symptoms, or laboratory test error. Isolated Grade 3 electrolyte 
abnormalities meeting both of the following criteria:
o
is not associated with clinical signs or symptoms, and 
o
is reversed with appropriate maximal medical intervention within 2 days
It should be recognized that for patients who have received prior immune therapy, including 
check point inhibitor therapy, there is the potential for delayed manifestation of serious irAEs 
such as colitis, hepatitis, pneumonitis, and endocrinopathies.  Patients manifesting potential 
delayed irAEs should receive prompt evaluation and treatment. Potential DLTs recognized to be 
irAEs will not be evaluable for the purposes of dose selection.
Section 7.4. Dose Modification
…
A 14-hour observation period is required after the administration of LY3415244 in Cycles 1 to 3. 
During observation period, patients treated with LY3415244 should be closely monitored for 


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signs and symptoms indicative of an infusion-related reaction by medical staff from the start of 
the infusion until 1 hour4 hours after the end of the infusion, in an area where emergency 
medical resuscitation equipment and other agents (epinephrine prednisolone equivalents, etc.) are 
available.  LY3415244 infusion-related reactions will be defined according to the Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0 definition of IRRs.
Table JZDA.7.4JZDA.7.3 presents instructions for management of infusion-related reactions 
associated with LY3415244.
Table JZDA.7.3.
Management of Infusion-Related Reactions
Grade
Management
…
…
…
3 or 4
Immediately and permanently discontinue study treatment.
Patients who experience a Grade 3 IRR that resolves within 6 hours may 
continue on study treatment. For subsequent infusions, the patient should be 
premedicated 1.5 hours (±30 minutes) prior to the LY3415244 infusion with 
diphenhydramine (or other antihistamine), acetaminophen (or other antipyretic), 
steroids etc., at the discretion of treating physician.
If symptoms reappear, immediately and permanently discontinue study 
treatment.
Table JZDA.7.4 presents guidance for irAE management (including use of corticosteroids) and 
criteria for dose delays and discontinuations if the patient experiences a potential irAE 
considered at least possibly related to LY3415244.
Because of the potential for rapid and serious sequelae associated with irAEs, early intervention 
with corticosteroids is encouraged, concurrent with further diagnostic medical evaluations for 
possible nonimmune-related causes of AEs.  The treatment plan should always include a 
thorough workup of the issue to rule out other potential etiologies such as infection. Guidelines 
used by Llocal standards such as, but not limited to Haanen and colleagues (2017), Puzanov and 
colleagues (2017), or Brahmer and colleagues (2018), may supersede the guidelines provided in 
Table JZDA.7.4 if deemed appropriate by the investigator.  If a patient experiences an irAE that 
is not listed in this table, consult the Lilly CRP/CRS to discuss appropriate management.
Section 7.6.1.1. DLT-Evaluable Patients in Phase 1a
…
A patient may be deemed non-evaluable for assessment of a dose level in the event the patient 
experiences an AE which would meet DLT criteria, and furthermore has been determined 
through discussion between investigator and Lilly CRP/CRS to most likely be related to a 
concomitant medication or a prior line of immune therapy (in the case of irAEs) due to 
previously established linkage. Adverse events from DLT non-evaluable patients will also be 
reviewed throughout the dose escalation process in Phase 1a.


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Section 7.7 Concomitant Therapy
Table JZDA.7.77.5 describes medications, treatments, and drug classes that are restricted or 
prohibited for use during the study treatment period, including exceptions and conditions.  There 
are no prohibited therapies during the postdiscontinuation follow-up period.  Patients who, in the 
opinion of the investigator, require the use of any of the prohibited treatments for clinical 
management should be discontinued from the trial.  Patients may receive other supportive 
therapy that the investigator deems to be medically necessary.
Table JZDA.7.77.5.
Concomitant Medication Guidelines
Section 9.1. Efficacy Assessments
Tumor assessments will be performed for each patient at the times shown in the Schedule of 
Activities (Section 2). A secondary objective of the study is to document efficacy.
RECIST 1.1 (Eisenhauer et al. 2009) will be applied as the primary criteria for assessment of 
tumor response and disease progression.  Local tumor imaging (investigator assessment with site 
radiological reading) will be used.  Modified RECIST will be applied for patients with pleural 
mesothelioma whereby tumor thickness (perpendicular to chest wall or mediastinum) would be 
measured at 2 positions on 3 separate levels on transverse cuts of CT scan (Byrne 2004).
Section 9.1.1.2. Application of RECIST 1.1. with Confirmatory Scan for Disease 
Progression
For Study JZDA, based on the unique response to immunotherapy and guidelines from 
regulatory agencies (for example, the EMA guideline on the evaluation of anticancer medicinal 
products in man for immune-modulating anticancer compounds [EMA 2013]), the following will 
be applied, in addition to standard RECIST 1.1 criteria:

If radiologic imaging verifies initial PD, tumor assessment should be repeated 4 to 6 weeks 
later in order to confirm PD in the absence of clinically significant deterioration.  Study 
treatment will continue between the initial assessment of progression and confirmation for 
progression (see Section 9.1.1.3).
“Clinically significant deterioration” is considered to be rapid tumor progression that necessitates 
treatment with anticancer therapy other than study treatment, or symptomatic progression that 
requires urgent medical intervention (for example, rapid disease progression or threat to vital 
organs or critical anatomical sites, such as central nervous system metastasis, respiratory failure 
due to tumor compression, or spinal cord compression).
Section 9.1.1.3. Criteria Required to Receive Treatment during Confirmatory Scan Period
In order for patients to continue receiving LY3415244, the following criteria apply:

absence of clinically significant deterioration (defined in Section 9.1.1.2) 


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
absence of clinical symptoms indicating clinically significant disease 
progression

no decline in performance status

no significant, unacceptable or irreversible toxicities related to study treatment

patient must sign the addendum consent prior to being treated during this time 
period
Section 9.4.1. Other Safety Measures
…
The investigator’s (or qualified designee’s) ECG interpretation will be used for decisions about 
study entry and immediate patient management will be based on the investigator's or qualified 
designee's ECG interpretation. Data analysis will be based on ECG interpretations performed by 
the cardiologist at the central ECG laboratory.
Section 9.4.2. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods. 
For Phase 1a, safety data will be reviewed on a cohort by cohort basis.  For Phase 1b, a safety 
review will be performed when every 10 patients have been treated for approximately 1 cycle for 
the first 20 patients enrolled into Phase 1b across all expansion cohorts, then every 3 months 
after the last patient enters study treatment (LPET) for 1 year, and then at least once a year 
afterward.  The purpose of this Phase 1b safety review is to evaluate the safety and tolerability 
for each expansion cohort and determine if a dose-limiting equivalent toxicity (DLET) has been 
observed. For the first 20 patients enrolled into Phase1b, based on mTPI-2 method, if 7 or more 
DLETs are observed, accrual will be temporarily paused, and the available data from Phase 1a 
and 1b will be analyzed to potentially modify the RP2D, or the study; considerations for stopping 
recruitment should be given after discussion with investigator and sponsor.
Section 9.4.2.1. Special Hepatic Safety Data Collection
Hepatic data, such as lab tests should be collected (see Appendix 5), liver related signs and 
symptoms, results from hepatic monitoring procedures, and liver biopsy assessment if available, 
should be collected in the event that a patient meets one of the following conditions during the 
course of the study: 
Section 9.8.1. Tissue Samples for Biomarker Research
…
Newly acquired tumor biopsies are requested because they provide the most current biomarker 
characteristics of the tumor compared with biopsies taken at the time of diagnosis (tumor 


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characteristics may shift during subsequent lines of treatment).  Pre- and on-treatment 
assessments are critical for meaningful clinical data; paired biopsies are planned to be tested 
from baseline over time for changes in molecular markers to document any potential 
immunomodulatory activity of treatment with LY3415244 and should be performed if clinically 
feasible. A minimum paired sample size of 19 in total is expected to provide adequate precision 
to estimate the immune response. Samples will be examined for biomarkers as described in 
Section 9.8, including but not limited to, TIM-3 and PD-L1 expression by 
immunohistochemistry.
Section 10.3.4. Interim Analyses
…
An interim analysesanalysis will be performed after all patients in Phase 1a have completed the 
DLT evaluation period.  The Lilly study team will evaluate the data from the interim safety and 
PK/PD analyses before opening the dose expansion cohorts in Phase 1b.  In these interim 
analyses, early antitumor activity may also be explored.
Section 11. References
Agrawal S, Feng Y, Roy A, Kollia G, Lestini B. Nivolumab dose selection: challenges, 
opportunities, and lessons learned for cancer immunotherapy. J Immunother Cancer. 
2016;4:72. 
…
Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff 
MS, Gardner JM, Ginex P, Hallmeyer S, Holter Chakrabarty J, Leighl NB, Mammen JS, 
McDermott DF, Naing A, Nastoupil LJ, Phillips T, Porter LD, Puzanov I, Reichner CA, 
Santomasso BD, Seigel C, Spira A, Suarez-Almazor ME, Wang Y, Weber JS, Wolchok JD, 
Thompson JA; National Comprehensive Cancer Networkhyperlink. Management of Immune-
Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: 
American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 
2018;36(17):1714-1768.
Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant 
pleural mesothelioma. Ann Oncol. 2004;15(2):257-260.
…
Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, Jordan K; ESMO 
Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical 
Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 
4):iv119-iv142.
…
Martin Liberal J, Ochoa de Olza M, Hierro C, Gros A, Rodon J, Tabernero J. The expanding role 
of immunotherapy. Cancer Treat Rev. 2017;54:74-86.










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Appendix 8. Definition of Woman of Childbearing Potential
Definitions:
Woman of Childbearing Potential (WOCBP)
A female is not considered to be of childbearing potential due to surgical sterilization confirmed 
by medical history (at least 6 weeks post-surgical bilateral oophorectomy with or without 
hysterectomy or tubal ligation) or menopause.
Menopausal women include women with either:
a.
spontaneous amenorrhea for at least 12 months, not induced by a medical condition such as 
anorexia nervosa, and not taking medications during the amenorrhea that induced the 
amenorrhea (for example, oral contraceptives, hormones, gonadotropin-releasing hormone, 
antiestrogens, selective estrogen receptor modulators, or chemotherapy), or
b. spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone level 
>40 mIU/mL.
For individuals with permanent infertility due to an alternate medical cause other than the above,
(for example, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
Exceptions to those listed above would be if female and of childbearing potential, has a negative 
serum or urine pregnancy test within 7 days prior to the first dose of study medication, agrees to 
use a highly effective method of birth control during the study and for 6 months following the 
last dose of the study drugs, and is not breastfeeding. If the urine pregnancy test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.


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Appendix 10.Protocol Amendment J1C-MC-JZDA(b) 
Summary
Overview
Protocol J1C-MC-JZDA, A Phase 1a/1b Study of LY3415244, a Bispecific Antibody in Patients 
with Advanced Solid Tumorshas been amended.  The new protocol is indicated by 
Amendment(b) and will be used to conduct the study in place of any preceding version of the 
protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
Section 1. –Addedclarification in the Rationale section
Section 2. –Removed redundant vital signs from the “Physical examination” instructions 
in Table JZDA.2.1
Section 5.2. –Clarifiedthat during the Phase 1a DLT assessment period, a maximum of 
10 patients per dose, may be enrolled

 
Section 6.1. –Clarified language in criterion [4]; deleted thyroid restriction in criterion 
[9] in order to allow patients with manageable thyroid stimulating hormone in the study; 
and clarified language in criterion [13] regarding effective contraceptive methods of birth 
control, per Belgium competent authority request
Section 6.4. –Clarified instructions for repeat laboratory tests during screening
Section 7.4. –Updated dose modification guidelines and AE management in 
TableJZDA.7.4 for Endocrine and Hepatobiliary SOCs
Section 9.8.1. –Added text to clarify that biopsies should not be taken from areas that 
have been previously irradiated, unless the previously irradiated area has progressed
Appendix 1. –Added text for clarification for highly effective methods of contraception
Appendix 4.–Clarifiedsampling schedule for IG at “C2D15; then, Q2W”; “C3D1”; and 
“30 days post last LY3415244 dose”and clarified sampling windows for PKand 
pharmacodynamics sample collectionin footnote “b”and timing of ECGsin footnote“d”

CCI
Minor editorialchanges were incorporated that may not be included in this summary 


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of double underscore.
Section 1. Synopsis
Rationale:
T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3), a co-inhibitory
molecule, is expressed on T cells during activation and has been identified as a cell surface 
marker for “exhausted” T cells following chronic exposure to antigen (Wherry 2011) and marks 
the most exhausted or dysfunctional populations of T cells in the tumor microenvironment and 
during chronic viral infection.  TIM-3 is often co-expressed with PD-1 and cytotoxic 
T-lymphocyte antigen 4 on tumor-antigen-specific T cells in cancer patients.  Blocking TIM-3 
provides the opportunity to enhance antitumor T-cell immunity, much like targeting the PD-1 
axis, and provides the opportunity to combine anti-TIM-3 therapy with clinically validated 
checkpoint inhibitor antibodies such as PD-1 or PD-L1.




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Section 5.2 Number of Patients
Enrollment in each cohort will be adjusted if needed to allow adequate assessment of safety and 
preliminary antitumor activity at the LY3415244RP2D.  
Phase 1a:  Total enrollment will be determined by the incidence of DLTs.
o Cohorts A1 through A8:  approximately 27patients (minimum of 3patients per cohort) 
will be enrolled.  During Phase 1a DLT assessment period, a maximum of 10 patients, 
per dose level, may be enrolled.  
 
 
Section 6.1 Inclusion Criteria
[4] Patients with mesothelioma are not required to have received prior anti-PD-1 or anti-
PD-L1 therapy.  If the patient has received prior anti-PD-1 or anti-PD-L1 therapy, 
then inclusion criteria [2]a through [2]d and[3]a and [3]b would apply.  Additionally, 
patients must have: 
a.
confirmed unresectable or medically inoperable malignant pleural
mesothelioma (MPM) subtypeand progressive disease (PD) after at least one 
CCI
prior systemic treatment with a platinum-based doublet (both cisplatin and 
carboplatin are allowed) for unresectable MPM.  All prior cytotoxic toxicities 
must have resolved to Grade ≤2 prior to registration.






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Section 9.8.1 Tissue Samples for Biomarker Research
An attempt to obtain 4 core-needle biopsies or a surgical biopsy is required, unless medically 
contraindicated and discussed with Lilly CRP/CRS. Optimally, biopsies should be taken from the 
same lesion and from areas not previously irradiated. Biopsies should not be taken from areas 
that have been previously irradiated, unless the previously irradiated area has progressed.  
Appendix 1 Abbreviations and Definitions
highly effective methods 
of contraception
Methods include:

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:
o
oral
o
intravaginal
o
transdermal

Progestogen-only hormonal contraception associated with inhibition of 
ovulation :
o
oral
o
injectable
o
implantable 

Intrauterine device (IUD) 

Intrauterine hormone-releasing system ( IUS) 

Bilateral tubal occlusion 

Vasectomized partner (vasectomized partner is a highly effective birth 
control method provided that partner is the sole sexual partner of the 
woman of childbearing potential who is the trial participant and that the 
vasectomized partner has received medical assessment of the surgical 
success.)

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 treatments. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject.) 
combined oral contraceptive pill and mini pill, NuvaRing®, implantable 
contraceptives, injectable contraceptives (such as Depo Provera®), intrauterine 
device (such as Mirena® and ParaGard®), contraceptive patch for women <90 
Kg (<198 pounds), total abstinence, or vasectomy.
Also see the definition of effective method of contraception.




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b
The 2-, 4-, 24-, 72-, 120-, and 168-hour samples are relative to the START of the corresponding dosing event.  These samples must be collected after 
completion of the infusion.  Allowable sampling window for pre-dose C1D1 is -8 hours. Allowable sampling windows for 2-, 4-, 24-, 72-, 120-, and 168-
hour are ±30 minutes, ±60 minutes, ±8 hours, ±24 hours, ± 24 hours, and ± 48 hours, respectively.  If  LY3415244 infusion need to be increased up to 2 hours 
the allowable sampling windows for the 2-hour sample is increased to +60 minutes. Samples at 30, 60, and 90 days post last LY3415244 dose have allowable 
sampling windows of ±7 days.  However, it is essential that the exact infusion start and stop times (actual clock readings) are recorded.
d
Triplicate ECGs should be conducted immediately before the PK sample and after the patient has been supine for 5 minutes; collect at a minimum of 1-minute 
intervals, with all 3 replicate ECGs completed within 5 to 15 minutes. 


PPD
Leo Document ID = 4fea25e9-b30b-4192-93a9-54003b208979
Approver: 
Approval Date & Time: 12-Dec-2018 15:40:27 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 13-Dec-2018 01:11:44 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
Statistical Analysis Plan Version 1 J1C-MC-JZDA 
 
 
 
A Phase 1a/1b Study of LY3415244, a Bispecific Antibody in Patients with Advanced Solid 
Tumors 
 
NCT03752177 
 
Approval Date: 24-Oct-2018 
 
 
 


J1C-MC-JZDA Statistical Analysis Plan Version 1
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1.
Statistical Analysis Plan:  J1C-MC-JZDA
A Phase 1a/1b Study of LY3415244, a Bispecific Antibody 
in Patients with Advanced Solid Tumors
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities: this document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY3415244
Study J1C-MC-JZDA is a multicenter, nonrandomized, open-label, dose-escalation Phase 
1a study followed by Phase 1b cohort expansion of intravenous LY3415244 in patients with 
advanced solid tumors.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol J1C-MC-JZDA
[Phase 1a/1b]
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 24-Oct-2018 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:  J1C-MC-JZDA A Phase 1a/1b Study of 
LY3415244, a Bispecific Antibody in Patients with Advanced Solid 
Tumors ...............................................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................5
4.
Study Objectives.................................................................................................................6
4.1.
Primary Objective ..........................................................................................................6
4.2.
Secondary Objectives.....................................................................................................6
4.3.
Tertiary/Exploratory Objectives .....................................................................................6
5.
A Priori Statistical Methods ................................................................................................7
5.1.
Sample Size Determination ............................................................................................7
5.2.
General Considerations ..................................................................................................7
5.2.1.
Populations ............................................................................................................7
5.2.2.
Definitions and Conventions ..................................................................................8
5.3.
Adjustments for Covariates ............................................................................................8
5.4.
Handling of Dropouts or Missing Data...........................................................................8
5.5.
Multicenter Studies ........................................................................................................9
5.6.
Multiple Comparisons/Multiplicity.................................................................................9
5.7.
Patient Disposition .........................................................................................................9
5.8.
Patient Characteristics ....................................................................................................9
5.8.1.
Demographics........................................................................................................9
5.8.2.
Baseline Disease Characteristics ............................................................................9
5.8.3.
Prior Therapies.....................................................................................................10
5.8.4.
Historical Illnesses ...............................................................................................10
5.9.
Treatment Compliance .................................................................................................10
5.10. Concomitant Therapy...................................................................................................10
5.11. Postdiscontinuation Therapy ........................................................................................10
5.12. Safety Analyses............................................................................................................10
5.12.1.
Extent of Exposure...............................................................................................10
5.12.2.
Dose-Limiting Toxicity and DLT-Equivalent Toxicities.......................................11
5.12.3.
Adverse Events ....................................................................................................11
5.12.4.
Deaths..................................................................................................................12
5.12.5.
Clinical Laboratory Evaluation.............................................................................12
5.12.6.
Vital Signs and Other Physical Findings...............................................................12
5.12.7.
Electrocardiograms ..............................................................................................12


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5.13. Efficacy Analyses ........................................................................................................12
5.13.1.
Tumor Measurement ............................................................................................13
5.13.2.
Objective Response Rate and Disease Control Rate..............................................13
5.13.3.
Time to Response.................................................................................................14
5.13.4.
Progression-Free Survival ....................................................................................14
5.13.5.
Duration of Response...........................................................................................15
5.13.6.
Immuno-Related Efficacy Analysis Variables ......................................................15
5.13.7.
Overall Survival...................................................................................................16
5.14. Subgroup Analyses.......................................................................................................16
5.15. Immunogenicity Analysis.............................................................................................16
5.16. Pharmacokinetic/Pharmacodynamic Analyses..............................................................17
5.17. Biomarker Analysis......................................................................................................17
5.18. Interim Analysis...........................................................................................................17
5.19. Additional Reports to Support Clinical Trial Registry ..................................................18
6.
References ........................................................................................................................20


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Table of Contents
Table
Page
Table JZDA.5.1.
Definitions and Data Handling Conventions .............................................8
Table JZDA.5.2.
Rules for Determining Date of Progression or 
Censor for Progression-Free Survival .....................................................14


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior to the first visit when a subject 
receives study drug or any other protocol intervention.


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4.
Study Objectives
4.1.
Primary Objective
Phase 1a:  To assess the safety and tolerability of LY3415244 in patients with advanced solid 
tumors, thereby identifying a recommended Phase 2 Dose (RP2D) to be administered to patients 
in the Phase 1b portion of the study.
Phase 1b:  To assess the safety and tolerability of the RP2D dose of LY3415244 in patients with 
advanced solid tumors.
4.2.
Secondary Objectives
Phase 1a:  To assess the pharmacokinetics (PK) of LY3415244. 
Phase 1b:

to assess the PK of LY3415244 in patients in each of 4 expansion cohorts.

to assess early antitumor activity of LY3415244 in patients in each of 4 expansion 
cohorts.
4.3.
Tertiary/Exploratory Objectives
Phase 1a and 1b:

to characterize tumor tissue and blood biomarkers relevant to LY3415244, including but 
not limited to immune cells/immune functioning, mechanism of action of study drugs, 
cancer-related pathways, and disease state

to explore the association between biomarkers and clinical outcomes

to assess the immunogenicity of LY3415244

to assess overall survival (OS) of patients receiving LY3415244 administered as 
monotherapy


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5.
A Priori Statistical Methods
5.1.
Sample Size Determination
The sample size determination is described in Protocol J1C-MC-JZDA (JZDA), Section of 
Sample Size Determination.
5.2.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (Lilly) or its 
designee.
Sponsor standard tables, figures, and listings (TFLs) and supporting programs and software (eg,
SAS®) will be utilized for all analyses where a suitable standard exists. Data derivations in this 
SAP are defined based upon current sponsor reporting standards at the time of writing, and may 
be updated at the time of analysis in order to maintain accordance with the most current sponsor 
standards at that time.
Unless otherwise noted, summaries of continuous variables will include a mean, median, 
standard deviation, minimum, and maximum.  When appropriate, lower and upper quartiles will
also be presented.
Unless otherwise noted, summaries of categorical variables will include the frequency and 
percentage (relative to the population being analyzed) of each category.
In Part 1a, unless otherwise stated, data will be summarized by dose escalation cohorts which 
will indicate the assigned treatment regimen and dose schedule for LY3415244.  
In Part 1b, unless otherwise stated, data will be summarized by expansion cohorts.
In addition, safety data may be summarized by the same treatment regimen and dose schedule, 
and efficacy data may be summarized by the same indication, treatment regimen, and dose 
schedule by combination of the Phase 1a and 1b part.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
5.2.1. Populations
The following population will be defined for this study:
Entered Population:  will include all patients who sign the informed consent document.
Enrolled/Safety Population:  will include all patients who received any quantity of study 
treatment (LY3415244), regardless of their eligibility for the study. The safety and efficacy 
evaluation will be performed based on the first dose of study treatment a patient actually 
received.  This population will be used for all dosing/exposure, safety, and efficacy analyses.
Dose-Limiting Toxicity (DLT)-Evaluable Population (for Phase 1a):  will include all patients 
from Phase 1a portion of the study who have completed DLT observation period (Cycle 1) or 
discontinued treatment before the end of the DLT observation period but with a documented 
DLT assessment. Exposure and safety summaries will be repeated for this population.


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Pharmacokinetic population:  will include all enrolled patients from whom a valid assay result 
(according to laboratory guideline) has been obtained.
Biomarker population:  will include the subset of enrolled patients from whom a valid assay 
result has been obtained.  No imputation will be performed for missing data due to the limitation 
of small sample size.
5.2.2. Definitions and Conventions
The following definitions and data handling conventions will be used in the analysis.
Table JZDA.5.1.
Definitions and Data Handling Conventions
Term
Definition or Rule
Relative Study Day
If assessment is on or after date of first dose then
(date of assessment) – (date of first study drug dose) +1
If assessment precedes first dose of drug then
(date of assessment) – (date of first study drug dose)
There is no study day 0. Study day 1 is the date of first dose and study day -1 is the day 
before the first dose.
Cycle Day
If assessment is on or after date of first dose in cycle then
(date of assessment) – (date of first study drug dose in cycle) +1
There is no cycle day 0. Cycle day 1 is the date of first dose in that cycle.
Baseline
For change from baseline analyses, baseline value is defined as the last reported measure on 
or before the first dose date (prior to the dose administration), unless otherwise specified.
Age (years)
Age is based on date of birth and Informed consent date.  If only a year and month are 
provided in the date of birth, set day to 15.  If only a year is provided, set day to 1 and month 
to 7 (July).
Duration
Duration (days): (End Date – Start Date + 1)
Duration (weeks):
(End Date – Start Date + 1)/7
Duration (months):
(End Date – Start Date + 1)/30.4375 (Days in months = 
(1/12)*average number of days in a year)
Duration (years): (End Date – Start Date + 1)/365.25 (Average days in a year = 365.25, 
reflecting the Julian Year of 3 years with 365 days each and 1 leap year of 366 days)
Time-to-Event
The event or censoring time (days) is calculated as:
Date of event/censoring Date of first dose of study drug + 1
5.3.
Adjustments for Covariates
Given the small sample size for each tumor type and treatment, no formal analysis investigating 
the impact of covariates is planned.  If data warrant, exploratory analyses may incorporate 
patient disease characteristics in evaluation of efficacy parameters.
5.4.
Handling of Dropouts or Missing Data
Missing data, except for dates, will not be imputed. They will be kept as missing in the data 
analyses, except for dates when used in calculations of relative study day, for which sponsor 
reporting standards will be utilized for imputation rules, defined as: Missing start days will be 
replaced with 1 and missing day/month with 01 JAN. Missing end days will be replaced with the 


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last day of the month, and missing day/month with 31 DEC. The imputation rule may be 
updated at the time of study reporting if necessary to maintain accordance with most recent 
sponsor standards. Partial dates should be reported in all listings and not the imputed date.
For time-to-event endpoints, the method for handling missing data will be censoring. Additional 
sensitivity analyses may be conducted applying different censoring rules if data warrant and will 
follow sponsor defined standards.
5.5.
Multicenter Studies
Given the small number of patients for each tumor type and treatment, patients across all sites
will be grouped together for analysis purposes.
5.6.
Multiple Comparisons/Multiplicity
No formal hypothesis testing is planned for this study; thus, there will be no adjustments for
multiplicity.
5.7.
Patient Disposition
Patient disposition will be summarized and listed for all patients entered into the study. It will
include a summary of the number and percentage of patients entered into the study, enrolled in 
the study, and treated as well as number and percentage of patients completing the study, or 
discontinuing (overall and by reason for discontinuation of study drug). All patient 
discontinuation data collected on the case report form (CRF) will be listed.
Important protocol deviations that potentially compromise the data integrity and patients’ safety 
will be summarized for safety population.  These deviations will include those that can be 
identified programmatically and those that can only be identified by the clinical research 
associate during monitoring.  Important protocol deviations are described in another document 
within the study Trial Master File.
5.8.
Patient Characteristics
Patient characteristics will be summarized and listed for safety population. Details of the patient 
characteristics are described in the following sections. Other patient characteristics will be 
summarized as deemed appropriate.
5.8.1. Demographics
Patient demographics will include sex, race, ethnicity, country, age, age group (<65 years; 
≥65 years, <70 years; ≥70 years), height, weight, body mass index (BMI).
5.8.2. Baseline Disease Characteristics
Baseline disease characteristics will include Eastern Cooperative Oncology Group (ECOG) 
performance status (PS), initial pathological diagnosis, basis for initial diagnosis, disease stage, 
histopathological grade, tobacco usage (never, current, former), and alcohol use.


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5.8.3. Prior Therapies
Prior radiotherapy, surgery, and systemic therapy will be summarized.  Prior radiotherapy will be 
categorized by reason (neoadjuvant, adjuvant, neoadjuvant plus adjuvant, advanced/metastatic) 
for the regimen and prior surgery will be categorized by intent (curative, palliative).  Prior 
systemic therapies will be categorized by setting (neoadjuvant, adjuvant, locally advanced, 
metastatic).  Frequency of each specific therapy will be tabulated within each type of regimen 
and reason for regimen.  
The patients who received any prior anti-PD-1 and/or anti-PD-L1 therapies will be listed.
5.8.4. Historical Illnesses
Historical illnesses are events in the past that ended before the date informed consent is signed.  
Historical illnesses (coded according to the Medical Dictionary for Regulatory Activities 
[MedDRA] dictionary) will be listed for all enrolled patients.  
5.9.
Treatment Compliance
LY3415244 will be intravenously administered only at the investigational sites. As a result, 
patient compliance will be ensured. If there are any cases deemed as not compliance, they will 
be reported as protocol deviations.
5.10. Concomitant Therapy
Concomitant medications will be summarized and listed for the safety population.
For corticosteroids and/or immunosuppressives, the indication, administration route, individual 
dose, duration, and dose adjustment reason of the use will be summarized and listed.
5.11. Postdiscontinuation Therapy
The numbers and percentages of patients reporting postdiscontinuation therapies will be 
provided overall, by type of therapy (surgery, radiotherapy, or systemic therapy), and by drug 
name.
5.12. Safety Analyses
All patients who receive any quantity of LY3415244 will be evaluated for safety and toxicity.
Details of the analyses are described in the following subsections.
5.12.1. Extent of Exposure
A summary of exposure will be provided for study drug, including cycle received, cumulative 
dose and duration of therapy. Duration of therapy is defined as Discontinuation date - Date of 
first dose + 1.
A summary of dose intensity will be provided for study drug. Dose intensity expressed in 
mg/week will be calculated as the actual cumulative amount of drug taken divided by the
duration of exposure in weeks. Duration of exposure in weeks is defined as (Date of last dose –
Date of first dose + 14)/7.


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Relative dose intensity will be calculated as:
100% x (actual cumulative dose taken [mg] / planned cumulative dose [mg])
Note that planned dose is the same as actual dose if there is no dose modification or cycle delay.
A summary of dose adjustments will be provided for study drug, including dose omissions, dose 
reductions, dose increase, dose delays, treatment interrupted and the corresponding reasons for 
dose adjustments for each cohort.  
5.12.2. Dose-Limiting Toxicity and DLT-Equivalent Toxicities
The definition of the DLTs and the DLT-equivalent toxicities (DETs) is specified in Protocol 
J1C-MC-JZDA (JZDA), Section of Dose-Limiting Toxicity Determination.
Dose limiting toxicities will be summarized and listed for DLT-evaluable population.  
Dose limiting toxicities-equivalent toxicities (DETs) will also be listed and summarized for 
safety population.
5.12.3. Adverse Events
A listing of all adverse events (AEs) by patient will be presented. This listing will include 
patient number, AE (reported term and Preferred Term [PT]), event start and end dates, Common 
Terminology Criteria for Adverse Events (CTCAE) grade, relationship to study drug/procedure, 
seriousness, and outcome. A listing of serious adverse events (SAEs) will be produced using the 
similar format.
An overall summary will be provided for AEs. The summary will provide counts for all AEs, 
and AEs related to study treatment. Specifically, the number and percent of evaluable patients 
will be summarized by treatment for each category below:

patients with at least one treatment-emergent AE (TEAE)

patients with at least one Grade 3 or higher TEAE

patients with at least one SAE

patients who discontinued due to AE

patients who discontinued due to SAE

patients who died due to AE on study treatment

patients who died due to AE within 30 days of discontinuation from study treatment 
The following summaries will also be produced:

summary of all preexisting conditions

summary of TEAEs by PT (any grade and Grade ≥3)

summary of TEAEs by System Organ Class (SOC) and PT (any grade and Grade ≥3)

summary of TEAEs by SOC and PT and maximum grade (1-5)


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
summary of treatment-emergent SAEs by SOC and PT (any grade and Grade ≥3)

summary of AEs as reason for study treatment discontinuation by SOC and PT

summary of TEAEs leading to dose omissions, reductions, hospitalizations
In addition, immune-related adverse events (irAEs) may be summarized.  A list of what is 
considered an irAE will be defined in a separate document.
5.12.4. Deaths
All deaths recorded in this study will be included as part of the complete AE listing, where 
appropriate, and listed separately.  A summary of deaths may be presented for all patients on 
therapy if there are a sufficient number of events for this to be deemed useful.
5.12.5. Clinical Laboratory Evaluation
All laboratory results will be reviewed using Spotfire to assess changes over time and differences 
between cohort/dose levels.  Key findings will be summarized in tables and/or illustrated 
graphically using line plots over time or box plots, for example.  
Any abnormal results of clinical laboratory tests will be listed for all patients on therapy and 
where appropriate the calculated CTCAE grades using CTCAE v4.0 (or higher) will be given.  
Calculated CTCAE grades will also be summarized by cohort/dose level for laboratory 
parameters where CTCAE grades are available. A shift table of baseline grade by maximum 
postbaseline grade will be produced.
5.12.6. Vital Signs and Other Physical Findings
All vital sign results will be reviewed using Spotfire to assess changes over time and differences 
between cohorts/dose levels.  Key findings will be summarized in tables and/or illustrated 
graphically using line plots over time or box plots for example. 
Any significant physical examination findings and results will be listed.
5.12.7. Electrocardiograms
Any abnormal electrocardiogram (ECG) data based on local testing will be listed and 
summarized for safety population. Further exploratory analyses may be conducted as warranted.
5.13. Efficacy Analyses
All efficacy analyses will be performed on the safety population.  This study is not designed to 
perform hypothesis testing on efficacy; however, all efficacy data will be listed and summarized.
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Eisenhauer et al. 2009) will be 
applied as the primary criteria for assessment of tumor response.  Local tumor imaging 
(investigator assessment with site radiological reading) will be used.  Modified RECIST (Byrne 
and Nowak 2004) will be applied for patients with pleural mesothelioma. For the patients with 
both pleural mesothelioma and solid tumors, Modified RECIST will be applied to pleural 
mesothelioma and RECIST 1.1 will be applied to the solid tumors.


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Two sets of analyses will be provided, with 1 set based on RECIST 1.1 and the other set based 
on RECIST 1.1 with confirmatory scan for disease progression. The notation “ir” will be used to 
denote the analyses based on RECIST 1.1 with confirmatory scan for disease progression, it does 
not indicate that any of the assessments based on irRECIST, irRC, or iRECIST will be used in 
the study or analyses.
5.13.1. Tumor Measurement
For the patients with solid tumors only (assessed by RECIST 1.1), the tumor size is the sum of 
the uni-dimensional measurements for each lesion.
For the patients with pleural mesothelioma only (assessed by modified RECIST), the tumor size 
is the sum of the 6 pleural unidimensional measurements (2 positions, each with 3 levels). 
For the patients with both pleural mesothelioma (assessed by modified RECIST) and solid 
tumors (assessed by RECIST 1.1), the tumor size is the sum of 2 parts, the sum of the 6 pleural 
unidimensional measurements (2 positions, each with 3 levels) and the sum of the uni-
dimensional measurements for each solid lesion.
Individual changes in the tumor size over time will be presented graphically by waterfall and 
spider plots within a tumor type.  
5.13.2. Objective Response Rate and Disease Control Rate
Objective response rate (ORR) and disease control rate (DCR) are summary measures of best 
overall response (BOR) as defined by RECIST 1.1.  Best overall response is derived from time 
point responses.  All time point responses observed while on study treatment and during the 
short-term follow-up period will be included in the derivation.  Patients’ responses after 
objective progression or start of new anticancer therapy are excluded from the determination of 
best response.  Best overall response of complete response (CR) and partial response (PR) should 
be confirmed by repeated assessment at least 4 weeks following the initial observation.  Each 
patient’s BOR will be categorized as CR, PR, stable disease (SD), partial disease (PD), or not 
evaluable (NE).  If appropriate, the best overall tumor response may be calculated by Lilly using 
all available lesion measurement data to confirm the investigator assessments.  
Objective response rate (ORR) will be estimated by dividing the total number of confirmed 
responders (CR+PR) by the number of enrolled patients who have received any quantity of study 
treatment.
Disease control rate (DCR) is defined as the number of patients with stable disease, confirmed 
partial response or confirmed complete response (CR+PR+SD) divided by the number of 
enrolled patients who have received any quantity of study treatment.
The estimates of ORR and DCR along with exact 95% confidence interval (CI) will be reported. 


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5.13.3. Time to Response
Time to response (TTR) is the time from the date of first study treatment until the first evidence 
of a confirmed CR or PR.  If a patient did not experience a confirmed CR or PR, the TTR will be 
censored at the treatment starting date.
Time to response will be estimated using Kaplan-Meier (KM) method (Kaplan and Meier 1958) 
and summary statistics including median and 95% CI will be presented.  
5.13.4. Progression-Free Survival
Progression-free survival (PFS) is defined as the time from the date of first dose until the date of 
the first observed radiographic documentation of progression or death due to any cause, 
whichever is earlier.  
Table JZDA.5.2 lists rules for determining date of progression or censor for PFS.  
Table JZDA.5.2.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival
Abbreviations:  PD = partial disease.
Notes: (1) If there are multiple dates associated with 1 radiological tumor assessment, the 
assessment date will be set to the first date when the overall response is PD and the last date 
otherwise, (2) Symptomatic deteriorations (ie, symptomatic progressions, which are not 
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 radiological 
assessment or date of first dose
(whichever is later)
unless
No baseline radiological tumor assessment 
available
Censored
Date of first dose
No adequate post baseline radiological 
tumor  assessment available 
and death reported after 2 consecutively 
missed tumor assessment interval following
enrollment
Censored
Date of first dose
New anticancer treatment started
Censored
Date of adequate radiological
assessment prior to start of new 
therapy or date of first dose 
(whichever is later)
Tumor progression or death
documented immediately after 2 or more 
consecutively missed tumor assessment 
interval following last adequate radiological 
tumor assessment or enrollment (whichever 
is later)
Censored
Date of last adequate radiological 
assessment or date of first dose
(whichever is later)


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radiologically confirmed) will not be considered as progressions, (3) A radiological tumor 
assessment is considered adequate if its response is among CR, PR, SD, or PD.
Progression-free survival will be estimated using KM method.  Median PFS and 95% CI as well 
as PFS rates (and 95% CI) at 12, 18, 24 weeks will be presented. 
5.13.5. Duration of Response
The duration of response (DoR) time is defined only for responders (patients with a confirmed 
CR or PR).  It is measured from the date of first evidence of CR or PR to the date of the first 
observed radiographically documented PD, or the date of death due to any cause, whichever is 
earlier.  For clarity, the start date should be determined by the initial assessment of CR or PR, not 
the date of confirmation of CR or PR.  It is calculated as date of progression or death – date of 
first response evaluation of CR or PR + 1.
Duration of response will be censored according to the same rules as PFS, with the addition of 
the following rule:  if a patient begins postdiscontinuation therapy, DoR will be censored on the 
day of the last response evaluation prior to the initiation of postdiscontinuation therapy.
Duration of response will be estimated using KM method and summary statistics including 
median and 95% CI will be presented.  
5.13.6. Immuno-Related Efficacy Analysis Variables
Study JZDA will use RECIST 1.1 with confirmatory scan for disease progression. Detailed 
application of RECIST 1.1 with confirmatory scan for PD can be found in Protocol J1C-MC-
JZDA, Section 9.1.1.2.  
Immune-related objective response rate (irORR) is defined as the proportion of treated 
patients achieving a best overall response of CR or PR per RECIST 1.1 with confirmatory scan 
for PD.  Particularly, the best overall response by RECIST 1.1 with confirmatory scan for PD
closely related to confirmed response by RECIST. Immune-related objective response rate 
further captures responses after unconfirmed PD and it does not require confirmation.  For 
example:

If the best response by RECIST 1.1 is CR, then the best response by RECIST 1.1 with 
confirmatory scan for PD is CR.

If the best response by RECIST 1.1 is PR, SD, or PD, the best response by RECIST 1.1 
with confirmatory scan for PD is the best response over the initial assessment (prior to 
PD by RECIST) and the confirmation stage.
Overall, the best response by RECIST 1.1 with confirmatory scan for PD should be the same or 
better than the best response by RECIST criteria.  In addition, patients who do not have any 
postbaseline tumor response assessments for any reason are considered non-evaluable and will 
be included in the denominator when calculating the response rate.
Immune-related disease control rate (irDCR) is defined as the number of patients with 
immune-related stable disease (irSD), immune-related complete response (irCR), or immune-


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related partial response (irPR) divided by the number of enrolled patients who have received any 
quantity of study treatment.
Immune-related time to response (irTTR) is the time from the date of first study treatment 
until the first documented irCR or irPR.  
Immune-related PFS (irPFS):  The date from the treatment start date to the time of PD assessed 
by RECIST 1.1 with confirmatory scan for PD.

If the initial PD is confirmed, then the date of immune-related partial disease (irPD) is 
the initial PD date by RECIST 1.1.

If the initial PD is unconfirmed, then the date of irPD is the date of second PD.
Immune-related duration of response (irDOR):  The duration of response is defined from the 
date of first documented irCR or irPR (responder) to the date of irPD or the date of death due to 
any cause, whichever is earlier. 
In addition, the best response after initial PD may be listed.  
5.13.7. Overall Survival
Overall survival  is defined as the time from first study treatment until death due to any cause.  If 
the patient is not known to have died at the data inclusion cutoff date for the analysis (or is lost to 
follow-up), OS data will be censored on the last date the patient is known to be alive.
Overall survival will be estimated using KM method.  Median OS along with 95% CI as well as 
OS rates (and 95% CI) at 1 and 2 years will presented. 
5.14. Subgroup Analyses
Subgroup analyses of efficacy endpoints may be performed for each of the potential prognostic 
subgroup variables listed below.  

sex (male; female)

age (<65 years; ≥65 years; <70 years; ≥70 years)

baseline Eastern Cooperative Oncology Group (ECOG) PS (0; 1)

ethnicity (White; East Asian; others)

smoking status (never; current; former)

prior lines of therapy (such as first line, second line, third line and beyond)
Other subgroups may be added as deemed necessary.
5.15. Immunogenicity Analysis
Immunogenicity (anti- LY3415244 antibody) incidence will be tabulated, and correlation to drug
level, activity, and safety will be assessed, as appropriate, respectively.  The measures that will 
be analyzed include baseline presence and level of anti-drug antibodies (ADA), treatment-


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emergent ADA, levels of neutralizing ADA, and incidence and levels of ADA related to 
infusion-related reactions.
5.16. Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic parameter estimates for LY3415244 therapy will be calculated by population 
PK analysis methods using nonlinear mixed effects modeling. The version of any software used 
for the analysis will be documented, and the program will meet the Lilly requirements of 
software validation.  It is possible that other validated, equivalent PK software programs may be 
used if appropriate, warranted, and approved by Lilly global PK/pharmacodynamic management.  
In addition, selected PK parameters (based on actual sampling times), including maximum 
observed drug concentration (Cmax), time of Cmax , and area under the concentration versus time 
curve (AUC) may be calculated by noncompartmental analysis methods and/or model 
simulations.  As an exploratory analysis, PK parameter estimates for minimum observed drug 
concentration during a dosing interval (Cmin) at steady state following repeated dose may be 
evaluated. 
Pharmacokinetic/pharmacodynamic analyses will be conducted to explore exposure-response 
relationships between LY3415244 concentrations in systemic circulation and various 
pharmacodynamic measures, such as selected safety outcomes, receptor occupancy, and 
biomarkers. 
5.17. Biomarker Analysis
Biomarkers related to treatment, immune functioning, mechanism of action of study drugs, 
and/or cancer will be collected and reported.  In addition, the relationship between biomarkers 
and clinical outcome will be assessed.  Biomarker relationships by tumor type, changes in 
biomarker levels at baseline and over time, and differences among dose levels or exposure will 
be explored as possible. The pharmacodynamic effect from all patients undergoing 
pharmacodynamic assessments will be explored.
5.18. Interim Analysis
In the Phase 1a dose-finding portion of the study, safety, PK, and biomarker data (if available) 
will be reviewed on a cohort-by-cohort basis during the study, until the maximum tolerated dose
and/or RP2D is determined.  The purpose of these cohort-by-cohort data reviews is to evaluate 
the safety data at each dose level and determine if a DLT has been observed.  The decision 
whether to advance to the next dose level will be made following discussion between the 
investigators and Lilly and will be relayed to the sites prior to patients being treated on the 
subsequent cohort.
Safety and available PK data will be reviewed during the study to inform dose escalation,
modifications to the dose-escalation strategy, or other design elements.
An interim analyses will be performed after all patients in Phase 1a have completed the DLT 
evaluation period.  The Lilly study team will evaluate the data from the interim safety and 


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PK/PD analyses before opening the dose expansion cohorts in Phase 1b. In this interim analyses, 
early antitumor activity may also be explored.
An expansion-specific safety and efficacy interim analysis will be conducted approximately 
24 weeks (6 months) after the last patient enters/starts study treatment (LPET) for each of the 
expansion cohorts. These interim analyses may be combined if they are expected to occur within
approximately a month of each other.  Interim analyses may also be combined with any 
prespecified safety review or reporting (ie, Trial Level Safety Reviews, Development Safety 
Update Reviews, or Investigator Brochure update reviews).  The expansion-specific safety and 
efficacy primary analyses will be conducted approximately 52 weeks (12 months) after LPET for 
each of the expansion(s).
The final overall analysis of Study JZDA will coincide with the safety and efficacy primary 
analysis of the last expansion.
If it is deemed that enough data have been obtained to assess the primary and secondary 
objectives, a clinical study report might be created before the last patient visit.  In this case, all 
data until the data-cutoff date will be used for the analysis of safety, efficacy, PK, and 
pharmacodynamic biomarkers.  All data defined in the protocol will continue to be collected 
from patients on treatment after data-cutoff date and results will be listed.  However, summary 
tables including data after data-cutoff date will not be created.
5.19. Additional Reports to Support Clinical Trial Registry
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.
Analyses provided for the CTR requirements include the following:

Summary of AEs, provided as a dataset which will be converted to an XML file.  Both 
SAEs and “Other” AEs are summarized by treatment group and by MedDRA PT.

An AE is considered “Serious” whether or not it is a TEAE.

An AE is considered in the “Other” category if it is both a TEAE and is not serious.

For each SAE and “Other” AE, for each term and treatment group, the following are 
provided:
o
the number of participants at risk of an event (if certain subjects cannot be at risk 
for some reason, for example, gender-specific AEs, then the study team must 
adjust the number to only include the patients at risk)
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, a threshold for frequency of 
“Other” AEs can be implemented rather than presenting all “Other” AEs.  For example, 
“Other” AEs that occur in fewer than 5% of patients in any treatment group may not be 


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included if a 5% threshold is chosen.  The frequency threshold must be less than or equal 
to the allowed maximum of 5%.
A participant flow will be created that will describe how many patients completed the study, and 
for those who did not, the frequency of each reason for not completing.  This analysis will be 
based on study discontinuation, not treatment discontinuation.  A patient will be identified as 
having completed the study on the study discontinuation electronic case report form (eCRF), if 
available, or if information for both primary and secondary endpoints has been observed.


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6.
References
Byrne MJ, Nowak AK. Modified RECIST criteria for assessment in malignant pleural 
mesothelioma. Ann Oncol. 2004;15(2):257-260.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-247.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc.
1958;53(282):457-481.


Leo Document ID = 2e7a7e98-04bb-443e-bb4a-55a389bd674d
Approver: 
Approval Date & Time: 24-Oct-2018 18:10:07 GMT
Signature meaning: Approved
PPD