Clinical trial NCT04099277
Conditions: Solid Tumor Triple-negative Breast Cancer Gastric Adenocarcinoma Head and Neck Squamous Cell Carcinoma Cervical Carcinoma High Grade Serous Ovarian Carcinoma Hepatocellular Carcinoma Undifferentiated Pleomorphic Sarcoma Leiomyosarcoma
Keywords: immunotherapy CD226 agonist
Sponsor: Eli Lilly and Company
Start date: 2019-10-28; Completion date: 2020-03-05
Enrollment: 2 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The reason for this study is to see if the study drug LY3435151 is safe in participants with advanced solid tumors.

Detailed description:

Arms: arm 1: Participants received intravenous (IV) push or IV bolus infusion of 10 mg LY3435151. arm 2: Pembrolizumab was not administered as study was terminated before completion of Part A of the dose escalation period. arm 3: Participants were not enrolled in to this arm, as trial was terminated in dose escalation phase. arm 4: Participants were not enrolled in to this arm, as trial was terminated in dose escalation phase.
Interventions: intervention 1: LY3435151 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered IV

Protocol documents:
Prot_000.pdf: 
Protocol: J1Q-MC-JZIA(b)
A Phase 1a/1b Study of LY3435151 Administered to Patients With Advanced Solid 
Tumors
NCT04099277
Approval Date: 28-Jan-2020


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Approval Date: 28-Jan-2020 GMT


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
2
Protocol Amendment Summary of Changes
DOCUMENT HISTORY
Document
Date
Amendment (a)
09-Aug-2019
Protocol J1Q-MC-JZIA
21-Jun-2019
Amendment (b)
Overall Rationale for the Amendment:
The purpose of this amendment is to add updated informative language for pembrolizumab, as 
well as to provide additional clarity for sites and investigators.
Section # and Name
Description of Change
Brief Rationale
Throughout
Addition of pembrolizumab-
specific language
Language added to meet
pembrolizumab language 
requirements 
Section 1.1 Synopsis; 
Section 3 Objectives and 
Endpoints
Revision of Phase 1b C1 and 
D1 objectives
Clarification
Section 1.3 Schedule of 
Activities
Baseline radiologic imaging 
notes updated; revised 
concomitant medication notes
Additional instructions provided 
in notes
Section 1.3.1 Sampling 
Schedules for 
Pharmacokinetics, 
Biomarkers, and Safety
Removal of stool sample at 
V801 in Phase 1b schedule
Editorial error
Section 1.3.1 Sampling 
Schedules for 
Pharmacokinetics, 
Biomarkers, and Safety
C1D2 and C1D4 samples 
added; footnote added to 
Hematology CBC
Additional samples added to 
study; footnote added for 
sampling flexibility
Section 1.3.1 Sampling 
Schedules for 
Pharmacokinetics, 
Biomarkers, and Safety
Addition of ECGs at C2D1 1h 
post-dose and C3D1 1h post-
dose for Phases 1a and 1b 
Additional testing added to 
study
Section 1.3.1 Sampling 
Schedules for 
Pharmacokinetics, 
Biomarkers, and Safety
Revised footnotes for sampling 
schedules
Clarification 
Section 4.1.1 Dose 
Escalation Phase
Revision of patient enrollment 
for Cohort A and Cohort B1
Clarification for Cohort A, 
correction for Cohort B1


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
3
Section # and Name
Description of Change
Brief Rationale
Section 4.1.1.2 Dose-
Limiting Toxicity 
Determination
Added “immune-related” to 
Grade 3 endocrine disorder 
DLT exception
Clarification 
Section 4.1.2 Dose 
Expansion Phase
Additional language and 
instructions added for Cohorts 
C1,C2, and D3
Language added to provide 
details on Cohorts C1 and C2 
enrollment and randomization; 
Instructions added to confirm 
Cohort D3 patients are not 
eligible for any approved IO 
therapeutic drug treatment
Section 4.3 Justification for 
Dose
Addition of language for dose 
justification for Cohort A1
Clarification
Section 5.1 Inclusion 
Criteria
Revised criterion 2a, 2b
Language revised to remove 
redundancy and clarify 
requirements
Section 5.1 Inclusion 
Criteria
Added requirement for recovery 
from radiation toxicities
Language added to clarify 
requirements
Section 6.1 Study 
Intervention(s) 
Administered
Added source for determining 
infusion duration and order of 
administration
Information was missing and 
needed clarification
Section 6.5 Concomitant 
Therapy
Hormone therapy added to list 
of prohibited on-study therapies
Hormone therapy will not be 
permitted on study
Section 6.5 Concomitant 
Therapy
Revised language surrounding 
concomitant medication 
recording
Language revised for accuracy
Section 6.6 Dose 
Modification
Removal of language regarding 
resuming study treatment; 
revision of IRR management 
table
Clarification; management table 
revised to align with 
pembrolizumab language
Section 7.1 Discontinuation 
of Study Intervention
Clarified continuing treatment 
criteria and included need for 
new ICF if continuing treatment
Language revised for accuracy
Section 8.1.1 iRECIST for 
Immune-Based Therapies
Added upper limit to 
progression by iRECIST time 
window
Clarification
Section 8.2.1.1 
Immunogenicity 
Assessment
Clarified that additional blood 
and urine samples will be 
collected in the event of drug 
hypersensitivity reactions
Clarification


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
4
Section # and Name
Description of Change
Brief Rationale
Section 8.3.7 Events of 
Clinical Interest
Added section defining which 
events will be monitored
Based on regulatory feedback
Section 8.8 Biomarkers
Added whole blood would also 
be collected
Editorial error
Section 8.8.1 Tumor Tissue 
Samples for Detection of 
TILs
Clarifying statement on testing 
added
Clarified that TIL testing does 
not replace any companion 
diagnostic testing required for 
IO therapy eligibility 
determination
Section 9.4.1 General 
Statistical Considerations
Revised description of analysis 
set for efficacy and safety 
analyses
Language revised for clarity
Section 10.2 Appendix 2: 
Clinical Laboratory Tests
Removed duplicated direct 
bilirubin test; added T3 and free 
T3 test; changed FT4 to T4; 
footnotes revised
Editorial error; tests added per 
regulatory feedback; footnotes 
revised for clarity
Throughout protocol
Minor formatting and editorial 
changes
Minor, therefore not detailed


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
5
Table of Contents
1.
Protocol Summary......................................................................................................9
1.1.
Synopsis.......................................................................................................................9
1.2.
Schema.......................................................................................................................13
1.2.1.
Phase 1a:  Dose Escalation Schema ............................................................................13
1.2.2.
Phase 1b:  Dose Expansion Schema............................................................................14
1.3.
Schedule of Activities (SoA) ......................................................................................15
1.3.1.
Sampling Schedules for Pharmacokinetics and Biomarkers and 
Safety.........................................................................................................................25
2.
Introduction..............................................................................................................30
2.1.
Study Rationale ..........................................................................................................30
2.2.
Background ................................................................................................................32
2.3.
Benefit/Risk Assessment ............................................................................................33
3.
Objectives and Endpoints.........................................................................................34
4.
Study Design .............................................................................................................36
4.1.
Overall Design............................................................................................................36
4.1.1.
Dose Escalation Phase ................................................................................................36
4.1.2.
Dose Expansion Phase................................................................................................41
4.2.
Scientific Rationale for Study Design .........................................................................41
4.3.
Justification for Dose..................................................................................................41
4.4.
End of Study Definition..............................................................................................45
5.
Study Population ......................................................................................................46
5.1.
Inclusion Criteria........................................................................................................46
5.2.
Exclusion Criteria.......................................................................................................49
5.3.
Lifestyle Considerations .............................................................................................51
5.4.
Screen Failures...........................................................................................................52
6.
Study Intervention....................................................................................................53
6.1.
Study Intervention(s) Administered ............................................................................53
6.2.
Preparation/Handling/Storage/Accountability.............................................................54
6.3.
Measures to Minimize Bias:  Randomization and Blinding .........................................55
6.4.
Study Intervention Compliance...................................................................................55


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
6
6.5.
Concomitant Therapy .................................................................................................55
6.5.1.
Palliative Medicine and Supportive Care ....................................................................56
6.6.
Dose Modification......................................................................................................57
6.6.1.
Dose Modification and Toxicity Management for Immune-
Related AEs Associated with LY3435151, Pembrolizumab, or 
Combination Therapy .................................................................................................59
6.6.2.
Dose Modification of Pembrolizumab.........................................................................63
6.6.3.
Other allowed dose interruption for pembrolizumab ...................................................63
6.7.
Intervention after the End of the Study........................................................................64
6.7.1.
Treatment after Study Completion ..............................................................................64
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................65
7.1.
Discontinuation of Study Intervention ........................................................................65
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................66
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................66
7.3.
Lost to Follow-Up ......................................................................................................67
8.
Study Assessments and Procedures .........................................................................68
8.1.
Efficacy Assessments .................................................................................................68
8.1.1.
iRECIST for Immune-Based Therapies.......................................................................69
8.1.2.
Criteria Required to Receive Treatment during Confirmatory 
Scan Period.................................................................................................................71
8.2.
Safety Assessments ....................................................................................................71
8.2.1.
Clinical Safety Laboratory Assessments .....................................................................72
8.3.
Adverse Events and Serious Adverse Events ..............................................................74
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................76
8.3.2.
Follow-up of AEs and SAEs.......................................................................................76
8.3.3.
Regulatory Reporting Requirements for SAEs............................................................77
8.3.4.
Pregnancy...................................................................................................................77
8.3.5.
Cardiovascular and Death Events................................................................................77
8.3.6.
Complaint Handling ...................................................................................................77
8.3.7.
Events of Clinical Interest...........................................................................................78
8.4.
Treatment of Overdose ...............................................................................................78
8.5.
Pharmacokinetics........................................................................................................78


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
7
8.6.
Pharmacodynamics.....................................................................................................79
8.7.
Genetics .....................................................................................................................79
8.7.1.
Whole Blood Sample for Pharmacogenetic Research..................................................79
8.8.
Biomarkers.................................................................................................................79
8.8.1.
Tumor Tissue Samples for Detection of TILs..............................................................81
8.9.
Medical Resource Utilization and Health Economics..................................................82
9.
Statistical Considerations.........................................................................................83
9.1.
Statistical Hypotheses.................................................................................................83
9.2.
Sample Size Determination.........................................................................................83
9.3.
Populations for Analyses ............................................................................................84
9.4.
Statistical Analyses.....................................................................................................84
9.4.1.
General Statistical Considerations...............................................................................84
9.4.2.
Treatment Group Comparability .................................................................................85
9.4.3.
Efficacy Analyses.......................................................................................................85
9.4.4.
Safety Analyses ..........................................................................................................88
9.4.5.
Pharmacokinetic/Pharmacodynamic Analyses ............................................................88
9.4.6.
Evaluation of Immunogenicity....................................................................................88
9.4.7.
Other Analyses ...........................................................................................................89
9.5.
Interim Analyses.........................................................................................................89
10.
Supporting Documentation and Operational Considerations ................................90
10.1.
Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................90
10.1.1.
Regulatory and Ethical Considerations........................................................................90
10.1.2.
Informed Consent Process ..........................................................................................90
10.1.3.
Data Protection...........................................................................................................91
10.1.4.
Dissemination of Clinical Study Data .........................................................................91
10.1.5.
Data Quality Assurance ..............................................................................................91
10.1.6.
Source Documents......................................................................................................92
10.1.7.
Study and Site Closure................................................................................................92
10.2.
Appendix 2:  Clinical Laboratory Tests.......................................................................94
10.3.
Appendix 3:  Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................97


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
8
10.4.
Appendix 4:  Liver Safety:  Suggested Actions and Follow-up 
Assessments .............................................................................................................100
10.5.
Appendix 5:  Creatinine Clearance Formula..............................................................101
10.6.
Appendix 6:  Dose-Finding Algorithm of the Modified Toxicity 
Probability Interval Method Showing Number of Patients 
Treated .....................................................................................................................102
10.7.
Appendix 7:  Abbreviations ......................................................................................104
10.8.
Appendix 8:  Protocol Amendment History ..............................................................108
11.
References...............................................................................................................110


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
9
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Phase 1a/1b Study of LY3435151 Administered to Patients with Advanced 
Solid Tumors
Short Title: A Study of LY3435151 in Patients with Solid Tumors
Rationale:  Study J1Q-MC-JZIA (JZIA) is designed to investigate the safety and tolerability of 
LY3435151 when administered alone and in combination with pembrolizumab in patients with 
advanced cancers.
T cells play a central role in immune response to tumors.  However, tumors have adopted 
multiple mechanisms to evade host immune surveillance.  One of the key mechanisms is the up-
regulation of immune suppressive co-inhibitory molecules (immune checkpoint molecules) on 
the tumor cells. CD226 is a stimulatory receptor expressed by T cells that has been shown to 
play a critical role in the activation and differentiation of T cells leading to antitumor response in 
preclinical models. Upregulation of a high-affinity co-inhibitory receptor (TIGIT) on T cells in 
the tumor microenvironment can sequester the ligands on tumor cells (CD155 and CD112),
thereby leading to a reduced/loss of stimulatory signaling through the CD226 pathway. 
LY3435151 is a monoclonal antibody that is a CD226 agonist that potentially bypasses TIGIT 
suppression or tumor loss of CD226 ligands. Study JZIA will evaluate the impact of LY3435151 
on clinical response, and will assess multiple markers of T cell activation, expansion, and 
phenotypes in tumors to evaluate the impact of a CD226 agonist on tumor immunity.
Objectives and Endpoints
Objectives
Endpoints
Primary
Ph1a Dose Escalation (Part A & Part B):  
To assess the safety and tolerability of 
LY3435151, thereby identifying the RP2D,
administered as monotherapy and in 
combination with pembrolizumab, in patients 
with advanced solid tumors of the following 
types:  TNBC, gastric adenocarcinoma, 
HNSCC, squamous cervical carcinoma, high 
grade serous ovarian carcinoma, HCC, UPS, 
and LMS. 
DLTs
Safety (including, but not limited to):  
TEAEs, SAEs, deaths, and clinical 
laboratory abnormalities per CTCAE 
(version 5.0)


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
10
Objectives
Endpoints
Ph1b Dose Expansion (Part C & Part D):
To assess the safety and tolerability of 
LY3435151:
o
administered as monotherapy (Part C), 
must be PD-1/PD-L1 antagonist naïve:
C1:  TNBC (not eligible for IO therapies)
C2:  Gastric adenocarcinoma 
administered in combination with 
pembrolizumab (Part D), must be PD-
1/PD-L1 antagonist naive:
D1:  TNBC (not eligible for IO therapies)
D2:  Gastric adenocarcinoma 
D3:  TIL selected cohort with the 
following tumor types:  HNSCC, 
squamous cervical carcinoma, high grade 
serous ovarian carcinoma, HCC, UPS, 
and LMS.
Safety endpoints, including but not 
limited to the following:
o
TEAEs, SAEs
Clinical laboratory tests, vital signs, and 
physical examinations
Secondary
To assess the PK of LY3435151,
administered as monotherapy and in 
combination with pembrolizumab, in patients 
with solid tumors
Serum concentration of LY3435151
alone and when administered in 
combination with pembrolizumab
To document any antitumor activity per 
RECIST 1.1 observed with LY3435151,
when administered as monotherapy or in 
combination with pembrolizumab, in patients 
with solid tumors
ORR
DCR
DoR
TTR
PFS
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; DCR = disease control rate; DLT = 
dose-limiting toxicity; DoR = duration of response; HCC = hepatocellular carcinoma; HNSCC = head and neck 
squamous cell carcinoma; IO = immuno-oncology; LMS = leiomyosarcoma; ORR = overall response rate; PFS = 
progression-free survival; Ph = Phase; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid 
Tumors; RP2D = recommended phase 2 dose; SAE = serious adverse event; TEAE = treatment-emergent adverse 
event; TIL = tumor-infiltrating lymphocyte; TNBC = triple-negative breast cancer; TTR = time to response; UPS 
= undifferentiated pleomorphic sarcoma.
Overall Design:
Study JZIA is a Phase 1a/1b, multicenter, open-label dose-escalation study followed by a 
randomized dose-expansion study of LY3435151 as monotherapy and in combination with 
pembrolizumab in patients with the following cancers: triple-negative breast cancer (TNBC), 
gastric adenocarcinoma (including gastroesophageal junction adenocarcinoma), head and neck 


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
11
squamous cell carcinoma (HNSCC), squamous cervical carcinoma, high-grade serous ovarian
carcinoma, hepatocellular carcinoma (HCC), undifferentiated pleomorphic sarcoma (UPS), and 
leiomyosarcoma (LMS).
Disclosure Statement:  This is a sequential treatment study with 13 cohorts with no masking.
Number of Participants:
Approximately 170 patients with advanced solid tumors will be enrolled in this study.

Phase 1a:  Total enrollment will be determined by the incidence of dose-limiting toxicities 
(DLTs).
o
Monotherapy dose escalation (Part A): approximately 18 to 22 patients will be enrolled. 
An additional 12 patients in total may be enrolled at 2 selected dose levels to further 
inform safety, pharmacokinetics (PK), and pharmacodynamics (PD).
o
Combination dose escalation (Part B): approximately 6 to 8 patients will be enrolled.

Phase 1b:  Approximately 126 patients will be enrolled into Phase 1b in this study.
o
A randomization design will be applied to TNBC (C1 and D1) and gastric 
adenocarcinoma (including gastroesophageal junction) (C2 and D2) cohorts.  For each of 
the 2 tumor types:

Stage 1: approximately 16 patients will be initially enrolled and randomized with 1:1 
ratio to monotherapy dose expansion (Part C) or combination dose expansion (Part D)

Stage 2: additional approximately 32 patients will be enrolled to combination dose 
expansion (Part D). An interim data review will be performed based on safety, 
efficacy, and PK/PD data from the first 20 enrolled patients in combination dose 
expansion (including patients from both Stage 1 and Stage 2). 
o
Tumor-infiltrating lymphocyte (TIL) selected cohort with multiple tumor types in 
combination dose expansion (D3):  approximately 30 patients will be enrolled.
Intervention Groups and Duration:
Patients enrolled in this Phase 1a/1b study will receive LY3435151 monotherapy or in 
combination with pembrolizumab, as shown in the following table. The planned duration of 
treatment is not fixed; participants will remain on study until disease progression or unacceptable 
toxicity occurs; duration of pembrolizumab treatment will be fixed at up to 2 years. If 
participants are discontinued from pembrolizumab, they will be allowed to continue on 
LY3435151 treatment if receiving ongoing clinical benefit.  Likewise, if patients are 
discontinued from LY3435151 treatment, they will be allowed to continue on pembrolizumab if
receiving ongoing clinical benefit for up to 2 years.


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
12
Study Intervention Groups and Duration
Phase/Part 
Study Drug(s)
(Route of 
Administration)
Cohort / 
Dose Level 
Proposed
Doses 
Dose 
Schedule
Dose-
Escalation 
Phase
Monotherapy/ 
Part A
LY3435151 (IV)
A1: DL 1
10 mg
D1 of each 
21-day cycle 
(Q3W)
A2: DL2
30 mg
A3: DL 3 
100 mg
A4: DL 4
300 mg
A5: DL 5
900 mg
A6: DL 6 
1800 mg
Combination/ 
Part B
LY3435151 (IV)
B1: DL 1
TBD a,b
B2: DL 2 
TBD a
Pembrolizumab
(IV)
B1/B2
200 mg
Dose-
Expansion 
Phase
Monotherapy/
Part C
LY3435151 (IV)
C1/C2: 
Monotherapy 
RP2D
TBD a
Combination/ 
Part D
LY3435151 (IV)
D1/D2: 
Combination 
RP2D
TBD a
Pembrolizumab
(IV)
D1/D2 
200 mg
Abbreviations:  D = day; DL = dose level; IV = intravenous; RP2D = recommended phase 2 dose; Q3W = every 
3 weeks; TBD = to be determined.
a
Not to exceed maximum tolerated dose in dose escalation.
b
LY3435151 dosing in combination will be 1 dose level below the tolerated monotherapy dose level.
Data Monitoring Committee: No


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
13
1.2.
Schema
1.2.1.
Phase 1a:  Dose Escalation Schema
Abbreviations:  n = number of participants; RP2Dc = combination recommended Phase 2 dose; RP2Dm = monotherapy recommended Phase 2 dose; TBD = to 
be determined.
a
May include backfill participants as described in Section 4.1.1.
b
Refer to Section 9.5 for details of interim analyses.
c
LY3435151 dosing in combination will begin 1 dose level below the tolerated monotherapy dose level.


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
14
1.2.2.
Phase 1b:  Dose Expansion Schema
Abbreviations:  GC = gastric carcinoma; n = number of participants; IO = immuno-oncology; R = randomization; RP2Dc = combination recommended Phase 2 
dose; RP2Dm = monotherapy recommended Phase 2 dose; TIL = tumor-infiltrating lymphocyte; TNBC = triple negative breast cancer.
a
Refer to Section 9.5 for details of interim analyses.


CONFIDENTIAL
Protocol    J1Q-MC-JZIA(b)
LY3435151
15
1.3.
Schedule of Activities (SoA)
Schedule of Baseline Activities
Relative Day Prior to C1D1
≤28
≤14
≤7
Instructions
Procedure
Informed consent
X
ICF must be signed before any protocol-specific procedures are performed.
Inclusion/exclusion evaluation
X
Physical examination
X
Height/weight and vital signs
X
Vital signs include temperature, pulse rate, pulse oximetry, respiratory rate, and blood 
pressure.
ECOG performance status
X
Medical history
X
Including assessment of preexisting conditions, historical illnesses, substance usage (such 
as alcohol and tobacco), and other relevant habit assessments.
Cancer treatment history
X
Concomitant medication 
X
Record prior and concurrent medication/cancer treatments, includes 28 days prior to 
initiation of study treatments
AE collection / CTCAE grading
X
CTCAE version 5.0
Radiologic imaging
X
Baseline radiological tumor assessment per RECIST 1.1 should be done.  Radiologic 
assessments obtained previously as part of routine clinical care up to 28 days before 
treatment may be used as the baseline assessment. Baseline imaging should include at 
minimum chest/abdomen/pelvis while follow up scans can be focused on target region of 
interest. 
Tumor Biopsy
X
Mandatory pre-treatment biopsy. No intervening treatment between biopsy and study 
treatment initiation. See Section 8.8.
Archival tissue sample
X
An archival tumor sample may be requested if available and permitted by local regulations.  
See Section 8.8.
ECG
X
Single local ECG
ECHO
See Notes
Perform locally as clinically indicated to assess eligibility (optional) per exclusion criteria
14.j.i (See Section 5.2).
Hematology
X
See Appendix 2.
Coagulation
X
See Appendix 2.
Clinical Chemistry
X
See Appendix 2.
Urinalysis
X
See Appendix 2.
Serum pregnancy test
X
Applies to women of childbearing potential only.  See Appendix 2.


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Thyroid function
X
See Appendix 2.
Abbreviations:  AE = adverse event; C1D1 = Cycle 1 Day 1; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECHO = 
echocardiogram; ECOG = Eastern Cooperative Oncology Group; ICF = informed consent form; RECIST = Response Evaluation Criteria in Solid Tumors.


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Schedule of On-Treatment Activities
Procedure
All Treatment Periods (Cycle = 21 days)
Notes
Cycle 1
(± 3 days)
Cycle 2
(± 3 days)
Cycle 3-n
(± 3 days)
Relative Day within Dosing 
Cycle
1
8
15
1
8
15
1
Physical exam
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
Measure vital signs (weight, temperature, blood pressure, pulse 
rate, oxygen saturation, and respiration rate) as follows (±5 
minutes):

In Cycles 1 and 2:
o
Up to 15 minutes prior to each LY3435151 
infusion
o
Every 15 minutes during each LY3435151 
infusion
o
at the end of each LY3435151 infusion

A 4-hour observation period from the end of LY3435151 
administration will occur in Cycles 1 and 2.
o
every 30 (±5) minutes for the first hour and 60 
(±5) minutes thereafter during the 4-hour 
observation period

In Cycle 3 and beyond, if the patient has not 
experienced an infusion-related reaction or other 
infusion-related AE:
o
up to 15 minutes prior to each LY3435151 
infusion
o
at least once during each LY3435151 infusion
o
at the end of each LY3435151 infusion
ECOG performance status
X
X
X
Complete before treatment initiation.  May be completed up to 3 
days before the scheduled day.
PK sampling
See Section 1.3.1 for time points
Exploratory blood sample for 
biomarkers
See Section 1.3.1 for time points
Additional samples may be collected if clinically indicated.
ECG
See Section 1.3.1 for time points
Central triplicate ECGs.
ECHO
See Notes
Perform as clinically indicated


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Procedure
All Treatment Periods (Cycle = 21 days)
Notes
Cycle 1
(± 3 days)
Cycle 2
(± 3 days)
Cycle 3-n
(± 3 days)
Relative Day within Dosing 
Cycle
1
8
15
1
8
15
1
Whole blood 
pharmacogenomics
X
Collect once.  Sample can be collected at any time if not collected 
on C1D1.
Hematology
X
X
X
X
X
X
X
See Appendix 2.  If baseline laboratory tests were performed ≤3 
days prior to C1D1 and the results are deemed to be clinically valid 
by the investigator, laboratory tests do not need to be repeated on 
C1D1.  See Section 1.3.1 for additional time points in Cycle 1.
Clinical chemistry
X
X
X
X
X
X
X
See Appendix 2.  If baseline laboratory tests were performed ≤3 
days prior to C1D1 and the results are deemed to be clinically valid 
by the investigator, laboratory tests do not need to be repeated on 
C1D1.
Thyroid function
X
See Notes
Starting C2D1 and every other cycle thereafter (eg, C4D1, C6D1).  
See Appendix 2.
Urinalysis
X
X
X
See Appendix 2.  If baseline laboratory tests were performed ≤3 
days prior to C1D1 and the results are deemed to be clinically valid 
by the investigator, laboratory tests do not need to be repeated on 


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Procedure
All Treatment Periods (Cycle = 21 days)
Notes
Cycle 1
(± 3 days)
Cycle 2
(± 3 days)
Cycle 3-n
(± 3 days)
Relative Day within Dosing 
Cycle
1
8
15
1
8
15
1
C1D1.
Serum or urine pregnancy test
X
X
X
See Section 8.3.4 and Appendix 2.  If baseline laboratory tests were 
performed ≤3 days prior to C1D1 and the results are deemed to be 
clinically valid by the investigator, laboratory tests do not need to 
be repeated on C1D1.
Coagulation 
See Notes
Collect as clinically indicated
Stool sample
See Section 1.3.1
Refer to Section 1.3.1 for sample collection time points
Plasma sample
See Section 1.3.1
Refer to Section 1.3.1 for sample collection time points
On-treatment tumor biopsy
X
Mandatory on-treatment biopsy on C2D1 for all patients except 
during dose escalation Cohorts A1, A2, and A3.  See Section 8.8.
Optional tumor biopsy
See Notes
An optional tumor biopsy may be performed, if clinically feasible, 
after disease progression or at additional study time points, if 
warranted and agreed upon by the investigator and Lilly.
Radiologic imaging
See Notes
Scans will be performed and reviewed locally; done every 6 weeks 
± 7 days from Cycle 1 Day 1 for 36 weeks.  Afterwards, perform 
every 9 weeks ±7 days.  The same method of assessment and 
technique used at baseline should be used for each consecutive 
assessment thereafter.  RECIST 1.1/iRECIST should be used for all 
tumors.
AE Collection / CTCAE 
Grading
See Notes
CTCAE version 5.0.  Evaluated at each visit and continuously 
throughout study.  See Section 8.3 for more information about 
adverse events and adverse event collection.
Concomitant Medication 
Notation
See Notes
Evaluated at each visit and throughout study.  Refer to Section 6.5 
for more information about concomitant medications.
Administer LY3435151
X
X
X
Administer Q3W per Section 6.1.  May be administered up to 3 
days prior to scheduled visit.
Administer pembrolizumab
X
X
X
For Dose Escalation Part B and Dose Expansion Part D, administer 
Q3W per Section 6.1.  May be administered up to 3 days prior to 
scheduled visit.


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Abbreviations:  AE = adverse event; C = Cycle; CTCAE = Common Terminology Criteria for Adverse Events; D = Day; ECG = electrocardiogram; ECHO = 
echocardiogram; ECOG = Eastern Cooperative Oncology Group; iRECIST = immuno-Response Evaluation Criteria in Solid Tumors; PK = pharmacokinetic; 
RECIST = Response Evaluation Criteria in Solid Tumors; Q3W = every 3 weeks.


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Post-Treatment Follow-Up Schedule of Activities
Short-Term Follow-Upa
Long-Term 
Follow-Upb
Comments
Visit
801
802
803
804-X
Relative Day within 
Cycle
30-Day Follow-
Up ± 5 days
60-Day Follow-
Up ± 7 days
90-Day Follow-
Up ± 7 days
(90 ± 14 Days)
Physical exam
X
Vital signs
X
Including weight, temperature, pulse rate, pulse 
oximetry, blood pressure, respiratory rate
ECOG performance 
status
X
Radiologic imaging
X
X
Only for patients who discontinue study treatment 
without objectively measured progressive disease, 
continue to evaluate tumor response according to 
planned standard of care tumor assessment schedule until 
patient has objective disease progression or study
completion.  
Adverse events 
collection/CTCAE 
grading
X
X
CTCAE version 5.0.  Collect AEs for 30 days following 
cessation of study treatment and SAEs for 90 days or 30 
days following cessation of study treatment if the 
participant initiates new anticancer treatment, whichever 
comes first.
Note: All pregnancies and exposure during breastfeeding 
must be reported, from time of treatment through 120 
days following cessation of treatment, or 30 days 
following cessation of treatment.
Concomitant 
medication
X
All concomitant medications received up to 30 days after 
the last dose of study treatment should be recorded.  
Concomitant medications administered 30, 60, and 90 
days after the last dose of study treatment should be 
recorded for SAEs and events of clinical interest.
Optional tumor 
biopsy
X
An optional tumor biopsy may be performed, if clinically 
feasible, after disease progression or at additional study 
time points, if warranted and agreed upon by the 


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Short-Term Follow-Upa
Long-Term 
Follow-Upb
Comments
Visit
801
802
803
804-X
Relative Day within 
Cycle
30-Day Follow-
Up ± 5 days
60-Day Follow-
Up ± 7 days
90-Day Follow-
Up ± 7 days
(90 ± 14 Days)
investigator and Lilly.  
Hematology
X
See Appendix 2.
Clinical chemistry
X
See Appendix 2. 
Coagulation 
X
PT or INR and aPTT should be collected at the 
mandatory Safety Follow-Up Visit after discontinuation 
of study therapy.
Thyroid function
X
See Appendix 2.
Collection of post-
study-treatment 
anticancer therapy 
information
X
X
X
X
Discontinuation from study must occur prior to 
introduction of the new agent.
Collection of 
survival information
X
X
X
X
In-person office visits are not required; the site may 
confirm survival by contacting the patient directly via 
telephone or other means of communication (for 
example, email)
Serum or urine 
pregnancy test
X
X
X
See instructions
Perform pregnancy test for women of childbearing 
potential.  See Section 8.3.4 and Appendix 2.  Pregnancy 
test required at 120 days after study discontinuation per 
Section 8.3.4 or 30 days following cessation of study 
treatment if the participant initiates new anticancer 
therapy.
Abbreviations:  AE = adverse event; aPTT = activated partial thromboplastin time; CTCAE = Common Terminology Criteria for Adverse Events; ECOG = 
Eastern Cooperative Oncology Group; INR = international normalized ratio; PT = prothrombin time; SAE = serious adverse event.
a
Short-term follow-up begins when the patient and investigator agree that the patient will no longer continue study treatment.
b
Long-term follow-up begins when short-term follow-up period is completed and continues until death, study withdrawal, or the patient is lost to follow-up.  In 
all cases, no follow-up procedures, except for pregnancy follow-up, 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
Continued
Access 
Treatment
Continued Access Follow-up Visitsa
Visit
30-Day Follow-
Up
60-Day Follow-Up
90-Day Follow-Up
Notes
501-5XX
901
902
903
Procedure
AE collection
X
X
X
X
Per CTCAE version 5.0.  Collect AEs for 30 days 
following cessation of study treatment and SAEs for 90 
days or 30 days following cessation of study treatment if 
the participant initiates new anticancer treatment, 
whichever comes first.
As part of AE/SAE collection, monitor vital signs and 
perform standard laboratory tests (hematology, 
chemistry, urinalysis, and pregnancy testing) at the same 
frequency as the study treatment period.  All laboratory 
tests during the continued access period will be 
performed in the local laboratories only.
In the event of an IRR, blood samples will be collected 
for PK, IG, and exploratory hypersensitivity 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.  Exploratory 
hypersensitivity samples may be analyzed for markers of 
basophil/mast cell activation (eg, tryptase), immune 
complex formation (eg, C3 levels) and cytokine release 
(eg, IL-6) as appropriate for the clinical presentation.
Administer study 
intervention
X
See Section 6.1 for study intervention administration 
details and guidelines.


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Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; IG = immunoglobulin; IL = interleukin; IRR = infusion-
related reaction; PK = pharmacokinetics; SAE = serious adverse event.
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 30 days


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1.3.1.
Sampling Schedules for Pharmacokinetics and Biomarkers and Safety
Schedule for Phase 1a
Sampling Day
Time 
Relative to 
End of 
LY3435151 
Infusion
PK 
Collection
ECG
Serum
Cytokines and 
Exploratory 
Biomarkers
Whole 
blood 
for
Flow 
Profile
d
Immunogenicity 
Sample
Plasma 
Sample for 
Exploratory 
Biomarkers
Stool Sample 
for Microbiota 
Analysisg
Hematology 
CBC
(local 
testing)e
Baseline ≤7 days 
prior C1D1
X
X
X
Cycle 1 Day 1
predoseh
X
X c
X
X
X
Cycle 1 Day 1
1hr ± 15mn
X
X c
Cycle 1 Day 1
3hr ± 30mn
X
X
Cycle 1 Day 2
24hr ± 4hr
X
X c
X
X
Cycle 1 Day 4
72hr ± 24hr
X
X
X
Cycle 1 Day 8
168hr ± 
24hr
X
X
Cycle 1 Day 15
336hr ± 
24hr
X
Cycle 2 Day 1
predose h
X
X
X
X
Cycle 2 Day 1
1hr ± 15mn
X
X c
Cycle 2 Day 1
3hr ± 30mn
X
Cycle 3 Day 1
predoseh
X
X
X
X
X
X


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Sampling Day
Time 
Relative to 
End of 
LY3435151 
Infusion
PK 
Collection
ECG
Serum
Cytokines and 
Exploratory 
Biomarkers
Whole 
blood 
for
Flow 
Profile
d
Immunogenicity 
Sample
Plasma 
Sample for 
Exploratory 
Biomarkers
Stool Sample 
for Microbiota 
Analysisg
Hematology 
CBC
(local 
testing)e
Cycle 3 Day 1
1hr ± 15mn
X
X c
Cycle 4 Day 1
predoseh
X
Cycle 5-n Day 1
predoseh
X
See footnoteb
If IRR, at onset, 
resolution and 30 
days following 
IRRa
X
X
When/if any DLT 
or DLT equivalent 
occurs
X
EOTf
X
X
X
X
X
V801
X
X
X
X
V802
X
X
V803
X
X
X


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Abbreviations:  C = Cycle; CBC = complete blood count; D = Day; DLT = dose-limiting toxicity; ECG = electrocardiogram; EOT = end of treatment; hr = hours; 
IL = interleukin; IRR = infusion-related reaction; mn = minutes; PBMC = peripheral blood mononuclear cell; PK = pharmacokinetics; V = Visit.
a
Exploratory hypersensitivity immunogenicity and PK samples may be analyzed for markers of basophil/mast cell activation (eg, tryptase), immune complex 
formation (eg, C3 levels) and cytokine release (eg, IL-6) as appropriate for the clinical presentation.
b
Immunogenicity sample will be collected every fourth cycle from C1 (eg, C5D1, C9D1)
c
Central triplicate ECGs
d
Not applicable for Cohort A1
e
See Section 1.3 for more hematology sample time points.
f
End of Treatment (EOT) is the same as study treatment discontinuation, which happens when the subject and the investigator agree that the subject will no 
longer continue study treatment.
g may be collected ±3 days of scheduled time point
h predose samples should be collected prior to LY3435151 dosing and, if applicable, pembrolizumab dosing


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Schedule for Phase 1b
Sampling Day
Time 
Relative to 
End of 
Infusion
PK 
Collection
ECG
Serum Cytokines 
and Exploratory 
Biomarkers
Whole 
Blood 
for 
Flow 
Profile
Immunogenicity
Sample
Plasma 
Sample for 
Exploratory 
Biomarkers
Stool Sample for 
Microbiota Analysise
Baseline ≤ 7 days 
prior C1D1
X
X
X
Cycle 1 Day 1
predosef
X
X c
X
X
X
Cycle 1 Day 1
1hr ± 15mn
X
X c
Cycle 2 Day 1
predosef
X
X
X
X
Cycle 2 Day 1
1hr ± 15mn
X
X c
Cycle 3 Day 1
predosef
X
X
X
X
X
X
Cycle 3 Day 1
1hr ± 15mn
X
X c
Cycle 4 Day 1
predosef
X
X
Cycle 5-n Day 1
predosef
X
See footnote
b
If IRR, at onset, 
resolution, and 30 
days following 
IRRa
X
X
When/if any DLT 
equivalent occurs
X
EOTd
X
X
X
V801
X
X
X
X


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Sampling Day
Time 
Relative to 
End of 
Infusion
PK 
Collection
ECG
Serum Cytokines 
and Exploratory 
Biomarkers
Whole 
Blood 
for 
Flow 
Profile
Immunogenicity
Sample
Plasma 
Sample for 
Exploratory 
Biomarkers
Stool Sample for 
Microbiota Analysise
V802
X
X
V803
X
X
Abbreviations:  C = Cycle; D = Day; DLT = dose-limiting toxicity; ECG = electrocardiogram; EOT = end of treatment; hr = hours; IL = interleukin; IRR =
infusion-related reaction; mn = minutes; PBMC = peripheral blood mononuclear cell; PK = pharmacokinetics; V =Visit.
a
Exploratory hypersensitivity immunogenicity and PK samples may be analyzed for markers of basophil/mast cell activation (eg, tryptase), immune complex 
formation (eg, C3 levels) and cytokine release (eg, IL-6) as appropriate for the clinical presentation.
b
Immunogenicity sample will be collected every fourth cycle from C1 (eg, C5D1, C9D1)
c
Central triplicate ECGs
d
End of Treatment (EOT) is the same as study treatment discontinuation, which happens when the subject and the investigator agree that the subject will no 
longer continue study treatment.
e
may be collected ±3 days of scheduled time point
f
predose samples should be collected prior to LY3435151 dosing and, if applicable, pembrolizumab dosing


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2.
Introduction
2.1.
Study Rationale
Recent clinical success revealed the potential for potent antitumor activity in a variety of solid 
tumors by targeting T-lymphocyte inhibitory pathways using monoclonal antibodies that block 
inhibitory receptors on the surface of T cells.  The anti-cytotoxic T lymphocyte-associated 
antigen-4 (CTLA-4) antibody ipilimumab was approved by the US Food and Drug 
Administration (FDA) and the European Medicines Agency for the treatment of patients with 
advanced melanoma in 2011 (EMA 2019; FDA 2019). Blockade of the programmed cell death 
protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) pathway demonstrated durable 
responses in 30% to 35% of patients with advanced melanoma (Topalian et al. 2012; Hamid et 
al. 2013), which led to FDA approval of pembrolizumab and nivolumab in 2014 and European 
Commission approval of pembrolizumab in 2015.  Despite remarkable clinical activity of PD-
1/PD-L1 inhibitors demonstrated in several clinical studies in patients with a wide variety of 
malignancies, there are limitations to their efficacy and many patients do not respond to these 
therapies. For example, only 10-40% unselected patients of various solid tumors (including non-
small cell lung cancer, urothelial carcinoma, classic Hodgkin lymphoma, head and neck 
squamous cell carcinoma [HNSCC], renal cell carcinoma, Merkel cell carcinoma, hepatocellular 
carcinoma [HCC], and gastric carcinomas) show clinical response to anti-PD-1/PD-L1
monotherapy, and some initially responding patients eventually developed resistance and disease 
progression (Zou et al. 2016; Kim et al. 2017). 
During checkpoint blockade with anti-CTLA-4 and anti-PD-1/PD-L1 inhibitors, multiple other 
checkpoint inhibitors may become coordinately upregulated. The compensatory upregulation of 
these alternative checkpoint receptors, such as LAG-3, TIGIT, TIM-3, CD160, and VISTA axes, 
have been demonstrated in preclinical models (Syn et al. 2017) including head and neck cancer 
(Shayan et al. 2017), metastatic ovarian cancer (Huang et al. 2017), metastatic melanoma (Benci 
et al. 2016), lung adenocarcinoma (Koyama et al. 2016), and prostate cancer (Gao et al. 2017). 
This could be a result of interferon signaling and activation of various pathways in tumor-
infiltrating lymphocytes (TILs), which can negatively regulate T cell activity and eventually lead 
to treatment failure (Syn et al. 2017). Inhibition of these molecules alone or in combination may 
increase the frequency of objective responses and achieve efficacy in cancer types that have thus 
far been largely refractory to CTLA-4 and/or PD-1 blockade. Many clinical trials are currently 
underway to test antibodies against these inhibitory pathways, both as monotherapy and 
combination therapy strategies (Sharma et al. 2017).
CD226 is a co-stimulatory receptor, expressed on T, NK, platelets, DC, monocytes, and other 
immune cells. Ligands of CD226, PVR (CD155) and PVRL2 (CD112), are shared with the co-
inhibitory receptors TIGIT and CD96. Activation of CD226 leads to proliferation, 
differentiation and cytokine production in NK (innate) and T (adaptive) cells in primary human 
cells.  Anti-CD226 antagonist antibodies have shown to completely block the efficacy of 
anti-PD-L1 combination therapy in syngeneic mouse tumor models demonstrating the role of 
CD226 in antitumor immunity (Johnston et al. 2014).  We propose to include a combination of 
CD226 agonist with PD-1 antagonist (pembrolizumab) including subjects that are not eligible for 
approved therapy, including those with no PD-L1 expression as measured by 


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immunohistochemistry (IHC). The potential benefit could be induced by CD226 agonist 
modulation of the TIL state or changes to the tumor environment and PD-L1 expression to 
increase the likelihood of response to pembrolizumab that is not induced by pembrolizumab 
alone. This may be in addition to the predicted additive effect of CD226 agonist with PD-1 
antagonist in those patients that express PD-L1 and do not respond to pembrolizumab due to 
additional resistance mechanisms as discussed. 
Combinations of anti-TIGIT antibodies with a clinically validated checkpoint inhibitor such as 
PD-1 or PD-L1 antibodies are also being actively investigated for treatment of many other types 
of cancers as monotherapy and in combinations (Solomon and Garrido-Laguna 2018).
In addition, in order to appropriately select patients who are more likely to benefit from PD-1/L1 
inhibitors, various biomarkers have been investigated to predict clinical responses (Kim et al. 
2017), such as CD8+ T cells in the tumor microenvironment (Tumeh et al. 2014), high tumor 
mutational loads (Rizvi et al. 2015), neoantigen heterogeneity (McGranahan et al. 2016), and 
PD-L1 expression in the tumor microenvironment (Tumeh et al. 2014). Among these suggested 
biomarkers, PD-L1 expression in pretreatment tumor samples has been most extensively studied 
and confirmed to be correlated with better clinical outcome in various malignancies (Powles et 
al. 2014; Borghaei et al. 2015; Chow et al. 2016; Daud et al. 2016). Recently, TILs have become 
the focus of many studies. As reported in recent literature, increased levels of TILs in women 
receiving neoadjuvant chemotherapy were associated with increased complete response (CR) 
rate and survival benefit in both triple-negative breast cancer (TNBC) and human epidermal 
growth factor receptor 2 (HER2)-positive breast cancers (Denkert et al. 2017). In another study, 
researchers assessed TILs and PD-L1 expression as prescreening enrichment biomarkers to 
identify patients with better clinical benefit from checkpoint inhibitors. The response rate in 
patients with TILs ≥7% was 32% versus 9% in patients with TILs <7% (Fisher’s exact test 
p = 0.06) (Martin-Liberal et al. 2018). Therefore, quantifying TILs may help select patients for 
immunotherapy in early clinical trials from an otherwise unselected population (Teng et al. 
2015).
The predicted mechanism of action of LY3435151 suggests that it will primarily act within the 
tumor environment where TILs are inhibited as described above by either sequestration of 
CD226 ligand or loss of the ligand’s expression on tumor cells. While CD226 is frequently 
expressed on CD8+ TILs, not all tumors have TILs. As a result, TIL-negative tumors may not 
demonstrate a clinical response. The presence of TILs is therefore potentially essential for the 
drug effect in tumors. Based on this hypothesis, Study J1Q-MC-JZIA (JZIA) will:
1) Select solid tumors associated with TIL positivity.
2) Evaluate the presence of TILs prior to therapy to determine the impact of TIL 
presence and quantity on drug response. 
3) Limit treatment to patients that are found to have pre-existing TILs upon analysis of 
the pre-treatment biopsy (Cohort D3 only). 
The combined approach of selecting patients likely to have pre-existing TILs or using TIL 
selection based on pre-treatment biopsies will potentially increase the probability of observing a 
response in this study. 


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Study JZIA is a multicenter, open-label dose-escalation followed by a randomized dose-
expansion study designed to investigate the safety and tolerability of LY3435151 when 
administered as monotherapy and in combination with pembrolizumab for the treatment of
patients with advanced solid tumors associated with TIL positivity:

TNBC (Stanton et al. 2016)

Gastric adenocarcinoma (including gastroesophageal junction adenocarcinoma) (Steele et 
al. 2018)

HNSCC (Steele et al. 2018)

Squamous cervical carcinoma (Enwere et al. 2017)

High-grade serous ovarian carcinoma (Stumpf et al. 2009)

HCC (Xiao-Yan Cai et al. 2006)

Undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (LMS; Pollack et al. 
2017)
2.2.
Background
LY3435151 is a fully human immunoglobulin-G1 antibody with Fc effector-null mutations, 
targeting the CD226 receptor.  The activity of LY3435151 has been tested and confirmed in a 
variety of biological assays, including in vitro T cell functional assays.  In tumor models with 
humanized mice, LY3435151 has shown similar to superior antitumor efficacy compared to anti-
PD-L1 monotherapy.
The biological properties of antibody LY3435151 were characterized both in vitro and in vivo in 
nonclinical pharmacology studies, as described as follows:

Binds human and cynomolgus monkey CD226 proteins with similar affinity

Demonstrates no apparent binding to Fcreceptors or immune effector function 

Displays agonist functional activity and stimulates T cell activation in vitro 

Demonstrates no apparent platelet activation in vitro

Shows potent antitumor efficacy in humanized mouse models in vivo
As detailed in the Investigator’s Brochure (IB), overall preclinical safety data support the 
proposed LY3435151 starting dose and dose escalation design of Study JZIA.  Further details 
regarding the dosing rationale of LY3435151 for Study JZIA with supporting preclinical data 
may be found in Section 4.3.
Refer to the IB for detailed information pertaining to nonclinical efficacy, safety, and 
pharmacokinetics (PK).
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 
and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab
has high affinity and potent receptor blocking activity for PD-1. Pembrolizumab has an 
acceptable preclinical safety profile and is in clinical development as an intravenous (IV) 
immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated for the 
treatment of patients across a number of indications.  For more details on specific indications 


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refer to the IB.  Refer to the IB/approved labeling for detailed background information on MK-
3475.
Therapeutic studies in mouse models have shown that administration of antibodies blocking PD-
1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads to 
tumor rejection, either as a monotherapy or in combination with other treatment modalities 
(Strome et al. 2003; Blank et al. 2004; Hirano 2005; Curran 2010; Pilon et al.2010; Weber 2010; 
Spranger 2014).  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
acute myeloid leukemia and colorectal carcinoma (Strome et al. 2003; Zhang et al. 2004; Nomi 
et al. 2007; Curran et al. 2010; Pilon et al. 2010).  In such studies, tumor infiltration by CD8+ T 
cells and increased IFN-γ, granzyme B and perforin expression were observed, indicating that 
the mechanism underlying the antitumor activity of PD-1 checkpoint inhibition involved local 
infiltration and activation of effector T cell function in vivo (Curran 2010). Experiments have 
confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a monotherapy, as well as in 
combination with chemotherapy, in syngeneic mouse tumor models (see the IB).
2.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated adverse events (AEs) of LY3435151 are to be found in the IB.
Pembrolizumab is a PD-1 blocking antibody with global regulatory approvals in several 
indications (Keytruda USPI and SPC). The risk profile of pembrolizumab is well characterized, 
and the management of immune-related adverse events (irAEs) associated with pembrolizumab 
is part of national guidelines and clearly described in this protocol.
Section 2.1 provides the rationale for the expected benefit, supporting the investigation of
LY3435151 in combination with pembrolizumab. Pre-clinical data suggest that some of PD-1
signaling works through cross-talk with the CD226 signaling pathway. Therefore, the benefit of
combining CD226 agonist with PD-1 blockade may be stronger activation of tumor-specific
cytotoxic T-cells. This would potentially create better anti-tumor immune responses with
combination therapy compared to anti-PD-1 blockade alone. Likewise, the same mechanism has
the potential to make toxicities, such as irAEs, more frequent or more severe.


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary
Ph1a Dose Escalation (Part A & Part B):  
To assess the safety and tolerability of 
LY3435151, thereby identifying the RP2D, 
administered as monotherapy and in 
combination with pembrolizumab, in patients 
with advanced solid tumors of the following 
types: TNBC, gastric adenocarcinoma, 
HNSCC, squamous cervical carcinoma, high 
grade serous ovarian carcinoma, HCC, UPS, 
and LMS.
DLTs
Safety (including, but not limited to):  
TEAEs, SAEs, deaths, and clinical 
laboratory abnormalities per CTCAE 
(version 5.0)
Ph1b Dose Expansion (Part C & Part D):
To assess the safety and tolerability of 
LY3435151:
o
administered as monotherapy (Part C), all 
patients must be PD-1/PD-L1 antagonist 
naïve:
C1: TNBC(not eligible for IO therapies)
C2: gastric adenocarcinoma
o
administered in combination with 
pembrolizumab (Part D), all patients must 
be PD-1/PD-L1 antagonist naïve:
D1: TNBC (not eligible for IO therapies)
D2: Gastric adenocarcinoma
D3: TIL selected cohort with the 
following tumor types:  HNSCC, 
squamous cervical carcinoma, high grade 
serous ovarian carcinoma, HCC, UPS, 
and LMS. 
Safety endpoints, including but not 
limited to the following:
o
TEAEs, SAEs
Clinical laboratory tests, vital signs, and 
physical examinations


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Secondary

To assess the PK of LY3435151, 
administered as monotherapy and in 
combination with pembrolizumab, in 
patients with solid tumors

Serum concentration of LY3435151 
alone and when administered in 
combination with pembrolizumab

To document any antitumor activity per 
RECIST v1.1 observed with LY3435151, 
when administered as monotherapy or in 
combination with pembrolizumab, in 
patients with solid tumors

ORR

DCR

DoR

TTR

PFS
Tertiary/Exploratory

To assess the relationship between 
biomarkers, dose/exposure, and clinical 
outcomes, particularly in relation to tumor 
TIL levels

Results of biomarker assessments 

Clinical outcomes data

To document any antitumor activity per 
RECIST v1.1 observed with LY3435151 
when administered as monotherapy or in 
combination with pembrolizumab to patients 
with solid tumors associated with TIL 
positivity

OS

To document antitumor activity based on 
iRECIST observed with LY3435151 when 
administered as monotherapy or in 
combination with pembrolizumab to patients 
with solid tumors associated with high TIL 
positivity.

iORR

iPFS

iDoR
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; DCR = disease control rate; DLT = 
dose-limiting toxicity; DoR = duration of response; HCC = hepatocellular carcinoma; HNSCC = head and neck 
squamous cell carcinoma; iDoR = duration of response per iRECIST; IO = immuno-oncology; iORR = overall 
response rate per iRECIST; iPFS = progression-free survival per iRECIST; iRECIST= immuno-Response 
Criteria in Solid Tumors; LMS = leiomyosarcoma; ORR = overall response rate; OS = overall survival; Ph = 
Phase; PFS = progression-free survival; PK = pharmacokinetics; RECIST = Response Criteria in Solid Tumors; 
RP2D = recommended phase 2 dose; SAE = serious adverse event; TEAE = treatment-emergent adverse event; 
TIL = tumor-infiltrating lymphocyte; TNBC = triple-negative breast cancer; TTR = time to response; UPS = 
undifferentiated pleomorphic sarcoma.


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4.
Study Design
4.1.
Overall Design
Study JZIA is a Phase 1a/1b, multicenter, open-label dose-escalation study followed by a 
randomized dose-expansion study of LY3435151 as monotherapy and in combination with 
pembrolizumab in patients with advanced solid tumors.
Section 1.2.1 contains the study schema for Phase 1a and Section 1.2.2 contains the study 
schema for Phase 1b.
4.1.1.
Dose Escalation Phase
Phase 1a (dose escalation) will assess the safety and tolerability of LY3435151 to identify a 
monotherapy recommended phase 2 dose (RP2D) and a combination RP2D in patients with solid 
tumors associated with TIL positivity:

TNBC

Gastric adenocarcinoma (including gastroesophageal junction)

HNSCC

Squamous cervical carcinoma

High-grade serous ovarian carcinoma

HCC

UPS and LMS.
Patients enrolled in Part A (Cohorts A1 through A6) will receive LY3435151 monotherapy. 
Patients enrolled in Part B (Cohorts B1 and B2) will receive LY3435151 and pembrolizumab.
The RP2D will be determined based on the number of observed dose-limiting toxicities (DLTs) 
and PK/pharmacodynamic (PD) data, and may be below the maximum tolerated dose (MTD), 
which may not necessarily be reached during the dose escalations. The dose-escalation phase 
will employ a modified toxicity probability interval (mTPI-2) method and starting with Cohort 
A2 will enroll at least three evaluable patients per cohort. Treatment cycles will consist of 21 
days.  A 2-cycle DLT observation will apply to all cohorts in Phase 1a. Refer to Section 4.1.1.1
for additional details on the dose escalation method.
A minimum of 1 patient will be enrolled in Cohort A1 and will receive a 10-mg dose. If the 10-
mg dose level DLT period is cleared, Cohort A2 (30-mg dose level) will be initiated.
If a patient in Cohort A1 experiences a DLT, additional patients will be enrolled into Cohort A1 
following the mTPI-2 method. Based on the mTPI-2 method, at least additional 4 patients will 
need to be enrolled and experience no DLT during the DLT observing period before escalating to 
the next dose level (Cohort A2).
After the first patient in Cohort A2 receives the first dose of LY3435151, there will be a delay of 
1 week before the second patient receives LY3435151 to allow for safety observation.  In all 
subsequent cohorts, the first patient in each dose level will be observed for at least 24 hours 
before treatment of additional patients; no additional delays are required for subsequent patients.


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Patients in Cohorts A2, A3, A4, A5, and A6 will receive proposed doses of 30 mg, 100 mg, 
300 mg, 900 mg, and 1800 mg, respectively, provided safety is established in the preceding 
cohorts. Once the DLT period of 42 days is completed for respective dose levels within Cohorts 
A1 to A6, 2 selected cohorts can be expanded with an additional 6 patients each to further inform 
safety, PK, and PD. For example, additional patients at dose level 5 (900 mg Q3W) may be 
enrolled in parallel with Cohort A6 after Cohort A5 has cleared the DLT period.
In the Combination Dose Escalation (Part B), 2 dose levels will be explored. Dose level 1 in Part 
B will be decided based on, but not limited to, the safety and PK/PD data from monotherapy 
expansion cohorts. The dose of pembrolizumab will remain constant. Once enrollment to dose 
level 1 in Part B begins, dose escalation will occur in parallel for both Part A and Part B.
However, enrollment in a Part B cohort can begin only after all previous dose level cohorts in
monotherapy and combination dose escalation (as applicable) are complete, as determined by Eli 
Lilly and Company (Lilly). For example, if dose level 5 900 mg Q3W is decided as the starting 
dose level for Part B, Cohort B1 will only begin after the safety of dose level 6 in monotherapy
dose escalation is cleared, and Cohort B2 may begin only after both Cohort A6 and Cohort B1 
are complete.
If safety data from Part A indicate that de-escalation of the LY3435151 dose is warranted, no 
additional patients will be enrolled in Treatment Part A or Treatment Part B at dose levels higher 
than the de-escalated dose.
Lilly and the investigators will hold a meeting to review safety and available PK/PD results after 
completion of the DLT period for each cohort to ensure it is safe to continue with the next 
dose-escalation cohort.
4.1.1.1.
Dose Escalation Method
Dose escalation of LY3435151 will be driven by an mTPI-2 method taking into consideration 
available safety, PK, and PD data from previous dose levels for Cohorts A2 through A6.  A 
minimum of 3 evaluable patients will be enrolled in Cohorts A2 through A6.
Similar to the 3+3 design, the mTPI-2 method incorporates prespecified escalation rules.  
However, 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.
Following a discussion between the Lilly clinical research physician/clinical research scientist 
(CRP/CRS) and the investigators, a more conservative dose selection may be applied to the next 
cohort (for instance, if PK/PD 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 or be de-escalated to a lower level, or escalation may cease.  In the mTPI-
2, the cohort size is not fixed.  However, each cohort from Cohort A2 through A6 will contain a 
minimum of 3 evaluable 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.  If the dose 


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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 around the target toxicity rate.  For this study, the equivalence 
interval is elicited to be (25%, 35%), indicating that any values between 25% and 35% can be 
considered as accepted toxicity rates for MTD.  The final MTD will be the dose for which the 
estimated toxicity rate is the closest to the target toxicity rate of 30% and less than 35%.  The 
resulting mTPI-2 decision rules for any cohort size up to 20, and a hypothetical example for DLT 
determination after all patients complete DLT evaluations, are provided in Appendix 6.
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/PD results (for example, maximum 
concentration [Cmax], area under the concentration-time curve [AUC], PD results) will be used as 
secondary/supporting data for dose escalation.
Intermediate and/or higher dose schedules of administrations, as well as alternative schedules,
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.
4.1.1.2.
Dose-Limiting Toxicity Determination
A DLT is defined as any of the events listed in the table below if the event occurs during the 
DLT observation period (2 Cycles/42 days for Cohorts A1-A6 and B1-B2) in Phase 1a, and 
toxicity that is not clearly and directly related to the primary disease or another etiology.
Patients who experience a DLT in the DLT observation period will be discontinued from study 
treatment.
Dose-Limiting Toxicities of Study Treatment
Hematologic Toxicity

Grade 3 thrombocytopenia associated with clinically significant bleeding and /or requiring platelet 
transfusion or Grade 4 thrombocytopenia of any duration

Grade ≥3 febrile neutropenia and/or neutropenia requiring G-CSF

Grade 4 neutropenia lasting >7 days

Grade 3 anemia requiring a blood transfusion

Other Grade 4 toxicity lasting >7 days, excluding toxicities listed below and Grade 3 endocrine irAEs that 
can managed by steroids or hormone replacement therapy
Nonhematologic Toxicity – Nonlaboratory

Grade 4 AE (unless stated otherwise below)

Any Grade 3 colitis or noninfectious pneumonitis irrespective of duration

Any other Grade 3 AE, excluding toxicities listed below 

Grade ≥3 toxicity lasting >7 days despite optimal supportive care

Other Grade 2 irAE, excluding colitis or pneumonitis, that:


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o
does not downgrade to Grade 1 within 3 days after onset of the event despite optimal medical 
management including corticosteroid therapy, or
o
does not downgrade to Grade 1 or the patient’s baseline level within 14 days after onset of the event
Nonhematologic Toxicity – Laboratory/Investigations

Grade 3 or 4 laboratory value if:
o
Medical intervention or hospitalization is required to treat the patient, or
o
The abnormality persists for >7 days (excluding amylase and lipase)

ALT or AST:
o
>8 × ULN
o
≥2-fold above the patient’s baseline value that lasts >7 days, if the patient has HCC or liver 
metastasis and had ALT or AST >3.0 × ULN at baseline
o
≥3 × ULN with concomitant bilirubin >2 × ULN, in the absence of cholestasis

Total bilirubin >3 × ULN

Grade ≥3 amylase or lipase that is associated with symptoms or clinical manifestations of pancreatitis
Other Hematologic or Nonhematologic Toxicity

Grade 5 toxicity (that is, death)

Grade ≥3 electrolyte abnormality that lasts >72 hours unless the patient has clinical symptoms, in which case 
all Grade ≥3 electrolyte abnormality regardless of duration should count as a DLT.

Treatment delay of >14 days due to an adverse event during Cycle 1 or Cycle 2.

Toxicity deemed by the investigator and Lilly CRP/CRS to be dose-limiting, such as toxicity that is possibly 
related to study treatment and requires discontinuation of the patient from the study at any time during Cycle 
1 and 2.
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CRP/CRS = clinical research physician/clinical research scientist; DLT = dose-limiting toxicity; G-CSF = 
granulocyte colony-stimulating grown factor; HCC = hepatocellular carcinoma; irAE = immune-related adverse 
event; ULN = upper limit of normal. 
Potential DLTs that are AEs that are reasonably anticipated AEs for concomitant medication 
should be reviewed by the treating investigator and Lilly CRP/CRS before final determination as 
a DLT.  Review and discussion may include additional participating investigators.  Such review 
may determine that confounding factors render the case to be not evaluable for the purposes of 
dose selection.  Adverse events from such non-evaluable patients will also be reviewed 
throughout the dose escalation process in Phase 1a.
The definition excludes the following events:

Toxicity that is clearly and directly related to the primary disease or to another etiology is 
excluded from this definition
o
Immune-related Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal 
insufficiency) that is managed with or without systemic corticosteroid therapy and/or 
hormone replacement therapy and the patient is asymptomatic


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
Grade 3 inflammatory reaction attributed to a local antitumor response (such as inflammatory 
reaction in the lymph nodes or at sites of metastatic disease)

Any grade vitiligo or alopecia

First occurrence of Grade 3 infusion-related reaction (IRR) during infusion of LY3435151, if 
all of the following criteria are met:
o
the patient did not receive corticosteroid prophylaxis,
o
the Grade 3 IRR resolves within 6 hours with appropriate clinical management, and
o
if symptoms reappear, the event would be considered a DLT

Grade 3 or 4 neutropenia meeting both of the following criteria:
o
is not associated with fever or systemic infection, and
o
improves by at least 1 grade within 7 days

Grade 3 or 4 lymphopenia

Grade 3 nausea or vomiting < 72 hours with adequate antiemetic and other supportive care

Grade 3 fatigue < 1 week

≥ Grade 3 electrolyte abnormality that lasts <72 hours, is not clinically complicated, and 
resolves spontaneously or responds to conventional medical interventions

≥ Grade 3 amylase or lipase that is not associated with symptoms or clinical manifestations 
of pancreatitis
It should be recognized that, for patients who have received prior immune therapy, including 
checkpoint inhibitor therapy, there is the potential for delayed manifestation of serious immune-
related adverse events (irAEs) such as colitis, hepatitis, pneumonitis, and endocrinopathies.  
Patients manifesting potential delayed irAEs should receive prompt evaluation and treatment.
4.1.1.3.
DLT-Equivalent Toxicities
A DLT-equivalent toxicity (ET) is an AE that meets the DLT criteria as defined above and 
occurs in any cycle other than the DLT assessment period for cohorts in Phase 1a (42 days for 
Cohorts A1-A6 and B1-B2) and occurs in any cycle for cohorts in Phase 1b.  In addition to the 
DLT assessment period, available safety data beyond the DLT assessment period may also be 
taken into consideration prior to a decision to advance to the next dose level or the determination 
of the RP2D.
For individuals experiencing a DLT-ET, dose modifications can be made as outlined in Section 
6.6. If cumulative incidence of DLT-ET is 30% at any point during study, re-evaluation of dose 
will occur.
4.1.1.4.
Determination of Recommended Phase 2 Dose
The RP2D will be chosen following discussion between the Lilly CRP/CRS and the investigators 
based on consideration of the totality of the data during interim analyses and upon completion of 


C O N FI D E N TI A L
Pr ot oc ol     J 1 Q-M C -J ZI A( b)
L Y 3 4 3 5 1 5 1
4 1
P hase 1 a ( n ot i ncl usi ve of t he bac kfill c o h orts) , incl u di n g b ut n ot li mite d t o L Y 3 4 3 5 1 5 1 d ose 
a djust m e nts, A Es, c hr o nic i nt olera nce, P K/P D data, a n d i r A Es. All a vaila ble data will be use d 
i ncl u di n g A Es i n t he s h ort ter m ( 9 0 da y) foll o w -u p peri o d. If L Y 3 4 3 5 1 5 1 has a n acce pta ble 
cli nical safet y pr ofile a n d s h o ws s ufficie nt acti vit y,  a d ditio n al  st u dies a n d/ or c o h orts ma y be 
a d de d t o deter mi ne a safe d ose al o ne or i n c o m bi nati o n wit h ot her a ntica ncer t hera pies.  T u m or -
i nfiltrati n g l y m p h oc yt e level a n d ot her bi o mar kers will b e e val uate d a n d ma y infl ue nce 
e nric h me nt strate gies f or s u bse q ue nt st u dies a n d/ or c o h orts.
4. 1. 2.
D ose E x p a nsi o n P h ase
F or b ot h Part A a n d Part B, after all patie nts i n t he d ose- escalat i on p hase ha ve c o m p lete d t he 
D L T o bser vat i on p eri o d or di sc o nti n ue d, a n i nterim safety a n d P K/ P D a nal ysis will be c o n d ucte d 
bef ore o pe ni n g t he d ose e x pa nsi o ns.  M o n ot hera p y C o h orts ( C 1 a n d C 2) ca n start accr ui n g 
pati e nts as s o o n as t he Part A R P 2 D m decisi o n has bee n ma de.
I n t he d ose e x pa nsi on p hase 1 b , a 2- sta ge desi g n wi t h ra n d omizat i on will be i m ple me nte d t o 
deter mi ne t he treat me nt f or patie nts wit h i m m u ne-o nc ol o g y  (I O) naï ve T N B C a n d gastric 
a de n ocarci n o ma . Wit hi n eac h t u mor t y pe of  I O naï ve T N B C a n d g astric i n t he d ose e x pa nsi o n 
p hase , Sta ge 1 will e nr o ll 1 6 pat ien ts t o be ra n d o mize d wit h 1: 1 rati o t o recei ve eit her 
L Y 3 4 3 5 1 5 1 m o n ot hera p y ( C o h ort C 1 or C 2) or L Y 3 4 3 5 1 5 1 a n d pe m br o liz u ma b c o m bi nati o n 
t hera p y ( C o h ort D 1 or D 2). Ra n d o mizat i on will be gi n after t he R P 2 D c has bee n selecte d a n d 
c o nti n ue o nl y u ntil 8 p atie nt s ha ve accr ue d i nt o t he C 1 a n d C 2 c o h orts.  At Sta ge 2 , 
ap pr o xi matel y  a n ot her 3 2 patie nts i n eac h t u m or t y pe (t o a t otal of at least 4 0 patie nts) will be 
e nr o lle d t o recei ve L Y 3 4 3 5 1 5 1 i n c o m bi nati on wi t h pe m br o liz u ma b ( C o h ort D 1 or D 2). A n 
i nteri m data re vie w will be perf or me d base d o n safet y, efficac y, a n d P K/ P D data fr o m t he first 
2 0 e nr olle d pat ient s i n c o m bi nati on d ose e x pa nsi o n (i ncl u di n g patie nts fr o m b ot h Sta ge 1 a n d 
Sta ge 2) f or eac h t u mor t y p es of  I O naï ve T N B C a n d gastri c a de n ocarci n o ma .
A p pr o x i matel y 3 0 pat ient s wit h ot her I O naï ve t um o r t yp es will be selecte d f or e nr oll me nt base d 
o n TI L p osit i vity a n d will recei ve L Y 3 4 3 5 1 5 1 i n c o m bi nat i on wi t h pe m br o liz u ma b ( C o h ort D 3).
P ati e nts i n t his c o h ort s h o ul d be teste d f or all bi o mar kers or c o m pa ni o n di a g n ost ic tests re q uire d
t o c o nfir m t hat t he patie nt is n ot eli gi ble f or a n y a p pr o ve d I O t hera pe utic dr u g treat me nt pri or t o 
bei n g scree ne d f or eli gi bilit y t o recei ve L Y 3 4 3 5 1 5 1 i n c o m bi nat i on wi t h pe m br oliz u ma b base d 
o n TI L p osit i vity.
4. 2.
Scie ntific R ati o n al e f or St u d y Desi g n
T he o verall rati o nale f or t he st u d y  desi g n is descri be d i n t he I ntr o d ucti o n secti on u n der St u d y  
Rati o nale ( Sect i on 2. 1) a n d i n t he Statistical C o nsi derati o ns sectio n ( Sectio n 9).  D ose sel ect i on 
details ca n be f o u n d bel o w.
C CI


C O N FI D E N TI A L
Pr ot oc ol     J 1 Q-M C -J ZI A( b)
L Y 3 4 3 5 1 5 1
4 2
C CI


C O N FI D E N TI A L
Pr ot oc ol     J 1 Q-M C -J ZI A( b)
L Y 3 4 3 5 1 5 1
4 3
C CI


C O N FI D E N TI A L
Pr ot oc ol     J 1 Q-M C -J ZI A( b)
L Y 3 4 3 5 1 5 1
4 4
C CI


C O N FI D E N TI A L
Pr ot oc ol     J 1 Q-M C -J ZI A( b)
L Y 3 4 3 5 1 5 1
4 5
4. 4.
E n d of St u d y Defi niti o n
T he e n d o f t he st u d y is defi ne d as t he date of t he last visit of t he last partici pa nt i n t he st u d y or 
last sc he d ule d pr oce d ure s h o w n i n t he Sc he d ule of Acti vities ( S o A) f or t he last partici pa nt i n t he 
trial glo b ally.
C CI


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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Are, at the time of screening, 18 years old or of an acceptable age to provide 
informed consent according to local regulations, whichever is older.
Type of Participant and Disease Characteristics
2. Participants who have histological or cytological evidence of a diagnosis of a solid 
tumor that is advanced and/or metastatic.
a.
Part A and B Dose-Escalation Phase:  

The patient must have histological or cytologically proven TNBC, gastric 
adenocarcinoma (including gastroesophageal junction), HNSCC, cervical 
carcinoma, high-grade serous ovarian carcinoma, HCC, UPS, or LMS.

The patient must be, in the judgment of the investigator, an appropriate 
candidate for experimental therapy and should have progressed through or is 
intolerant to therapies known to confer clinical benefit (including prior IO 
therapies). 
b. Part C (1 and 2) and Part D Expansion Phase (IO naïve TNBC and gastric 
carcinoma):  

The patient must be, in the judgment of the investigator, an appropriate 
candidate for experimental therapy and should have progressed through or is 
intolerant to therapies known to confer clinical benefit (including IO 
therapies). 

Patients with a cancer that is eligible for IO therapy based on a companion 
diagnostic test must have testing performed and be determined to be not 
eligible.

Gastric carcinoma patients who are microsatellite instability-high or Epstein-
Barr Virus-positive will be excluded
o
Gastric carcinoma patients that have HER2 amplification should 
have received prior anti-HER2 therapy.

All patients must be PD-1/PD-L1 antagonist naïve.  Patients that were not 
eligible for pembrolizumab based on PD-L1 expression status will be eligible 
for inclusion as discussed in Section 2.1. 

Patients must have histological or cytologically proven:
i.
Cohort C1 and D1:  recurrent/metastatic, unresectable TNBC and not 
eligible for approved IO therapies.
ii.
Cohort C2 and D2:  recurrent/metastatic, unresectable gastric 
adenocarcinoma (including gastroesophageal junction)


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iii.
Cohort D3:  recurrent/metastatic, unresectable HNSCC, squamous 
cervical carcinoma, high-grade serous ovarian carcinoma, HCC, UPS, 
or LMS, that are associated with TIL positivity.
Screening for TILs is required (threshold to be determined 
by the sponsor).
3. Have at least 1 measurable lesion assessable using standard techniques by Response 
Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 (Eisenhauer et al. 2009).  
Use of positron emission tomography scans and ultrasounds for diagnostic purposes 
is not permitted.
4. Are able and willing to provide the protocol required biopsies from a newly obtained 
core, endoscopic, or excisional pre-treatment biopsy of a tumor lesion and a newly 
obtained core, endoscopic, or excisional biopsy collected during the study treatment 
period (see Section 8.8).
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(Oken et al. 1982).
6. Have discontinued all previous treatments for cancer for at least 14 days and
recovered from the acute effects of therapy.  Patients must have discontinued from 
previous treatments, as shown below:
Previous Treatment
Length of Time Prior to First Dose of Study Treatment
Cytotoxic therapies or targeted agents that are 
small-molecule inhibitors
14 days
Mitomycin-C or nitrosoureas
≥42 days
Biologic agents (for example, antibodies such as 
anti-PD-1 or anti-PD-L1)
14 days
Radiotherapy
28 days if greater than 30% of bone marrow is irradiated 
or 7 days if less than 30% of bone marrow is irradiated.
Participants must have recovered from all radiation-related 
toxicities, not require corticosteroids, and not have had 
radiation pneumonitis.
Limited field radiotherapy for palliative intent
14 days
Major surgery, excluding biopsy
Patients with recent major surgery must have recovered, in 
the opinion of the investigator, from the toxicity and/or 
complications from the intervention before starting therapy.
Abbreviations:  PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1.
7. For Phase 1a, prior anti-PD-1 or anti-PD-L1 therapy or other immunotherapy is 
allowed as long as the following criteria are met:


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a.
did not experience a Grade 4 immune-related toxicity or any immune-related 
toxicity that led to permanent discontinuation of prior anti-PD-1, anti-PD-L1, or 
other immunotherapy
b. did not experience a less than or equal to Grade 3 irAE that has not recovered to 
Grade 1 after use of high-dose corticosteroids that occurred during prior 
immunotherapy
i.
Patients with an endocrine AE are permitted to enroll if they are stably 
maintained on appropriate replacement therapy and are asymptomatic
c.
did not experience any of the following irAEs during prior anti-PD-1, anti-PD-L1, 
or other immunotherapy:
i.
any grade ocular irAE
ii. serious neurologic irAE, Guillain-Barre, Myasthenia Gravis, encephalitis
iii. serious cardiovascular irAE, such as myocarditis
d. did not require immunosuppressive agents, other than corticosteroids for the 
management of an AE; or does not currently require maintenance doses of > to 
10 mg prednisone/prednisolone (or equivalent) per day for irAE
8. Have adequate organ function, as defined below:
System
Laboratory Value
Hematologic
ANC
1.5 × 109 cells/L
Platelets
150 × 109 cells/L
Hemoglobin
9 g/dL
PT/INR or aPTT 
1.5 × ULN
Hepatic
Total bilirubin
1.5 × ULN OR
<3.0 x ULN for patients who have Gilbert’s syndrome
ALT and AST
2.5 × ULN OR
5 × ULN if the liver has tumor involvement
Renal
Serum creatinine OR
Calculated creatinine clearance (see Appendix 5)
1.5 × ULN OR
50 mL/min
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; PT/INR = prothrombin time-international normalized 
ratio; ULN = upper limit of normal.


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9. Are able and willing to make themselves available for the duration of the study and 
are willing to follow study procedures.
10. Have an estimated life expectancy of ≥12 weeks, in the judgment of the investigator.
Sex
11. Men with partners of childbearing potential or women with childbearing potential 
(WOCBP) must agree to use a highly effective contraceptive method of birth control 
(Appendix 3) during study treatment and for at least 6 months following the last dose 
of study drug.
12. Women of childbearing potential must have a negative serum pregnancy test 
documented within 7 days prior to initiation of treatment (see Appendix 3).
Informed Consent
13. Have given written informed consent/assent prior to any study-specific procedures.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
14. Have a serious concomitant systemic disorder that, in the opinion of the investigator, 
would compromise the patient’s ability to adhere to the protocol, such as the 
following:
a.
human immunodeficiency virus (HIV)-positive patients (HIV 1 and/or 2; 
screening not required) are excluded unless they are well-controlled on highly 
active antiretroviral therapy with:
i. No evidence of acquired immunodeficiency syndrome-defining 
opportunistic infections within the last 2 years, and
ii. CD4 count > 350 cells/l
b. active or uncontrolled clinically relevant hepatitis B virus or hepatitis C virus 
infection. Patients with stable and chronic viral hepatitis are eligible. 
i. Not more than one of the following: viral hepatitis, nonalcoholic
steatohepatitis, and alcohol induced hepatitis.
c.
current or known history of tuberculosis
d. active infection requiring systemic therapy
e.
prior or second concurrent primary malignancies that, in the judgment of the 
investigator and the Lilly CRP/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 


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immunosuppressive agents.  Patients at risk of vascular AEs, such as those with a 
history of angiitis, arteritis, or hypersensitivity vasculitis as an AE to medication, 
for example, are not eligible
Note:  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, 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 exceeding 10 mg/day of prednisone or 
equivalent).  Use of topical, ophthalmic, inhaled, and intranasal corticosteroids is 
permitted
Note:  This criterion does not apply to patients with:  (i) controlled 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; (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 
electrocardiogram (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; 
recent myocardial infarction; or mean corrected QT interval [QTc] ≥470 ms 
calculated using Fridericia's correction and confirmed by triplicate ECG)
15. 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 currently receiving corticosteroids and/or anticonvulsants to treat 


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CNS metastases, and their disease is asymptomatic and radiographically stable for at 
least 30 days.
16. Have unresolved toxicities from prior anticancer therapy, including irAE, that have 
not resolved to the baseline levels prior to starting the prior anticancer therapy.
17. 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 are live attenuated 
vaccines and are not allowed.
18. Are pregnant, breastfeeding, or planning to become pregnant during the study or 
within 6 months of the last dose of study intervention. Plan to be breastfeeding from 
Cycle 1 Day 1 of study or within 6 months of the last dose of study intervention.
19. 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 
20. Have current or history of allergy or hypersensitivity to study drug components
21. Have previously received a CD226 agonist.
22. Have experienced a venous thromboembolic event (deep vein thrombosis 
[DVT]/pulmonary embolism [PE]) within 12 weeks of screening
23. Have a history of recurrent (≥2) venous thromboembolic event (DVT/PE).
24. Have a history of significant bleeding disorders or history of bleeding that required 
medical intervention to stop or prevent bleeding or known platelet dysfunction.
25. Require chronic granulocyte colony-stimulating factor (G-CSF) use to prevent 
neutropenia prior to Cycle 1 Day 1 of study.
26. For Parts B and D only: have severe hypersensitivity to pembrolizumab and/or any of 
its excipients.
27. Have had an allogenic tissue/solid organ transplant.
Prior/Concurrent Clinical Study Experience
28. Are currently 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
29. Have participated, within the last 30 days, in a clinical study involving an 
investigational product. If the previous investigational product has a long half-life, 
5 half-lives or 30 days, whichever is longer, should have passed
5.3.
Lifestyle Considerations
There are no specific lifestyle restrictions required by this study.


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5.4.
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical study 
but are not subsequently enrolled.  A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities.  
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Individuals may be rescreened up to 2 times.  The interval between rescreening 
should be ≥2 weeks.  Each time rescreening is performed, the individual and/or the individual’s 
legally acceptable representative, parent(s), or legal guardian (when applicable) must sign a new 
ICF and will be assigned a new identification number.  Repeating of laboratory tests during the 
screening period or repeating screening tests to comply with the protocol-designated screening 
period does not constitute rescreening.


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6.
Study Intervention
Study intervention is defined as any investigational intervention(s) or marketed product(s) 
intended to be administered to a study participant according to the study protocol.
6.1.
Study Intervention(s) Administered
All enrolled patients will receive LY3435151 administered as an IV infusion. Refer to the 
Pharmacy Manual for additional details regarding LY3435151 infusion duration.  For patients 
enrolled in a combination cohort (Phase 1a or Phase 1b, Part B or Part D), pembrolizumab will 
be administered as an IV infusion over approximately 30 minutes prior to the LY3435151 
infusion.
The table below shows the treatment regimens for Phase 1a/1b.  Doses will be administered at 
approximately the same times on each day.
Pembrolizumab will be administered using IV infusion on Day 1 of each 3-week treatment cycle 
after all procedures and assessments have been completed. LY3435151 will be administered 
30 to 60 minutes post administration of pembrolizumab.
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window between -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes (-5 min/+10 min).
Study Intervention Groups and Duration
Phase/Part 
Study Drug(s)
(Route of 
Administration)
Cohort / Dose 
Level 
Proposed
Doses 
Dose Schedule
Dose-
Escalation 
Phase
Monotherapy/
Part A
LY3435151 (IV)
A1: DL 1
10 mg
D1 of each 
21-day cycle 
(Q3W)
A2: DL2
30 mg
A3: DL 3
100 mg
A4: DL 4
300 mg
A5: DL 5
900 mg
A6: DL 6
1800 mg
Combination/ 
Part B
LY3435151 (IV)
B1: DL 1
TBD a,b
B2: DL 2 
TBD a
Pembrolizumab (IV)
B1/B2
200 mg


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Phase/Part 
Study Drug(s)
(Route of 
Administration)
Cohort / Dose 
Level 
Proposed
Doses 
Dose Schedule
Dose-
Expansion 
Phase
Monotherapy/
Part C
LY3435151 (IV)
C1/C2: 
Monotherapy 
RP2D
TBD a
D1 of each 
21-day cycle 
(Q3W)
Combination/ 
Part D
LY3435151 (IV)
D1/D2: 
Combination 
RP2D
TBD a
Pembrolizumab (IV)
D1/D2 
200 mg
Abbreviations:  D = Day; DL = dose level; IV = intravenous; RP2D = recommended phase 2 dose; Q3W = every 3 
weeks; TBD = to be determined.
a
Not to exceed maximum tolerated dose in dose escalation.
b
LY3435151 dosing in combination will be 1 dose level below the tolerated monotherapy dose level
The investigator or his/her designee is responsible for the following:
explaining the correct use of the drug(s) and the planned duration of each individual’s 
treatment to the patient and study site personnel
verifying that instructions are followed properly
maintaining accurate records of study drug dispensing and collection
at the end of the study, returning all unused medications to Lilly, or its designee, unless 
Lilly and sites have agreed all unused medications are to be destroyed by the site, as 
allowed by local law
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and that any discrepancies 
are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual.


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5. Investigators should consult the study drug information provided in the Pharmacy 
Manual or label for the specific administration information (including warnings, 
precautions, contraindications, adverse reactions, and dose modifications).
6.3.
Measures to Minimize Bias:  Randomization and Blinding
This is an open-label study. The Phase 1b dose expansion part will implement a randomization 
design to mitigate the selection bias in allocating patients with TNBC or gastric adenocarcinoma 
to either monotherapy dose expansion (Part C) or combination therapy dose expansion (Part D)
for the first 16 patients enrolled into the TNBC or into the gastric cohorts. 
6.4.
Study Intervention Compliance
Participant compliance with study intervention will be assessed at each visit. Study intervention 
is administered intravenously only at the investigational sites by the authorized study site 
personnel.  As a result, treatment compliance is ensured. Deviation(s) from the prescribed 
dosage regimen should be recorded in the electronic case report form (eCRF).
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins,
antibiotics, prebiotics, synbiotics, and/or herbal supplements) that the participant is receiving at 
the time of enrollment or receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.
The Lilly CRP/CRS should be contacted if there are any questions regarding concomitant or 
prior therapy.  No other chemotherapy, hormone therapy, immunotherapy, herbal supplements 
and/or herbal drugs intended to treat cancer, or experimental drugs will be permitted while the 
patients are in this study.
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required.  The investigator should discuss any questions regarding this with the Sponsor.  The 
final decision on any supportive therapy or vaccination rests with the investigator and/or the 
participant's primary physician.  However, the decision to continue the participant on study 
treatment requires the mutual agreement of the investigator, the Sponsor and the participant.
Listed below are specific restrictions for concomitant therapy or vaccination during the course of 
the study:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol


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
Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy 
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion. 

Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines are live attenuated 
vaccines and are not allowed. 

Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE 
that is suspected to have an immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.
Note: Inhaled steroids are allowed for management of asthma. 
Participants who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. 
All concomitant medications received within 28 days prior to the first dose of study treatment 
and up to 30 days after the last dose of study treatment should be recorded.  Concomitant 
medications administered 30, 60, and 90 days after the last dose of study treatment should be 
recorded for SAEs and events of clinical interest.
6.5.1.
Palliative Medicine and Supportive Care
The need for any form of radiotherapy (including palliative) in Cycles 1-2 will be cause for early 
discontinuation from the study. In Cycle 3 and beyond, palliative radiotherapy will be allowed if 
the parameters below are met.
Palliative radiation therapy is permitted after discussion with and agreement of the Lilly 
CRP/CRS or designee for irradiating small areas of painful metastases that cannot be managed 
adequately using systemic or local analgesics. Such areas must not be an identified target lesion 
and must not constitute progressive disease or meet RECIST/immuno-Response Evaluation 
Criteria in Solid Tumors (iRECIST) criteria for progressive disease. Any symptomatic 
deterioration or clinical disease progression requiring, in the opinion of the investigator, other 
forms of specific antitumor systemic therapy will be cause for discontinuation of study therapy.
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 


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premedications, supportive care, and concomitant medications must be captured on the case 
report form (CRF). Replacement hormonal therapy initiated before study entry will be allowed.
Patients should receive full supportive care. Hematopoietic growth factors (eg, G-CSFs) may be 
administered according to institutional guidelines and the local Package Insert, except in the 
DLT observation period.  Hematopoietic growth factors will be allowed in the DLT observation 
period if a patient experiences neutropenia that is declared an AE.  Administration of G-CSFs
prior to first occurrence of neutropenia is prohibited.  Blood product transfusions are permitted 
throughout the study.
Prophylactic antibiotic treatment should be consistent with American Society of Clinical 
Oncology (ASCO) guidelines (Flowers et al. 2013).
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) with adherence to 
the local Package Insert. All concomitant medications should be recorded throughout the 
patient’s participation in the study.
6.6.
Dose Modification
Dose reductions are not allowed in this study.
No dose modification for either LY3435151 or pembrolizumab (delays or omissions greater than 
14 days) is allowed during the DLT observation period (42 days for Cohorts A1-A6 and B1-B2).  
Starting at Cycle 3, dose delays will be permitted.  See Section 7 for discontinuation criteria.  
After the DLT observation period, doses of the LY3435151 or pembrolizumab may be delayed, 
omitted, or discontinued to manage specific AEs or other toxicities.  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 
treatments and apply the dose modification guidelines.  Investigators are encouraged to consult 
Lilly for additional guidance.
A cycle is defined as an interval of 21 days as shown in the SoA (Section 1.3).  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. 
Starting at Cycle 3, if a patient requires a cycle delay for any safety reasons other than those 
above, study treatment should be resumed within 21 days, if possible and appropriate.  In rare 
circumstances, a cycle delay of >21 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.  Longer delays may be allowed for irAEs, as 
described in Section 6.6.1. 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.  


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A 4-hour observation period from the end of LY3435151 administration will occur in Cycles 1 
and 2.  During the observation period, patients treated with LY3435151 should be closely 
monitored for signs and symptoms indicative of an IRR by medical staff from the start of the 
infusion, in an area where emergency medical resuscitation equipment and other agents (eg, 
epinephrine, prednisolone, or equivalents) are available.  LY3435151 IRRs will be defined 
according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 
definition of IRRs.
The table below presents instructions for management of infusion-related reactions associated 
with LY3435151, pembrolizumab, or combination therapy.
Management of Infusion-Related Reactions
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated

Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs.

Stop Infusion.

Additional appropriate medical therapy may 
include but is not limited to:

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics

Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator.

If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 
100 mL/hr. to 50 mL/hr.). Otherwise dosing 
will be held until symptoms resolve and the 
participant should be premedicated for the 
next scheduled dose.
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Participant may be 
premedicated 1.5 h (± 30 
minutes) prior to infusion of 
LY3435151 or 
pembrolizumab with:
Diphenhydramine 50 mg PO
(or equivalent dose of 
antihistamine).
Acetaminophen 500 to 1000 
mg PO (or equivalent dose of 
analgesic).


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Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilator 
support indicated

Stop Infusion.

Additional appropriate medical therapy may 
include but is not limited to:

Epinephrine**

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids

Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator.

Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used 
immediately.
Participant is permanently discontinued from further 
study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration. For further information, please refer to the CTCAE v5.0 at http://ctep.cancer.gov
If an IRR is clearly attributable to only one of the drugs, then the patient may continue to receive 
the other drug after consultation with the sponsor.
6.6.1.
Dose Modification and Toxicity Management for Immune-Related AEs 
Associated with LY3435151, Pembrolizumab, or Combination Therapy
An irAE may be defined as an AE consistent with an immune-mediated chronic inflammatory 
reaction associated with drug exposure.  These irAEs may occur shortly after the first dose or 
several months after the last dose of drug and may affect more than 1 body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data of immune checkpoint inhibitors, most 
irAEs are reversible and can be managed with interruptions of therapy, administration of 
corticosteroids, and/or other supportive care. For suspected irAEs, ensure adequate evaluation to 
confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, and skin biopsy may be included as part of the evaluation.  Based on the severity of 
irAEs, withhold or permanently discontinue therapy and administer corticosteroids. Dose 
modification and toxicity management guidelines for potential irAEs are provided in the 
following table. 


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Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Study Treatment 
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 
2.
Study treatment must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is 
not ≤10 mg/day within 12 weeks of the last pembrolizumab or LY3435151 treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If study treatment has been withheld, study treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper.


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irAEs
Toxicity grade 
(CTCAE V5.0)
Action with 
study treatment
Corticosteroid 
and/or other 
therapies 
Monitoring and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper

Add 
prophylactic 
antibiotics for 
opportunistic 
infections

Monitor participants 
for  signs and 
symptoms of 
pneumonitis

Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid 
treatment
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper

Monitor participants 
for signs and 
symptoms of 
enterocolitis (ie,
diarrhea, abdominal 
pain, blood or mucus 
in stool with or 
without fever) and of 
bowel perforation (ie, 
peritoneal signs and 
ileus)

Participants with 
≥Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing endoscopy 
to rule out colitis

Participants with 
diarrhea/colitis should 
be advised to drink 
liberal quantities of 
clear fluids. If 
sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted 
via IV infusion
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue


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AST or ALT 
elevation or 
Increased 
Bilirubin
Grade 2 a
Withhold

Administer 
corticosteroids 
(initial dose of 
0.5 - 1 mg/kg 
prednisone or 
equivalent) 
followed by 
taper

Monitor with liver 
function tests 
(consider weekly or 
more frequently until 
liver enzyme value 
returned to baseline or 
is stable)
Grade 3 b or 4 c
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d

Initiate insulin 
replacement 
therapy for 
participants 
with T1DM

Administer 
anti-
hyperglycemic 
in participants 
with 
hyperglycemia

Monitor participants 
for hyperglycemia or 
other signs and 
symptoms of diabetes
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated

Monitor for signs and 
symptoms of 
hypophysitis 
(including 
hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism 
Grade 2
Continue

Treat with non-
selective beta-
blockers (eg,
propranolol) or 
thionamides as 
appropriate

Monitor for signs and 
symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hypothyroidism
Grade 2, 3, 4
Continue

Initiate thyroid 
replacement 
hormones (eg,
levothyroxine 
or liothyronine) 
per standard of 
care

Monitor for signs and 
symptoms of thyroid 
disorders
Nephritis:
grading according 
to increased 
creatinine or 
acute kidney 
Grade 2
Withhold

Administer 
corticosteroids 
(prednisone 1 –
2 mg/kg or 
equivalent) 

Monitor changes of 
renal function
Grade 3 or 4
Permanently 
discontinue


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injury
followed by 
taper
Myocarditis
Grade 1 or 2
Withhold

Based on 
severity of AE 
administer 
corticosteroids

Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes
Grade 3 or 4
Permanently 
discontinue
All Other 
immune-related 
AEs
Persistent Grade 2
Withhold

Based on 
severity of AE 
administer 
corticosteroids

Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes
Grade 3
Withhold or 
discontinue 
based on the 
event e
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; 
bilirubin:>3.0 - 10.0 x ULN if baseline normal; >3.0 - 10.0 x baseline if baseline abnormal
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d The decision to withhold or permanently discontinue study treatment is at the discretion of the investigator or 
treating physician. If control achieved or ≤Grade 2, study treatment may be resumed.
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, 
Stevens-Johnson Syndrome and toxic epidermal necrolysis.
NOTE: The frequency or severity of known potential immune-related adverse events with 
pembrolizumab may be increased in combination with LY3435151.  Therefore, particularly close 
monitoring for irAEs should be standard.  For all irAEs of grade 2 or above, would consider 
specialist consultation and/or additional work-up including labs and biopsy to confirm diagnosis.  
For certain toxicities of more serious clinical consequence, such as myocarditis, neurologic, or 
ophthalmologic irAE, consider withholding therapy for grade 2 toxicities and early 
hospitalization for close monitoring for grade 3 toxicities.  For any grade 2 or greater suspected 
irAE, please consult with Lilly CRS/CRP.
6.6.2.
Dose Modification of Pembrolizumab
No dose reductions of pembrolizumab are permitted, but the dose may be withheld or 
discontinued for toxicity management. Guidelines for management of IRRs are located in 
Section 6.6 and for irAEs in Section 6.6.1.
6.6.3.
Other allowed dose interruption for pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record.


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6.7.
Intervention after the End of the Study
The end of study definition is provided in Section 4.4. Investigators will continue to follow the 
SoA (Section 1.3) until notified by Lilly that end of study has occurred. 
6.7.1.
Treatment after Study Completion 
Study completion will occur following the final analysis of primary and secondary objectives, as 
determined by Lilly.  Investigators will continue to follow the SoA (Section 1.3) for all patients 
until notified by Lilly that study completion has occurred.
6.7.1.1.
Continued Access
Participants who are still on study intervention at the time of study completion may continue to 
receive study intervention if they are experiencing clinical benefit and no undue risks. The 
continued access period will apply to this study only if at least 1 participant is still receiving 
study intervention 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.
The continued access period will begin after study completion and ends at End of Study.  The 
participant’s continued access to study treatment will end when a criterion for discontinuation is 
met (Section 7).  Continued access follow-up will begin when the participant and the investigator 
agree to discontinue study treatment.  Follow-up procedures will be performed as shown in the 
SoA (Section 1.3).
Participants who are in short-term follow-up when the continued access period begins will 
continue in short-term follow-up until the short-term follow-up visit is completed. Long-term 
follow-up does not apply.
Participants 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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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention 
Possible reasons leading to permanent discontinuation of investigational product:

Participant Decision
o
the participant or the participant’s designee (for example, parents or legal guardian)
requests to discontinue investigational product.
If a clinically significant finding is identified (including but not limited to changes from baseline 
in QTc using Fridericia’s formula after enrollment, the investigator or qualified designee will 
determine if the participant can continue in the study and if any change in participant 
management is needed. This review of the ECG printed at the time of collection must be 
documented. Any new clinically relevant finding should be reported as an AE.
In addition, participants will be discontinued from the investigational product in the following 
circumstances:

the patient becomes pregnant during the study

the patient is significantly noncompliant with study procedures and/or treatment

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 patient requires a dose delay of >21 days, excepted as described in Section 6.6.

disease progression.  Disease progression should be confirmed per iRECIST by the site 4 
to 8 weeks after site-assessed first radiologic evidence of progressive disease in clinically 
stable participants. Participants, who have unconfirmed disease progression (iPUD) may 
continue on treatment at the discretion of the investigator until progression per iRECIST 
criteria is confirmed by the site. Patients continuing treatment in these circumstances 
must provide additional informed consent to continue therapy.  A separate ICF will be 
created for this purpose.  Any participant deemed clinically unstable should be 
discontinued from study treatment at first radiologic evidence of progressive disease and
is not required to have repeat tumor imaging for confirmation of progressive disease by 
iRECIST.

unacceptable toxicity

the patient experiences a DLT or a DLT-equivalent toxicity

occurrence of a venous thromboembolic event (DVT/PE) during the study

the investigator decides that the patient should be discontinued from study treatment

the patient experiences any of the following abnormal hepatic parameters, with the 
exception of patients who have existing liver metastases and elevated liver enzymes 
(>2×ULN) at baseline:
o
ALT or AST >8×ULN
o
ALT or AST >5×ULN for more than 1 week


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o
ALT or AST >3×ULN and (TBL >2×ULN or INR >1.5)
o
ALT or AST >3×ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia

Pembrolizumab will be discontinued after completion of approximately 2 years of 
treatment with pembrolizumab (completion of 35 treatments with pembrolizumab)
Note: The number of treatments is calculated starting with the first dose of 
pembrolizumab in Study JZIA. 
Participants discontinuing from the investigational product prematurely for any reason should 
complete AE and other follow-up procedures per Section 1.3 (Schedule of Activities), Section
8.3 (Adverse Events and Serious Adverse Events), and Section 8.2 (Safety Assessments) of the 
protocol.
7.2.
Participant Discontinuation/Withdrawal from the Study
Participants will be discontinued in the following circumstances:  

enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study

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)

patient decision
o
the patient or the patient’s designee requests to be withdrawn from the 
study

the patient becomes pregnant during the study.  See Section 8.3 regarding 
regulatory reporting requirements on fetal outcome.
Participants discontinuing from the study prematurely for any reason should complete AE and 
other safety follow-up per Section 1.3 (Schedule of Activities), Section 8.3 (Adverse Events and 
Serious Adverse Events), and Section 8.2 (Safety Assessments).
Participants who withdraw their consent from the study and request to discard their genetic and 
biomarker samples will have their samples destroyed. Analysis results that are available before 
the consent withdrawal may be published in articles or other disclosures without an identifiable 
individual patient information. 
7.2.1.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the patient should be discontinued from study treatment unless 
there are extenuating circumstances that make it medically necessary for the patient to continue 
on study treatment.  If the investigator and the sponsor CRP/CRS agree it is medically 
appropriate to continue, the investigator must obtain documented approval from the sponsor 
CRP/CRS to allow the inadvertently enrolled participant to continue in the study with or without 


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treatment with investigational product. Safety follow up is as outlined in Section 1.3 (Schedule 
of Activities), Section 8.3 (Adverse Events and Serious Adverse Events), and Section 8.2 (Safety 
Assessments) of the protocol.
7.3.
Lost to Follow-Up
A participant 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.  Site personnel are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get investigational product.  Public sources may be searched for vital status 
information.  If vital status is determined, this will be documented and the participant will not be 
considered lost to follow-up.
Lilly personnel will not be involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Section
10.1.7.2. 


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8.
Study Assessments and Procedures

Unless otherwise stated in the subsections below, 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.

Study procedures and their timing are summarized in the SoA (Section 1.3).  Protocol
waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA
(Section 1.3), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Section 1.3).

Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1.
Efficacy Assessments
Tumor assessments will be performed for each patient at the times shown in the SoA (Section 
1.3).
Response Evaluation Criteria in Solid Tumors v1.1 (Eisenhauer et al. 2009) and iRECIST 
(Seymour et al. 2017) will be applied as the primary criteria for assessment of tumor response 
and date of tumor progression.  The method of tumor assessment used at baseline must be used 
consistently throughout the study.  Local tumor imaging (investigator assessment with site 
radiological reading) will be used.  See Section 8.1.1 for detailed information regarding iRECIST
for immune-based therapies.
Computed tomography (CT) scans, including spiral CT, are the preferred methods of 
measurement (CT scan thickness recommended to be ≤5 mm); however, magnetic resonance 
imaging is also acceptable in certain situations, such as when body scans are indicated or if there 
is a concern about radiation exposure associated with CT.  Intravenous and oral contrast are 
required unless medically contraindicated.
See Section 9.4.3 for definitions of the efficacy endpoints.


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8.1.1.
iRECIST for Immune-Based Therapies
Rationale of Using iRECIST after First Radiologic PD by RECIST 1.1
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy, including the following (Wolchock et al. 2009; Nishino et al. 2013):

Response to immunotherapy may be delayed.

Response to immunotherapy may occur after progressive disease by conventional criteria.

The appearance of new lesions may not represent progressive disease with 
immunotherapy.
Therefore, to adequately characterize additional patterns of response and progression specific to 
patients treated with immunotherapy, which cannot be captured using conventional criteria such 
as RECIST v1.1, alternative measures of tumor assessment have been developed.  The iRECIST 
standard was developed by the RECIST working group for the use of modified RECIST version 
1.1 in cancer immunotherapy trials (Seymour et al. 2017).
After initial disease progression defined by RECIST 1.1, iRECIST guidelines will be applied in 
the following tumor assessments. In iRECIST, any new lesions are categorized as measurable or 
non-measurable. Up to 5 lesions total (up to 2 per organ) can be selected as new lesion-target
(NL-T). All other new lesions will be followed as new lesion-non-target (NL-NT). The NL-T 
sum of diameters will be calculated and recorded separately from the sum of diameters for target 
lesions identified at baseline. 
Tumor response by iRECIST will be classified as confirmed progression (iCPD), or unconfirmed 
progression (iUPD), or stable disease or response (iSD/iPR/iCR) at all subsequent imaging. The 
initial tumor scan showing disease progression by RECIST 1.1 will be assigned as unconfirmed 
progression (iUPD) for overall response.
Progression is considered confirmed (iCPD), if the previous response status was iUPD and any 
of the following happens:
o
For target lesions: any further increase in the previously identified target lesion sum of 
diameters by 5mm or more after iUPD.
o
For non-target lesions: any further increase in the size of previously identified non-target 
lesion iUPD (the increase doesn’t need to meet RECIST 1.1 criteria for unequivocal 
progression)
o
For new lesions: 
o
an increase in the NL-T previously identified as iUPD and increase ≥5mm in sum 
of diameter OR
o
any increase for NL-NT OR
o
any appearance of additional new lesions
The overall response remains iUPD, IF


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o
target lesions were the cause of the initial iUPD AND
o
target lesions haven’t worsened, but they are still above PD threshold (20% increase 
from the nadir), AND
o
no above factors of iCPD occur. 
When progression is considered not unconfirmed, the overall response can become iSD/iPR/iCR 
instead of iUPD if any of the following criteria are met: 
o
iCR: Target lesions and non-target lesions have regressed completely AND no new 
lesions.
o
iPR: Target lesions have regressed to >=30% decrease from baseline (iCR or iPR) 
AND non-target lesions remain non-iCR/non-iUPD AND no new lesion
o
iSD: Target lesions have regressed to < 20% increase from nadir AND non-target 
lesions remain non-iCR/non-iUPD AND no new lesion.
Imaging and Treatment Guideline for Patients Who Have Radiologic Evidence of 
Progressive Disease by RECIST 1.1
If a patient is clinically stable at the first radiologic PD by RECIST 1.1, the patient should not be 
discontinued from the study until progression is confirmed no less than 4 weeks and no more 
than 8 weeks later by iRECIST.  The continuation of treatment after initial radiologic PD takes 
into consideration the observation that some patients may experience transient tumor flare or 
pseudoprogression with immunotherapy, but could have disease response later.  Patients who 
receive confirmatory imaging do not need to undergo the next scheduled tumor imaging if it is 
less than 4 weeks later; tumor assessment will resume at the next scheduled imaging time point, 
if clinically stable.  Patients will be discontinued from study treatment if disease progression is 
confirmed by iRECIST (Seymour et al. 2017).  
If a patient is clinically unstable, the patient should be discontinued from the study treatment at 
the first radiological PD by RECIST 1.1.  The repeat tumor imaging for confirmation of PD by 
iRECIST is not required.
Clinical stability is defined as the following (Seymour et al. 2017):  no worsening of 
performance status; absence of signs or symptoms that are associated with clinically significant 
disease progression; no requirement for intensified management, including increased analgesia, 
radiotherapy, or other palliative care.  Clinical stability is ultimately defined by the treating 
investigator.
A summary of imaging and treatment guidelines for patients who have first radiologic PD is 
listed in the table below.


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Imaging and Treatment Guideline for Patients who have First Radiologic PD by RECIST 
1.1
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of 
progressive disease
by RECIST 1.1
Repeat imaging at 4 
to 8 weeks to 
confirm PD by 
iRECIST
May continue study 
treatment while 
waiting for 
confirmatory scan 
by iRECIST
Not required; 
Repeat imaging at 4 
to 8 weeks to 
confirm PD per 
investigator’s 
discretion only
Discontinue 
treatment
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST
No additional 
imaging required 
Discontinue 
treatment 
No additional 
imaging required
Not applicable
Repeat tumor 
imaging shows 
iUPD by iRECIST
Repeat imaging at 4 
to 8 weeks to 
confirm PD by 
iRECIST.  May 
occur at next 
regularly scheduled 
imaging visit 
Continue treatment 
at the investigator’s 
discretion
Repeat imaging at 4 
to 8 weeks to 
confirm PD per 
investigator’s 
discretion only
Discontinue 
treatment. 
Repeat tumor 
imaging shows iSD, 
iPR, or iCR by 
iRECIST per 
Investigator 
assessment.
Continue regularly 
scheduled imaging 
assessments.
Continue study 
treatment at the 
Investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments.
Discontinue 
treatment
Abbreviations:  iCPD = iRECIST confirmed progressive disease; iCR = iRECIST confirmed complete response; 
iSD =  iRECIST confirmed stable disease; iUPD = iRECIST unconfirmed progressive disease; RECIST = 
Response Evaluation Criteria in Solid Tumors.
8.1.2.
Criteria Required to Receive Treatment during Confirmatory Scan Period
In order for patients to continue receiving study drugs, the following criteria apply:

absence of clinically significant deterioration 

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
8.2.
Safety Assessments
For each patient, ECGs, vital signs, laboratory tests, and other tests should be collected as shown 
in the SoA (Section 1.3).  Results from any clinical laboratory test analyzed by a central 
laboratory (refer to Appendix 2) will be provided to investigative sites by Lilly or its designee.


C O N FI D E N TI A L
Pr ot oc ol     J 1 Q-M C -J ZI A( b)
L Y 3 4 3 5 1 5 1
7 2
Refer t o Secti o n 8. 3 f or details o n t he rec or di n g of A Es.
Lill y will peri o dicall y  re vie w e v ol vi n g a g gre gate safety data wi t hi n t he st u d y b y a p pr o priate 
met h o ds.
S eri o us a d verse e ve nts will
 as s o o n as t he y are re p orte d.  C u m ulati ve S A Es, 
reas o na bl y a ntici pate d S A Es, a n d rele va nt literat ure will be re vie we d at least q uarterl y b y  
.  
S af et y fi n di n gs (i ncl u di n g ne w precli nical data), will be re vie we d b y a br oa der gr o u p ( 
 
) o n a re g ular 
basis.  Seri o us safet y fi n di n gs ca n be escalate d t o a n i n de pe n de nt i nter nal safety re vie w 
co m mittee.
8. 2. 1.  
Cli nic al S afet y L a b or at or y Assess me nts

Lill y or i ts desig nee will  pr o vi de t he i n vestig at or wi t h t he res ults of safet y la b orat or y tests 
a nal yze d b y a ce ntral ve n d or, if a ce ntral ve n d or is use d f or t he cli nical trial.  

See A p pe n di x 2 f or t he list of cli nical la b orat or y  tests t o be perf or me d a n d t o t he S o A 
( Sectio n 1. 3) f or t he ti mi n g a n d fre q ue nc y .

T he i n vest i gat or m ust re vie w t he la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y in t he A E secti o n of t he C R F .  T he 
la b orat or y re p orts must be file d wit h t he s o urce d oc u me nts .  Cli nicall y si g nifica nt 
a b n or mal la b orat or y fi n di n gs are t h ose w hic h are n ot ass ociate d wit h t he u n derl yi n g 
di sease, u nless j u d ge d b y t he i n vesti gat or t o be more se vere t ha n e x pecte d f or t he 
parti ci pa nt's c o n dit i on.

All la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifica ntl y a b n or mal d uri n g 
parti ci pat i on i n t he st u d y or u ntil t he c om p leti on of V isit 8 0 1 after t he last d ose of st u d y  
i nter ve nt i on s h o uld be re peate d u ntil t he val ues ret ur n t o n or mal or baseli ne or are n o 
l on ger c o nsi dere d cli nicall y si g nifica nt b y  t he i n vestigat or or m e dical m o nit or.
o
If s uc h val ues d o n ot ret ur n t o n or mal/ baseli ne withi n a perio d of  ti me j u d ge d 
reas o na ble b y t he i n vesti gat or, t he eti ol og y  s h o uld be i de nt ifie d a n d t he s p o ns or 
n otifie d.
o
All pr ot oc ol -re q uire d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2, m ust be 
c o n d ucte d i n acc or da nce wit h t he la b orat or y ma n u al a n d t he S o A ( Sectio n 1. 3).
If t here is a n a b n or mal la b orat or y val ue or a b n or mal val ue f or a n y ot her dia g n ostic or scree ni n g 
test (f or e xa m ple, bl o o d press ure i ncrease d or ne utr o p hils decrease d) a n d it is k n o w n t o be 
r elate d t o a disease dia g n osis (f or e xa m ple, h y perte nsi o n or ne utr o pe nia) t his s h o ul d be re p orte d 
i n t he C R F as a n A E .  D o not e nter t he test a b n or malit y,  e nter t he disease dia g n osis or 
cate g orical ter m.  If la b orat or y val ues fr o m n o n- pr ot oc ol -s pecifie d la b orat or y assess me nts 
perf or m e d at t he i nst ituti o n’s l o c al  la b orat or y re q uire a c ha n ge i n partici pa nt ma na ge me nt or are 
c o nsi dere d cli nicall y si g nifica nt b y t he i n vestigat or ( f or e xa m ple, S A E or A E or d ose 
m o dificati o n), t he n t he e ve nt(s) m ust be re p orte d i n t he C R F as A E (s).
C CI
C CI
C CI
C CI


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8.2.1.1.
Immunogenicity Assessment
Where local regulations and ethical review boards (ERBs) allow, blood samples for 
immunogenicity testing will be collected to determine antibody production against LY3435151
as specified in the SoA (Section 1.3).
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
to determine antibody production against the investigational product.  To interpret the results of 
immunogenicity, a venous blood PK sample will be collected at the same time points to 
determine the plasma concentrations of LY3435151.  All samples for immunogenicity will be 
taken pre-dose.  In the event of drug hypersensitivity reactions (immediate or non-immediate), 
additional blood and urine samples will be collected as close to the onset of the event as possible, 
at the resolution of the event, and 30 days following the event to evaluate antidrug antibodies 
(ADA), PK, and additional exploratory biomarkers of hypersensitivity, which could include 
tryptase, complement levels, and cytokine measurements.  Instructions for the collection and 
handling of blood samples will be provided by the sponsor.  The actual date and time (24-hour 
clock time) of each sampling will be recorded.  
Treatment-emergent antidrug antibodies (TE-ADA) are defined in Section 9.4.6.
Immunogenicity will be assessed by a validated assay designed to detect ADA in the presence of 
the investigational product at a laboratory approved by the sponsor.  Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of the investigational 
product.  
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and ERBs allow, at a facility selected by the sponsor.  The duration 
allows the sponsor to respond to future regulatory requests related to LY3435151.  Any samples 
remaining after 15 years will be destroyed.
8.2.1.2.
Hepatic Safety Monitoring
If a study participant experiences elevated alanine aminotransferase (ALT) ≥3 × upper limit of 
normal (ULN), alkaline phosphatase (ALP) ≥2 × ULN, or elevated total bilirubin (TBL) ≥2 × 
ULN, liver testing (Appendix 4) should be repeated within 3 to 5 days including ALT, aspartate 
aminotransferase (AST), ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine 
kinase 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 and in consultation with the study medical monitor.  Monitoring of ALT, AST, TBL, 
and ALP should continue until levels normalize or return to approximate baseline levels.
Hepatic data should be collected in the event that 1 (or more) of the following conditions is met 
for the patient during the course of the study:  

elevation of serum ALT level to ≥10 × ULN

patients without liver tumors or liver metastasis:  ALT ≥5 × ULN and total 
bilirubin ≥2 × ULN

patients with liver tumors or liver metastasis:  ALT ≥8 × ULN and total 
bilirubin ≥2 × ULN


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
discontinuation from study treatment due to a hepatic event or abnormality of 
liver test results

occurrence of a hepatic event considered to be an SAE
8.2.1.3.
Venous Thromboembolic Event Assessment
If a patient develops clinical features of a DVT or PE, appropriate local laboratory tests and 
imaging should be performed as necessary for the diagnosis of the event. For confirmed cases, 
additional laboratory testing is recommended.  Selected tests may be obtained in the event of a 
confirmed venous thromboembolic event and may be required in follow-up with patients in 
consultation with Lilly, its designee, or the Lilly designated medical monitor.
8.3.
Adverse Events and Serious Adverse Events
Investigators are responsible for monitoring the safety of participants who have entered 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 participant.
The investigator is responsible for the appropriate medical care of participants during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the participant to discontinue the investigational product 
before completing the study.  The participant should be followed until the event resolves, 
stabilizes with appropriate diagnostic evaluation, or is otherwise explained.  The frequency of 
follow-up evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via CRF the occurrence and nature of 
each participant’s preexisting conditions, including clinically significant signs and symptoms of 
the disease under treatment in the study.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record their assessment of the 
potential relatedness of each AE to protocol procedure, investigational product, via CRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device, and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.


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If a participant’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via CRF, clarifying if possible, the circumstances leading 
to any dosage modifications, or discontinuations of treatment.
Serious Adverse Events
An SAE is any AE from this study that results in 1 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 hospitalization but may jeopardize the participant or may require 
intervention to prevent 1 of the other outcomes listed in the definition above.  
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
All AEs occurring after signing the ICF are recorded in the CRF and assessed for serious criteria.  
The SAE reporting to the sponsor begins after the participant has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the sponsor as per SAE 
reporting requirements and timelines (see Section 8.3.1) if it is considered reasonably possibly 
related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 24-
hour notification requirement refers to the initial SAE information and all follow-up SAE 
information. Participants with a serious hepatic AE should have additional data collected using 
the CRF.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements, any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in participants once they have 
discontinued and/or completed the study (the participant disposition CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a participant
has been discharged from the study, and he/she considers the event reasonably possibly related to 
the study treatment or study participation, the investigator must promptly notify Lilly.


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Serious adverse events, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to LY3435151, pembrolizumab, or the
combination of LY3435151 and pembrolizumab.
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 investigational product or procedure.  
United States 21 Code of Federal Regulations (CFR) 312.32 and European Union Clinical Trial 
Directive 2001/20/EC and the associated detailed guidances or national regulatory requirements 
in participating countries require the reporting of SUSARs. Lilly has procedures that will be 
followed for the identification, recording, and expedited reporting of SUSARs that are consistent 
with global regulations and the associated detailed guidances.
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to Lilly begins after the patient has signed the ICF and has received study drug.  
However, if an SAE occurs after signing the ICF, but prior to receiving LY3435151, it needs to 
be reported ONLY if it is considered reasonably possibly related to study procedures.
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the AE CRF. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours.  The investigator will submit any updated SAE data to 
the sponsor within 24 hours of it being available.  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.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant and/or legal guardian is the preferred method to 
inquire about AE occurrences.
Refer to the SoA (Section 1.3) for the timing of AE/SAE collection.
8.3.2.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 


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8.3.3.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, institutional review board 
(IRB)/Independent Ethics Committee (IEC), and investigators.

Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate,
according to local requirements.
8.3.4.
Pregnancy

Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 3.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.

All pregnancies and exposure during breastfeeding, from the time of treatment through 
120 days following cessation of study treatment, or 30 days following cessation of study 
treatment if the participant initiates new anticancer therapy must be reported by the 
investigator.
8.3.5.
Cardiovascular and Death Events
Not applicable.
8.3.6.
Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements.
Participants 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.


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8.3.7.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this trial include: 
1. an overdose of Sponsor's product, as defined in Section 8.4 – Treatment of Overdose, that 
is not associated with clinical symptoms or abnormal laboratory results.
2. an elevated AST or ALT lab value that is greater than or equal to 3× the ULN and an 
elevated total bilirubin lab value that is greater than or equal to 2× the ULN and, at the same 
time, an alkaline phosphatase lab value that is less than 2× the ULN, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The trial site guidance for assessment and 
follow up of these criteria can be made available. It may also be appropriate to conduct 
additional evaluation for an underlying etiology in the setting of abnormalities of liver blood 
tests including AST, ALT, bilirubin, and alkaline phosphatase that do not meet the criteria 
noted above. In these cases, the decision to proceed with additional evaluation will be made 
through consultation between the study investigators and the Lilly CRP/CRS. However, 
abnormalities of liver blood tests that do not meet the criteria noted above are not ECIs for 
this trial.
8.4.
Treatment of Overdose
There is no known antidote to LY3435151 overdose. In case of overdose, the patient should 
receive supportive measures. 
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or ≥5 
times the indicated dose. 
No specific information is available on the treatment of overdose of pembrolizumab and/or 
LY3435151.  In the event of overdose, the participant should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated.
8.5.
Pharmacokinetics
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
to determine the serum concentrations of LY3435151.
A maximum of 3 samples may be removed or collected at additional time points during the study 
if warranted and agreed upon between both the investigator and sponsor.  Instructions for the 
collection and handling of blood samples will be provided by the sponsor.  The actual date and 
time (24-hour clock time) of each sampling will be recorded.
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.  Concentrations of LY3435151 will be assayed using a validated 
enzyme-linked immunosorbent assay method. 


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Bioanalytical samples collected to measure LY3435151 concentration will be retained for a 
maximum of 1 year following last patient visit for the study. During this time, samples 
remaining after the bioanalyses may be used for exploratory analyses such as additional 
metabolism or exploratory analyses including bioanalytical assay validation or cross-validation 
exercises.
8.6.
Pharmacodynamics
See Section 8.8 for PD samples to be collected in this study.
8.7.
Genetics
8.7.1.
Whole Blood Sample for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the SoA
(Section 1.3) where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to LY3435151 and to 
investigate genetic variants thought to play a role in cancer. Samples may also be used to 
determine the somatic or germline origin of identified genetic alterations in tumor samples.  
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 investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and/or 
ERBs/IRBs impose shorter time limits.  This retention period enables use of new technologies, 
response to regulatory questions, and investigation of variable response that may not be observed 
until later in the development of LY3435151 or after LY3435151 becomes commercially 
available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome and exome 
sequencing, genome wide association studies, and candidate gene studies.  Regardless of 
technology utilized, data generated will be used only for the specific research scope described in 
this section.
8.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of participant response (including safety), and 
clinical outcome as well as broader mechanisms pertaining to tumor-immune response as well as 
tumor pathogenesis.  Sample collection is incorporated into clinical studies to enable 
examination of these questions through measurement of biomolecules including
deoxyribonucleic acid, ribonucleic acid (RNA), proteins, lipids, and other cellular elements.
Plasma, serum, whole blood, stool, and tumor tissue samples for biomarker research will be 
collected at the times specified in the SoA (Section 1.3) where local regulations allow.  A 


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maximum of 5 samples may be drawn, collected, or removed 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.
Samples will be used for research on the drug target, disease process, variable response to 
LY3435151, pathways associated with cancer, mechanism of action of LY3435151, and/or used 
to develop research methods or to validate diagnostic tools or assay(s) related to cancer.
Collection of the following tumor tissue sample(s) is required for all patients to participate in 
this study:

a newly obtained core, excisional, or endoscopic pre-treatment biopsy of a tumor lesion 
from primary or metastatic site and

a tumor tissue sample from a newly obtained core, excisional, or endoscopic biopsy 
specimen collected during the study treatment period as shown in the SoA (Section 1.3)
Collection of the following tumor tissue sample(s) is optional for all patients participating in this 
study:

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.

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, as indicated in the SoA [Section 1.3].)
For patients requiring a fresh biopsy, the participant must be willing to undergo baseline and on-
study biopsies (as applicable) that should not put participants at undue risk greater than that 
which comes with a core biopsy (ie, a procedure to obtain biopsy should have a serious/severe 
complication risk no greater than 2%).
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 to evaluate changes in molecular markers over time and to document any 
potential immunomodulatory activity of treatment with LY3435151 and should be performed if 
clinically feasible.  Samples may be examined for biomarkers of immune microenvironment 
changes including by immunohistochemistry and RNA expression analysis.
The tissue samples should be obtained using an appropriate method.  Tumor tissue should be 
submitted as a newly acquired endoscopic core needle (minimum 18 gauge) or surgical biopsy.  
Cytological or fine-needle aspiration specimens are not acceptable.  An attempt to obtain up to 4 


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core-needle biopsies, surgical biopsy, or endoscopic biopsy is required, unless medically 
contraindicated or unsafe and discussed with the Lilly CRP/CRS.  Optimally, biopsies should be 
taken from the same metastatic lesion and from areas not previously irradiated (except if the 
patient had progressed after radiation).  Fresh tumor biopsies are planned to be evaluated with 
the isolation of TILs locally for subsequent analysis.  The isolation of TILs needs to be
performed immediately post-biopsy locally on-site.  The single-cell preparation may be 
characterized by flow cytometry, additional analysis to be determined, or cryopreservation as 
discussed with the sponsor.  Cores should be allocated:  2 for formalin fixation and 2 for fresh 
TIL isolation.  When 4 cores are not feasible, the first 2 cores should be fixed in formalin.  Fresh 
TIL isolation will be optional for Cohorts A1, A2, and A3 in the dose escalation.  Formalin fixed 
tissue will be used for immunohistochemistry, RNA analysis, and additional analysis as feasible.  
See the Laboratory Manual for details regarding sample handling.  If additional tumor biopsies 
are collected as part of clinical care, they should be submitted, along with pathology reports, for 
further analysis.  When a biopsy is submitted, due diligence should be used to ensure that tumor 
specimens (not a normal adjacent or a tumor margin sample) are provided and that the tumor 
sample contains tumor cells prior to shipment to the central laboratory.  If a biopsy does not 
contain adequate tissue for analysis, the patient may be replaced.  Lilly may replace up to 10% of 
total patients if unable to submit an adequate tumor sample.  The pathology report accompanying 
archival tissue will also be requested.  The pathology report must be coded with the patient 
number.  Personal identifiers, including the patient’s name and initials, must be removed from 
the institutional pathology report prior to submission.  Lilly has a right to retain a portion of the 
submitted tissue. Archival blocks will be sectioned and returned to the study site.  Slides and 
tissue samples collected on-study will not be returned.
All samples will be coded with the participant number.  These samples and any data generated 
can be linked back to the participant only by the investigator site personnel.
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and ERBs 
impose shorter time limits.  This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of LY3435151 or after LY3435151 becomes commercially available.
Technologies are expected to improve during the 15-year storage period and therefore cannot be 
specifically named.  Existing approaches, including mutation profiling, copy number variability 
analysis, gene expression assays, multiplex assays, and/or immunohistochemistry may be 
performed on these tissue samples to assess potential associations between these biomarkers and 
clinical outcomes.
It is possible that biomarker data for patients in the study have already been generated from 
samples that were collected and analyzed prior to enrolling in this study.  This may include data 
generated from genetic analyses.  If available, these data may be requested from medical records 
for use in the research described in Sections 8.7 and 8.8.
8.8.1.
Tumor Tissue Samples for Detection of TILs
Documented evidence of the presence of TILs from either a local laboratory or Study JZIA 
central laboratory test result will be used to meet study eligibility criteria into Cohort D3 of 


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Phase 1b. This testing does not replace any companion diagnostic test that would be required to 
determine eligibility for an IO therapy approved for the patient’s indication. 
8.9.
Medical Resource Utilization and Health Economics
Medical resource utilization parameters and health economics will not be evaluated in this study.


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
In the dose escalation phase (Part A and Part B), the hypothesis is that there is a tolerable dose 
level for LY3435151 in both monotherapy and in combination with pembrolizumab. 
In the dose expansion phase (Part C and Part D), the objective is to evaluate the safety and 
tolerability, as well as preliminary antitumor activity, of LY3435151 in both monotherapy and in 
combination with pembrolizumab in the pre-specified tumor types. No formal hypothesis testing 
will be performed to demonstrate any statistically significant improvement in objective response 
rate. Therefore, specification of alternative hypotheses on the overall response rate (ORR) does
not apply.
9.2.
Sample Size Determination
The primary objective of this study is to assess the safety and tolerability of LY3435151, thereby 
identifying and confirming the RP2D of LY3435151, to be administered as monotherapy and in 
combination with pembrolizumab, in patients with solid tumors associated with high TIL 
positivity.  The secondary objective is to evaluate PK and any observed evidence of clinical 
efficacy.  
With at least 3 patients treated at the RP2D in the dose-escalation phase and additional patients 
treated at the RP2D in the dose-expansion phase, 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 (partial response [PR]/CR) to treatment.
In the dose-expansion phase for both TNBC and gastric adenocarcinoma, approximately n=16 
patients in each of these 2 tumor types will be randomized with 1:1 ratio to receive LY3435151 
as monotherapy or in combination with pembrolizumab (Stage 1). The sample size of n=16 in 
each tumor type is required to evaluate the PK/PD and safety data between monotherapy and 
combination therapy.  Following the randomization stage, approximately additional 32 patients 
in each of the 2 tumor types will be enrolled to receive LY3435151 in combination with 
pembrolizumab (Stage 2). At each interim analysis for TNBC and gastric adenocarcinoma, 
clinical data from approximately 20 patients in combination dose expansion (8 from Stage 1 and 
12 from Stage 2) will be available to evaluate the antitumor activity of the combination therapy.
If the interim results suggest continuation of enrollment for the evaluated tumor type in TNBC 
and gastric adenocarcinoma, additional patients will be enrolled to receive combination therapy
until approximately 32 patients in Stage 2 to achieve a total of approximately n=40 patients for 
the evaluation of antitumor activity of combination therapy in the corresponding tumor type. 
In the dose-expansion phase for other tumor types associated with TIL positivity, the sample size 
of N=30 in combination therapy provides data to evaluate the safety and PK/PD profile, and to
potentially assess the antitumor activity of LY3435151 in combination with pembrolizumab in 
tumor types other than TNBC and gastric adenocarcinoma.


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With a total sample size of n=20 or n=40, example point estimates of incidence rates and 
corresponding 2-sided 95% confidence intervals (CIs) are summarized in the table below. 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 dose-expansion phase (Iasonos 
and O’Quigley 2013).
Estimated Incidence Rate and 2-Sided 95% CI
N=20
N=40
Number 
of Cases
Estimated 
Rate
95% Cia
Number 
of Cases
Estimated 
Rate
95% CIa
Lower 
Limit
Upper 
Limit
Lower 
Limit
Upper Limit
0
0.0
0.0
0.17
0
0.0
0.0
0.09
3
0.15
0.03
0.38
5
0.13
0.04
0.27
5
0.25
0.09
0.49
10
0.25
0.13
0.41
10
0.50
0.27
0.73
15
0.38
0.23
0.54
15
0.75
0.51
0.91
20
0.50
0.34
0.66
Abbreviations:  CI = confidence interval; N = number of patients.
a
95% Clopper-Pearson interval for binomial distribution. 
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign informed consent
Biomarker
All enrolled patients from whom a valid assay result has been obtained
Pharmacokinetic
All enrolled patients who have received ≥1 full dose of LY3435151 and have baseline and ≥1 
postbaseline evaluable PK sample
Safety
All enrolled patients who have received ≥1 dose of study treatment, regardless of their 
eligibility for the study.  The safety population will be used for all dosing/exposure and safety 
analyses.
DLT-evaluable
All treated patients who have completed 2 cycles (6 weeks) of treatment (having taken at least 
75% of the planned doses of LY3435151) or have discontinued treatment due to a DLT.
Abbreviations:  DLT = dose-limiting toxicity; PK = pharmacokinetics.
9.4.
Statistical Analyses
9.4.1.
General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.


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The efficacy and safety analyses will be conducted on the full analysis set. This set includes all 
data from all participants receiving at least 1 dose of the investigational product according to the 
treatment the participants were assigned and actually received.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.
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 clinical study report (CSR).  Additional exploratory analyses of the data will be conducted 
as deemed appropriate.
9.4.2.
Treatment Group Comparability
9.4.2.1.
Participant 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 statistical 
analysis plan (SAP), or discontinuing (overall and by reason for discontinuation).  A summary of 
all important protocol deviations will be provided.
9.4.2.2.
Participant 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. 
9.4.2.3.
Concomitant Therapy
A summary of prior and concomitant medications will be reported.
9.4.2.4.
Treatment Compliance
The number of cycles received, dose omissions, dose delays, and dose intensity will be 
summarized for all treated patients by treatment cohort.
9.4.3.
Efficacy Analyses
9.4.3.1.
Primary Analyses
The overall response rate is defined as the number of patients who achieve a best overall
response of CR or PR divided by the total number of patients treated (safety population). The 
ORR, with 95% CI, will be summarized for each study part.
9.4.3.2.
Secondary Analyses
The disease control rate, defined as the proportion of patients who achieved a CR or PR or 
stable disease (SD) out of all patients treated, will also be summarized.  Best response is 
determined from a sequence of responses assessed. Two objective status determinations of CR 
before progression are required for a best response of CR. Two determinations of PR or better 


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before progression, but not qualifying for a CR, are required for a best response of PR. In the 
case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval not less than 6 weeks ±7 days measured from study entry.
The duration of response is defined as 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.  Duration of SD will 
be calculated only for patients with best response of SD.  It is measured from the date of start of 
treatment to the date of first progression of disease or the date of death due to any cause, 
whichever is earlier.  For each patient who is not known to have died or to have had a 
progression of disease as of the data inclusion cut-off date, duration of SD will be censored at the 
date of last objective response assessment prior to the date of any subsequent systemic anticancer 
therapy.
Change in tumor size (CTS) will be assessed in each patient with measurable disease using
radiographic imaging. Tumor size is the sum of the tumor measurements for target lesions at
each tumor evaluation. Change in tumor size is defined as the percent CTS from the baseline
evaluation to the post-dose evaluation at each assessment. Other definitions of CTS may be
explored (including specific time points and AUC formulations).
Progression-free survival (PFS) is defined as the time from the date of start of treatment to the
first date of the observed clinical or radiologically documented progressive disease or death due 
to any cause, whichever occurs first. For patients who are not known to have died or progressed 
as of the data inclusion cut-off date, PFS time will be censored at the date of the last objective
progression-free disease assessment prior to the date of any subsequent systematic anticancer
therapy.


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PFS Event/Censoring Scheme
Situationa
Event/Censor
Date of Event or Censor
Tumor progression or death
Event
Earliest date of progressive disease
or death
No tumor progression and no death
Censored
Date of last adequate tumor 
assessment per RECIST 1.1, or date 
of first dose (whichever is later)b
Unless
No baseline radiologic tumor 
assessment available 
Censored
Date of first dose
No adequate postbaseline tumor 
assessment available and death 
reported after 2 scan intervals 
following the first doseb, c
Censored
Date of first dose
Tumor progression or death 
documented immediately after 2 or 
more scan intervals following last 
adequate tumor assessment or 
randomization (whichever is later)b,c
Censored
Date of last adequate tumor 
assessment, per RECIST 1.1, or date 
of first dose (whichever is later)b
New therapeutic anticancer 
treatment started prior to tumor 
progression or death
Censored
Date of last adequate radiological 
assessment prior to new therapeutic 
anticancer therapyb
Abbreviations:  CR = complete response; PFS = progression-free survival; PR = partial response; RECIST = 
Response Evaluation Criteria in Solid Tumors; SD = stable disease.
a
Symptomatic deterioration (ie, symptomatic progression that is not confirmed per RECIST 1.1) will not be 
considered as tumor progression.
b
Adequate tumor assessment per RECIST 1.1 refers to an assessment with one of the following responses:  CR, 
PR, SD, or PD.
c
Refer to the statistical analysis plan for the definition of 2 scan intervals, including any adjustment for scan 
window. 
Time to response (TTR) is defined as the time from the date of start of treatment to the date
measurement criteria for confirmed CR or PR (whichever is first recorded) are first met. For
patients who are not known to have achieved CR or PR as of the data inclusion cut-off date, TTR
will be censored at the date of the last objective disease assessment prior the date of any
subsequent systematic anticancer therapy.
9.4.3.3.
Tertiary/Exploratory Analyses 
Overall survival, as well as the efficacy parameters based on iRECIST, will also be analyzed as 
the exploratory objectives. Details on the exploratory efficacy parameters are discussed in the 
SAP.


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9.4.4.
Safety Analyses
All patients who receive at least 1 dose of any study therapy will be evaluated for safety and 
toxicity. 
The Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 (or higher) will be
used when reporting AEs by MedDRA terms.  The MedDRA Lower Level Term will be used in 
the treatment-emergent computation. Treatment-emergent adverse events will be summarized by 
System Organ Class (SOC) and by decreasing frequency of Preferred Term within SOC.
Safety analyses will include summaries of the following:

DLTs at each dose level in Part A and Part B;

AEs, including severity and possible relationship to study drug;

DLT-equivalent AEs, including severity and possible relationship to study drug;

SAEs, including possible relationship to study drug;

AEs leading to dose delays or omissions;

discontinuations from study treatment due to AEs or death;

treatment-emergent abnormal changes in laboratory values;

treatment-emergent abnormal changes in vital signs and ECGs.
9.4.5.
Pharmacokinetic/Pharmacodynamic Analyses
Selected PK descriptors for LY3435151 (based on actual sampling times), including Cmax, 
approximate time of Cmax, and AUC will be calculated by noncompartmental analysis methods 
and/or model simulations. As an exploratory analysis, PK descriptor estimates for trough 
concentrations at steady state following repeated dose may be evaluated.  
In addition, PK parameter estimates for LY3435151 as a single agent and in combination will be 
calculated by population PK analysis methods using NONMEM, data allowing. 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 Global PK/PD management.
Pharmacokinetic/pharmacodynamic analyses may be conducted to explore exposure-response 
relationships between LY3435151 concentrations in systemic circulation and various PD
measures as second step if dose-response relationship is positively assessed.
9.4.6.
Evaluation of Immunogenicity
The frequency and percentage of participants with preexisting ADA and with TE-ADA+ to 
LY3435151 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 TE-ADA+ 
participants, the distribution of maximum titers will be described.  The frequency of neutralizing 
antibodies will also be tabulated in TE-ADA+ patients if assessed.
The relationship between the presence of antibodies to LY3435151 and the PK parameters and 
PD response, including safety and efficacy, to LY3435151 may be assessed.


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9.4.7.
Other Analyses
9.4.7.1.
Biomarker Analyses
Single-marker and/or multi-marker statistical analysis may be performed to explore the 
association between biomarkers, dose/exposure, and clinical outcomes.
9.5.
Interim Analyses 
Because this is a dose-finding study, safety and PK/PD data (if available) will be reviewed on a 
cohort-by cohort basis during the study, until the MTDs (or the highest dose levels if MTDs are 
not reached) are determined for each treatment part.  The purpose of these cohort-by-cohort 
reviews is to evaluate the safety data at each dose level and determine if a DLT has been 
observed that would suggest the MTD has been met or exceeded.  After all patients who are 
deemed evaluable for the assessment of dose levels complete the DLT observation period or the 
MTD is determined, an interim safety and PK analysis will be conducted for planning next 
studies.
For the dose-expansion phase, when the clinical efficacy data and PK/PD data of approximately 
the first 20 participants are available in each combination dose-expansion cohort of TNBC and 
gastric adenocarcinoma (Cohort D1 and Cohort D2), an interim data review including but not 
limited to safety, efficacy, and PK/PD will be conducted within each cohort.  If the results of the 
data review for a particular cohort under combination therapy warrant a positive benefit-risk-
profile, additional patients will be enrolled to the corresponding tumor type in the combination 
dose expansion (Cohort D1 or Cohort D2) until approximately 40 patients are enrolled.
It is planned that enrollment can continue while interim analyses are conducted, but the sponsor 
may decide to pause the enrollment, if necessary.  Other interim analyses may be conducted if 
deemed appropriate by the sponsor.  The interim analyses may be combined with any pre-
specified safety review or annual reporting (eg, an update to the IB or Development Safety 
Update Review).
If it is deemed that enough data are obtained to assess the primary objective and the secondary
objectives, a CSR might be created before the last patient visit.  In this case, all data until the 
data cut-off 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 the data
cut-off date.  These data may be reported separately and the analyses on all patients including 
these data may not be performed.


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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (eg,
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, International Council for Harmonisation (ICH)
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
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.  
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.
10.1.2.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study, including 
the risks and benefits, to the participant or his/her legally authorized representative and 
answer all questions regarding the study.

Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 


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Insurance Portability and Accountability Act requirements, where applicable, and the 
IRB/IEC or study center.

The medical record must include a statement that written informed consent was obtained 
before the participant was entered in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative and is kept on file.
Participants who are rescreened are required to sign a new ICF.
10.1.3.
Data Protection

Participants will be assigned a unique identifier by the investigator.  Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable will 
not be transferred.

The participant and/or legal representative, when applicable, must be informed that 
his/her personal study-related data will be used by the sponsor in accordance with local 
data protection law.  The level of disclosure must also be explained to the participant.

The participant and/or legal representative, when applicable, must be informed that 
his/her medical records may be examined by Clinical Quality Assurance auditors or other 
authorized personnel appointed by the sponsor, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
10.1.4.
Dissemination of Clinical Study Data
Dissemination of study data will be performed according to all applicable Lilly and international 
policies.
10.1.5.
Data Quality Assurance
To ensure accurate, complete, and reliable data, the sponsor 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 


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In addition, the sponsor or its representatives will periodically check a sample of the participant 
data recorded against source documents at the study site.  The study may be audited by the 
sponsor 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.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture (EDC) system 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-party.  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 results will be provided to the investigator for review 
and retention.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
10.1.6.
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available.
10.1.7.
Study and Site Closure
10.1.7.1.
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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10.1.7.2.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.


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10.2.
Appendix 2:  Clinical Laboratory Tests

The tests detailed below will be performed as indicated in the table below.

If a local sample is required, it is important that the sample for central analysis is 
obtained at the same time (if applicable).  If there is an abnormal laboratory value or 
abnormal value for any other diagnostic or screening test (e.g., blood pressure increased, 
neutrophils decreased, etc.) and it is known to be related to a diagnosis (e.g., 
hypertension, neutropenia, etc.), this should be entered into the CRF.  Do not enter the 
test abnormality, enter the diagnosis or categorical term.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations and any clinically significant 
abnormalities recorded in the AE eCRF.
Investigators must document their review of each laboratory safety report.  Enrollment and 
treatment decisions may be based upon local laboratory results.  Discrepancies between 
local and central laboratory results will not be considered a protocol deviation.


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Clinical Laboratory Tests
Hematologya,c
Clinical Chemistrya,b
Leukocytes (WBC)
Serum Concentrations of:
Neutrophils
Alanine aminotransferase (ALT)
Lymphocytes
Albumin
Monocytes
Alkaline phosphatase
Eosinophils
Aspartate aminotransferase (AST)
Basophils
Bilirubin, direct
Erythrocytes (RBC)
Bilirubin, total
Hemoglobin (HGB)
Blood urea nitrogen (BUN) or blood urea
Hematocrit (HCT)
Calcium
Platelets (PLT)g
Creatine Kinase
Creatinine 
Urinalysisc
Glucose (random)
Blood
Magnesium
Glucose
Phosphorous
Ketones
Potassium
pH
Total Protein
Protein
Sodium
Specific gravity
Urine leukocyte esterasee
Pregnancy Testc,d
Thyroid functiona,b
Serum or urine pregnancy test
Thyroid-stimulating hormone (TSH)
Thyroxine (T4)
Coagulationc
Triiodothyronine (T3)
PT/INR
Free Triiodothyronine (FT3)
aPTT
Exploratory Hypersensitivity and Immunogenicity Testinga, b, f
Anti-LY3435151 antibodies (immunogenicity)
Tryptase
Drug-specific IgE
Basophil activation test
Complements
Cytokine panel
N-methylhistamine
Abbreviations:  aPTT =  activated partial thromboplastin time; CRF = case report form; IgE = immunoglobulin E; 
INR = international normalized ratio; PT/INR = prothrombin time-international normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
Note:  Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. When a manual differential is needed to report the neutrophils, the segmented and band forms should be 
added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands.
a
Treatment and enrollment decisions may be based on local laboratory results.
b
Central laboratory.  In addition, local labs may be collected at investigator’s discretion.
c
Local or investigator-designated laboratory.


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d
For female patients of childbearing potential.
e
Urine microscopy may be used in place of the urine leukocyte esterase assessment to test for the presence of 
WBC.
f
Basophil activation test will be performed if a drug-specific IgE assay is unavailable.
g
When available, include mean platelet volume, platelet distribution width, and reticulated platelets.


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10.3.
Appendix 3:  Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, 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.
3. Postmenopausal female
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
o
A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT).  However, 
in the absence of 12 months of amenorrhea, confirmation with more than 1
FSH measurement >40 mIU/mL is required.  
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.


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


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Collection of Pregnancy Information
Male participants with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the sponsor. Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination 
of the pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure.  
Female participants who become pregnant

The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the sponsor within 24 hours of learning of a participant's pregnancy.

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date.  Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.  A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy-related SAE considered reasonably related to the study intervention by the 
investigator will be reported to the sponsor, as described in Section 8.3.1. While the 
investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting.

Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study.


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10.4.
Appendix 4:  Liver Safety:  Suggested Actions and Follow-up 
Assessments
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with participants in consultation with the Lilly CRP/CRS, or that of its 
designee.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
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
ALT
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
Anti-smooth muscle antibody (or anti-actin antibody)a
CPK
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cells; WBC = white blood cells.
a
Central laboratory.  In addition, local labs may be collected at investigator’s discretion.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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10.5.
Appendix 5:  Creatinine Clearance Formula
Note:  This formula is to be used for calculating creatinine clearance (CrCl) from local 
laboratory results only.
Patients aged ≥18 years
Cockcroft-Gault prediction of CrCl from serum creatinine (1976)
For serum creatinine concentration in mg/dL:
CrCl=
(mL/min)
(140 – agea) (wt) 0.85 (if female), or 1.0 (if male)
72 serum creatinine (mg/dL)
For serum creatinine concentration in µmol/L:
CrCl=
(mL/min)
(140 – agea) (wt) 0.85 (if female), or 1.0 (if male)
0.81 serum creatinine (mol/L)
a
Age in years, weight (wt) in kilograms.
Source:  Cockcroft and Gault 1976.


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10.6.
Appendix 6:  Dose-Finding Algorithm of the Modified Toxicity 
Probability Interval Method Showing Number of Patients Treated
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

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.


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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 will never be used again in the trial (see “DU” at column 7, 
row 5).
The final MTD will be determined when all patients complete DLT evaluation.  A hypothetical 
example for the MTD determination is shown below for illustration (based on the pre-specified 
parameters, number of DLTs, and number of DLT-evaluable patients).


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10.7.
Appendix 7:  Abbreviations
Term
Definition
ADA
antidrug antibody(ies)
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
participant administered a pharmaceutical product that does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BED
biological effect dose
CFR
Code of Federal Regulations
CI
confidence interval
Cmax
maximum concentration
CNS
central nervous system
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CR
complete response
CrCl
creatinine clearance
CRF
case report form
CRP/CRS
clinical research physician/clinical research scientist: Individual responsible for the 
medical conduct of the study.  Responsibilities of the CRP/CRS may be performed by a 
physician, clinical research scientist, global safety physician or other medical officer.
CSR
clinical study report
CT
computed tomography
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTS
change in tumor size
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate


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DLT
dose-limiting toxicity
DVT
deep vein thrombosis
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
enroll
The act of assigning a participant to a treatment.  Participants who are enrolled in the 
study are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
ERB
ethical review board
ET
equivalent toxicity
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
FT3
Free triiodothyronine
FT4
Free thyroxine
GCP
good clinical practice
G-CSF
granulocyte colony-stimulating factor
GLP
Good Laboratory Practice
GPS
Global Patient Safety
HCC
hepatocellular carcinoma
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HNSCC
head and neck squamous cell carcinoma
HRT
hormonal replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
iCPD
confirmed progression per iRECIST
iCR
complete response per iRECIST
IEC
Independent Ethics Committee
Informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate.  Informed consent is 
documented by means of a written, signed and dated informed consent form.


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interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IO
immuno-oncology
IP
intraperitoneal(ly)
iPR
partial response per iRECIST
irAE
immune-related adverse event
IRB
institutional review board
iRECIST
immuno-Response Evaluation Criteria in Solid Tumors
IRR
infusion-related reaction
iSD
stable disease per iRECIST
iUPD
unconfirmed progression per iRECIST
IV
intravenous(ly)
LMS
leiomyosarcoma
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
mTPI-2
modified toxicity probability interval
NL-NT
new lesion-non-target
NL-T
new lesion-target
ORR
overall response rate
PD
pharmacodynamic(s)
PD-1
programmed cell death protein 1
PD-L1
programmed death-ligand 1
PE
pulmonary embolism
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
Q3W
every 3 weeks
QTc
corrected QT interval
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid


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RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SD
stable disease
SoA
Schedule of Activities
SOC
System Organ Class
SUSAR
suspected unexpected serious adverse reaction
T3
triiodothyronine
TBL
total bilirubin
TE-ADA
treatment-emergent antidrug antibody(ies)
TIL
tumor-infiltrating lymphocyte
TNBC
triple-negative breast cancer
TTR
time to response
ULN
upper limit of normal
UPS
undifferentiated pleomorphic sarcoma
WOCBP
woman/women of childbearing potential


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10.8.
Appendix 8:  Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment (a)
Overall Rationale for the Amendment:
This amendment incorporates changes requested by regulatory agencies.  In addition, this 
amendment includes changes made to correct and clarify information for sites.
Section # and 
Name
Description of Change
Brief Rationale
Section 1.1. 
Synopsis
Replaced “anti-PD-1/L1” with 
“Pembrolizumab”; Added in 
pembrolizumab dose
Based on FDA feedback
Section 1.2.1. 
Phase 1a: Dose 
Escalation 
Schema
Replaced “PD-1/L1 
Combination” with 
“Pembrolizumab” for Part B of 
the study schema
Based on FDA feedback
Section 1.3. 
Schedule of 
Activities
Changed “Single local ECG” to 
“Central triplicate ECGs” for on-
treatment activities 
Updated to be in line with common Lilly 
practice
Section 1.3. 
Schedule of 
Activities
Addition of plasma and stool 
sample collection information
Clarification
Section 1.3. 
Schedule of 
Activities
Addition of “Pregnancy Test” to 
Post-Treatment Schedule of 
Activities
Based on pembrolizumab specific 
language
Section 1.3. 
Schedule of 
Activities
Changed “PBMC” to “Whole 
Blood for Flow Profile”
Clarification 
Section 2.3. 
Benefit/Risk 
Assessment
Addition of language regarding 
pembrolizumab benefit/risk 
information
Based on FDA feedback
Section 4.1.1.2. 
Dose-Limiting 
Toxicity 
Determination
DLT table modified 
Based on FDA feedback
Section 4.1.1.4. 
Determination 
of 
Recommended 
Addition of text regarding the use 
of data in the 90-day follow-up 
period.
Based on FDA feedback


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Section # and 
Name
Description of Change
Brief Rationale
Phase 2 Dose
Section 4.3. 
Justification for 
Dose
Addition of language regarding 
dose of pembrolizumab in parts B 
and D of the study.
Based on FDA feedback
Section 5.1. 
Inclusion 
Criteria
Modification of inclusion criteria 
[2] and [8] 
Based on FDA feedback
Section 6.1. 
Study 
Intervention(s) 
Administered
Replaced “anti-PD-1/L1” with 
“Pembrolizumab”; Added in 
footnote regarding combination 
dose levels
Based on FDA feedback
Section 6.6. 
Dose 
Modification
Addition of language regarding 
dose delays and omissions
Based on FDA feedback
Section 6.6.2. 
Dose 
Modifications
of 
Pembrolizumab
Addition of language regarding 
dose modifications for 
pembrolizumab
Based on FDA feedback
Section 7.1. 
Discontinuation 
of Study 
Intervention
Addition of language regarding 
the discontinuation of 
pembrolizumab; Addition of 
bullet point regarding abnormal 
hepatic parameters; Addition of 
language for patients who will 
continue study treatment beyond 
radiographic progression 
Based on FDA feedback
Appendix 2: 
Clinical 
Laboratory 
Tests
Added Creatine Kinase to 
Clinical Laboratory Tests
Based on PMDA feedback
Throughout 
protocol
Addition of pembrolizumab-
specific language
Based on pembrolizumab specific 
language 
Throughout 
protocol
Minor formatting and editorial 
changes
Minor, therefore not detailed


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11.
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L e o  D o c u m e n t  I D  =  3 d b e e d 3 9 - e a c 9 - 4 e 2 b - 9 4 2 5 - c b 6 0 7 6 b e d 5 f 1
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 7 - J a n - 2 0 2 0  1 7 : 2 2 : 0 3  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  2 8 - J a n - 2 0 2 0  1 3 : 3 7 : 5 9  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D

SAP_001.pdf: 
Statistical Analysis Plan: J1Q-MC-JZIA(b)
A Phase 1a/1b Study of LY3435151 Administered to Patients With Advanced Solid 
Tumors
NCT04099277
Approval Date: 04-Oct-2019


J1Q-MC-JZIA Statistical Analysis Plan
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1.
Statistical Analysis Plan: 
J1Q-MC-JZIA:  A Phase 1a/1b Study of LY3435151 
Administered to 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.
LY3435151 Solid Tumors
Study JZIA is a Phase 1a/1b, multicenter, open-label dose-escalation study followed by a 
randomized dose-expansion study of LY3435151 as monotherapy and in combination with 
pembrolizumab in patients with the following cancers:  triple-negative breast cancer 
(TNBC), gastric adenocarcinoma ([GC] including gastroesophageal junction 
adenocarcinoma), head and neck squamous cell carcinoma (HNSCC), squamous cervical 
carcinoma, high-grade serous ovarian carcinoma, hepatocellular carcinoma (HCC), 
undifferentiated pleomorphic sarcoma (UPS), and leiomyosarcoma (LMS).
Eli Lilly and Company
Indianapolis, Indiana USA 46285
[Protocol J1Q-MC-JZIA]
[Phase 1a/1b]
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 04-Oct-2019 GMT


J1Q-MC-JZIA Statistical Analysis Plan
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:  J1Q-MC-JZIA:  A Phase 1a/1b Study of 
LY3435151 Administered to Patients with Advanced Solid Tumors ...................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................7
4.1.
Primary Objective ..........................................................................................................7
4.2.
Secondary Objectives.....................................................................................................7
4.3.
Exploratory Objectives...................................................................................................7
5.
A Priori Statistical Methods ................................................................................................9
5.1.
Summary of Study Design..............................................................................................9
5.1.1.
Dose Escalation Phase............................................................................................9
5.1.2.
Dose Expansion Phase .........................................................................................11
5.2.
Determination of Sample Size ......................................................................................12
5.2.1.
Statistical Hypotheses ..........................................................................................12
5.2.2.
Sample Size Determination ..................................................................................12
5.3.
Handling of Dropouts or Missing Data.........................................................................14
5.4.
Statistical Analyses ......................................................................................................15
5.4.1.
Analysis Population .............................................................................................16
5.4.2.
Patient Disposition...............................................................................................16
5.4.3.
Demographics and Baseline Characteristics..........................................................16
5.4.3.1.
Demographics and Disease Characteristics .....................................................16
5.4.3.2.
Historical Illnesses and Prior Therapies ..........................................................16
5.4.4.
Concomitant Therapy...........................................................................................17
5.4.5.
Postdiscontinuation Therapy ................................................................................17
5.4.6.
Exposure..............................................................................................................17
5.4.7.
Safety Analyses....................................................................................................17
5.4.8.
Efficacy Analyses ................................................................................................18
5.4.8.1.
Primary Efficacy Analyses .............................................................................18
5.4.8.2.
Secondary Efficacy Analyses..........................................................................19
5.4.8.3.
Exploratory Efficacy Analyses........................................................................20
5.5.
Pharmacokinetic/Pharmacodynamic Analyses..............................................................22
5.6.
Evaluation of Immunogenicity .....................................................................................22
5.7.
Biomarker Analyses.....................................................................................................23
5.8.
Interim Analyses ..........................................................................................................23


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6.
References ........................................................................................................................24


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Table of Contents
Table
Page
Table JZIA.5.1.
Estimated Incidence Rate and 2-Sided 95% Confidence Interval...............14
Table JZIA.5.2.
Progression-Free Survival Event/Censoring Scheme.................................20
Table JZIA.5.3.
Progression-Free Survival (iPFS) Event/Censoring Scheme......................21


J1Q-MC-JZIA Statistical Analysis Plan
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Table of Contents
Figure
Page
Figure JZIA.1.
JZIA Study Design Scheme – Dose Escalation ...............................................10
Figure JZIA.2.
JZIA Study Design Schema – Dose Expansion ...............................................12


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior to first patient visit.


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4.
Study Objectives
4.1.
Primary Objective

Phase 1a Dose Escalation (Part A & Part B):  to assess the safety and tolerability of 
LY3435151, thereby identifying the recommended Phase 2 dose (RP2D), 
administered as monotherapy and in combination with pembrolizumab, in patients 
with advanced solid tumors of the following types:  triple-negative breast cancer
(TNBC), gastric adenocarcinoma (GC), head and neck squamous cell carcinoma
(HNSCC), squamous cervical carcinoma, high-grade serous ovarian carcinoma, 
hepatocellular carcinoma (HCC), undifferentiated pleomorphic sarcoma (UPS), and 
leiomyosarcoma (LMS).

Phase 1b Dose Expansion (Part C & Part D):  to assess the safety and tolerability 
of LY3435151:
o
administered as monotherapy (Part C), all patients must be programmed 
death-1 (PD-1) /programmed death-ligand 1 (PD-L1) antagonist naïve:

C1:  TNBC (not eligible for atezolizumab-containing therapies)

C2:  GC (including gastroesophageal junction)
o
administered in combination with pembrolizumab (Part D), all patients must 
be PD-1/PD-L1 antagonist naïve:

D1:  TNBC (not eligible for atezolizumab-containing therapies)

D2:  GC (including gastroesophageal junction)

D3:  tumor-infiltrating lymphocyte (TIL)-selected cohort with the 
following tumor types:  HNSCC, squamous cervical carcinoma, high-
grade serous ovarian carcinoma, HCC, UPS, and LMS
4.2.
Secondary Objectives

to assess the pharmacokinetics (PK) of LY3435151, administered as monotherapy 
and in combination with pembrolizumab, in patients with solid tumors

to document any antitumor activity per Response Evaluation Criteria in Solid Tumors
(RECIST) v1.1 observed with LY3435151, when administered as monotherapy or in 
combination with pembrolizumab, in patients with solid tumors
4.3.
Exploratory Objectives

to assess the relationship between biomarkers, dose/exposure, and clinical outcomes, 
particularly in relation to tumor TIL levels

to document survival status observed with LY3435151 when administered as 
monotherapy or in combination with pembrolizumab to patients with solid tumors 
associated with TIL positivity


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
to document antitumor activity based on immuno-RECIST (iRECIST) observed with 
LY3435151 when administered as monotherapy or in combination with 
pembrolizumab to patients with solid tumors associated with high TIL positivity


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5.
A Priori Statistical Methods
5.1.
Summary of Study Design
Study JZIA is a Phase 1a/1b, multicenter, open-label dose-escalation study followed by a 
randomized dose-expansion study of LY3435151 as monotherapy and in combination with 
pembrolizumab in patients with advanced solid tumors.  
5.1.1. Dose Escalation Phase
Phase 1a (dose escalation) will assess the safety and tolerability of LY3435151 to identify a 
monotherapy RP2D and a combination RP2D in patients with solid tumors associated with TIL
positivity:

TNBC

GC (including gastroesophageal junction)

HNSCC

squamous cervical carcinoma

high-grade serous ovarian carcinoma

HCC

UPS and LMS
Patients enrolled in Part A (Cohorts A1 through A6) will receive LY3435151 monotherapy.  
Patients enrolled in Part B (Cohorts B1 and B2) will receive LY3435151 and pembrolizumab.
The RP2D will be determined based on the number of observed dose-limiting toxicities (DLTs) 
and PK/pharmacodynamic (PD) data, and may be below the maximum tolerated dose (MTD), 
which may not necessarily be reached during the dose escalations.  The dose-escalation phase 
will employ a modified toxicity probability interval-2 (mTPI-2) method and, starting with Cohort 
A2, will enroll at least 3 evaluable patients per cohort.  Treatment cycles will consist of 21 days.  
A 2-cycle DLT observation period (42 days) will apply to all cohorts in Phase 1a.    
One patient will be enrolled in Cohort A1 and will receive a 10-mg dose on Cycle 1 Day 1.  If 
the 10-mg dose level DLT period is cleared, Cohort A2 (30-mg dose level) will be initiated.  If 
the patient in Cohort A1 experiences a DLT, additional patients will be enrolled into Cohort A1 
following the mTPI-2 method.  Based on the mTPI-2 method, at least 4 additional patients will 
need to be enrolled and experience no DLTs during the DLT observing period before escalating 
to the next dose level (Cohort A2).
After the first patient in Cohort A2 receives the first dose of LY3435151, there will be a delay of 
1 week before the second patient receives LY3435151 to allow for safety observation.  In all 
subsequent cohorts, the first patient in each dose level will be observed for at least 24 hours 
before treatment of additional patients; no additional delays are required for subsequent patients.


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Patients in Cohorts A2, A3, A4, A5, and A6 will receive proposed doses of 30 mg, 100 mg, 
300 mg, 900 mg, and 1800 mg, respectively, provided safety is established in the preceding 
cohorts.  Once the DLT period of 42 days for every 3 weeks (Q3W) is completed for respective 
dose levels within Cohorts A1 to A6, 2 selected cohorts can be expanded with an additional 
6 patients each to further inform safety, PK, and PD.  For example, additional patients at Dose 
Level 5 (900 mg Q3W) may be enrolled in parallel with Cohort A6 after Cohort A5 has cleared 
the DLT period.
In the Combination Dose Escalation Period (Part B), 2 dose levels will be explored.  Dose Level 
1 in Part B will be decided based on, but not limited to, the safety and PK/PD data from 
monotherapy expansion cohorts.  The dose of pembrolizumab will remain constant.  Once 
enrollment to Dose Level 1 in Part B begins, dose escalation will occur in parallel for both Part 
A and Part B.  However, enrollment in a Part B cohort can begin only after all previous dose 
level cohorts in monotherapy and combination dose escalation (as applicable) are complete, as 
determined by Eli Lilly and Company (Lilly).  For example, if Dose Level 5, 900 mg Q3W, is 
decided as the starting dose level for Part B, Cohort B1 will only begin after the safety of Dose 
Level 5 in monotherapy dose escalation is cleared, and Cohort B2 may begin only after both 
Cohort A6 and Cohort B1 are complete.
If safety data from Part A indicate that de-escalation of the LY3435151 dose is warranted, no 
additional patients will be enrolled in Part A or Part B at dose levels higher than the de-escalated 
dose.  
Abbreviations:  n = number of participants; RP2Dc = combination recommended Phase 
2 dose; RP2Dm = monotherapy recommended Phase 2 dose; TBD = to be determined.
a May include backfill participants.
b Refer to Section 5.8 of Interim Analyses.
c LY3435151 dosing in combination will begin 1 dose level below the tolerated 
monotherapy dose level.
Figure JZIA.1.
JZIA Study Design Scheme – Dose Escalation


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5.1.2. Dose Expansion Phase
For both Part A and Part B, after all patients in the dose escalation phase have completed the 
DLT observation period or discontinued, an interim safety and PK/PD analysis will be conducted 
before opening the dose expansions.  That is, the randomized Dose Expansion Cohort will begin 
after the completion of both Dose Escalation Part A and Dose Escalation Part B.
In Dose Expansion Phase 1b, a 2-stage design with randomization will be implemented to 
determine the treatment for patients with immuno-oncology (IO) naïve TNBC and GC.  Within 
each tumor type of IO-naïve TNBC and GC in the dose expansion phase, Stage 1 will enroll 16 
patients to be randomized with 1:1 ratio to receive either LY3435151 monotherapy (Cohort C1 
or C2) or LY3435151 and pembrolizumab combination therapy (Cohort D1 or D2).  At Stage 2, 
approximately 32 additional patients in each tumor type will be enrolled to receive LY3435151 
in combination with pembrolizumab (Cohort D1 or D2).  An interim data review will be 
performed based on safety, efficacy, and PK/PD data from the first 20 enrolled patients in the 
combination dose expansion (including 8 patients from Stage 1 and the first 12 patients from
Stage 2) for each of the 2 tumor types of IO-naïve TNBC and GC. When the interim analysis in 
Stage 2 is performed for each tumor type, enrollment might still continue to enroll additional 20 
patients, unless the totality of evidence suggests otherwise.
Approximately 30 patients with other IO-naïve tumor types will be selected for enrollment based 
on TIL positivity and will receive LY3435151 in combination with pembrolizumab (Cohort D3).


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Abbreviations:  GC = gastric adenocarcinoma; n = number of participants;
R = randomization; RP2Dc = combination recommended Phase 2 dose; 
RP2Dm = monotherapy recommended Phase 2 dose; TIL = tumor-infiltrating 
lymphocyte; TNBC = triple-negative breast cancer.
a Refer to Section 5.8 of Interim Analyses.
Figure JZIA.2.
JZIA Study Design Schema – Dose Expansion
5.2.
Determination of Sample Size
5.2.1. Statistical Hypotheses
In the dose escalation phase (Part A and Part B), the hypothesis is that there is a tolerable dose 
level for LY3435151 in both monotherapy and in combination with pembrolizumab.  
In the dose expansion phase (Part C and Part D), the objective is to evaluate the safety and 
tolerability, as well as preliminary antitumor activity, of LY3435151 in both monotherapy and in 
combination with pembrolizumab in the prespecified tumor types.  No formal hypothesis testing 
will be performed to demonstrate any statistically significant improvement in objective response 
rate.  Therefore, specification of alternative hypotheses on the overall response rate (ORR) does 
not apply.
5.2.2. Sample Size Determination 
The primary objective of this study is to assess the safety and tolerability of LY3435151, thereby 
identifying and confirming the RP2D of LY3435151, to be administered as monotherapy and in 
combination with pembrolizumab, in patients with solid tumors associated with high TIL 


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positivity.  The secondary objective is to evaluate PK and any observed evidence of clinical 
efficacy.  
With at least 3 patients treated at the RP2D in the dose escalation phase and additional patients 
treated at the RP2D in the dose expansion phase, 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 (partial response [PR]/complete response[CR]) to treatment
In the dose expansion phase for both TNBC and GC, approximately 16 patients in each of these 
2 tumor types will be randomized with a 1:1 ratio to receive LY3435151 as monotherapy or in 
combination with pembrolizumab (Stage 1).  The sample size of n=16 in each tumor type is
determined in order to minimize the patients receiving monotherapy but still provide sufficient 
precisionto evaluate the PK/PD and safety data between monotherapy and combination therapy.  
Following the randomization stage, approximately 32 additional patients in each of the 2 tumor 
types will be enrolled to receive LY3435151 in combination with pembrolizumab (Stage 2).  At 
each interim analysis for TNBC and GC, clinical data from approximately 20 patients in the 
combination dose expansion (8 from Stage 1 and 12 from Stage 2) will be available to evaluate 
the antitumor activity of the combination therapy.  If the interim results suggest continuation of 
enrollment for the evaluated tumor type in TNBC and GC, an additional 20 patients will be 
enrolled to receive combination therapy in Stage 2 in the corresponding tumor type. Therefore, a 
total of approximately 40 patients will be enrolled in each tumor type for the evaluation of 
antitumor activity of combination therapy.  
In the dose expansion phase for other tumor types associated with TIL positivity, the sample size 
of n=30 in combination therapy provides data to evaluate the safety and PK/PD profile. The 
sample size of n=30 also allows to potentially assess the antitumor activity of LY3435151 in 
combination with pembrolizumab in tumor types other than TNBC and GC.
With a total sample size of n=20 or n=40, example point estimates of incidence rates and 
corresponding 2-sided 95% confidence intervals (CIs) are summarized in the table below.  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 dose expansion phase (Iasonos and 
O’Quigley 2013).


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Table JZIA.5.1.
Estimated Incidence Rate and 2-Sided 95% Confidence Interval
n=20
n=40
Number 
of Cases
Estimated 
Rate
95% Cia
Number 
of Cases
Estimated 
Rate
95% CIa
Lower 
Limit
Upper 
Limit
Lower 
Limit
Upper Limit
0
0.0
0.0
0.17
0
0.0
0.0
0.09
3
0.15
0.03
0.38
5
0.13
0.04
0.27
5
0.25
0.09
0.49
10
0.25
0.13
0.41
10
0.50
0.27
0.73
15
0.38
0.23
0.54
15
0.75
0.51
0.91
20
0.50
0.34
0.66
Abbreviations:  CI = confidence interval; n = number of participants.
a 95% Clopper-Pearson interval for binomial distribution.  
5.3.
Handling of Dropouts or Missing Data
Rules for handling dropouts or missing data are listed by type of analysis alphabetically.  Unless
otherwise specified, observed data will be used and missing data will not be imputed or carried
forward.
General rules for imputing dates related to adverse events (AEs) or concomitant therapy:

Onset date of an AE or start date of a concomitant therapy:
o
if only the day is missing, the date will be set to:

the first day of the month that the event occurred, if the onset yearh-
month (yyyy-mm) is after the yyyy-mm of first study treatment

the day of the first study treatment, if the onset yyyy-mm is the same 
as yyyy-mm of the first study treatment
o
if both the day and month are missing, the complete date will be set to:

January 1 of the year of onset, if the onset year is after the year of the 
first study treatment

the date of the first dose, if the onset year is the same as the year of the
first study treatment

Resolution date of an AE or end date of a concomitant therapy:
o
If only the day is missing, the date will be set to the last day of the month of 
the occurrence, or to the date of death if the patient died in the same month.
o
If both the day and month are missing, the date will be set to 31 December of 
the year of occurrence.
If a date is completely missing, then the AE will be considered treatment emergent.  In case of
additional therapies, the therapy will be considered concomitant.


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General rule for imputing other dates: If a date variable is needed for an analysis, use the
following general rule to impute the incomplete date:

If the date has no missing year and month but the day is missing, then assign Day 1 to 
the day.

If the date has no missing year, but has missing month, then assign January to the 
month.
However, after imputation, check if the imputed date is logically consistent with other relevant
date variable(s) and make the appropriate correction if necessary.  For example, if a visit start 
date was 10 May 2019 and a tumor assessment date was xx May 2019 (missing day) but it was 
known that it occurred after that visit, then after imputation, the tumor assessment date became 
01 May 2019.  In this case, the imputed tumor assessment date should be compared to the visit 
start date and then corrected to be the visit start date, 10 May 2019.
5.4.
Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee.
Unless otherwise specified, the statistical summaries on Phase 1a will be performed by dose 
levels for Part A and Part B, respectively.  For dose expansion phase, the analyses will be 
performed on patients by treatment arms (monotherapy and combination therapy) for each tumor 
type of TNBC and GC, and on all patients in the TIL-selected cohort D3.  
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 clinical study report (CSR).  Additional exploratory analyses of the data will be conducted 
as deemed appropriate.


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5.4.1. Analysis Population
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign informed consent
Biomarker
All enrolled patients from whom a valid assay result has been obtained
Pharmacokinetic
All enrolled patients who have received ≥1 full dose of LY3435151 and have baseline and ≥1 
postbaseline evaluable PK sample
Intent-to-Treat 
All patients who are randomized (enrolled) to study treatment.  Patients will be grouped 
according to randomized treatment.  This ITT population will be used for all baseline and 
efficacy analyses.
Safety
All randomized (enrolled) patients who have received ≥1 dose of LY3435151, regardless of 
their eligibility for the study.  Patients will be grouped according to treatment received in 
Cycle 1.  The safety population will be used for all dosing/exposure and safety analyses.
DLT-evaluable
All treated patients who have completed 2 cycles (6 weeks) of treatment (having taken at least 
75% of the planned doses of LY3435151) or have discontinued treatment due to a DLT.
Abbreviations:  DLT = dose-limiting toxicity; ITT = intent-to-treat; PK = pharmacokinetics.
5.4.2. Patient Disposition
All patient discontinuation data collected on the electronic case report form will be listed, 
including the extent of the patient’s participation in the study.  If known, a reason for 
discontinuation from treatment and from the study will be listed and summarized.  All patients 
entered in the study will be included in the summary and listing.
All significant protocol deviations will be listed by predetermined categories.
5.4.3. Demographics and Baseline Characteristics
5.4.3.1.
Demographics and Disease Characteristics
Patient demographic and baseline characteristics will be summarized and listed for all enrolled
patients.  At a minimum, sex, age, race, basis for initial diagnosis, initial pathological diagnosis,
stage at initial diagnosis, baseline Eastern Cooperative Oncology Group performance status,
height, and weight will be summarized.  For some subsets of patients, intermediate and study 
entry pathological diagnosis data will also be listed.
5.4.3.2.
Historical Illnesses and Prior Therapies
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]) will be listed for all enrolled patients.
Prior therapies, including systemic therapy, radiotherapy, and surgeries will be listed for all
enrolled patients.  Prior radiotherapy and systemic therapy will be summarized by the number of
patients with at least 1 of each type of treatment, as well by reason for regimen (for example, 


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palliative, curative, etc.).  Additionally, the number of regimens of prior systemic therapy and, 
where available, the reason for prior regimens will be summarized.
5.4.4. Concomitant Therapy
Concomitant medications will be summarized and listed for the safety population.  
5.4.5. 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.  
5.4.6. Exposure
The following exposure-related variables will be reported using summary by phase and treatment
group:

exposure:  duration of treatment, number of cycles received, number of patients
completing ≥1 cycle, ≥2 cycles, …, x cycles, mean, and standard deviation

reasons for dose modification (delays, omissions, and reductions, scheduling conflict,
and AE summarized by preferred term [PT])

dose intensity:  weekly dose intensity and relative dose intensity
Details of study drug administration will be included in patient listings.
5.4.7. Safety Analyses
All patients who receive at least 1 dose of any study therapy will be evaluated for safety and 
toxicity.  
Safety measureas that will be used in the study include AEs, DLT (defined in protocol) in dose 
escalation phase, clinical laboratory test results and vital signs.  The MedDRA Version 22.0 (or 
higher) will be used when reporting AEs by MedDRA terms.  A treatment-emergent adverse 
event (TEAE) is defined as an event that first occurred or worsened in severity between the first 
dose of study treatment and 30 days after the last dose of study treatment and related serious AEs 
(SAEs) reported beyond 30 days after the last dose of study treatment. Immune-related adverse 
event (irAE) is also indicated in the database and will be summarized in the safety analysis. 
Safety analyses will include summaries of the following:

DLTs at each dose level in Part A and Part B

AEs, including severity and possible relationship to the study drug

DLT-equivalent AEs, including severity and possible relationship to the study drug

SAEs, summarized by PT and repeated for events deemed by the investigator to be 
possibly related to study treatment


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
irAEs, summarized by PT and repeated for events leading to dose delays or 
omissions, for events leading to discontinuations from study treatment, and for events 
leading to death

AEs leading to dose delays or omissions, summarized by PT

AEs leading to discontinuations from study treatment, summarized by PT and 
repeated for events deemed by the investigator to be possibly related to study 
treatment

AEs leading to death, summarized by PT and repeated for events deemed by the 
investigator to be possibly related to study treatment

reasons for deaths, summarized for all deaths, deaths on therapy, and deaths within 30 
days of treatment discontinuation

treatment-emergent abnormal changes in laboratory values

treatment-emergent abnormal changes in vital signs and electrocardiograms

Listings of all AEs, TEAEs, SAEs, and deaths will also be provided.

Listings of all laboratory data will be provided with a flag for values outside of the 
laboratory normal.  Abnormal results will be listed separately for all enrolled patients.  
5.4.8. Efficacy Analyses
The antitumor activity of LY3435151 in combination with pembrolizumab will be assessed 
based on RECIST 1.1 and iRECIST, respectively.  
The Kaplan-Meier method (Kaplan and Meier 1958) will be used to estimate the curves, median 
time, and 95% CI of time-to-event parameters such as overall survival (OS), progression-free 
survival (PFS), and duration of response (DoR) based on RECIST 1.1; iPFS (“i” indicates 
immune responses assigned using iRECIST) and iDoR based on iRECIST for each arm.  Overall 
response rate (ORR based on RECIST 1.1 and iORR based on iRECIST), with corresponding 
95% exact CI, will be summarized for each arm.  The details of the efficacy paramters are 
described below.
5.4.8.1.
Primary Efficacy Analyses
The ORR is defined as the number of patients who achieve a best overall response of CR or PR 
divided by the total number of patients treated (safety population).  The ORR, with 95% CI, will 
be summarized for each study part. Per RECIST 1.1 criteria, ORR for the single arm treatment 
within each tumor type will be calculated by confirmed best responses. Therefore, best overall 
response will be determined from a sequence of response assessments. Two objective status 
determinations of CR before progression are required for a best response of CR.  Two 
determinations of PR or better before progression, but not qualifying for a CR, are required for a 
best response of PR.  In the case of SD, measurements must have met the SD criteria at least 
once after study entry at a minimum interval not less than 6 weeks ±7 days measured from study 
entry.


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5.4.8.2.
Secondary Efficacy Analyses
The disease control rate (DCR), defined as the proportion of patients who achieved a CR or PR 
or stable disease (SD) out of all patients treated, will also be summarized. Per RECIST 1.1 
criteria, DCR for the single arm treatment within each tumor type will be calculated by 
confirmed best responses. See above for the details on the calculation of best responses with 
confirmation. 
The DoR is defined as the time from the date measurement criteria for CR or PR (whichever is 
first recorded) are first met until the first date of objective progression is observed, per RECIST 
1.1 criteria, or the date of death.  If a responder is not known to have died or have objective
progression, then the patient will be censored at the date of last evaluable tumor assessment.
Progression-free survival is defined as the time from the date of start of treatment to the first 
date of the observed clinical or radiologically documented progressive disease or death due to 
any cause, whichever occurs first.  For patients who are not known to have died or progressed as 
of the data inclusion cut-off date, PFS time will be censored at the date of the last objective 
progression-free disease assessment prior to the date of any subsequent systematic anticancer 
therapy. See Table JZIA.5.2 for details. 


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Table JZIA.5.2.
Progression-Free Survival Event/Censoring Scheme
Situationa
Event/Censor
Date of Event or Censor
Tumor progression or death
Event
Earliest date of progressive disease
or death
No tumor progression and no death
Censored
Date of last adequate tumor 
assessment, per RECIST 1.1, or date 
of first dose (whichever is later)b
Unless
No baseline radiologic tumor 
assessment available 
Censored
Date of first dose
No adequate postbaseline tumor 
assessment available and death 
reported after 2 scan intervals 
following the first doseb,c
Censored
Date of first dose
Tumor progression or death 
documented immediately after 2 or 
more scan intervals following last 
adequate tumor assessment or 
randomization (whichever is later)b,c
Censored
Date of last adequate tumor 
assessment, per RECIST 1.1, or date 
of first dose (whichever is later)b
New therapeutic anticancer 
treatment started prior to tumor 
progression or death
Censored
Date of last adequate radiological 
assessment prior to new therapeutic 
anticancer therapyb
Abbreviations:  CR = complete response; PR = partial response; RECIST = Response Evaluation Criteria in Solid 
Tumors; SD = stable disease.
a Symptomatic deterioration (that is, symptomatic progression that is not confirmed per RECIST 1.1) will not be 
considered as tumor progression.
b Adequate tumor assessment per RECIST 1.1 refers to an assessment with 1 of the following responses:  CR, PR, 
SD, or progressive disease.
c Refer to the statistical analysis plan for the definition of 2 scan intervals, including any adjustment for scan 
window.  
Time to response (TTR) is defined as the time from the date of start of treatment to the date 
measurement criteria for confirmed CR or PR (whichever is first recorded) are first met.  For 
patients who are not known to have achieved CR or PR as of the data inclusion cut-off date, TTR 
will be censored at the date of the last objective disease assessment prior the date of any 
subsequent systematic anticancer therapy.
5.4.8.3.
Exploratory Efficacy Analyses
Overall survival, as well as the efficacy parameters based on iRECIST, will also be analyzed as 
the exploratory objectives.  
The efficacy parameters based on iRECIST will also be analyzed as the exploratory objective.  
Overall response rate (iORR) is measured by the percentage of patients who achieved a iCR or 
iPR as their best overall response (iBOR) out of all treated patients (safety population).  The 


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iBOR is defined as the best response across all time point assessments based on RECIST 1.1 and 
iRECIST.  
Progression-free survival (iPFS) should be the date of randomization (the date of first dose for 
single-arm study) to the date at which progression criteria are first met (that is, the date of first 
unconfirmed progression [iUPD]) provided that iUPD or a sequence of consecutive iUPDs is 
confirmed by a confirmed progression (iCPD), the iUPD followed by only iUPDs at subsequent 
assessments, no more tumor assessments, or to the death date from any cause in the absence of 
progressive disease.  Patients known to be alive and without the iUPD as mentioned above as of 
the data inclusion cut-off date for a particular analysis will be censored at the time of the last 
adequate tumor assessment (a detailed iPFS event/censoring scheme is provided in the table 
below).  
Table JZIA.5.3.
Progression-Free Survival (iPFS) Event/Censoring Scheme
Situationa
Event/Censor
Date of Event or Censor
iUPD confirmed at next 
assessment (iCPD) or 
consecutive iUPD followed by 
an iCPD
Event
(First) iUPD date
iUPD followed by only iUPD 
at subsequent assessments and 
no further tumor assessment 
available.
Event
First iUPD date of the 
consecutive iUPDs
iUPD without subsequent 
assessment
Event
iUPD date
Death
Event
Death date if no iUPD date as 
in the above 3 situations 
before death.
No Death and no iUPD or 
iUPD is followed by 
iSD/iPR/iCR/
Censored
Date of last adequate tumor 
assessment per iRECIST, or 
date of randomization (first 
dose for single-arm study) 
(whichever is later)b
Confirmed iUPD (iCPD) or
death reported after 2 scan 
intervals following the last 
adequate tumor scan 
Censored
Date of last adequate tumor 
scan prior to confirmed iUPD 
(iCPD) or death
No baseline radiologic tumor 
assessment available 
Censored
Date of randomization (first 
dose for single-arm study)


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No adequate postbaseline 
tumor assessment available 
and death reported after 2 scan 
intervals following the first 
doseb,c
Censored
Date of randomization (first 
dose for single-arm study)
Abbreviations:  i = immune responses assigned using iRECIST; iCR = complete response; iPR = partial response; 
iSD = stable disease; iUPD=unconfirmed progression; iCPD = confirmed progression; iPFS = progression-free 
survival; RECIST  = Response Evaluation Criteria in Solid Tumors; SAP = statistical analysis plan.
a Symptomatic deterioration (that is, symptomatic progression that is not confirmed per iRECIST) will not be 
considered as tumor progression.
b Adequate tumor assessment per iRECIST refers to an assessment with one of the following responses:  iCR, iPR, 
iSD, iUPD, or iCPD.
c Refer to the statistical analysis plan for the definition of 2 scan intervals, including any adjustment for scan 
window (new anticancer therapy in SAP).
Duration of response (iDoR) is defined as the time from the date measurement criteria for iCR 
or iPR (whichever is first recorded) are first met until the first date that disease is recurrent or 
objective progression (as assessed by investigators) is observed, or the date of death from any 
cause in the absence of objectively determined disease progression or recurrence.  Patients 
known to be alive and without disease progression as of the data inclusion cut-off date for a 
particular analysis will be censored at the time of the last adequate tumor assessment.  Duration 
of response will follow the same censoring scheme as iPFS.  Duration of response will be 
analyzed for the treated patients who achieve iCR/iPR as the iBOR.  
5.5.
Pharmacokinetic/Pharmacodynamic Analyses
Selected PK descriptors for LY3435151 (based on actual sampling times), including maximum 
concentration under the area versus time curve (Cmax), approximate time of Cmax, and area under 
the concentration versus time curve (AUC) will be calculated by noncompartmental analysis 
methods and/or model simulations.  As an exploratory analysis, PK descriptor estimates for 
trough concentrations at steady state following a repeated dose may be evaluated.  
In addition, PK parameter estimates for LY3435151 as a single agent and in combination may be 
calculated by population PK analysis methods using NONMEM, data allowing.  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 Global PK/PD management.
Pharmacokinetic/PD analyses may be conducted to explore exposure-response relationships 
between LY3435151 concentrations in systemic circulation and various PD measures as second 
step if dose-response relationship is positively assessed.
5.6.
Evaluation of Immunogenicity
The frequency and percentage of participants with preexisting antidrug antibodies (ADAs) and 
with treatment-emergent ADA positive (TE-ADA+) to LY3435151 will be tabulated.  
Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) greater than the 


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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 TE-ADA+ participants, the distribution of maximum 
titers will be described.  The frequency of neutralizing antibodies will also be tabulated in TE-
ADA+ patients if assessed.
The relationship between the presence of ADAs to LY3435151 and the PK parameters and PD 
response, including safety and efficacy, to LY3435151 may be assessed.
5.7.
Biomarker Analyses
Single-marker and/or multimarker statistical analysis may be performed to explore the 
association between biomarkers, dose/exposure, and clinical outcomes.  Details will be described 
in a separate Biomarker SAP.  
5.8.
Interim Analyses
Because this is a dose-finding study, safety and PK/PD data (if available) will be reviewed on a 
cohort-by-cohort basis during the study, until the MTDs (or the highest dose levels if MTDs are 
not reached) are determined for each treatment part.  The purpose of these cohort-by-cohort 
reviews is to evaluate the safety data at each dose level and determine if a DLT has been 
observed that would suggest the MTD has been met or exceeded.  After all patients who are 
deemed evaluable for the assessment of dose levels complete the DLT observation period or the 
MTD is determined, an interim safety and PK analysis will be conducted for planning next 
studies.
For the dose expansion phase, when the clinical efficacy data and PK/PD data of approximately 
the first 20 participants are available in each combination dose expansion cohort of TNBC and 
GC (Cohort D1 and Cohort D2), an interim data review, including but not limited to safety, 
efficacy, and PK/PD will be conducted within each cohort.  If the results of the data review for a 
particular cohort under combination therapy warrant a positive benefit-risk profile, additional 
patients will be enrolled to the corresponding tumor type in the combination dose expansion 
(Cohort D1 or Cohort D2) until approximately 40 patients are enrolled.
It is planned that enrollment can continue while interim analyses are conducted, but the sponsor 
may decide to pause the enrollment, if necessary.  Other interim analyses may be conducted if 
deemed appropriate by the sponsor.  The interim analyses may be combined with any 
prespecified safety review or annual reporting (for example, an update to the Investigative 
Brochure or Development Safety Update Review).
If it is deemed that enough data are obtained to assess the primary objective and the secondary 
objectives, a CSR might be created before the last patient visit.  In this case, all data until the 
data cut-off 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 the data
cut-off date.  These data may be reported separately and the analyses on all patients, including 
these data, may not be performed.


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6.
References
Iasonos A, O’Quigley J. Design considerations for dose-expansion cohorts in phase I trials. J 
Clin Oncol. 2013;31(31):4014-4021.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Am Stat Assoc.
1958;53:457-481.


Leo Document ID = 7c644556-2002-42a3-b0e1-0589c7af8047
Approver: 
Approval Date & Time: 04-Oct-2019 13:09:11 GMT
Signature meaning: Approved
PPD