A Phase 1 Multicenter Global First in Human Study of the CD73 Inhibitor LY3475070 as Monotherapy or in Combination With Pembrolizumab in Patients With Advanced Solid Malignancies
Phase: PHASE1
Conditions: Advanced Cancer
Sponsor: Eli Lilly and Company

 
 
 
 
Protocol J2I-MC-JZMA(d) 
 
 
A Phase 1 Multicenter Global First in Human Study of the CD73 Inhibitor 
LY3475070 as Monotherapy or in Combination with Pembrolizumab in Patients 
with Advanced Solid Malignancies 
 
 
NCT04148937 
 
 
Approval Date: 02-Sep-2020 

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
1
Title P a ge
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al 
i n v e sti g ati o n of L Y 3 4 7 5 0 7 0 , u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d C o m p a n y or it s 
s u b si di ari e s.  
N ot e t o R e g ul at or y A ut h oriti e s:   T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or c o m m er ci all y c o nfi d e nti al 
i nfor m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.  Eli Lill y a n d C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y 
p u bli c r el e a s e.  I n t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) E x e m pti o n 4 a n d m a y n ot b e 
r epr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
Pr ot oc ol Title:
A P hase 1 M ul tice nter Glo b al  First i n H u ma n St u d y  of t he C D 7 3 In hi bit or 
L Y 3 4 7 5 0 7 0 as M o n ot hera p y  or i n C o m bi nat i on wit h P e m br o liz u ma b i n Patient s wit h A d va nce d 
S oli d Mali g na ncies
Pr ot oc ol N u m ber:
J 2I-M C -J Z M A
A me n d me nt N u m ber : d
C o m p o u n d N u m ber:
L Y 3 4 7 5 0 7 0
St u d y P h ase: Earl y P h ase 1 
S h ort Title: A P hase 1 St u d y o f t he C D 7 3 I n hi bitor L Y 3 4 7 5 0 7 0 i n Patie nts wit h A d va nce d 
S oli d Mali g na ncies
S p o ns or N a me: El i Lill y a n d C o m pa n y
Le g al Re gistere d A d dress:
I n dia na p olis, I n dia na U S A 4 6 2 8 5 
Re g ul at or y A ge nc y I de ntifier N u m ber(s)
I N D:  1 4 4 9 0 3
E u dr a C T:  2 0 1 9- 0 0 3 2 7 0- 6 4
A p pr o v al D ate:   Pr ot oc ol El e ctr o nicall y Si g ne d a n d A p pr o ve d b y Lill y : 2 3 -A u g -2 0 1 9 G M T .
Pr ot oc ol A me n d me nt (a) Electr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n : 0 2-Oct -2 0 1 9 G M T .
Pr ot oc ol A me n d me nt ( b ) Ele ctr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n : 2 4- Fe b- 2 0 2 0 G M T.
Pr ot oc ol A me n d me nt ( c) Electr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n : 2 2- Mar -2 0 2 0 G M T.
Pr ot oc ol  A me n d me nt (d ) Electr o nicall y Si g ne d a n d A p pr o ve d b y Lill y o n t he date bel o w.
A p pr o v al D at e: 0 2- S e p- 2 0 2 0 G M T

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
2
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Protocol J2I-MC-JZMA
23-Aug-2019
Protocol J2I-MC-JZMA Amendment (a)
02-Oct-2019
Protocol J2I-MC-JZMA Amendment (b)
24-Feb-2020
Protocol J2I-MC-JZMA Amendment (c)
22-Mar-2020
Amendment d
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union.
Overall Rationale for the Amendment:
The purpose of this amendment is to allow metastatic castrate-resistant prostate cancer (mCRPC)
patients with non-measurable disease for trial participation.
Section # and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis; 
Section 4.1 Overall Design; 
4.1.1 Dose Escalation; 
Section 9.2 Sample Size 
Determination
Added language for backfill 
patients; updated language for 
sample size
Backfill patients included to 
improve understanding of 
safety, PK, and 
pharmacodynamics of 
LY3475070
Section 1.1 Synopsis; 
Section 4.1 Overall Design; 
Section 6.1 Study 
Intervention(s) 
Administered
Added additional guidance on
BID dosing
Additional guidance and 
clarity regarding BID dosing
Section 1.3, Schedule of 
Activities (Baseline, On-
Study and Post-Study 
Treatment Follow-up)
Revised CT/MRI assessment 
window
Updated to correct 
discrepancy between Section 
1.3 and Section 8.1 for 
enrollment and study 
participation purposes
Section 1.3, Schedule of 
Activities (Baseline, On-
Study and Post-Study 
Treatment Follow-up)
Added additional PSA sampling, 
radionuclide bone scan
Updated for enrollment and 
study participation purposes
Section 1.3, Schedule of 
Activities (Continued 
Access Follow-up Visits)
Clarified pregnancy testing 
requirements during continued 
access period
Clarification
Section 1.3.1 Sampling 
Schedule for 
Pharmacokinetics and 
Biomarkers
Added sampling for circulating 
tumor cells for mCRPC patients 
only
Updated for enrollment and 
study participation purposes

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
3
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 5. 1 I ncl usi o n 
Cri teria
F or I ncl usi on Cri t eria 3f a n d 7f, 
a d de d e xcl usi o n f or C R P C 
pati e nts wit h s mall-cell or 
ne ur oe n d ocri ne hist o l ogies.
I ncl usi on Cri t eria 1 1, a d de d 
e xce pti o n f or pati e nts i n P hase 1a 
p orti o n of  trial ( d ose escalati on) 
a n d m C R P C pat ient s i n C o h orts 
D 1 a n d D 2 t hat t hese pat ient s are 
n ot re q uire d t o ha ve meas ura ble 
di sease.
U p date d f or e nr oll me nt a n d 
st u d y partici patio n p ur p oses
Secti o n 6. 5 C o nc o mita nt 
T hera p y
U p date d c o nc o mita nt me dicat i on 
la n g ua ge t o reflect greater 
certai nt y re gar di n g e nz y mes 
i n v ol ve d i n t he meta b olis m of 
L Y 3 4 7 5 0 7 0.
U p date d l a n g ua ge re gar di n g 
c o nc o mita nt use of z ole dr o nic 
acid a n d de n os u m a b.
Re m o ve d r efere nces t o s pecific 
f oo ds or be ha vi ors t o a v oid.
Cl arificat i on
Secti o n 8. 1. 3 Efficac y 
Assess me nt f or m C R P C 
P ati e nts
A d de d ne w sect i on t o descri be 
assess me nts t o be use d f or 
m C R P C patie nts wit h meas ura ble 
or n o n -meas ura ble disease.
U p date d f or e nr oll me nt a n d 
st u d y partici patio n p ur p oses
Secti o n 8. 8 Bi o m ar kers
A d de d te xt t o all o w f or 
s u b missi on of arc hi val tiss ue 
fr o m rece nt bio ps y .  
A d de d te xt f or use of fi ne -nee dle 
as pirati on s peci me ns f or N S C L C 
pati e nts o nl y u p o n disc ussio n  
wi t h Lill y C R P/ C R S .
U p date d f or e nr oll me nt a n d 
st u d y partici patio n p ur p oses
Secti o n 1 0. 2 A p pe n di x 2: 
Cli nical La b orat or y  Tests
A d de d a m ylase a n d li pase t o 
l ocal cli nical c he mistr y a nal yt es
A m ylase a n d li pase were 
a d de d i n or der t o detect a n y 
p ossi ble cases of 
i m m u ne-me diate d pa ncreatit is
T hr o u g h o ut pr ot oc ol
Mi n or f or m atti n g a n d e dit orial 
c ha n ges
Mi n or, t heref ore n ot
detaile d
C CI

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
4
Table of Contents
Protocol Amendment Summary of Changes Table..................................................................2
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.......................................................................................................................11
1.3.
Schedule of Activities (SoA) ......................................................................................13
1.3.1.
Sampling Schedule for Pharmacokinetics and Biomarkers..........................................22
2.
Introduction..............................................................................................................25
2.1.
Study Rationale ..........................................................................................................25
2.2.
Background ................................................................................................................26
2.2.1.
LY3475070 ................................................................................................................26
2.2.2.
Pembrolizumab...........................................................................................................27
2.3.
Benefit/Risk Assessment ............................................................................................27
3.
Objectives and Endpoints.........................................................................................29
4.
Study Design .............................................................................................................33
4.1.
Overall Design............................................................................................................33
4.1.1.
Dose Escalation ..........................................................................................................34
4.1.2.
In Vitro Diagnostic Utilization....................................................................................35
4.2.
Scientific Rationale for Study Design .........................................................................36
4.3.
Justification for Dose..................................................................................................36
4.3.1.
LY3475070 ................................................................................................................36
4.3.2.
Pembrolizumab...........................................................................................................37
4.4.
End of Study Definition..............................................................................................38
5.
Study Population ......................................................................................................39
5.1.
Inclusion Criteria........................................................................................................39
5.2.
Exclusion Criteria.......................................................................................................43
5.3.
Lifestyle Considerations .............................................................................................46
5.4.
Screen Failures...........................................................................................................46
6.
Study Intervention....................................................................................................47
6.1.
Study Intervention(s) Administered ............................................................................47
6.1.1.
Definition of DLT and DLT-ET..................................................................................48
6.1.2.
Definition of RP2D.....................................................................................................50
6.2.
Preparation/Handling/Storage/Accountability.............................................................50
6.3.
Measures to Minimize Bias:  Randomization and Blinding .........................................50
6.4.
Study Intervention Compliance...................................................................................50
6.5.
Concomitant Therapy .................................................................................................51
6.5.1.
Palliative Medicine and Supportive Care for LY3475070 ...........................................52
6.6.
Dose Modification......................................................................................................53
6.6.1.
Dose Modification and Toxicity Management of LY3475070 for 
Non-immune-mediated AEs Associated with LY3475070 and/or 
in Combination with Pembrolizumab..........................................................................53

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
5
6.6.2.
Dose Modification and Toxicity Management for Immune-
Related AEs Associated with LY3475070 and/or in Combination 
with Pembrolizumab...................................................................................................62
6.6.3.
Other allowed dose interruption for pembrolizumab ...................................................67
6.7.
Intervention after the End of the Study........................................................................67
6.7.1.
Treatment after Study Completion ..............................................................................67
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................68
7.1.
Discontinuation of Study Intervention ........................................................................68
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................69
7.2.1.
Discontinuation of Inadvertently Enrolled Patients .....................................................69
7.3.
Lost to Follow up .......................................................................................................70
8.
Study Assessments and Procedures .........................................................................71
8.1.
Efficacy Assessments .................................................................................................71
8.1.1.
RECIST V1.1 for Tumor Response Assessment..........................................................71
8.1.2.
iRECIST For Confirmation of PD in Clinically Stable Patients 
and Radiologic PD per RECIST v1.1..........................................................................72
8.1.3.
Efficacy Assessment for mCRPC Patients ..................................................................75
8.2.
Safety Assessments ....................................................................................................75
8.2.1.
Clinical Safety Laboratory Assessments .....................................................................76
8.3.
Adverse Events and Serious Adverse Events ..............................................................78
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................80
8.3.2.
Follow-up of AEs and SAEs.......................................................................................81
8.3.3.
Regulatory Reporting Requirements for SAEs............................................................81
8.3.4.
Pregnancy...................................................................................................................81
8.3.5.
Cardiovascular and Death Events................................................................................81
8.3.6.
Complaint Handling ...................................................................................................82
8.3.7.
Events of Clinical interest...........................................................................................82
8.4.
Treatment of Overdose ...............................................................................................82
8.5.
Pharmacokinetics........................................................................................................82
8.6.
Pharmacodynamics.....................................................................................................83
8.7.
Genetics .....................................................................................................................83
8.7.1.
Whole Blood Sample for Pharmacogenetic Research..................................................83
8.8.
Biomarkers.................................................................................................................84
8.8.1.
Tumor Tissue Samples for Determination of CD73 Expression...................................86
8.9.
Medical Resource Utilization and Health Economics..................................................86
9.
Statistical Considerations.........................................................................................87
9.1.
Statistical Hypotheses.................................................................................................87
9.2.
Sample Size Determination.........................................................................................87
9.3.
Populations for Analyses ............................................................................................89
9.4.
Statistical Analyses.....................................................................................................89
9.4.1.
General Statistical Considerations...............................................................................89
9.4.2.
Treatment Group Comparability .................................................................................89
9.4.3.
Efficacy Analyses.......................................................................................................90

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
6
9. 4. 4.
S af et y A nal yses ..........................................................................................................9 2
9. 4. 5.
P har mac o ki net ic/ P har mac o d y na mic A nal yses ............................................................9 2
9. 4. 6.
Ot her A nal yses ...........................................................................................................9 3
9. 5.
I nteri m A nal yses.........................................................................................................9 3
1 0.
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns ................................9 5
1 0. 1.
A p pe n di x 1:  Re g ulat or y , Et hical, a n d St u d y O versi g ht 
C o nsi derati o ns ............................................................................................................9 5
1 0. 1. 1.
Re g ulat or y  a n d Et hical C o nsi derati ons ........................................................................9 5
1 0. 1. 2.
I nf or me d C o nse nt Pr ocess ..........................................................................................9 5
1 0. 1. 3.
Data Pr otecti o n ...........................................................................................................9 6
1 0. 1. 4.
Di sse mi nati on of Cli nical St u d y  Data .........................................................................9 6
1 0. 1. 5.
Data Q ualit y Ass ura nce ..............................................................................................9 6
1 0. 1. 6.
S o urce D oc u me nts ......................................................................................................9 7
1 0. 1. 7.
St u d y  a n d Sit e Clos ure ................................................................................................9 8
1 0. 2.
A p pe n di x 2:  Cli nical La b orat or y  Tests.......................................................................9 9
1 0. 3.
A p pe n di x 3:  C o ntrace pti ve G ui da nce a n d C ollecti o n of 
Pre g na nc y I nf or mati o n .............................................................................................1 0 2
1 0. 4.
A p pe n di x 4:  Li ver Safet y:   S u g geste d Actio ns a n d F oll o w -u p 
Assess me nts .............................................................................................................1 0 5
1 0. 5.
.................................................1 0 6
1 0. 6.
A p pe n di x 6:  Creati ni ne Cleara nce F or m ula ..............................................................1 0 8
1 0. 7.
A p pe n di x 7:  C o u ntr y -s pecific Re q uire me nts............................................................1 0 9
1 0. 7. 1.
Di sc o nti n uatio n of  I na d verte ntl y Enr olle d Patie nts i n t he U K ...................................1 0 9
1 0. 8.
A p pe n di x 8:  D ose -Fi n di n g Al g orit h m of t he M o difie d T o xicit y 
Pr o ba bilit y I nter val -2 Met h o d S h o wi n g N u m ber of Patie nts 
Treate d .....................................................................................................................1 1 0
1 0. 9.
A p pe n di x 9:  A b bre viat i ons ......................................................................................1 1 1
1 0. 1 0.
A p pe n di x 1 0:  Pr ot oc ol A me n d me nt Hist or y ............................................................1 1 6
1 1.
Refere nces ...............................................................................................................1 2 0
C CI

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
7
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Phase 1 Multicenter Global First in Human Study of the CD73 Inhibitor
LY3475070 as Monotherapy or in Combination with Pembrolizumab in Patients with Advanced 
Solid Malignancies
Short Title: A Phase 1 Study of the CD73 Inhibitor LY3475070 in Patients with Advanced 
Solid Malignancies
Rationale: Approximately 50 to 80% of advanced cancers patients experience progressive 
disease (PD) as their best objective response to immune checkpoint inhibitors (ICIs) such as 
ipilimumab, nivolumab, pembrolizumab or atezolizumab, suggesting the presence of tumor 
clones that are primarily resistant to ICI monotherapy. In addition, most patients whose tumor 
initially responded to ICI eventually develop PD, further suggesting that tumor clones can
acquire resistance in the face of active therapies. 
While immune escape by cancer is likely a multi-faceted phenomenon, adenosine signaling 
within the tumor microenvironment has been shown to promote immunosuppression and cancer 
growth. CD73, an ecto-5′-nucleotidase, catalyzes the conversion of adenosine monophosphate to 
adenosine, an immune suppressive metabolite.  The CD73-adenosine axis facilitates cancer cell 
immune escape and promotes resistance to ICIs; therefore, targeting CD73 has the potential to 
become a novel cancer treatment. J2I-MC-JZMA (hereafter known as JZMA) will evaluate
safety, tolerability and anti-tumor activity of LY3475070 alone or in combination with 
pembrolizumab in advanced cancer patients. 
Objectives and Endpoints: 
Phase 1a: 
Objectives
Endpoints
Primary

To determine a safe dose of 
LY3475070 as monotherapy and in 
combination treatment with 
pembrolizumab to be further evaluated 
and confirmed in the Phase 1b portion 
of the study (recommended Phase 1b 
dose)

DLTs 

Assessment of safety including, but not 
limited to, TEAEs, SAEs, deaths, and 
clinical lab abnormalities per CTCAE 
v5.0 
Secondary

To characterize the LY3475070 PK 
profile as monotherapy and in 
combination with pembrolizumab

Cmax, trough (Cmin, Csteady state), AUCsteady
state

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
8
Objectives
Endpoints

To characterize the clinical activity of 
LY3475070 as monotherapy and in 
combination with pembrolizumab as 
assessed by the investigator using 
RECIST v1.1

ORR

DCR

PFS 
Abbreviations:  AUC = area under the curve; Cmax = maximum blood plasma concentration; Cmin = minimum blood 
plasma concentration; CTCAE = Common Terminology Criteria in Adverse Events; DLT = dose limiting 
toxicities; DCR = disease control rate; ORR = overall response rate; PFS = progression-free survival; PK = 
pharmacokinetics; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; 
TEAE = treatment-emergent adverse event.
Phase 1b: 
Objectives
Endpoints
Primary

To establish the RP2D of LY3475070 
as monotherapy and in combination 
treatment with pembrolizumab

To assess the safety, tolerability and 
clinical activity of LY3475070 as 
monotherapy and in combination with 
pembrolizumab

Assessment of safety including, but 
not limited to, TEAEs, SAEs, deaths, 
and clinical lab abnormalities per 
CTCAE v5.0

Investigator assessed ORR per 
RECIST v 1.1
Secondary

To characterize the LY3475070 PK 
profile as monotherapy and in 
combination with pembrolizumab

Cmax, trough (Cmin, Csteady state), 
AUCsteady state

To characterize the clinical activity of 
LY3475070 as monotherapy and in 
combination with pembrolizumab as 
assessed by the investigator using 
RECIST v1.1

DOR

DCR

TTR

PFS 

OS
Abbreviations:  AUC = area under the curve; Cmax = maximum blood plasma concentration; Cmin = minimum blood 
plasma concentration; CD73 = cluster of differentiation 73;CTCAE = Common Terminology Criteria in Adverse 
Events; DCR = disease control rate; DOR = duration of response; NSCLC = non-small cell lung cancer; ORR = 
overall response rate; OS = overall survival; PD-1/L1 = programmed cell death protein-1/ligand 1; PFS = 
progression-free survival; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid Tumors; 
SAE = serious adverse event; RCC = renal cell carcinoma; RP2D = recommended phase 2 dose; TEAE = 
treatment-emergent adverse event; TTR = time to response.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
9
Overall Design:
Study JZMA is an open-label, multi-center, Phase 1 study of LY3475070, a CD73 inhibitor,
alone or in combination with pembrolizumab in patients with advanced solid tumors.
In Cohort A of Phase 1a, single agent LY3475070 will be evaluated in at least 3 evaluable 
patients per dose level (DL). Dose escalation will be guided by the modified toxicity probability 
interval 2 (mTPI-2) method.  It is anticipated that 4 dose levels will be evaluated to determine the 
recommended phase 1b dose of single agent LY3475070.  Once the dose level DL2 (300 mg 
once a day [QD]) for single agent LY3475070 has been determined safe and tolerable, 
LY3475070 in combination with pembrolizumab is planned to be evaluated at 3 dose levels in 
Cohort B, starting at combination dose level 1 (150 mg QD). 
Phase 1b of the study aims to confirm the recommended phase 2 dose (RP2D) for LY3475070 
monotherapy and LY3475070 in combination with pembrolizumab, and to further evaluate 
safety and preliminary efficacy in 3 patient cohorts: 

Cohort C will consist of patients with programmed cell death protein-1/ligand 1 
(PD-1/L1) refractory non-small cell lung cancer, renal cell cancer, or melanoma who are
positive for CD73 expression centrally-assessed by immuno-histochemistry.  To 
minimize physician/patient selection bias, patients will be randomized to either single 
agent LY3475070 (Cohort C2) or combination therapy of LY3475070 and 
pembrolizumab (Cohort C1).

Cohort D will consist of men with metastatic castrate resistant prostate cancer; eligible 
patients must be naïve to PD-1/L1 therapy.  To minimize physician/patient selection bias, 
patients will be randomized to either single agent LY3475070 (Cohort D2) or
combination therapy of LY3475070 and pembrolizumab (Cohort D1).

Cohort E will consist of patients with metastatic triple negative breast cancer who have
received at least 1 line of systemic treatment for metastatic disease; prior PD-1/L1 
inhibitor is allowed but not required. Patients will receive combination therapy of 
LY3475070 and pembrolizumab.
Disclosure Statement: This is a treatment study with dose escalation and dose expansion phases
that has no blinding or masking.
Number of Participants:
Dose Escalation (Phase 1a): Maximum of 62 patients

Monotherapy Cohort (Cohort A): Approximately 12 to 24 patients will be enrolled.

Combination Cohort (LY3475070 with pembrolizumab; Cohort B): Approximately 9 to
18 patients will be enrolled.

Backfill patients to both Cohort A and Cohort B: up to 20 patients.
In the dose escalation phase, once a given DL is cleared for DLT evaluation and is deemed safe, 
the dose cohort may be expanded (i.e., backfilled) to further investigate the safety, 
pharmacokinetic (PK), pharmacodynamic, and clinical activity.  
Dose expansion (Phase 1b):  Approximately up to 140 patients

Cohort C (patients with CD73+ tumors): up to 50 patients will be enrolled

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
10

Cohort D (castrate resistant prostate cancer): up to 50 patients will be enrolled

Cohort E (triple negative breast cancer): up to 40 patients will be enrolled
Intervention Groups and Duration
Cohort
Dose Level
Oral LY3475070
IV Pembrolizumab
Cohort A
DL1
150mg QD
N/A
DL2
300mg QD
N/A
DL3
600mg QD
N/A
DL4
1000mg QD
N/A
Cohort B
CDL1
150mg QD
200 mg Q3W
CDL2
300mg QD
200 mg Q3W
CDL3
600mg QD
200mg Q3W
Cohorts C1, D1 and E
RP1Dc
RP1D/MTD
200 mg Q3W
Cohorts C2 and D2
RP1Dm
RP1D/MTD
N/A
Abbreviations:  CDL = combination dose level; DL = dose level; IV = intravenous; MTD = maximum tolerated 
dose; N/A = not applicable; Q3W = every 3 weeks; QD = once a day; RP1D = recommended phase 1 dose; 
RP1Dc = recommended phase 1 dose (for combination therapy); RP1Dm = recommended phase 2 dose (for 
monotherapy).
Note:  Pembrolizumab should be administered for a maximum duration of 24 months (35 cycles).
LY3475070 is to be administered until PD, unacceptable toxicity or other criterion for study 
discontinuation is met. In the absence of PD, unacceptable toxicity or other criterion for study 
discontinuation is met; pembrolizumab may be administered for a maximum duration of 24 
months (35 cycles). 
The above table shows the provisional dose levels that will be explored, ranging from 150 mg to 
1000 mg QD of LY 3475070. Depending on PK, pharmacodynamic, and safety data observed,
not all the provisional dose levels may be explored.  A dose level −1 (DL−1 = 75 mg) may be 
explored if a dose of 150 mg QD (DL1) is not tolerated or if otherwise warranted based on the 
assessment of PK, PD, and safety data.  Intermediate and/or higher dose levels as well as 
alternative schedules (e.g., 2 times a day [BID] dosing instead of QD) may be explored after 
discussion between Lilly and investigators if deemed appropriate based on the assessment of 
patient safety, PK, and PD data.  The total dose of LY3475070 is not planned to exceed 1200 mg 
per 24 hours. If BID dosing is evaluated, patients will take doses 12±2 hours apart (i.e., 10 to 14 
hours between doses). There should at least be 10 hours between each subsequent dose. 
Data Monitoring Committee:  No

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
11
1.2.
Schema

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
12
Abbreviations: CD73 = cluster of differentiation 73; CDL = combination dose level; DL = dose level; mCRPC = 
metastatic castrate resistant prostate cancer; MTD = maximum tolerated dose; NSCLC = non-small cell lung 
cancer; PD-1 = programmed cell death-1; PD-1/L1 = programmed cell death-1/ligand 1; R = randomization; 
RCC = renal cell carcinoma; ref = refractory; RP1D = recommended phase 1 dose; TNBC = triple negative 
breast cancer.
a
If supported by data analysis, an additional 20 patients will be added (i.e., backfilled)

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
13
1.3.
Schedule of Activities (SoA)
This section includes the following SoAs:

Baseline, On-Study and Post-Study Treatment Follow-Up SoA 

Continued Access SoA

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
14
Baseline, On-Study and Post-Study Treatment Follow-up SoA
Baseline
Cycle = 21 days
Short-Term Follow Upa
Long-
Term 
Follow-Upb
(Day Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 
3-n
801
802
803
804-X
Instructions
(±3 days)
(±3 days)
(±3 
days)
30 day 
follow-
up ±5 
days
60 day 
follow-
up ±5 
days
90 day 
follow-
up ±5 
days
Q90D
≤28
≤7
D1
D2
D8
D15
D1
D2
D1
Procedure
Informed consent (Main 
and Phase 1b Cohort C 
consent)
X
Main ICF must be signed before any 
protocol-specific procedures are performed 
and Phase 1b Cohort C ICF prior to tissue 
collection for CD73 testing
Inclusion/exclusion criteria
X
Medical history
X
Including assessment of preexisting 
conditions and historical illnesses, and 
habits (such as tobacco and alcohol use).
Cancer treatment history
X
Record prior anticancer therapy
Concomitant medication
X
X
X
X
X
See Section 6.5
Physical examination
X
X
X
X
X
X
Collect weekly during Cycle 1, and then on 
D1 of every cycle thereafter.
A partial physical examination may be 
performed by a healthcare professional other 
than the physician on C1D8 and C1D15.
Vital signs
X
See Section 1.3.1.
X
X
Collect weekly during Cycle 1, and then on 
D1 of every cycle thereafter.
Please collect vitals as follows:
- At baseline only:  Height,
- At D1 of every cycle:  Weight, 
- At every schedule visit:  Temperature, 
blood pressure, pulse rate, respiratory rate, 
and pulse oximetry. 
Please refer to Section 1.3.1. for detailed 
collection pertaining to collection on C1D1-
C3-n (D1). 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
15
Baseline, On-Study and Post-Study Treatment Follow-up SoA
Baseline
Cycle = 21 days
Short-Term Follow Upa
Long-
Term 
Follow-Upb
(Day Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 
3-n
801
802
803
804-X
Instructions
(±3 days)
(±3 days)
(±3 
days)
30 day 
follow-
up ±5 
days
60 day 
follow-
up ±5 
days
90 day 
follow-
up ±5 
days
Q90D
≤28
≤7
D1
D2
D8
D15
D1
D2
D1
Procedure
AE collection
X
X
Collect continuously at every visit and 
throughout the study using CTCAE Version 
5.0.  During the 30-, 60-, and 90-day follow-
up visits, collect all AEs/SAEs.  Thereafter, 
collect only SAEs related to study treatment 
or protocol procedures
Collection of survival 
information
X
Telephone contact is acceptable.
Collection of poststudy-
treatment anticancer 
therapy information
X
ECOG PS
X
X
X
X
X
During study treatment, perform ≤3 days 
prior to scheduled visits
ECHO or MUGA
X
Please perform locally.
ECG
See Section 
1.3.1.
See Section 1.3.1.
See 
Section 
1.3.1.
Please perform locally.
Hematology
X
X
X
X
X
X
X
See Appendix 2.  Please collect weekly
during cycle 1, then Q3W thereafter.  If 
baseline testing is collected ≤3 days prior to 
C1D1, repeat testing is not required.
Coagulation
X
X
X
X
X
X
X
See Appendix 2.  Please collect weekly 
during cycle 1, then Q3W thereafter.  If 
baseline testing is collected ≤3 days prior to 
C1D1, repeat testing is not required.

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
1 6
B aseli ne, O n -St u d y a n d P ost -St u d y Tre at me nt F oll o w -u p S o A
B aseli ne
C ycle = 2 1 d a ys
S h ort -Ter m F oll o w U p a
L o n g -
Ter m 
F oll o w -U p b
( D a y Rel ati ve t o 
C 1 D 1)
C ycle 1
C ycle 2
C ycle 
3- n
8 0 1 
8 0 2 
8 0 3 
8 0 4 - X
I nstr ucti o ns
( ± 3 da ys)
( ± 3 da ys)
( ± 3 
da ys)
3 0 da y 
f oll o w-
u p ± 5 
da ys
6 0 da y 
f oll o w-
u p ± 5 
da ys
9 0 da y 
f oll o w-
u p ± 5 
da ys
Q 9 0 D
≤2 8
≤7
D 1  
D 2  
D 8
D 1 5
D 1  
D 2  
D 1
Pr oce d ure
Cli nical c he mis tr y
X
X
X  
X  
X
X  
X
Please c ollect wee kl y d uri n g c ycle 1, t he n 
Q 3 W t hereafter .  If baseli ne testi n g is 
c ollecte d ≤3 da ys pri or t o C 1 D 1, re peat 
testi n g is n ot re q uire d.  See A p pe n di x 2. 
Uri nal ysis
X
X
X
X  
X
Please c ollect p er S o A .  If baseli ne testi n g is 
c ollecte d ≤3 da ys pri or t o C 1 D 1, re peat 
testi n g is n ot re q uire d.  See A p pe n di x 2. 
X
X
X
X  
X
Please c ollect D 1 of first 3 c ycles .  T h e n 
Q 6 W t hereafter ( e. g., C 5 D 1, C 7 D 1 etc .).  If 
baseli ne testi n g is c ollecte d ≤7 da ys pri or t o 
C 1 D 1, re peat testi n g is n ot re q uire d .  See 
A p pe n di x 2. 
T h yr oi d f u ncti o n testi n g
X
X
See 
I nstr u
cti o ns
X
Starti n g C 3 D 1, t he n D 1 e ver y ot her c ycle .  
If baseli ne testi n g is c ollecte d ≤3 da ys pri or 
t o C 1 D 1, re peat testi n g is n ot re q uire d.  See 
A p pe n di x 2. 
T u m or mar kers 
X
See I nstr ucti o ns
C ollect t u m or mar kers o nl y f or 
c orres p o n di n g t o ca ncer t y pe:
P S A - Pr ostate
F or m C R P C patie nts wit h n o n meas urea ble 
disease , P S A s h o ul d be c ollecte d e ver y 
3 wee ks (f or t he first 1 2 wee ks of t hera p y) 
a n d e val uate d e ver y 9 wee ks f or pr o gressi o n 
after t he first e val uati o n peri o d (at 
1 2 wee ks).
See Secti o n  8. 1. 3 a n d 
A p pe n di x 2 f or f urt her details.
C E A - Pa ncreatic
C A -1 2 5 - O varia n
C A 1 9 -9 - Pa ncreatic
F or ot her i n dicati o ns please c ollect rele va nt 
t u m or mar kers (e. g., C A 1 9-9) Q 6 W 
C CI

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
17
Baseline, On-Study and Post-Study Treatment Follow-up SoA
Baseline
Cycle = 21 days
Short-Term Follow Upa
Long-
Term 
Follow-Upb
(Day Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 
3-n
801
802
803
804-X
Instructions
(±3 days)
(±3 days)
(±3 
days)
30 day 
follow-
up ±5 
days
60 day 
follow-
up ±5 
days
90 day 
follow-
up ±5 
days
Q90D
≤28
≤7
D1
D2
D8
D15
D1
D2
D1
Procedure
throughout the study (C1D1, C3D1, etc.).  
See Appendix 2.
Pregnancy test
X
≤24h
See Instructions
X
X
X
Applies only to women of childbearing 
potential. See Section 8.3.4. for 
pembrolizumab-specific requirements and 
Appendix 2. Pregnancy test required at 
monthly intervals during study treatment in 
both treatment arms and up to 120 days after 
study treatment discontinuation for patients 
receiving LY3475070 and pembrolizumab 
and at 7 days after study treatment 
discontinuation for patients receiving 
LY3475070 monotherapy per Section 8.3.4.
Tumor assessment-
radiological imaging
X
See Instructions
See Instructions
Perform locally according to RECIST 1.1, 
using the same imaging method (e.g., CT or 
MRI) at each assessment every 9 weeks ± 7
days for the first year and every 12 weeks 
(±7 days) thereafter until a discontinuation 
criteria is met. 
Disease progression should be confirmed per 
iRECIST by the site 4 to 8 weeks after site-
assessed first radiologic evidence of PD in 
clinically stable participants. Participants, 
who have unconfirmed disease progression 
may continue on treatment at the discretion 
of the investigator until progression is 
confirmed by the site.
Note:  Imaging must be performed within 28 
days before C1D1.  See Section 8.1
Radionuclide bone scan
X
See Instructions
See Instructions

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
18
Baseline, On-Study and Post-Study Treatment Follow-up SoA
Baseline
Cycle = 21 days
Short-Term Follow Upa
Long-
Term 
Follow-Upb
(Day Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 
3-n
801
802
803
804-X
Instructions
(±3 days)
(±3 days)
(±3 
days)
30 day 
follow-
up ±5 
days
60 day 
follow-
up ±5 
days
90 day 
follow-
up ±5 
days
Q90D
≤28
≤7
D1
D2
D8
D15
D1
D2
D1
Procedure
Radionuclide bone scans should be 
performed only for patients with mCRPC.  
See Section 8.1.3.
Tumor assessment-
measurement of palpable 
and/or visible lesions
X
See Instructions
See Instructions
See Section 8.1
Whole blood (PK)
See Section 1.3.1.
See Section 8.5.
Urine (PK)
See 
Sec
tion 
1.3.
1.
See Section 8.5.
Serum 
(Pharmacodynamics)
See Section 1.3.1.
See Section 8.6.
Whole Blood (PGx)
See Section 1.3.1.
See Section 8.8.
Plasma
See Section 1.3.1.
See 
Section 
1.3.1.
See Section 8.8.
Serum (Biomarkers)
See Section 1.3.1.
See Section 8.8.
Whole Blood (CTCs)
See 
Section 
1.3.1
See Section 1.3.1
See
Section 
1.3.1
For mCRPC patients only.  Samples to be 
taken every 3 weeks. See Section 8.8.
Tissue
See 
Section 
1.3.1
See Section 1.3.1.
See Section 8.8., 8.8.1.
Patient dosing diary
X

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
1 9
B aseli ne, O n -St u d y a n d P ost -St u d y Tre at me nt F oll o w -u p S o A
B aseli ne
C ycle = 2 1 d a ys
S h ort -Ter m F oll o w U p a
L o n g -
Ter m 
F oll o w -U p b
( D a y Rel ati ve t o 
C 1 D 1)
C ycle 1
C ycle 2
C ycle 
3- n
8 0 1 
8 0 2 
8 0 3 
8 0 4 - X
I nstr ucti o ns
( ± 3 da ys)
( ± 3 da ys)
( ± 3 
da ys)
3 0 da y 
f oll o w-
u p ± 5 
da ys
6 0 da y 
f oll o w-
u p ± 5 
da ys
9 0 da y 
f oll o w-
u p ± 5 
da ys
Q 9 0 D
≤2 8
≤7
D 1  
D 2  
D 8
D 1 5
D 1  
D 2  
D 1
Pr oce d ure
A d mi nister L Y 3 4 7 5 0 7 0
X
See Secti o n 6. 1
A d mi nister pe m br oliz u ma b
(f or patie nts assi g ne d t o 
c o m bi nati o n treat me nt) 
X
X
X
See Secti o n 6. 1
A b bre viati o ns: A E = a d verse e ve nt; C A -1 2 5 = ca ncer a nti ge n ; C A 1 9-9 = car b o h y drate a nti ge n 1 9 - 9; C E A = carci n oe m br y o nic a nti ge n ; 
 
; C T = c o m p ute d t o m o g ra p h y; C T C = circ ulati n g t u m or cell; C T C A E = C o m m o n Ter mi n ol o g y ; E C G = electr ocar di o gra m; E C H O = 
ec h ocar di o gra m; E C O G P S = Easter n C o o perati ve O nc ol o g y Gr o u p perf or ma nce stat us; I C F = i nf or me d c o nse nt f or m; i RE CI S T = i m m u ne Res p o nse 
E val uati o n Criteria i n S oli d T u m ors ; m C R P C = metastatic castrate -resista nt pr ostate ca ncer; M RI = ma g netic res o na nce i ma gi n g; M U G A = m ulti gate d 
ac q uisiti o n; P D = pr o gressi ve disease; P G x = p har mac o ge netics ; P K = p har mac o ki netics; P S A = pr ostate -s pecific a nti ge n; Q 3 W = e ver y 3 wee ks; Q 6 W = 
e ver y 6 wee ks; Q 9 0 D = e ver y 9 0 da y s; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors; S A E = seri o us a d verse e ve nt ; S O A = sc he d ule of acti vities.
a
S h ort -ter m f oll o w-u p be gi ns w he n t he patie nt a n d i n vesti gat or a gree t hat t he patie nt will n o l o n ger c o nti n ue st u d y treat me nt.
b
L o n g -ter m f oll o w-u p be gi ns w he n s h ort -ter m f oll o w-u p peri o d is c o m plete d a n d c o nti n ues u ntil deat h, st u d y wit h dra wal, or t he patie nt is l ost t o f oll o w -u p.  I n 
all cases, n o f oll o w-u p pr oce d ures will be pe rf or me d f or a patie nt w h o wit h dra ws i nf or me d c o nse nt u nless he or s he has e x plicitl y pr o vi de d per missi o n a n d 
c o nse nt.
C CI
C CI

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
20
Continued Access Schedule of Activities
Continued Access Treatment
Continued Access
Follow-Up Visits
a
Instructions
Visit
30-Day
60-Day
90-Day
501-5XX
901
902
903
Procedure
AE collection
X
X
X
X
Per CTCAE v5.0, for post follow-up, the investigator should only be made aware 
of collected SAEs related to study regimen or protocol procedures.  As part of 
AE collection, monitor vital signs and perform standard laboratory tests 
(hematology, chemistry, urinalysis, and pregnancy testing) at the same frequency 
as during the study treatment period.  All laboratory tests during the continued 
access period will be performed in the local laboratories only. Pregnancy testing 
applies only to women of childbearing potential.  See Section 8.3.4 for 
pembrolizumab-specific requirements and Appendix 3.  Pregnancy test required 
at monthly intervals during study treatment in both treatment arms and up to 120 
days after study treatment discontinuation for patients receiving LY3475070 and 
pembrolizumab and at 7 days after study treatment discontinuation for patients 
receiving LY3475070 monotherapy per Section 8.3.4 and Appendix 3.
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.
PK, IG and exploratory hypersensitivity
In the event of hypersensitivity, 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 hypersensitivity, (ii) the resolution of the 
hypersensitivity, and (iii) 30 [±3] days following the hypersensitivity.  
Exploratory hypersensitivity samples may be analyzed for markers of:

Tryptase

ADA and LY3475070 concentration (PK)

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
21
Continued Access Schedule of Activities
Continued Access Treatment
Continued Access
Follow-Up Visits
a
Instructions
Visit
30-Day
60-Day
90-Day
501-5XX
901
902
903
Procedure
Administer LY3475070
X
See Section 6.1 for Dosing.
Administer pembrolizumab
X
See Section 6.1 for Dosing.
Abbreviations:  ADA= antidrug antibody; AE = adverse event; IG = immunoglobulin; PK = pharmacokinetics.
a
Continued access follow-up begins when the patient and the investigator agree that the patient will no longer continue treatment in the continued access 
period and lasts approximately 90 days.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
22
1.3.1. Sampling Schedule for Pharmacokinetics and Biomarkers
Sampling Day
Time 
relative to 
LY3475070 
dose
Vital Signsd
ECG
Whole 
Blood (PK)
Urine (PK)
Serum 
(Pharmaco
dynamics)
Whole 
Blood 
(PGx)
Plasma
Serum (Bio-
markers)
Whole 
Blood for 
CTCs –
mCRPC 
Patients 
Only
Tissue
Baseline ≤28 
days prior C1D1
X
X
X
Xa
Cycle 1 Day 1
Predose
X
X
X
X
X
X
X
X
Cycle 1 Day 1
0.5h±5m
Xc
X
Xe
X
Cycle 1 Day 1
1h±5m
Xc
X
X
Cycle 1 Day 1
2h±10m
Xc
X
X
X
Cycle 1 Day 1
4h±30m
Xc
X
X
Cycle 1 Day 1
6h±30m
Xc
X
X
Cycle 1 Day 1
8h±30m
Xc
X
X
Cycle 1 Day 2
Predose
X
X
X
X
Cycle 1 Day 2
1h±5m
Xc
Cycle 1 Day 8
Predose
X
X
X
X
Cycle 1 Day 15
Predose
X
X
X
X
X
X
Xb
Cycle 2 Day 1
Predose
X
X
X
X
X
Cycle 2 Day 1
0.5h±5m
Xc
X
X

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
23
Sampling Day
Time 
relative to 
LY3475070 
dose
Vital Signsd
ECG
Whole 
Blood (PK)
Urine (PK)
Serum 
(Pharmaco
dynamics)
Whole 
Blood 
(PGx)
Plasma
Serum (Bio-
markers)
Whole 
Blood for 
CTCs –
mCRPC 
Patients 
Only
Tissue
Cycle 2 Day 1
1h±5m
Xc
X
X
Cycle 2 Day 1
2h±10m
Xc
X
X
Cycle 2 Day 1
4h±30m
Xc
X
X
Cycle 2 Day 1
6h±30m
Xc
X
X
Cycle 2 Day 1
8h±30m
Xc
X
X
Cycle 2 Day 2
Predose
X
X
X
Cycle 3 Day 1
Predose
X
X
X
X
X
X
X
Cycle 4-6 Day 1
Predose
X
X
X
X
X
Cycle 7-n Day 1
Predose
X
X
X
At progression
X
X
X
Xf
V801
X
X
X
X
X
Xf

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
24
Abbreviations: C1D1 = cycle 1 day 1; CTCs = circulating tumor cells; ECG=electrocardiogram; h = hour; m = min; mCRPC = metastatic castrate resistant 
prostate cancer; PGx = pharmacogenetics; PK = pharmacokinetics.
a
Phase 1a = optional; Phase1b = mandatory (exceptions apply to Cohorts D1 and D2, see section 8.8) fresh biopsy collection required following determination 
of eligibility and before initiating study treatment.  This final screening procedure will serve as the pre-treatment sample for biomarker testing (See Sections 
5.1, 8.8, and 8.8.1).
b
Phase 1a = optional; Phase 1b = mandatory (exceptions apply to Cohorts D1 and D2, see section 8.8) fresh biopsy collection required on-treatment (see 
Section 8.8) within C1D15 to C2D1 window.
c
Only blood pressure and pulse are required at postdose collections
d
Vital signs should be taken after at least 5 minutes supine and prior to any scheduled blood draws at the same time point.
e
Urine output following dose administration, from 0 to 8 hours on Cycle 1 Day 1 will be pooled for a total collection and sampled for PK and creatinine.
f
Optional collection

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
2 5
2.
I ntr o d ucti o n
2. 1.
St u d y R ati o n ale
T he i m m u ne s yste m has de vel o pe d m ult i ple re g ulat or y mec ha nis ms t o c o ntr ol for self -t olera nce 
a n d li mit tiss ue a n d or ga n da ma ge d uri n g act i ve res p o nses t o pat h o ge ns. T hi s is partl y ac hie ve d 
b y a h ost of i n hi bit or y rece pt ors e x presse d o n cells of t he i m m u ne s yste m t hat u p o n acti vati on 
s u p presses t he i nfla m mat or y res p o nses of i m m u ne cells. T hese pat h wa ys are referre d t o as 
“i m m u ne c hec k p o i nts” (Bra h mer a n d Par d oll 2 0 1 3). Se veral s uc h c hec k p o i nts ha ve bee n 
i de nt ifie d o ver t he last deca des, wit h pr o gra m me d cell deat h pr otei n 1 (P D - 1) a n d c yt ot o xic T -
l y m p h oc yt e-ass ociate d pr otei n 4 (C T L A - 4) n o w ha vi n g bee n vali date d as tar gets t o m o d ulate t he 
i m m u ne s yste m t o fi g ht ca ncer. I n a d diti on t o t he i n hi bit or y  rece pt ors e x presse d o n t he i m m u ne 
cells, t here are als o s ol u ble li ga n ds a n d meta b o lites wit hi n t he t u mor micr oe n vir o n me nt t hat ca n 
trig ger t he c hec k p oi nt pat h wa y s ( Le o ne et al. 2 0 1 5). 
E xtracell ular n ucle oti des s uc h as a de n osi ne -trip h os p hate ( A T P) pla y  a n i m p ortant  r ole i n cell 
meta b o lis m a n d bi ol ogical pr ocesses ( D u b ya k a n d El -M oatassi m 1 9 9 3). 
I n t he e xtracell ular 
s pace, A T P gets c o n verte d t o a de n osi ne m o n o p h os p hate ( A M P) b y t he ect o- 5’-n ucle oti dase
C D 3 9. S u bse q ue ntl y, C D 7 3, a d o w nstrea m ect o- 5′-n ucle oti dase, c atal yzes t he c o n versi o n of 
A M P t o a de n osi ne, w hic h acts as a n i m m u ne s u p pressi ve meta b olite ( H ore nstei n et al. 2 0 1 9).  
A de n osi ne si g nals b y  bi n di n g t hr o u g h f our G pr otei n -c o u ple d rece pt ors, A 1 A , A2 A, A2 B a n d A 3
( R o be va et al. 1 9 9 6).  T he m ost u bi q uit o usl y e x presse d rece pt or s u bt y pe o n i m m u ne cells is A 2 A
a n d u p o n acti vati o n e xerts a s u p pressi ve effect of t he i nfla m mat or y im m u ne res p o nse b y 
m o d ulat i n g C D 4 a n d C D 8+ T- cells a n d d o w nre g ulati n g c yt o ki ne e x pressi o n ( Fis h ma n et al .
2 0 0 9).  T he i m m u ne s u p pressi ve effect of A 2 A R acti vat i on is s o pr of o u n d t hat i n A2 AR k n oc k o ut
mice , trig geri n g a n i nfla m mat or y  res p o nse b y e xter nal sti m uli has a let hal effect ( O hta a n d 
Si t k o vs k y 2 0 0 1).  Ot her a de n osi ne rece pt ors, s uc h as A 2 BR a n d A 3 rece ptors, ha ve als o bee n 
s h o w n t o be e x presse d b y i m m u ne cells (Le o ne a n d E m e ns 2 0 1 8; Va n Der P utte n et al. 2 0 1 9), 
s u g gesti n g a de n osi ne ca n si g nal t hr o u g h differe nt rece pt or s u bt y pes t hat ha ve differe nt bi n di n g 
affi nit y t o war ds a de n osi ne as well as dist i nct d o wnstrea m effects , res ultin g i n c o nte xt de pe n de nt 
i m m u ne-m o d ul at i on . D ue t o t he c o m ple xit y a n d t he differe nt e x pressi o n of a de n osi ne rece pt ors 
o n t he vari o us i m m u ne cells, a n d t he vari o us affi nit y  a de n osi ne rece pt ors ha ve t o its li ga n d, 
l oweri n g a de n osi ne c o nce ntrati o ns wi t hi n t he t u mor micr oe n vir o n me nt ( T M E) b y tar geti n g t he 
ect o -e nz y mes ma y be a better strate g y t ha n tar geti n g s pecific a de n osi ne rece pt or s u bt yp e s. 
 
Im m u ne c hec k p o i nt i n hi bit ors (I CI) ha ve yiel de d si g nifica nt i m pr o ve me nts i n t u mor res p o nse 
rates, d urati o n of t u m or res p o nses a n d o verall s ur v i val i n m ult i ple a d va nce d ca ncer settin gs s uc h 
as me la n oma, re nal cell carci n o ma, a n d n o n -s mall cell l u n g ca ncer (F u k u m u ra et al. 2 0 1 8 ).  
H o we ver, des pite t he o bser ve d efficac y wit h I CIs, de pe n di n g u p o n t he t u m or t y pe, 5 0 t o 8 0 % of  
a d va nce d ca ncer patie nts will e x perie nce disease pr o gressi o n w hile recei vi n g I CI treat me nt or 
wi t hi n 3 t o 6 m o nt hs of treat me nt c o m plet i on . T his varia bilit y ma y be d ue t o varia bilit y i n t he
T M E t hat ca n s u p press T cell acti vati on , necessitati n g n o vel  c o m bi nati on treat me nt a p pr oac hes 
t o o verc o me resista nce t hat de vel o ps t o I CI treat me nt ( O’ D o n nell 2 0 1 6 ; F u k u m u ra et al. 2 0 1 8).
C CI
C CI

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
2 6
Se veral A 2 A R i n hi bit ors, s o me of  w hic h ha vi n g bee n e val uate d i n lar ge P hase 3 tri als f or 
ne ur o de ge nerat i ve diseases, h ave rece ntl y e ntere d t he cli nic, e val uat i n g t heir utilit y in tr e ati n g 
pa tie nts wit h a d va nce d s oli d ma li g na ncies ( Le o ne a n d E me ns 2 0 1 8). C PI -4 4 4, a n a nta g o nist of 
A 2 AR, has s h o w n res p o nses as a si n gle a ge nt a n d i n c o m bi nati o n wit h atez oliz u ma b i n pat ient s 
wi t h metastatic n o n- s mall cell l u n g ca ncer (N S C L C ) a n d metastatic re nal cell carci n o ma (R C C )
( F o n g et al. 2 0 1 7).  P at ient s t hat ha d bee n o n a pr o gra m me d cell deat h pr otei n -1/li ga n d 1 ( P D -
1 / L 1) f or a pr olo n ge d d urati o n pri or t o st u d y  e ntr y s h o we d e vi de nce of ele vate d A 2 A R a n d C D 7 3 
e x pressi o n, s u g gesti n g t he a de n osi ne pat h wa y ma y pla y  a r ole i n ac q uire d resista nce t o P D- 1/ L1 
treat me nt ( H ots o n et al. 2 0 1 7).   Rece nt p u blis he d data fr o m a n o n g oi n g P hase 1 tri al e val uati n g 
t he A 2 AR a nta g o nist A Z D 4 6 3 5 as si n gle a ge nt or i n c o m bi nati o n wit h t he P D - 1/L 1 tar gete d 
a nt i b o d y d ur val u ma b, has s h o w n ra di ol ogi cal res p o nses i n metastatic castrate resista nt pr ostate 
pati e nts, a n i n dicat i on t hat has n ot ge nerall y bee n res p o nsi ve t o a nti- P D - 1/ L 1 treat me nt alo ne
(De B o n o et al. 2 0 1 8 ; Be n dell et al ., 2 0 1 9).  A d diti o nall y, C D 7 3 u pre g ulat i on has als o bee n 
d e m o nstrate d i n t u m ors wi t h o nc o ge nic dri ver mut ati o ns s uc h as e pider mal gr o wt h fact or 
rece pt or m utati o n (E G F R m ) N S C L C, a n d ma y  e x plai n t he li mite d res p o nse patient s wit h 
E G F R m ha ve t o I CI treat me nt ( Strei c her et al. 2 0 1 7; Hig gs et al. 2 0 1 8).
Gi ve n t he r ole t he a de n osi ne bala nce pla ys i n t he i m m u ne s yste m, t he c urre nt st u d y , J 2I-M C -
J Z M A (J Z M A), will e val uate safety,  t olera bility a n d a nti-t u mor c o ntr ol  of C D 7 3 i n hi bit or 
L Y 3 4 7 5 0 7 0 (a d mi nistere d as m o n ot hera p y or i n c o m bi nat i on wi th pe m br oliz u ma b ) i n a d va nce d 
ca ncer patie nts wit h mali g na ncies tra dit i onall y  u nres p o nsi ve t o si n gle a ge nt I CI treat me nt.  
2. 2.
B ac k gr o u n d
2. 2. 1.
L Y 3 4 7 5 0 7 0
L Y 3 4 7 5 0 7 0 is a n orall y bi oa vaila ble u nc o m pet iti ve, p ote nt, a n d selecti ve i n hi bit or of C D 7 3 wi t h 
cleara nce t hat a p pears relate d t o meta b o lis m b y 
.  T he m o d e of  actio n is b y
bi n di n g t o t he e nz y me -p h os p hate c o mple x of  C D 7 3.  In precli nical m o dels , L Y 3 4 7 5 0 7 0 has
d e m o nstrate d r o b ust resc ue of a de n osi ne-me diate d s u p pressi o n of T -cell pr o liferati on a n d 
c yt o ki ne secreti on, c orrel ate d wit h a re d uctio n i n a de n osi ne le vels u n der e x peri me ntal c o n ditio n s 
w here A M P/a de n osi ne le vels are hi g h . A n i m m u ne-s u p pressi ve T M E is ofte n c haracterize d b y 
sig nifica nt l y ele vate d le vels of a de n osi ne, li kel y li miti n g t he cli nical utility of  c o mp eti tive 
i n hi bit ors of C D 7 3 a n d a de n osi ne rece pt or a nta g o nists. O wi n g t o its dist i nct u nc om pet iti ve 
mec ha nis m o f actio n ( M O A), it is a nt ici pate d t hat L Y 3 4 7 5 0 7 0 ma y d e m o n str at e m or e c o m plete 
tar get i n hi biti on a n d s u p pressi o n of i m m u ne -s u p pressi ve a de n osi ner gic si g nali n g. 
T he p har mac o l ogi cal pr o perti es of L Y 3 4 7 5 0 7 0 were c haracterize d b ot h i n vi v o a n d i n vitr o i n 
n o ncli nical p har mac o l og y  st u dies, a n d ca n be s u m marize d as f o ll ows: 

It is orall y bi oa vaila ble

It s h o ws ro b ust tar get i n hi bit i on e x vi v o i n w h o le bl o o d a n d i n t u mor s m o d el s wi t h a 
well -defi ne d p har mac o ki net ic (P K )/p har mac o d y na mic relat i ons hi p

It de m o nstrate s a n acce pta ble t o xic o l og y  pr ofile i n 1-m o nt h r at a n d d o g re peat d ose 
t o xic o l og y  st u dies (see Sect i on 2. 3 of cli nical pr ot oc ol a n d Secti o n 4. 2. 1 of I B)

T he pr oj ecte d h u ma n efficaci o us d ose ( 1 4 8 m g o nce a da y  [Q D ]) a n d hi g h Ma xi m u m 
A bs or ba ble D ose ( 8 6 0 mg) pr oj ect i ons all o w greater d osi n g fle xi bilit y i n cli nic
C CI

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
2 7
A d dit i onal i nf or mati o n ma y b e fo u n d i n t he I B f or L Y 3 4 7 5 0 7 0 .
2. 2. 2.
Pe m br oliz u m a b
Pe m br oliz u ma b is p ote nt h u ma nize d i m m u n o gl o b uli n G 4 (I g G 4) m o n ocl o nal  ant i b o d y (m A b)  
wi t h hi g h s pecificity of  bi n di n g t o t he pr o gra m me d cell deat h 1 ( P D -1) rece pt or, t hus i n hi biti n g 
its i nteractio n wi t h pr o gra m me d cell deat h li ga n d 1 ( P D-L 1) a n d pr o gra m me d cell deat h li ga n d 2 
( P D-L 2) .  Base d o n precli nical i n vitr o data, pe m br oliz u ma b has hi g h affi nit y a n d p ote nt rece pt or 
bl oc ki n g acti vit y f or P D - 1.  Pe m br ol iz u ma b has a n acce pta ble precli nical safety pr ofile a n d is i n 
cli nical de vel o p m e nt as a n i ntra ve n o us (I V) i m m u n ot hera p y for a d va nce d mali g na ncies .  
Ke ytr u da ®
(pe m br o liz u ma b) is i n dicate d f or t he treat me nt of  patie nts acr oss a n u m ber of 
i n dicati ons .  F or m o re details o n s pecific i n dicati o ns refer t o t he I n vesti gat or’s a Br oc h ure.
Refer t o t h e I n vesti gat or’s Br oc h ure (I B)/a p pr o ve d la beli n g f or detaile d bac k gr o u n d i nf or mati on 
o n M K - 3 4 7 5 ( Pe m br oliz u ma b).
T hera pe ut ic st u dies i n m o use m o dels ha ve s h o w n t hat a d mi nistrati o n of a nt i b o dies bl oc ki n g P D-
1/ P D -L 1 i nteracti o n e n ha nces i nfiltrati o n of t u m or -s pecific C D 8 + T cells a n d ulti matel y lea ds t o 
t u mor r ej ect i on, ei t her as a mo n ot hera p y  or i n c om bi nat i on wi t h other treat me nt m o dalit ies 
( Str o me et al. 2 0 0 3; Bla n k et al. 2 0 0 4; Hira n o 2 0 0 5; C urra n 2 0 1 0; Pil on et al . 2 0 1 0; We ber 2 0 1 0; 
S pra n ger 2 0 1 4) .  A nti-m o use P D -1 or a nti -m o use P D -L 1 a nt i b o dies ha ve de m o nstrate d 
a nt itu m or res p o nses i n m o dels o f s q ua m o us cell carci no m a, pa ncreat ic carci n oma, m ela n o ma, 
ac ute m yel o i d le u ke mia a n d c olorectal  carci n oma ( Str o me et al. 2 0 0 3; Z ha n g et al. 2 0 0 4; N o mi 
et al. 2 0 0 7; C urra n et al. 2 0 1 0; Pil on et al . 2 0 1 0).  I n s uc h st u dies, t u m or i nfiltrati o n b y C D 8 + T 
cells a n d i ncrease d I F N-γ, gra nz y me B a n d perf ori n e x pressi o n were o bser ve d, i n dicat i n g t hat 
t he mec ha nis m u n derl yi n g t he a ntit u m or acti vit y of P D -1 c hec k p o i nt i n hi biti on i n v ol ve d l ocal 
i nfiltrati on a n d act i vati on of effect or T cell f u nct i on i n vi v o ( C urra n 2 0 1 0). E x peri me nts ha ve
c o nfir me d t he i n vi v o efficac y o f a nt i-m o use P D -1 a nti b o d y  as a mo n ot hera p y , as well as i n 
c o m bi nat i on wi t h c he mot h era p y, i n s y n ge neic mo us e t u m or m o d el s (see t he I B).
2. 3.
Be nefit / Ris k Assess me nt
L Y 3 4 7 5 0 7 0 was e val uate d i n 1 -m o nt h dail y  or al-d osi n g t o xi c o l og y st u dies i n S prag ue- Da wle y  
rats a n d Bea gle d o gs.  Safety p har mac o l og y  para meters were e val uate d i n vitr o ( h u ma n et her á-
g o- g o – relate d ge ne) a n d as part of t he re peat-d ose t o xicit y st u d y in d o gs.  Ge net ic t o xicity was 
e val uate d i n a bacterial m utati o n ( A mes) assa y, a n i n vitr o micr o n ucle us ( M N) assa y a n d a n i n 
vi v o rat M N assa y .  Base d o n n o ncli nical st u d y fi n di n gs, p ote ntial t o xicities i ncl u de 
 
 All n o ncli nical t o xic ol o g y  fi n di n gs i n rats a n d d o gs were 
re versi ble after a 1-m o nt h rec o ver y  p erio d.  
T he e x perie nce s o far wit h ot her A 2 AR a nta g o ni sts a n d C D 7 3 i n hi bit ors i n cli nic s u g gest 
treat me nt t o be we ll t olerate d ( Ha user et al. 2 0 1 4; F o n g et al. 2 0 1 7 ; H ots o n et al . 2 0 1 7; C hia p p ori  
et al. 2 0 1 8; S ui  et al. 2 0 1 8; Be n dell et al. 2 0 1 9; L u ke et al 2 0 1 9). T he ma i n t o xicities t hat ha ve 
e mer ge d ha ve bee n m ai nl y gastr o -i ntest i nal ( na usea, v o miti n g, diarr hea), ne ur olo gi cal 
( hea dac he, dizzi ness, s o m n olence, i ns o m nia), a n d c o nstit uti o nal ( wei g ht l oss, fat i g ue). P ossi ble 
C CI
C CI
C CI

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
28
immune related adverse events (irAEs), such as pruritis, pneumonitis, rash, hypothyroidism and 
hepatitis have also been reported. Based on these reports and the preclinical safety of 
LY3475070, GI-related events such as vomiting, nausea and fatigue may be expected. Due to 
the immune stimulatory mechanism of action, irAEs such as rash, colitis, and hypothyroidism 
may also be experienced. In combination treatment with other checkpoint inhibitors, there may 
be potential for increased incidence of irAEs.  More information about the known and expected 
benefits, risks, serious adverse events (SAEs) and reasonably anticipated adverse events (AEs) of 
LY3475070 may be found in the IB.
More detailed information about the known and expected benefits and risks of pembrolizumab 
may be found in the locally approved product label.
Pembrolizumab is a PD-1 blocking antibody with global regulatory approvals in several 
indications (pembrolizumab USPI).  The risk profile of pembrolizumab is well characterized, and 
the management of 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
LY3475070 in combination with pembrolizumab. Preclinical and clinical data suggest that 
adenosine mediated signaling may be involved in mediating resistance to inhibition of PD-1/L1
signaling. Therefore, combining the CD73 inhibitor LY3475070 with PD-1/L1 blockade is 
hypothesized to increase efficacy in settings where adenosine mediated immune-suppression 
may limit clinical responses seen with PD-1/L1 blockade. Agents targeting the purinergic 
pathway, such as A2AR antagonists or CD73 monoclonal antibodies, have not shown incidence 
of irAEs to the same degree as PD-1 or CTLA-4 inhibitors. However, a combination of 2 agents 
targeting the immune system has the possibility to induce more frequent irAEs than each agent 
alone. Although it is not possible to extrapolate findings from other studies that have combined 
2 checkpoint inhibitors to the combination of LY3475070 and pembrolizumab, the treatment 
protocol will provide clear dose modifications for irAEs to mitigate for possible irAEs.  Given 
limited treatment options for the targeted patient population, and well established protocols for 
the management of irAEs, the risk remains acceptable. 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
29
3.
Objectives and Endpoints
Phase 1a: 
Objectives
Endpoints
Primary

To determine a safe dose of 
LY3475070 as monotherapy and in 
combination treatment with 
pembrolizumab to be further evaluated 
and confirmed in Phase 1b portion of 
the study (recommended Phase 1b 
dose)

DLTs 

Assessment of safety including, but not 
limited to, TEAEs, SAEs, deaths, and 
clinical lab abnormalities per CTCAE 
v5.0 
Secondary

To characterize the LY3475070 PK 
profile as monotherapy and in 
combination with pembrolizumab

Cmax, trough (Cmin, Csteady state), AUCsteady 
state

To characterize the clinical activity of 
LY3475070 as monotherapy and in 
combination with pembrolizumab as 
assessed by the investigator using 
RECIST v1.1

ORR

DCR

PFS 
Tertiary/Exploratory

To evaluate target occupancy of 
LY3475070 

Percentage of target inhibition of 
adenosine in peripheral serum

To assess the relationship between 
biomarkers, dose/exposure, and clinical 
outcomes

Results of biomarker assessments

Clinical outcomes data

To characterize the anti-tumor activity, 
as determined by the investigator, of 
LY3475070 in combination with 
pembrolizumab in subjects with 
indicated tumor types based on 
iRECIST criteria 

iORR

iPFS

iDCR

To estimate the renal clearance of 
LY3475070 and conduct exploratory 
metabolite identification on blood and 
urine samples.

Metabolite profiling 

Renal clearance

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
30
Abbreviations: AUC = area under the curve; Cmax = maximum blood plasma concentration; Cmin = minimum blood 
plasma concentration; CTCAE = Common Terminology Criteria in Adverse Events; DLT = dose limiting 
toxicities; DCR = disease control rate; iDCR = immune disease control rate; iORR = immune overall response 
rate; iPFS = immune progression-free survival; iRECIST = immune Response Evaluation Criteria in Solid 
Tumors; ORR = overall response rate; PFS = progression-free survival; PK = pharmacokinetics; RECIST = 
Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; TEAE = treatment-emergent 
adverse event.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
31
Phase 1b: 
Objectives
Endpoints
Primary

To establish the RP2D of LY3475070 
as monotherapy and in combination 
treatment with pembrolizumab

To assess the safety, tolerability and 
clinical activity of LY3475070 as 
monotherapy and in combination with 
pembrolizumab

Assessment of safety including, but not 
limited to, TEAEs, SAEs, deaths, and 
clinical lab abnormalities per CTCAE 
v5.0

Investigator assessed ORR per RECIST 
v 1.1
Secondary

To characterize the LY3475070 PK 
profile as monotherapy and in 
combination with pembrolizumab

Cmax, trough (Cmin, Csteady state), AUCsteady 
state

To characterize the clinical activity of 
LY3475070 as monotherapy and in 
combination with pembrolizumab as 
assessed by the investigator using 
RECIST v1.1

DOR

DCR

TTR

PFS 

OS
Tertiary/Exploratory

To assess the relationship between 
biomarkers, dose/exposure, and clinical 
outcomes

Results of biomarker assessments

Clinical outcomes data

To characterize the immune mediated 
anti-tumor activity of LY3475070 as 
monotherapy or in combination with 
pembrolizumab based on iRECIST 
criteria

iORR

iPFS

iDOR

iDCR

To evaluate the relationship between 
anti-tumor activity of LY3475070, as 
monotherapy and in combination with 
pembrolizumab, and biomarkers 
predicting efficacy and resistance in 
obtained tumor tissues or blood samples

Results of biomarker analyses

Clinical outcomes

To evaluate target occupancy of 
LY3475070

Percentage of target inhibition of 
adenosine in peripheral serum

To estimate the renal clearance of 
LY3475070 and conduct exploratory 

Metabolite profiling 

Renal clearance

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
32
metabolite identification on blood and 
urine samples.
Abbreviations:  AUC = area under the curve; Cmax = maximum blood plasma concentration; Cmin = minimum blood 
plasma concentration; CD73 = cluster of differentiation 73;CTCAE = Common Terminology Criteria in Adverse 
Events; DCR = disease control rate; DOR = duration of response; iDCR = immune disease control rate; iDOR = 
immune duration of response; iORR = immune overall response rate; iPFS = immune progression-free survival; 
iRECIST = immune Response Evaluation Criteria in Solid Tumors; NSCLC = non-small cell lung cancer; ORR 
= overall response rate; OS = overall survival; PD-1/L1 = programmed cell death protein-1/ligand 1; PFS = 
progression-free survival; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid Tumors;  
RP2D = recommended phase 2 dose; SAE = serious adverse event; RCC = renal cell carcinoma; RP2D = 
recommended phase 2 dose; TEAE = treatment-emergent adverse event; TTR = time to response

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
33
4.
Study Design
4.1.
Overall Design
Study JZMA is an open-label, multicenter, global, 2-part Phase 1 study of LY3475070 alone or 
in combination with pembrolizumab in advanced cancer patients. 
Phase 1a of the study will target the following tumor types: triple negative breast cancer, 
pancreatic cancer, PD-1 refractory NSCLC, PD-1 refractory RCC, PD-1 refractory melanoma, 
metastatic castrate resistant prostate cancer (mCRPC) and ovarian cancer.  In Cohort A in 
Phase 1a, escalating doses of single agent LY3475070 will be evaluated in at least 3 evaluable 
patients per dose level (i.e., DLA1-A4, see Schema in Section 1.2). However, based on the 
observed PK, pharmacodynamic, and safety data observed, not all provisional dose levels may be 
explored. Intermediate and/or higher dose as well as alternative schedules of administration 
(BID dosing) will be explored if deemed necessary after discussion between Lilly and 
investigators. The dose limiting toxicity (DLT) observation period will be 28 days. The first 
patient of each DL will be observed for 48 hours before additional patients are enrolled to that 
DL. The totality of safety data will be reviewed by the Lilly clinical research physician/clinical 
research scientist (CRP/CRS) and study investigators prior to escalating to a next DL. 
Intrapatient dose escalation is not allowed. In the dose escalation phase, once a given DL is 
cleared for DLT evaluation and is deemed safe, the dose cohort may be expanded (i.e., 
backfilled) to a maximum of 20 patients to further investigate the safety, PK, pharmacodynamic,
and clinical activity.  Enrollment of patients to the dose cohort for DLT evaluation/dose 
escalation will take precedent.  To ensure that patients are not unnecessarily enrolled to 
subtherapeutic dose levels, these backfills will not be undertaken until a DL already declared 
safe also demonstrates evidence of therapeutic exposures.  However, continuous safety 
monitoring (Section 9.2) will be implemented to ensure ongoing evaluation of patient safety in 
backfill patients. In the event that backfill enrollment/escalation is paused, the aggregated safety 
data will be evaluated to determine if the dose level in question (and higher dose levels) should 
be permanently discontinued. In general, all available toxicity and PK data will be utilized, 
including DLT equivalents observed from backfill patients, to recommend an escalation/de-
escalation decision, and to inform the selection of the RP2D.
It is anticipated that a minimum of 4 DLs will be evaluated in Cohort A to determine the MTD of 
single agent LY3475070, or, in the absence of MTD, a recommended Phase 1b dose of single 
agent LY3475070. The 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 recommended Phase 2 dose (RP2D) to 
be formally established in Phase 1b part of the study will be based upon the totality of safety, PK 
and pharmacodynamic data, and thus may be lower than the MTD or the recommended Phase 1b 
dose identified in the Phase 1a part of the study. 
Once the DLA2 (300 mg QD) for single agent LY3475070 is determined safe and tolerable, 
LY3475070 in combination with pembrolizumab is planned to be evaluated in Cohort B starting 
at combination DL1 (150 mg QD LY3475070 and pembrolizumab) and escalated, independently 
from ongoing monotherapy dose escalation, to the recommended Phase 1b dose or MTD of 
LY3475070 single agent.  At the first dose level, there will be at least a 48-hour delay between 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
34
dosing the first patient and additional patients.  There will be no dose escalations for 
pembrolizumab, which will be given at 200 mg every 3 weeks (Q3W). The dose given in the 
dose escalation in Cohort B should not exceed the maximum dose shown to be safe in Cohort A.
In Phase1b of the study, the recommended phase 1 dose (RP1D) or MTD, as determined in the 
Phase 1a part, of LY3475070 alone or in combination with pembrolizumab will be evaluated in
3 distinct cohorts:  Cohorts C, D, and E.  The RP2D will be determined at the end of the Phase 
1b part of the study based on the totality of data.
Cohort C will consist of patients that have been treated with and are refractory to PD-1/L1
inhibitor treatment with the following malignancies: NSCLC, RCC or melanoma. To be 
eligible, Cohort C will consist of patients with NSCLC, RCC, or melanoma that progressed on 
anti-PD1-L1 inhibitor therapy. Exception for prior anti- PD-1/L1 requirement will be given for 
NSCLC patients with EGFR activating mutations, as these patients do not respond to PD-1/L1 
directed therapy, which may be due to high CD73 expression (Higgs et al. 2017; Streicher et al. 
2017).  In addition, patients must undergo a pretreatment biopsy and be positive for CD73 
expression by central immunohistochemistry (IHC) testing.
Cohort D will consist of men with mCRPC; eligible patients must be PD-1/L1 inhibitor naïve. 
To minimize physician/patient bias and to promote balanced patient characteristics between 
treatments, patients in Cohorts C and D will be randomized to either single agent LY3475070 or 
LY3475070 and pembrolizumab.
Cohort E will consist of patients with previously treated metastatic triple negative breast cancer 
(mTNBC) who will receive LY3475070 and pembrolizumab. Patients must have received at 
least one prior cytotoxic regimen.  Prior anti PD-1/L1 treatment is not a requirement. 
4.1.1.
Dose Escalation
Dose escalation of LY3475070 will be driven by the modified toxicity probability interval-2 
(mTPI-2) method (Guo et al. 2017) where a pre-calculated decision table (Appendix 8) will 
guide the dose recommendations until the MTD is determined (e.g., when all planned patients 
have been tested, or when no higher candidate DL can be tested). Dose escalation decision will 
also take into consideration available PK and pharmacodynamic data from previous DLs.  
Although mTPI-2 allows flexible number of patients in each dosing cohort, a minimum of 3 
evaluable patients are required for the DLT evaluation at each DL.  The first patient of each DL
(in Phase 1a) will be observed for 48 hours before additional patients are enrolled to that DL.  
Intrapatient dose escalation is not allowed.
Like the 3+3 design, the mTPI-2 method incorporates prespecified escalation rules.  In contrast, 
the mTPI-2 method is based on quantitative models that incorporate uncertainty into the decision 
rules, thereby allowing more precise RP2D selection.  If 3 or 6 patients are enrolled in a cohort, 
the escalation rule parallels a traditional 3+3 design. However, it allows flexible number of 
patients in a cohort. For example, with 2 DLTs per 6 patients enrolled, the mTPI-2 would 
recommend staying at the current dose, as analogy to 1 DLT per 3 patients enrolled in 3+3 
design; therefore, it allows more patients for a more precise estimate of the DLT rate at this DL.
Following a discussion between the Lilly CRP/CRS and the investigators, a more conservative 
dose selection may be applied to the next cohort (for instance, if PK/pharmacodynamics data 
suggest that further dose increase would not be expected to yield additional benefit).  For 

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
3 5
e xa m ple, if t he r ule i n dicates “ E” t o escalate, t he d ose ma y st a y at t he c urre nt D L , be de -
escalate d t o a l o wer le vel, or escalat i on ma y cease .  I n t he m T PI- 2, t he c o h ort size is n ot fi xe d.  
H o we ver, eac h D L i n t his st u d y will be teste d wit h a mi ni m u m o f 3 e val ua ble pat ient s, u nless t he 
escalat i on r ul es dictate t hat t he d ose s h o ul d be de -escalate d ( “ D” or “ D U”).  D oses ca n be 
escalate d, de -escalate d, a n d re -escalate d. If t he d ose decisio n  was “D U,” t he d ose ca n n ot be re -
escalate d t o t hat le vel.
T his st u d y  is desi g ne d t o i de ntif y a D L wi t h a d ose-li miti n g tar get t o xicity rate of 3 0 %.  T he 
m T PI -2 m et h o d c o nsiders a n e q ui vale nce i nter val ( EI) ar o u n d t he tar get t o xicit y rate.  F or t his 
st ud y, t he EI is elicit e d t o be ( 2 5 %, 3 5 %), res ult i n g i n t he r ules bel o w.
S af et y data, i n partic ular D L T s, will be t he pri mar y criteria f or t he d ose escalat i on.  I n a d di tio n, 
if a vaila ble at t he ti me of d ose escalati on decisi o n, P K /p har mac o d y na mics res ults (for e xa m ple, 
C ma x, area u n der t he c o nce ntrati o n c ur ve (A U C ), p har mac o d y na mics res ults) will be use d as 
sec o n dar y/s u p p ortin g data f or d ose escalati o n.
I nter me diate a n d/ or hig her d ose as well as alter nat i ve sc he d ules of a d mi nistrati o n will be 
e x pl ore d if dee me d necessar y after disc ussio n  bet wee n Lill y a n d i n vesti gat ors a n d ta ki n g i nt o 
acc o u nt patie nt safet y a n d P K/p har mac o d y na mics data.   If nee de d, a d dit i onal patie nts ma y  be 
e nr o lle d t o f urt her assess P K/p har mac o d y na mics or t ol era bilit y.
I n or der t o be D L T-e val ua ble, patie nts m ust ha ve recei ve d 7 5 % of L Y 3 4 7 5 0 7 0 sc he d ule d d ose 
wi t hi n t he 2 8-d a y  D L T p erio d u nl ess patie nts ha ve a D L T q ualif yi n g e ve nt. F o r patie nts treate d 
wi t h t he c o m bi nati on treat me nt, patie nts m ust ha ve recei ve d 7 5 % of L Y 3 4 7 5 0 7 0 a n d a mi ni m u m 
of  1 pe m br oliz u ma b i nf usi on wi t hi n t he 2 8-d a y  D L T perio d.
I n t he d ose escalati on p hase , o nce a gi ve n D L is cleare d f or D L T e val uati o n a n d is dee me d safe, 
t he d ose c o h ort ma y be e x pa n de d t o f urt her i n vesti gate t he safet y,  P K, p har mac o d y na mic , a n d 
cli nical act i vity of  L Y 3 47 5 0 7 0 a n d t he c o m bi nati o n wit h pe m br oliz u ma b. T here will be u p t o 
2 0 bac kfill pat ient s e nr olle d acr oss all d ose le vels i n c o h ort s A a n d B c o m bi ne d i n t he p hase 1a 
st u d y. A n y  AEs re p orte d b y  t h ose bac kfille d patient s t hat meet t he D L T crit eria as defi ne d i n 
Secti o n  6. 1. 1. 1 a n d occ ur i n t he D L T peri o d are c o nsi dere d D L T -e q ui vale nt t o xicit ies 
( Sectio n 6. 1. 1. 2 ).  T he c u m ulati ve safety data fr o m t he c o h orts pre vi o usl y  declare d safe a n d t he 
c urre nt d ose c o h ort u n der e val uat i on will be c o nti n u o usl y m o nit ore d.  A Ba yesia n t o xicit y 
m o nit ori n g r ul e will be i m ple me nte d f or D L T -e q ui vale nt t o xicit ies a d de d fr o m bac kfill pat ient s 
(Secti o n  9. 2 ). T hese a g gre gate safet y data will be i ncl u de d i n defi ni n g t he R P 2 D.
4. 1. 2.
I n V itr o D i a g n ostic U tiliz ati o n
A n i n vesti gati onal C D 7 3 I H C assa y will  be utilize d t o deter mi ne C D 7 3 pr otei n e x pressi on stat us 
i n patie nts t hat ot her w ise meet all ot her eli gi b ility criteria f or e nr oll me nt i n P hase 1 b C o h ort C.
T he t est will be perf or m e d at a ce ntral la b orat or y f oll o wi n g r o uti ne pr ocessi n g f or hist olo gical  
e val uat i on usi n g a c o m mercial a ut ostai ner platf or m a n d will be int er pret e d b y q ualifie d 
pat h ol o gi sts. P at ient s will be re q uire d t o u n der g o a ma n dat or y fres h bi o ps y  of  a pri mar y or 
metas t atic sit e t o o btai n t u m or tiss ue f or deter mi ni n g C D 7 3 e x pressi on.   Pati e nts t hat are n ot 
p osi tive f or C D 7 3 e x pressi o n, des pite meeti n g all ot her eli gi bilit y criteria, will be scree n fail ures. 
I n a n i nitial s ur ve y of 
f or mali n-fi xe d paraffi n-e m be d de d ( F F P E) t u mor sa m ples c o n d ucte d 
wi t h a n i n vesti gati o nal I H C assa y, C D 7 3 e x pressio n  was o bser ve d i n 
 of lu n g t u mors
.  Rece ntl y discl o se d e xter nal st u dies, usi n g I H C-base d assess me nt of C D 7 3 e x pressi o n, 
C CI
C CI
C CI

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
36
have reported an overall prevalence of CD73 in RCC of 22% (25/112 [Tripathi et al. 2019]). 
Tumor cell CD73 expression has been detected in 54% (62/114) of metastatic melanoma 
(Monteiro et al. 2018), and in 73% and 40% of adenocarcinoma and squamous cell carcinoma of 
the lung respectively (Salazar et al. 2018).
4.2.
Scientific Rationale for Study Design
Multiple tumor types have shown CD73 expression to have a prognostic value (Allard et al.
2019), including tumors insensitive to PD-1/L1 or CTLA-4 checkpoint blockade such as TNBC 
(Loi et al. 2013) and mCRPC (Leclerc et al. 2015). In preclinical models of such “immune cold” 
tumors, combined treatment targeting CD73 and checkpoints CTLA4 or PD-1/L1 showed 
synergy in comparison to single agent treatment (Allard et al. 2012).  Several agents targeting 
A2AR and CD73 have recently entered the clinic and are being evaluated in patients with solid
tumors (Leone and Emens 2018). Responses have been noted either as single agent treatment, or 
in combination with PD-1/L1 targeting antibodies, including in immune “cold” tumors not 
sensitive to ICI such as mCRPC, ovarian and pancreatic cancer (Sui et al. 2018; Bendell et al. 
2019). In addition, translational data from the ongoing Phase 1/2 study with CPI-444, an 
antagonist of A2AR, has suggested that patients with higher tumoral expression of CD73 and 
A2AR benefit from treatment (Hotson et al. 2017).  Interestingly, patients that had been on a PD-
1/L1 for a prolonged duration prior to study entry had elevated A2AR and CD73 expression 
suggesting the adenosine pathway may play a role in acquired resistance to PD-1/L1 treatment.
Additional work on patient samples from this study also revealed patients that had a high 
intratumoral activation of the adenosine pathway to benefit from study treatment in comparison 
to patients with a low activation signature (Willingham et al. 2018).
Study JZMA will evaluate the safety and efficacy of LY3475070 either as single agent or in 
combination with pembrolizumab in tumors known to be immune “cold” such as mCRPC, as 
well as immune “inflamed” tumors that are unresponsive to check point inhibition, as a 
consequence of an immune suppressive TME infiltrated by myeloid and other immune 
regulatory cells. The underlying clinical hypothesis is that targeting CD73 within the TME will 
reduce local adenosine levels, an important immune-suppressive metabolite. This can be 
expected to reduce the inhibitory signals of immune suppressive cells, which may lead to 
increased T-cell infiltration and activation within the TME and lead to improved clinical 
responses.
Owing to the primary focus on patient safety in early clinical development an open label study is 
appropriate and an mTPI-2 based dose escalation is an appropriate design feature as it allows for 
more comprehensive and nuanced decision making in Phase 1a of this study. In Phase 1b, 
randomization of patients to monotherapy or combination therapy in 2 of 3 cohorts is an 
appropriate means of ensuring balanced patient characteristics in both treatment arms.
4.3.
Justification for Dose
4.3.1.
LY3475070
A clinical starting dose of 150 mg QD of LY3475070 administered orally in humans is 
anticipated to be safe and have the potential for clinical efficacy.  Based on predicted human 
pharmacokinetics and a PK/pharmacodynamic model established on the basis of 

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
3 7
p har mac o d y na mic data 
 
a d ose of 1 5 0 m g Q D is 
a nt ici pate d t o res ult i n a n a vera ge tar get i n hi biti on of  
 o ver t he d osi n g i nter val a n d  
 at 
C mi n (r efer t o S ecti o n 4. 2. 3 of t he I B f or details).  Tar get i n hi bit i on of t his ma g nit u de is e x pecte d 
t o res ult i n cli nicall y mea ni n gf ul re d ucti on of a de n osi ne f or mat i on b y C D 7 3.  Mar gi n of Safet y 
f or or al a d mi nistratio n of  L Y 3 4 7 5 0 7 0 base d o n a d mi nistere d d ose a n d pre dicte d e x p os ure is 
prese nte d bel o w .
M ar gi n of S afet y f or Or al A d mi nistr ati o n of L Y 3 4 7 5 0 7 0 B ase d o n A d mi nistere d D ose a n d 
Pre dicte d E x p os ure
D ose
( m g/ k g)
D ose
( m g/ m2 )
D ose M ulti ple
a t o 
St arti n g D ose (t o 
m a xi m u m d ose)
A U C
( n g * h/ m L)
E x p os ure M ulti ple
b
t o St arti n g D ose (t o 
m a xi m u m d ose)
H u m a n ( 1 5 0 m g)
c
–
–
H u m a n ( 1 0 0 0 m g)
d
–
–
R at N O A E L
e
3 2 x ( 4. 9 x)
4 3 x ( 6. 5 x)
D o g N O A E L
f
2 2 x ( 3. 2 x)
1 4 x ( 2. 2 x)
A b bre viati o ns:  A U C = area u n der t he c ur ve; I VI V E = i n vitr o t o i n vi v o e xtra p olati o n; N O A E L = n o -o bser ve d -
a d verse-effect le vel.
a
D ose m ulti ple is t he d ose i n a ni mals/ d ose i n h u ma ns base d o n m g/ m 2.  D oses were c o n verte d fr o m m g/ k g t o 
m g/ m 2 usi n g a k m c o n versi o n fact or of 6 f or t he rat, 2 0 f or t he d o g, a n d 3 7 f or a 6 0 -k g h u ma n .  
b
E x p os ure m ulti ple is t he calc ulate d A U C i n a ni mals/ pre dicte d A U C i n h u ma ns. 
c
Cli nical starti n g d ose ( 1 5 0 m g) .  E x p os ure is pre dicte d A U C usi n g I VI V E of he pat oc yte cleara nce.
d
Ma xi m u m pla n ne d cli nical d ose ( 1 0 0 0 m g) .  E x p os ure is pre dicte d A U C usi n g I VI V E of he pat oc yte cleara nce.
e
N O A E L i n a rat 1 -m o nt h re peat d ose t o xicit y st u d y ( St u d y 8 4 0 1 9 1 3) .  Avera ge of male a n d fe male rat A U C o n 
Da y  2 8. 
f
N O A E L i n a d o g 1 -m o nt h re peat d ose t o xicit y st u d y ( St u d y 8 4 0 1 9 1 4) .  A vera ge of male a n d fe male d o g A U C o n 
Da y  2 8. 
4. 3. 2.
Pe m br oliz u m a b
T he pl a n ne d d ose of pe m br o liz u ma b f or t his st u d y is 2 0 0 mg Q 3 W. Base d o n t he t otalit y of  data 
ge nerate d i n t he Ke ytr u da de vel o p me nt pr o gra m, 2 0 0 m g Q 3 W is t he a p pr o priate d ose of 
pe m br o liz u ma b f or a d ults acr oss all i n dicati ons a n d re gar dless of t u m or t y pe .  As o utli ne d bel o w, 
t his d ose is j ustifie d b y:

Cli nical data fr o m  8 ra n d o mize d st u dies de m onstrati n g flat d ose- a n d e x p os ure -efficac y 
r elat i ons hi ps fr o m 2 m g/ k g Q 3 W t o 1 0 m g/ k g e ver y  2 wee ks ( Q 2 W), 

Cli nical data s h o wi n g mea ni n gf ul i m pr o ve me nt i n be nefit -ris k i ncl u di n g o verall s ur vi val 
at 2 0 0 mg Q 3 W acr oss m ul tiple i n dicat i ons, a n d

P har mac o l og y  data s h o wi n g f ull tar get sat urati o n i n b ot h s yste mic circ ulati on (i nferre d 
fr om P K  data) a n d t u mor (i nferre d fr o m  p h ysi ol ogicall y - base d P K [ P B P K] a nal ysis) at 
2 0 0 m g Q 3 W .
C CI
C CI
C CI
C CI
C CI

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
38
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and 
KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, 
KN001 Cohort F2 and KN006). All of these studies demonstrated flat dose- and exposure-
response relationships across the doses studied representing an approximate 5- to 7.5-fold 
difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to 
the highest doses studied. Subsequently, flat dose-exposure-response relationships were also 
observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer and 
classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of 
the tumor type. These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols.
4.4.
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA (Section 1.3) for the last participant in the study
globally.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
39
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
Type of Participant and Disease Characteristics for Phase 1a
Participants are eligible to be included in the study only if the following cohort-specific criteria 
apply:
1. Patients must be, in the judgement of the investigator, an appropriate candidate for 
experimental therapy and must have progressed through or be intolerant to therapies known 
to confer clinical benefit.
2. Patients must have archived tumor tissue available for biomarker analysis or be able and 
willing to undergo a baseline biopsy. On-treatment biopsy is optional (See Section 8.8).
3. Male or female participant with histological or cytological evidence of 1 of the following 
cancers that is metastatic, unresectable locally advanced, or locally recurrent: 
a.
Triple negative breast cancer. Triple-negative receptor status is defined as ≤10% for 
estrogen and progesterone receptor expression, and human epidermal growth factor 
receptor 2 (HER2) negative per ASCO/CAP HER2 testing guideline. 
i.
Patient must have received treatment for metastatic disease
ii.
Prior PD-1/L1 inhibitor is allowed;
b.
Pancreatic cancer
i.
Must have received chemotherapy for advanced or metastatic disease (e.g.
gemcitabine containing regimen or modified FOLFIRINOX);
ii.
Patients with known microsatellite instability-high (MSI-H) tumor should have 
received prior PD-1/L1 inhibitor therapy;
c.
Non-small cell lung cancer
i.
Patient must have experienced progressive disease on or within 3 months of 
completing prior PD-1/L1 based inhibitor therapy (i.e., have refractory disease).
ii.
Patients must have received treatment for metastatic disease. Patients with 
targetable mutations (e.g., ROS1, ALK, BRAF, and EGFR) must have received 
approved mutation-targeted therapy; 
iii.
Patients with targetable mutations are not required to have received PD-1/L1
inhibitors 
d.
Renal cell carcinoma, clear cell predominant subtype
i.
Patient must have experienced progressive disease on or within 3 months of 
completing prior PD-1/L1-based inhibitor therapy (i.e., have refractory disease).
e.
Cutaneous melanoma (CM)
i.
Patient must have experienced progressive disease on or within 3 months of 
completing prior-PD-1/L-based inhibitor therapy (i.e., have refractory disease).
f.
Castrate resistant prostate cancer

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
40
i.
Patient must have received treatment for metastatic disease; which should have
included at least 1 next generation hormonal agent (e.g., Abiraterone, 
enzalutamide)
ii.
Patients with small-cell or neuro-endocrine histologies will be excluded 
g.
Epithelial ovarian cancer
i.
Patient must have received treatment for metastatic disease, including a 
platinum-based therapy. Patients in first relapse after adjuvant platinum therapy 
whose disease is platinum-sensitive should have received treatment with 
platinum-based therapy for recurrent disease.
Type of Participant and Disease Characteristics for Phase 1b
4. Patients must be, in the judgement of the investigator, an appropriate candidate for 
experimental therapy and must have either refused, progressed through or be intolerant to 
therapies known to confer clinical benefit.
5. Patients must have metastatic, unresectable locally advanced, or locally recurrent disease.
6. Patients must be able and willing to provide the protocol required biopsies at baseline and 
during study treatment period (See Section 8.8). For patients enrolled in Cohorts D1 and D2,
biopsies are only required if patient has accessible soft tissue metastasis. 
7. Cohorts C1 and C2: Patients positive for CD73 expression (CD73 expression determined by
central IHC testing of pretreatment tumor biopsy; cut-off will be determined by the Sponsor)
a) Patients must have NSCLC, RCC or melanoma;
b) Patients must be refractory to prior PD-1/L1 inhibitor defined as: patients must have 
had prior PD-1/L1 therapy within 12 weeks of starting dosing on this study. Patients 
must have progressed on treatment with an anti-PD-1/L1 mAb administered either as 
monotherapy, or in combination with other checkpoint inhibitors or other therapies, 
with no intervening therapy prior to the start of study.  
PD-1/L1 treatment progression is defined by meeting all of the following criteria: 
i.
Patients must have had complete response (CR)/partial response (PR) or stable 
disease (SD) for a duration of at least 6 months prior to progression. 
ii.
Disease progression must have been demonstrated per Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer et al. 2009).  
iii.
The initial evidence of disease progression is to be confirmed by a second 
assessment no less than 4 weeks from the date of the first documented disease 
progression, in the absence of rapid clinical progression.
c) NSCLC patients with targetable mutations (e.g., ROS1, ALK, BRAF, and EGFR) must 
have received prior targeted therapy with an approved agent.  PD-1/L1 directed 
treatment is not a requirement for EGFR-mutant patients. 
Cohorts D1 and D2: Patients with metastatic CRPC
d) Patients must be PD-1/L1 inhibitor therapy naïve;
e) Patients must have received treatment for metastatic disease; which should have 
included at least 1 next generation hormonal agent (e.g., Abiraterone, enzalutamide)
f)
Patients with small-cell or neuro-endocrine histologies will be excluded 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
41
Cohort E: Patients with mTNBC
g) Prior PD-1/L1 inhibitor therapy allowed;
h) Patients must have received treatment for metastatic disease (at least 1 regimen of 
cytotoxic chemotherapy for metastatic disease);
Participants are eligible to be included in the study only if all of the following criteria apply:
8. Must be able to provide informed consent, as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the informed consent form (ICF) 
and in this protocol, according to local regulations and are at least 18 years of age. 
9. Men with partners of childbearing potential must use a condom during intercourse.  Men 
with partners of childbearing potential or women with childbearing potential must agree to 
use 2 effective methods of contraception including a highly effective contraceptive method of 
birth control (Appendix 3) during study treatment and for at least 120 days following the last 
dose of LY3475070 and pembrolizumab or country requirements, whichever is longer. For 
patients receiving LY3475070 only, contraception should be maintained for 7 days following 
the last dose.  Additional guidance for contraception during and after study intervention are 
located in Appendix 3.
10. Women of childbearing potential must have a negative urine pregnancy test at the screening 
visit followed by a negative serum pregnancy test documented within 24 hours prior to 
initiation of treatment. If the screening urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required. Additional guidance for pregnancy testing 
during and after study intervention is located in Appendix 2 and Appendix 3. 
11. Have at least 1 measurable lesion using standard techniques by RECIST version 1.1 
(Eisenhauer et al. 2009). Exception:  patients enrolled in the dose escalation phase and 
mCRPC patients enrolled in Cohort D1 and D2 are not required to have measurable disease.
12. Have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) scale (Oken et al. 1982).
13. Previous treatments: Have discontinued all previous treatments for cancer and recovered 
from the acute effects of therapy (except alopecia). Patients must have discontinued from 
previous treatments, as shown below:

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
42
Previous Treatment
Length of Time Prior to First Dose of LY3475070
Endocrine therapies
≥14 days
Cytotoxic therapies or targeted agents that are small 
molecule inhibitors
≥21 days or ≥5 half-lives, whichever is shorter
Biologic agents that are large molecules including 
immunotherapy (except for patients enrolled in cohorts
C1 and C2)
≥28 days
Limited-field radiotherapy (eg, stereotactic body 
radiation therapy [SBRT]) with palliative intent
≥14 days
Other radiotherapy
≥28 days
Participants must have recovered from all radiation-
related toxicities, not require corticosteroids, and not 
have had radiation pneumonitis.
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.
14. Have adequate organ function, as defined below:
System
Laboratory Value
Hematologic
ANC
≥1.5×109/L
Platelets
≥100×109/L
Hemoglobin
≥9 g/dL
Note:  transfusions to increase a patient’s hemoglobin level or initiation of erythropoietin or G-CSF therapy to meet 
enrollment criteria are not allowed in the 14 days preceding the first dose of study drug.  If a patient receives 
transfusions, erythropoietin, or G-CSF therapy ≥14 days prior to the first dose, the hematologic criteria listed above 
must be met following the 14-day window and prior to the first dose of study therapy.
Hepatic
Total bilirubin
≤1.5×ULN
Isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin is within normal limits, 
total serum bilirubin <3xULN, and Gilbert’s Syndrome is 
confirmed.
ALT and AST
<2.5x ULN 
Renal
Calculated creatinine clearance
based upon the Cockcroft-Gault formula
≥50 mL/min/1.73 m2

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
43
(see Appendix 6)
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; G-CSF = granulocyte-colony stimulating factor; ULN = upper limit of normal
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
15. For patients who have received prior immunotherapy, the following patients will be 
excluded:
a) Experienced 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) Experienced 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 [exceptions: endocrine disorders where patients with prior 
endocrine AEs are permitted to enroll if they are asymptomatic, considered 
clinically stable, and maintained on appropriate replacement therapy]
c) Any grade:
i.
ocular irAE, 
ii.
serious neurologic irAE (e.g., Guillain-Barre syndrome, myasthenia 
gravis, encephalitis) 
iii.
Serious cardiovascular irAE (e.g., myocarditis)
d) Required immunosuppressive agents other than corticosteroids for the 
management of irAE; or currently requires maintenance doses of 10 mg 
prednisone/prednisolone (or equivalent) per day for irAE
16. Have interstitial lung disease or (noninfectious) pneumonitis; patients with a history 
of (noninfectious) pneumonitis Grade 2 or greater that required steroids (>7 days) to 
assist with management
17. Have a serious concomitant systemic disorder that, in the opinion of the investigator, would 
compromise the patient’s ability to adhere to the protocol
18. 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

No evidence of acquired immunodeficiency syndrome (AIDS)-defining 
opportunistic infections within the last 2 years, and

CD4 count >350 cells/µl

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
44

HIV infected participants with a history of Kaposi’s sarcoma and/or Multicentric 
Castleman’s Disease are not eligible.
19. Have active hepatitis B or C virus infection (screening required)
20. Have current untreated tuberculosis
21. Have active infection requiring systemic therapy
22. Have 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
23. Have active or suspected autoimmune disease (e.g., autoimmune vasculitis, autoimmune 
myocarditis) or any illness or treatment that could compromise the immune system (e.g., 
prior solid organ transplant) within the past 2 years, or a syndrome or condition that requires 
continuous systemic corticosteroids or immunosuppressive agents. 
This criterion does not apply to patients with:  (i) vitiligo, alopecia, or type I diabetes 
mellitus; (ii) residual hypothyroidism due to an autoimmune condition requiring only 
hormone replacement; or (iii) psoriasis not requiring chronic systemic 
immunosuppressive treatment within the past 2years, not expected to recur in the absence 
of an external trigger, (iv) autoimmune-mediated hypothyroidism that is stable on 
hormone replacement; (v) Raynaud’s syndrome; or (vi) Sjogren’s syndrome.  Patients 
with resolved childhood asthma/atopy are allowed.
24. Are at risk of vascular inflammation, such as those with a history of angiitis, arteritis, or 
hypersensitivity vasculitis as an adverse reaction to medication, for example, are not eligible.
25. Are being treated with 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, intermittent steroid injections, and intranasal corticosteroids 
permitted.
26. Patients with conditions that may impact absorption of LY3475070, such as bowel 
obstruction, uncontrolled diarrhea, or extensive intestinal resection.
27. Have moderate or severe cardiovascular disease, such as the following:
a) presence of cardiac disease, including a myocardial infarction or any other arterial 
thrombotic event, blood clots not limited to deep vein thrombosis, 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

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
45
b) severe, moderate, or clinically significant valvulopathy; documented major ECG 
abnormalities that, in the judgment of the investigator, are clinically significant 
(for example, symptomatic arrhythmias or arrhythmias requiring treatment; 
myocardial infarction within the last 3 months; or mean corrected QT interval 
(QTc) >450 msec for male participants or QTc >470 msec for female participants 
or QTc >480 msec in participants with bundle branch block calculated using 
Fredericia’s correction and confirmed by triplicate ECG.
c) previous cardiotoxic cancer treatment associated with type 1 damage such as 
anthracyclines (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin) and 
previous thoracic radiotherapy with a field involving the heart.
28. Have symptomatic central nervous system (CNS) malignancy or metastasis and/or 
carcinomatous meningitis (screening not required).  Patients with treated CNS metastases are 
eligible for this study if they are not currently receiving corticosteroids (exceeding 10 mg/day 
prednisone or equivalent) and/or anticonvulsants to treat CNS metastases, and their disease is 
asymptomatic and radiographically stable for at least 30 days.
29. 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.
30. Post-partum patient who is or plans to breast-feed during the study 
31. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study
32. Have current or history of allergy or hypersensitivity to LY3475070 components including 
allergy to beta lactam antibiotics.
33. Has severe hypersensitivity to pembrolizumab and/or any of its excipients.
34. Has had an allogenic tissue/solid organ transplant.
Prior Therapy
35. Has received prior purinergic based inhibitors defined as adenosine A2AR, A2BR, A3, CD39 
or CD73.  
36. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 
5 years. Patients who have had a transplant greater than 5 years ago are eligible as long as 
they have no symptoms of graft versus host disease.
Prior/Concurrent Clinical Study Experience
37. Patient is 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 by the investigator and Lilly CRP/CRS.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
46
5.3.
Lifestyle Considerations
Not applicable.
5.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Rescreened participants should be assigned a new participant identification number.  
The interval between rescreening should be ≥2 weeks.  Each time rescreening is performed, the 
individual must sign a new ICF and will be assigned a new identification number.  A patient may 
not be rescreened in an effort to obtain a different CD73 result.  Repeating of laboratory tests 
during the screening period or repeating screening tests to comply with the protocol designated 
screening period does not constitute rescreening.  This includes 1 repeat for CD73 expression to 
determine Phase 1b Cohort C eligibility if CD73 expression was not able to be determined by the 
patient’s initial sample.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
47
6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol.
6.1.
Study Intervention(s) Administered
Cohort
Dose Level
Oral LY3475070
IV Pembrolizumab
Cohort A
DL1
150mg QD
N/A
DL2
300mg QD
N/A
DL3
600mg QD
N/A
DL4
1000mg QD
N/A
Cohort B
CDL1
150mg QD
200 mg Q3W
CDL2
300mg QD
200 mg Q3W
CDL3
600mg QD
200mg Q3W
Cohorts C1, D1 and E
RP1Dc
RP1D/MTD
200 mg Q3W
Cohorts C2 and D2
RP1Dm
RP1D/MTD
N/A
Abbreviations:  CDL = combination dose level; DL = dose level; IV = intravenous; N/A = not applicable; MTD = 
maximum tolerated dose; RP1D = recommended phase 1 dose; RP1Dc = recommended phase 1 dose (for 
combination therapy); RP1Dm = recommended phase 1 dose (for monotherapy); Q3W = every 3 weeks; QD = 
once a day.
Note: Pembrolizumab should be administered for a maximum duration of 24 months (35 cycles).
A delay of a treatment day up to 7 days due to holidays, weekends, bad weather, unrelated 
medical events, or other unforeseen circumstances will be permitted and not be counted as a 
protocol deviation.  The reason for interruption should be documented on the electronic case 
report form (eCRF).
The doses of LY3475070 will be administered at approximately the same times on each day, 
generally at home. Patients should be instructed take LY3475070 on an empty stomach, if 
possible.  Otherwise, drug capsules may be taken a minimum of 1 hour before eating or 2 hours 
after consumption of food.  A LY3475070 administration patient diary must be kept for dosing 
compliance monitoring. The actual time of dose administrations will be transcribed and 
provided to the sponsor.
If BID dosing is evaluated, patients will take doses 12±2 hours apart (i.e., 10 to 14 hours 
between doses).  There should at least be 10 hours between each subsequent dose. 
At clinic visits, patients will be directed to take LY3475070 at the site.  LY3475070 will be 
administered 30 to 60 minutes post administration of pembrolizumab.
Pembrolizumab will be administered using IV infusion on Day 1 of each 3-week treatment cycle 
after all procedures and assessments have been completed. 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 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
48
infusion pumps from site to site, a window between 5 minutes prior to and 10 minutes after 
administration is permitted (i.e., infusion time is 30 minutes (-5 min/+10 min).
The actual time of dose administrations will be transcribed and provided to the sponsor.
If LY3475070 is discontinued, pembrolizumab may be continued alone for up to 2 years 
(35 cycles).  Conversely, if pembrolizumab is discontinued, LY3475070 may be continued alone.
6.1.1. Definition of DLT and DLT-ET
6.1.1.1.
DLT
A DLT is defined as any of the events listed in the table below, if both of the following criteria 
are met:

the event occurs during the DLT observation period (28 days) in Phase 1a, and

the event cannot, in the opinion of the investigator, be definitely attributed to primary 
disease or extraneous causes, such as accident.
Patients who experience a DLT in the DLT observation period will be discontinued from study 
treatment.
Dose-Limiting Toxicities 
Hematologic Toxicity

Grade 3 thrombocytopenia associated with clinically significant bleeding and requiring platelet transfusion or 
Grade 4 thrombocytopenia of any duration

Grade 3 febrile neutropenia

Grade 3 anemia requiring a blood transfusion

Other Grade 4 toxicity, excluding toxicities listed below this table
Nonhematologic Toxicity – Nonlaboratory

Grade ≥3 irAE

Grade 3 colitis or noninfectious pneumonitis 

Grade 3 pneumonitis or Grade 2 pneumonitis that does not show clinical improvement within 3 days after 
initiation of optimal medical management including corticosteroids therapy, which is then treated as Grade 3

Grade 3 nausea, vomiting or diarrhea that lasts more than 48 hrs despite optimal supportive care 

Grade 3 fatigue lasting >7 days

Grade 3 hypertension despite maximal medical therapy

Grade 3 tachycardia

Any other Grade 3 toxicity 

Immune-related adverse event that necessitated permanent discontinuation of study drug(s), regardless of grade
Nonhematologic Toxicity – Laboratory/Investigations

Any Grade 3 laboratory abnormality except for specific exceptions listed below

ALT or AST:
o
>8 × ULN
o
≥2-fold above the patient’s baseline value that lasts >7 days, 
o
≥3 × ULN with concomitant bilirubin >2 × ULN, in the absence of cholestasis
o
Total bilirubin >3 × ULN
o
≥Grade 3 amylase or lipase that is associated with symptoms or clinical manifestations of pancreatitis
Please refer to Section 8.2.1.1 for additional hepatic safety monitoring guidance.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
49
Other Hematologic or Nonhematologic Toxicity That May Be a DLT.

Toxicity deemed by the investigator and Lilly CRP to be dose limiting, such as:
o
toxicity that is possibly related to study treatment and requires discontinuation of the patient from the 
study at any time within the DLT observation period, or
o
persistent Grade >2 toxicities causing a delay of LY3475070 study treatment >14 days during the DLT 
observation period.
Abbreviations:  AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; CRP = clinical 
research physician; HCC = hepatocellular carcinoma; irAE = immune-related adverse event; IV = intravenous; 
ULN = upper limit of normal. 
The following adverse events are not considered DLTs:

Toxicity that is clearly and directly related to the primary disease or to another etiology

Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency), if both the 
following criteria are met:
o
the disorder is manageable with or without systemic corticosteroid therapy and/or 
hormone replacement therapy, and 
o
the patient is asymptomatic

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

≥Grade 3 electrolyte abnormality that lasts <72 hours, is not clinically complicated and
resolves spontaneous or responds to conventional medical interventions

≥Grade 3 amylase or lipase that is not associated with symptoms or clinical manifestations of 
pancreatitis

Grade 3 or 4 neutropenia, provided both of the following criteria are met:
o
is not associated with fever or systemic infection, and
o
improves by at least 1 grade within 5 days

Grade 3 or 4 lymphopenia
6.1.1.2.
DLT-ET
A DLT-equivalent toxicity (ET) is any event listed in Section 6.1.1.1 occurring after the DLT 
observation period in Phase 1a or any cycle in Phase 1b. 
A DLT-ET is an AE that meets the DLT criteria as defined above and occurs in any cycle other 
than the DLT assessment period (28 days for Cohorts A1 through A4 and B1 through B3). 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 DL or the 
determination of the RP2D.
Potential DLTs that are AEs, which 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 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
50
may determine that confounding factors render the case to be not evaluable for the purposes of 
dose selection.
6.1.2. Definition of RP2D
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
Phase 1, including but not limited to LY3475070 dose adjustments, AEs, chronic intolerance, 
PK/pharmacodynamics data, and irAEs. 
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 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 (i.e., 
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.
5. Investigators should consult the site training, Pharmacy Manual or label for the specific study 
drug information.
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label dose finding study.
The Phase 1b dose expansion part will implement a randomization design for Cohorts C and D to 
mitigate the selection bias in allocating patients to either monotherapy dose expansion or 
combination therapy dose expansion.
6.4.
Study Intervention Compliance
Participant compliance with study intervention will be assessed at each visit. Compliance will be 
assessed by direct questioning, counting returned capsules/tablets/packages, and reviewing 
patient diaries. Deviation(s) from the prescribed dosage regimen should be recorded in the 
eCRF. Seventy-five percent of LY3475070 treatment doses must have been received by the 
patient in order to be considered compliant.
For IV medication, study intervention that is administered intravenously will be administered 
only at the investigational sites by the authorized study personnel. As a result, treatment 
compliance is ensured. 

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
5 1
6. 5.
C o nc o mit a nt T her a p y
At  baseli ne, rec or d pri or a n d c o nc urre nt me dicati ons.  Rec or d all pre me dicat i on, s u p p orti ve care, 
a n d c o nc o mit a nt me dicatio n c o nt i n u o usl y at e ver y visit a n d t hr o u g h o ut t he st ud y.
T he Lill y C R P/ C R S s h o uld be c o ntacte d if t here are a n y  q u estio ns re gar di n g c o nc o mit a nt or 
pri or t hera p y . Patie nts wit h metastatic C R P C ma y c o nti n ue wit h l utei nizi n g h or m o ne-releasi n g 
h or m o ne a nalo g u e f or test oster o ne s u p pressi o n. Z ol e dr o nic aci d or d e n os u ma b gi ve n f or b o ne 
s u p p ort is all o we d t o be c o nti n ue d if starte d 1 wee k pri or t o st u d y treat me nt d osi n g.  H o we ver, 
z ole dr o nic aci d or de ns o u ma b s h o ul d n ot be i nit iate d, es peciall y i n metastatic C R P C patie nts, 
after st u d y tr e at me nt has c o m me nce d.  N o  ot her c he m ot hera p y, i m m u n ot hera p y, her bal 
s u p ple me nts a n d/ or her bal dr u gs i nte n de d t o treat ca ncer, or e x peri me ntal dr u gs will be per mitte d 
w hile t he patie nts are i n t his st u d y.
If patients ca n’t be s witc he d t o alter nati ve t hera p y 
Lill y C R P/ C R S m ust be c o ns ulte d. F or a list please c o ns ult A p pe n di x 5.  I m m u ne -s u p pressi ve 
gl uc oc orti c oster oids ot her t ha n t o treat treat me nt relat e d ir A E are als o pr o hi bite d.  
A d mi nistrati o n of  li ve vacci nes is pr o hi bite d d uri n g t he st u d y a n d for 3 m o nt hs f o ll owi n g t he 
fi nal d ose of st u d y dr u g.   A n y me dicat i on or vacci ne (i ncl u di n g o ver -t he-c o u nter or prescri pt i on 
me dici nes, vit a mi ns, a n d/ or her bal s u p ple me nts) t hat t he partici pa nt is recei vi n g at t he ti me of 
e nr o ll me nt or recei ves d uri n g t he st u d y m ust be rec or de d al o n g wit h:

Reas o n f or use

Dates of a d mi nistrati o n i ncl u di n g start a n d e n d dates
Me dicat i ons or vacci nat i ons s pec ificall y pr o hi bite d i n t he e xcl usio n  crit eria are n ot all o we d 
d uri n g t he o n g oi n g trial.  If t here is a cli nical i n dicati o n f or a n y me dicat i on or vacci nat i on 
s pecificall y pr o hi bite d d uri n g t he trial, disc o nti n uati o n fr o m trial t hera p y or vacci nati on ma y be 
re q uire d.  T he i n vesti gat or s h o ul d disc uss a n y q uesti o ns re gar di n g t his wit h t he S p o ns or.  T he 
fi nal decisi on o n a n y s u p p orti ve t hera p y or vacci nati o n rests wit h t he i n vest i gat or a n d/ or t he 
parti ci pa nt's pri mar y p h ysicia n.  H o we ver, t he decisi o n t o c o nti n ue t he partici pa nt o n st u d y 
treat me nt re q uires t he mut u al  a gree me nt of t he i n vesti gat or, Lill y C R P/ C R S, a n d t he partici pa nt.
Liste d bel o w are s pecific restrict i ons f or c o nc o mit a nt t hera p y or vacci nati on d uri n g t he c o urse of 
t he st u d y:

A nt i ne o plastic s yste mic c he m ot hera p y or bi ol ogi c al t hera p y 

I mm u n ot hera p y  not s pecifie d i n t his pr ot oc ol

C he m ot h era p y not s pecifie d i n t his pr ot oc ol

I n vesti gati onal a ge nts ot her t ha n pe m br o liz u ma b

Ra diati o n t hera p y  
N ote:  Ra diati o n t hera p y t o a s y m pt o mati c s o litar y lesi o n or t o t he brai n ma y be all o we d 
at t he i n vesti gat or’s discret i on. 
C CI
C CI

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
52

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 Lilly CRP/CRS.
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 medication will be recorded on the eCRF including all prescription, over-the-
counter products, herbal supplements, and IV medications and fluids. If changes occur during 
the study period, documentation of drug dosage, frequency, route, and date should also be 
included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study treatment 
and up to 90 days after the last dose of study treatment should be recorded. Concomitant 
medications administered up to 90 days after the last dose of study treatment should be recorded 
for SAEs and events of clinical interest (Section 8.3.7).
6.5.1. Palliative Medicine and Supportive Care for LY3475070
The need for any form of radiotherapy (including palliative) in Cycles 1 and 2 will be cause for 
early discontinuation from the study. In Cycle 3 and beyond, palliative radiotherapy will be 
allowed.
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 
premedications, supportive care, and concomitant medications must be captured on the case 
report form.
Patients should receive full supportive care. The use of granulocyte-colony stimulating factor 
(G-CSF) is permitted at the discretion of the investigator based on American Society for Clinical 
Oncology (ASCO) (Smith et al. 2015) and European Society for Medical Oncology (Crawford et 
al. 2009) guidelines. 
If clinically indicated at any time during the study, erythropoietin and packed red blood cell 
transfusions may be used according to ASCO guidelines (Rizzo et al. 2008). Prophylactic 
antibiotic treatment should be consistent with ASCO guidelines (Flowers et al. 2013).
All concomitant medications should be recorded throughout the patient’s participation in the 
study.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
53
6.6.
Dose Modification
6.6.1. Dose Modification and Toxicity Management of LY3475070 for Non-immune-
mediated AEs Associated with LY3475070 and/or in Combination with 
Pembrolizumab
Patient may receive up to 2 dose reductions for AEs attributed to LY3475070. LY3475070
treatment may be interrupted, dose reduced or discontinued due to toxicity per the tables below.
Patients who have dose delays of more than 14 days, unless a different duration is specified in 
the above table, should permanently discontinue from the study. 
Due to its MOA, LY3475070 may induce irAEs that could affect any organ of the body.  
Previous trials with agents inhibiting the adenosine pathway have not reported irAEs to the same 
incidence rate as seen with other check point inhibitors such as CTLA4 or PD-1/L1.  From the 
ongoing A2AR antagonist single agent data only rash/pruritus, and elevated LFTs have been 
reported.  In the event other irAEs occur please consult the table provided in Section 6.6.1.2 for 
management of irAEs.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
54
Related AEs
Toxicity Grade 
or Conditions 
(CTCAE v5.0)
Action Taken to Therapy
AE Management
Monitor and Follow-up
Non hematologic
Acneiform Rash
Grade 1
Continue treatment 
Initiate topical prophylactic antibiotic 
(e.g., clindamycin).
Consider using low potency topical 
steroids (e.g., hydrocortisone 2.5%)
Monitor for worsening signs and 
symptoms.  
Grade 2
Withhold therapy until ≤ Grade 1 (for 
recurrent Grade 2, or toxicity lasting 
more than 2 weeks proceed as Grade 
3).
If immune mediated rash is suspected 
see below table for management of 
immune mediated AE’s).
Initiate oral antibiotic (e.g., 
doxycycline).
Initiate low potency topical steroid, if 
not already started. 
Consider skin biopsy if immune 
mediated toxicity is suspected
Monitor for worsening signs and 
symptoms weekly
Grade 3 
Withhold therapy until ≤ grade 1 then 
dose reduce LY3475070
(if rash worsens or does not improve 
in two weeks permanently 
discontinue) 
If Stevens–Johnson syndrome or toxic 
epidermal necrosis permanently 
discontinue patient
Initiate oral antibiotic (e.g., 
doxycycline).
Initiate systemic corticosteroid (e.g., 
prednisone 0.5 mg/kg daily 
(maximum dose, 40 mg).
Consider dermatology consultation.
Monitor for worsening signs and 
symptoms weekly until improvement 
to ≤Grade 1.
Resume LY treatment with 1 DL
reduction.
If rash does not improve or worsens 
after 2 weeks of treatment, 
discontinue LY permanently. 
If Stevens–Johnson syndrome or toxic 
epidermal necrolysis is suspected, 
discontinue permanently.
Grade 4
Permanently discontinue 
Initiate oral antibiotic (e.g.,
doxycycline).
Initiate systemic corticosteroid (e.g., 
prednisone 0.5 mg/kg daily 
(maximum dose, 40 mg).
Consider dermatology consultation.
Diarrhea
Grade 1
Continue LY3475070 treatment.
Start loperamide 4 mg initially, 
followed by 2 mg every 4 hours or 
after each stool.
Consider discontinue of lactose 
containing products

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
55
Related AEs
Toxicity Grade 
or Conditions 
(CTCAE v5.0)
Action Taken to Therapy
AE Management
Monitor and Follow-up
Grade 2
Continue LY3475070 treatment if 
Grade 2 diarrhea lasts <48 hours.
Hold LY3475070 treatment if Grade 2 
diarrhea lasts ≥48 hrs treatment until 
resolution to ≤ Grade 1.
Start loperamide 4 mg initially, 
followed by 2 mg every 4 hours or 
after each stool.
Encourage oral hydration.
If immune mediated colitis is 
suspected, consider GI consultation 
and biopsy.
Grade 3
Hold LY3475070 until resolution to 
Grade ≤ 1.
Resume LY at 1 DL lower upon 
recovery.
If not already done, start loperamide 4 
mg initially, followed by 2 mg every 4 
hours or after each stool.
Consider hospitalization for symptom 
and fluid management and GI 
consultation. 
Grade 4
Permanently discontinue LY3475070
treatment
Consider hospitalization for symptom 
and fluid management, hydration and 
GI consultation. 
AST/ALT elevation or Increased 
bilirubin
Grade 1
Continue LY3475070 treatment
Review concomitant medications and 
alcohol use
Grade 2
Continue treatment if immune 
mediated transaminitis is not 
suspected.
Hold LY3475070 if immune mediated 
transaminitis is suspected (see below 
table for management of immune 
mediated AE’s).
Review concomitant medications and 
alcohol use
Consider hepatology consultation and 
rule out biliary obstruction due to 
disease progression
Consider biopsy if immune mediated 
transaminitis suspected.
Monitor LFTs every 2-5 days until 
≤Grade 1 (see protocol section 
8.2.1.1)
Grade 3 
Hold LY3475070 until ≤Grade 1.
Resume LY3475070 treatment at 1 
DL lower if the patient has no 
evidence of drug induced 
hepatocellular injury. 
Patients with evidence of drug 
induced hepatocellular injury (i.e., 
transaminase ≥3XULN and total 
bilirubin ≥2XULN should 
Review concomitant medications and 
alcohol use
Consider hepatology consultation
Monitor LFTs every 2-5 days until 
≤Grade 1 (see protocol section 
8.2.1.1)

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
5 6
Rel ate d A Es
T o xicit y G r a de 
or C o n diti o ns 
( C T C A E v 5. 0)
Act i o n T a ke n t o T her a p y
A E M a n a ge me nt
M o nit or a n d F oll o w -u p
per ma ne ntl y disc o nti n ue L Y 3 4 7 5 0 7 0
treat me nt.
Gra de 4
Per ma ne ntl y disc o nti n ue L Y 3 4 7 5 0 7 0
treat me nt
Re vie w c o nc o mita nt me dicati o ns a n d 
alc o h ol use
C o nsi der he pat ol o g y c o ns ultati o n .
M o nit or L F Ts e ver y 2 -5 da y s u ntil 
≤Gra de 1 (see pr ot oc ol secti o n 
8. 2. 1. 1) .
Fati g ue
Gra de 1
C o nti n ue treat me nt
Ma na ge per r o uti ne cli nical practice 
a n d/ or i nstit uti o nal g ui deli nes
Gra de 2
C o nti n ue treat me nt
Ma na ge per r o uti ne cli nical practice 
a n d/ or i nstit uti o nal g ui deli nes
Gra de 3
Wit h h ol d L Y 3 4 7 5 0 7 0 u ntil res ol uti o n 
≤ gra de 1 , if res ol ve d wit hi n 7 da ys 
t he n res u me treat me nt. 
Ma na ge per r o uti ne cli nical pract ice 
a n d/ or i nstit uti o nal g ui deli nes
C CI

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
5 7
Rel ate d A Es
T o xicit y G r a de 
or C o n diti o ns 
( C T C A E v 5. 0)
Act i o n T a ke n t o T her a p y
A E M a n a ge me nt
M o nit or a n d F oll o w -u p
If gra de 3 persist o ver 7 da ys t he n 
d ose re d uce o ne le vel.
If rec urre nce after c o nti n ui n g 
treat me nt d ose re d uce o ne le vel.
N o n -He mat ol o gic T o xicit y 
Gra de 1
C o nti n ue L Y 3 4 7 5 0 7 0 treat me nt
Ma na ge per r o uti ne cli nical practice 
a n d/ or i nstit uti o nal g ui deli nes 
Gra de 2
Wit h h ol d L Y 3 4 7 5 0 7 0 treat me nt u ntil 
res ol uti o n t o ≤gra de 1 f or rec urre nt 
Gra de 2, or t o xicit y lasti n g m ore t ha n 
2 wee ks pr ocee d as Gra de 3
Ma na ge per r o uti ne cli nical practice 
a n d/ or i nstit uti o nal g ui deli nes
Gra de 3 or 
rec urre nt 
Gra de 2
Wit h h ol d treat me nt u ntil res ol uti o n t o 
≤gra de 1 a n d t he n re d uce d ose o ne 
le vel. 
Ma na ge per r o uti ne cli nical practice 
a n d/ or i nstit uti o nal g ui deli nes
Gra de 4
Per ma ne ntl y disc o nti n ue
Ma na ge per r o uti ne cli nical practice 
a n d/ or i nstit uti o nal g ui deli nes.
He m at ol o gic t o xicit y
Ne utr o pe nia
Gra de 1
C o nti n ue treat me nt 
Gra de 2
C o nti n ue treat me nt 
Gra de 3
Wit h h ol d L Y 3 4 7 5 0 7 0 u ntil res ol uti o n 
≤gra de 1 f or rec urre nt Gra de 3 , or 
t o xicit y lasti n g m ore t ha n 2 wee ks 
pr ocee d as gra de 4 .
If fe brile ne utr o pe nia t he n d ose re d uce 
o ne le vel u p o n res ol uti o n ≤gra de 1
If patie nt is a b o ve 3 8. 0° C o n 2
se parate occasi o ns a n d or ass ociate d 
wit h si g ns or s y m pt o ms of se psis start 
i ntra ve n o us i n acc or da nce wit h t he 
l ocal h os pital ne utr o pe nic se psis
g u i deli nes
G -C S F s u p p ort ma y be gi ve n as 
dee me d a p pr o priate b y t he p h ysicia n 
per i nstit uti o nal g ui deli nes
Perf or m C B C wee kl y ≤Gra de 3  
Gra de 4
Wit h h ol d L Y 3 4 7 5 0 7 0 u ntil res ol uti o n 
≤gra de 1 t he n res u me at o ne re d uce d 
D L .
If ne utr o pe nia is l o n ger t ha n 5 da ys 
disc o nti n ue patie nt
If patie nt is a b o ve 3 8. 0° C o n t w o 
se parate occasi o ns a n d or ass ociate d 
wit h si g ns or s y m pt o ms of se psis start 
i ntra ve n o us i n acc or da nce wit h t he 
l ocal h os pital ne utr o pe nic se psis
g ui deli nes .
Perf or m C B C wee kl y ≤Gra de 3  
C CI

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
58
Related AEs
Toxicity Grade 
or Conditions 
(CTCAE v5.0)
Action Taken to Therapy
AE Management
Monitor and Follow-up
G-CSF support may be given as 
deemed appropriate by the physician 
per institutional guidelines.
Anemia
Grade 1
Continue dose 
Grade 2
Continue dose
Grade 3
Withhold LY3475070 until resolution 
≤grade 1 then resume at one reduced 
DL
Blood transfusions as per local 
institutional guidelines 
Perform CBC weekly ≤Grade 3  
Grade 4
Discontinue treatment 
Blood transfusions as per local 
institutional guidelines 
Thrombocytopenia
Grade 1 (LLN > 
75,000 mcL)
Continue dose 
Grade 2 
(75,000>25,000)
Continue dose 
Grade 3 (<25,000 
mcL) with 
significant 
bleeding 
Withhold LY3475070 until resolution 
≤Grade 1 and resume treatment.  If 
associated with bleeding, or Grade 3 
reoccurs, then resume at one reduced 
DL.
If thrombocytopenia Grade 3 reoccurs 
at lower DL discontinue patient.
Platelet transfusion per local 
institutional guidelines.
Perform CBC weekly ≤Grade 3.  
Grade 4 life 
threatening 
spontaneous 
bleeding
Permanently discontinue.
Platelet transfusion per local 
institutional guidelines 

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
5 9
A b bre viati o ns : C B C = c o m plete bl o o d c o u nt; 
; 
; G-C S F 
= gra n ul oc yte c ol o n y -sti m ulati n g fact or; L F Ts = li ver f u ncti o n tests; 
.
6. 6. 1. 1.
D ose m o dific ati o n a n d t o xicit y m a n a ge me nt of i nf usi o n -re acti o ns rel ate d t o 
pe m br oliz u m a b
Pe m br oliz u ma b
ma y 
ca use se vere or life-t hreate ni n g i nf usi on- reacti ons i ncl u di n g se vere 
h y perse nsit i vity or a na p h yla xis.  Si g ns a n d s y m pt o ms us uall y  de v elo p d uri n g or s h ortl y aft er 
dr u g i nf usi o n a n d ge nerall y res ol ve c o mpletel y wit hi n 2 4 h o urs of c o m plet i on of  inf usi o n .  D ose 
m o dificati o n a n d t o xi cit y ma na ge me nt g uideli nes o n pe m br oliz u ma b ass ociate d i nf usi o n react i on 
are pr o vi de d i n t he ta ble belo w.
C CI
C CI
C CI

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
60
Pembrolizumab Infusion-Related Reaction Dose Modification and Treatment Guidelines
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 hrs (±30 minutes) prior to 
infusion of pembrolizumab with:

Diphenhydramine 50 mg po
(or equivalent dose of 
antihistamine).

Acetaminophen 500 to
1000 mg po (or equivalent 
dose of analgesic).
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; 
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:

Epinephrine**

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics

Oxygen

Pressors
No subsequent dosing

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
61
NCI CTCAE Grade
Treatment
Premedication at
Subsequent Dosing
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilator support indicated

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.
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 Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov
Abbreviations:  IV = intravenous; NSAID = non-steroidal anti-inflammatory drug; po = by mouth

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
62
6.6.2. Dose Modification and Toxicity Management for Immune-Related AEs Associated 
with LY3475070 and/or in Combination with Pembrolizumab
An immune-related AE (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 one
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, 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 table 
below.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
63
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.
Pembrolizumab 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 treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤Grade 1 after corticosteroid taper.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
64
irAEs
Toxicity grade 
(CTCAE V5.0)
Action with 
pembrolizumab and 
LY3475070
Corticosteroid and/or other 
therapies 
Monitoring and follow-up
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids 
(initial dose of 1 to 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 to 2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for signs and 
symptoms of enterocolitis (i.e.,
diarrhea, abdominal pain, blood, or 
mucus in stool with or without 
fever) and of bowel perforation 
(i.e., 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
AST or ALT 
elevation or 
Increased 
Bilirubin
Grade 2a
Withhold

Administer corticosteroids 
(initial dose of 0.5 to 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 3b or 4c
Permanently 
discontinue

Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
65
irAEs
Toxicity grade 
(CTCAE V5.0)
Action with 
pembrolizumab and 
LY3475070
Corticosteroid and/or other 
therapies 
Monitoring and follow-up
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
Withholdd

Initiate insulin replacement 
therapy for participants with 
T1DM

Administer 
antihyperglycemic 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 
discontinued
Hyperthyroidism 
Grade 2
Continue

Treat with nonselective 
beta-blockers (eg,
propranolol) or thionamides 
as appropriate

Monitor for signs and symptoms of 
thyroid disorders
Grade 3 or 4
Withhold or 
permanently 
discontinued
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 
injury
Grade 2
Withhold

Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by 
taper

Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
66
irAEs
Toxicity grade 
(CTCAE V5.0)
Action with 
pembrolizumab and 
LY3475070
Corticosteroid and/or other 
therapies 
Monitoring and follow-up
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 evente
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
a AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:  >1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:  >3.0 to 10.0 x ULN if baseline 
normal; >3.0 to 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 pembrolizumab is at the discretion of the investigator or treating physician. If control 
achieved or ≤Grade 2, pembrolizumab 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.
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate transaminase; GI = gastrointestinal; irAE = immune-related adverse event;
IV = intravenous; ULN = upper limit of normal
NOTE: The frequency or severity of known potential irAEs with pembrolizumab may be increased in combination with LY3475070.  
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.
For any other dose modifications, toxicities, or infusion-related reactions related to pembrolizumab, please consult the product label.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
67
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.
6.7.
Intervention after the End of the Study
The end of study definition is defined in Section 4.4. Investigators will continue to follow the 
SoA provided in 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 on study 
intervention when study completion occurs.  Lilly will notify investigators when the continued 
access period begins.
If LY3475070 is discontinued, pembrolizumab may be continued alone for up to 2 years 
(35 cycles). Conversely, if pembrolizumab is discontinued, LY3475070 may be continued alone.
Participants are not required to sign a new ICF before treatment is provided during the continued 
access period; the initial ICF for this study includes continued access under this protocol.
The participant’s continued access to study intervention 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 intervention and lasts approximately 90 days.
Follow-up procedures will be performed as shown in the Continued Access SoA.
Participants who are in short-term follow-up when the continued access period begins will 
continue in short-term follow-up until the 90-day short-term follow-up visit is completed. Long-
term follow-up does not apply.
Participants who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.
In all cases, no follow-up procedures will be performed for a participant who withdraws 
informed consent unless he or she has explicitly provided permission and consent.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
68
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
The reasons for treatment and study discontinuation and dates of discontinuation will be 
collected for all patients.
Patients who discontinue during the study treatment period, whether or not they received study 
treatment, will have follow-up procedures performed as shown in the SoA (Section 1.3).
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
7.1.
Discontinuation of Study Intervention 
Discontinuation of study treatment does not represent withdrawal from the study.
Participants may discontinue study treatment at any time for any reason or be discontinued from 
the study treatment at the discretion of the investigator should any untoward effect occur. In 
addition, a subject may be withdrawn by the investigator or the sponsor if enrollment into the 
trial is inappropriate, the trial plan is violated or for administrate and/or other safety reasons. 
A subject must be discontinued from the trial for the following reasons:

the participant or the participant’s designee, for example, parents or legal guardian
requests to discontinue investigational product.

the subject is lost to follow -up
A subject must be discontinued from trial treatment but continue to be followed for any of the 
following reasons:

the patient becomes pregnant during the study

the patient is significantly noncompliant with study procedures and/or treatment

disease progression.  Disease progression should be confirmed per iRECIST 4 to 8 weeks 
after site-assessed first radiologic evidence of PD in clinically stable participants.
Participants, who have unconfirmed disease progression may continue on treatment at the 
discretion of the investigator until progression per iRECIST. Any participant deemed 
clinically unstable should be discontinued from study treatment at first radiologic 
evidence of PD and is not required to have repeat tumor imaging for confirmation of PD 
by iRECIST.  

unacceptable toxicity

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 invention will occur prior to introduction of the new agent.

Recurrent Grade 2 pneumonitis

Discontinuation of treatment may be considered for participants who have attained a
confirmed complete response (CR) and have been treated for at least 8 cycles (at least 
24 weeks), receiving [for monotherapy:  at least 2 doses of pembrolizumab; for 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
69
combination treatment:  2 cycles of the combination including 2 doses of 
pembrolizumab and at least 75% of the planned doses of LY3475070] beyond the date
when the initial CR was declared.

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.
Participants discontinuing from the investigational product prematurely for any reason should 
complete adverse event 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)

subject decision
o
the participant or the patient’s designee, for example, parents or legal 
guardian 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) of this protocol.
7.2.1. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify 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 agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the sponsor CRP to allow the 
inadvertently enrolled participant to continue in the study with or without 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.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
70
Please refer to Appendix 7 for discontinuation of inadvertently enrolled patients in the United 
Kingdom.
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.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
71
8.
Study Assessments and Procedures

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 (e.g., 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).
8.1.
Efficacy Assessments
8.1.1. RECIST V1.1 for Tumor Response Assessment
Please follow the guidelines below when assessing tumor response:

Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 will be applied as the 
primary criteria for assessment of tumor response (Eisenhauer et al. 2009).

The extent of computed tomography (CT) or magnetic resonance imaging needed to 
establish baseline tumor burden is based upon the investigator’s determination. 

Tumor assessments will be performed for each patient at the times shown in the SoA 
(Section 1.3). Counting from C1D1, for the first year of study treatment, disease status 
should be evaluated radiologically per RECIST v1.1 guidelines every 9 weeks (±7 days)
for the first year, and every 12 weeks (±7 days) thereafter (until a discontinuation 
criterion is met).  

Perform assessments as scheduled, even if study treatment is delayed or omitted, except 
when deemed not feasible in the opinion of the investigator because of the patient’s 
clinical status.

Standard of care scan (pre-ICF) may be used as baseline provided it meets technical 
requirements for inclusion criteria and occurred within 28 days of treatment.
Per RECIST v1.1 imaging guidelines:

imaging modality (e.g., CT or magnetic resonance imaging [MRI]) obtained for the study 
baseline should be repeated throughout the study as described in SoA; 

Intravenous and oral contrast should be used as clinically indicated;

While CT imaging with slices ≤5 mm, MRI imaging is also acceptable;

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
72

CT images from positron emission tomography-CT scans may be used for response 
assessment if the associated CT scan has the same quality as a diagnostic CT.
Best overall response (BOR; e.g., complete or partial response, stable disease or unknown) will 
be determined locally by the investigator per RECIST v1.1; there will be no independent review 
of BOR.  When the RECIST v1.1 criteria for progressive disease are met, clinically stable 
patients may undergo additional radiologic imaging progression for confirmation of PD per 
iRECIST (Section 8.1.1, Seymour et al 2017).  For patients who meet criteria to continue
treatment after initial progression (either awaiting confirmation by iRECIST or have iUPD by 
iRECIST), reconsenting is required. Patients who discontinue treatment without documented 
progression should continue to be assessed for patients who discontinue study treatment without 
confirmed PD, periodic imaging per SoA (Section 1.3) for PD confirmation will continue until 
PD, or initiation of subsequent therapy or withdrawal of consent. If the patient is still on study 
treatment after 1 year, perform tumor imaging Q12W.
8.1.2. iRECIST For Confirmation of PD in Clinically Stable Patients and Radiologic PD 
per RECIST v1.1. 
RECIST v1.1 will be applied as the primary criteria for assessment of tumor response 
(Eisenhauer et al. 2009).  The response to immunotherapy may differ from the typical responses 
observed with cytotoxic chemotherapy, including the following (Wolchok et al. 2009; Nishino et 
al. 2013):

Response to immunotherapy may be delayed.

Response to immunotherapy may occur after 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 v1.1, 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 v1.1 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:

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
73
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 v1.1 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
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.
Management Guidelines for Patients Who Have Radiologic Evidence of Progressive 
Disease by RECIST v1.1
If a patient is clinically stable at the first radiologic PD by RECIST v1.1 (Eisenhauer et al 2009), 
the patient may be considered for continuation on the study until progression is confirmed. 
Confirmation of progression must occur no less than 4 weeks later by iRECIST.  For patients to 
be considered for continuation, the following criteria must all be met: 
a.
Absence of symptoms and signs indicating clinically significant progression of disease;
b. No decline in ECOG or Karnofsky performance status;
c.
Absence of symptomatic rapid disease progression requiring urgent medical intervention 
(e.g., symptomatic pleural effusion, spinal cord compression).
The continuation of treatment after initial radiologic PD takes into consideration the observation 
that some patients may experience transient tumor flare or pseudo-progression with 
immunotherapy but could have disease response later.  Patients may continue to receive 
treatment after reconsenting.  For patients who meet criteria to continue treatment after initial 
progression (either awaiting confirmation by iRECIST or have iUPD by iRECIST), reconsenting 
is required.  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

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
74
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 v1.1.  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.
Imaging and Treatment Guideline for Patients who have First Radiologic PD by 
RECIST v1.1
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST v1.1
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

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
75
Abbreviations:  iCPD = iRECIST confirmed progressive disease; iCR = iRECIST confirmed complete response; 
iSD = iRECIST confirmed stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive 
disease; RECIST= Response Evaluation Criteria in Solid Tumors.
8.1.3.
Efficacy Assessment for mCRPC Patients 
For mCRPC patients enrolled in this trial (both during dose escalation, Cohorts A and B, and 
dose expansion Cohorts D1 and D2), response criteria set forth by the Prostate Cancer Clinical 
Trials Working Group 3 will be utilized (Scher et al. 2016). Efficacy will be evaluated on a 
combination of RECIST v.1.1 (if patient has measurable disease), prostate-specific antigen 
(PSA) measurements, and bone scintigraphy using 99mTc-methylene diphosphonate 
radionucleotide (99mTc MDP). Multi-parametric MRI may also be used to evaluate response or 
progression in bone-only disease. Central measurement of circulating tumor cells is planned at a 
frequency of every 3 weeks but will not be required for efficacy evaluation. 
For patients with measurable disease, RECIST v1.1, as described above in Section 8.1.1, will be 
utilized with the following caveats: 
I.
For nodal lesions, separate pelvic vs extra-pelvic disease and record up to 5 nodal 
lesions in total.
II.
In order to classify as progression, previously normal lymph nodes (<1 cm) must 
have grown by at least 0.5 cm in the short axis from baseline scan or nadir and be 
≥1 cm in the short axis. 
III.
Nodes that have progressed to 1.5 cm in the short axis are considered 
measurable; nodes that have progressed to 1 cm to <1.5 cm are considered 
pathologic but subject to clinical discretion and non-measurable.
IV.
Visceral disease should be designated separately as lung, liver, adrenal, or CNS.
All mCRPC patients will undergo a 99mTc MDP scintigraphy at baseline to evaluate skeletal 
disease involvement. Bone lesions should be evaluated every 9 weeks (±7 days) and can be 
scheduled around CT/MRI disease staging. Due to possible bone flare that can be part of bone 
healing in response to treatment, and not actual progression, a 2+2 rule should be used for 
assessment. Progression should only be called if at least 2 new lesions are seen on the first 
on-treatment scan, followed by at least 2 additional lesions on the second or subsequent 
post-treatment scans.
For patients with non-measurable disease, PSA evaluations will be utilized for response 
assessment to treatment. Prostate-specific antigen will be measured at each treatment cycle 
(every 3 weeks), but because favorable PSA response to treatment may be delayed, early PSA 
rises should be ignored until 12 weeks unless patient is rapidly progressing (new lesions on 
image assessment) with clinical deterioration. After the first evaluation at 12 weeks, PSA 
response should be evaluated at every 9 weeks for progression. A PSA increase of 25% and 2 
ng/dL from baseline/nadir, confirmed with a second measurement at least 3 weeks apart, will be 
considered progression. A PSA decrease from baseline that is 50% will be considered a 
response and should be confirmed with a repeat measurement at least 3 weeks apart.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
76
For each patient, ECGs, vital signs, laboratory tests, and other tests should be collected as shown 
in the SoA (Section 1.3).
Refer to Section 8.3 for details on the recording of AEs.
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
8.2.1.
Clinical Safety Laboratory Assessments

Lilly or its designee will provide the investigator with the results of safety laboratory tests 
analyzed by a central vendor, if a central vendor is used for the clinical trial.  

See Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA 
(Section 1.3) for the timing and frequency.

The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the case report 
form (CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or until the completion of Visit 803 should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by 
the investigator or medical monitor.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3).
o
If there is an abnormal laboratory value or abnormal value for any other diagnostic or 
screening test (for example, blood pressure increased, neutrophils decreased, etc.) and 
it is known to be related to a disease diagnosis (for example, hypertension, 
neutropenia, etc.) this should be reported in the CRF as an AE.  Do not enter the test 
abnormality, enter the disease diagnosis or categorical term. If laboratory values 
from non-protocol specified laboratory assessments performed at the institution’s 
local laboratory require a change in participant management or are considered 
clinically significant by the investigator (e.g., SAE or AE or dose modification), then 
the event(s) must be reported in the CRF as AE(s).
8.2.1.1.
Hepatic Safety Monitoring
In study participants with baseline ALT/AST< 1.5× ULN
If a study participant enrolled with baseline alanine aminotransferase (ALT)/aspartate 
aminotransferase (AST) <1.5× ULN, experiences elevated ALT/AST ≥3× ULN, liver testing 
(Appendix 4) should be repeated within 2 to 5 days including ALT, AST, alkaline phosphatase 

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
7 7
(A L P ), t otal bilir u bi n (T B L ), direct bilir u bi n, ga m ma-gl uta m yl tra nsferase, a n d creati ne ki nase t o 
c o nfir m t he a b n or malit y a nd t o deter mi ne if it is i ncreasi n g or decreasi n g. If t he a b n or mality 
persists or w orse ns, cli nical a n d la b orat or y  mo ni t ori n g a n d e val uati on f or p ossi ble ca uses of 
a b n or mal li ver tests, s h o uld be i ni tiate d b y t he i n vestigat or i n c o ns ulta tio n wi t h t he st u d y me dical 
m o nit or.  M o nit ori n g of A L T, A S T, T B L, a n d A L P s h o ul d c o nti n ue u nt il le vels n or malize or 
ret ur n t o a p pr o xi mate baseli ne le vels.  
I n st u d y p artici p a nts wit h b aseli ne A L T/ A S T ≥1. 5 x U L N
If a st u d y p artici pa nt e nr olle d wit h baseli n e A L T/ A S T ≥1. 5 × U L N, e x perie nces ele vate d 
A L T/ A S T ≥2 × baseli ne, li ver testi n g ( A p pe n di x 4) i ncl u di n g A L T, A S T, T B L, direct bilir u bi n, 
ga m ma -gl uta m yl  tra nsferase, a n d creati ne ki nase s h o ul d be re peate d wit hi n 3 t o 5 da ys t o 
c o nfir m t he a b n or malit y a n d t o det er mi ne if it is i ncreasi n g or decreasi n g.  If t he a b n or mality 
persists or w orse ns, cli nical a n d la b orat or y  mo ni t ori n g a n d e val uati on f or p ossi ble ca uses of 
a b n or mal li ver tests, s h o uld be i ni tiate d b y t he i n vestigat or i n c o ns ultat i on wi t h t he st u d y 
C R P/ C R S. M o ni t ori n g of A L T, A S T, a n d T B L s h o ul d c o nti n ue u ntil le vels n or malize or ret ur n 
t o a p pr o xi mate baseli ne le vels.
8. 2. 1. 1. 1.
S peci al He p atic S afet y D at a C ollecti o n
A d dit i onal safety data s h o ul d be c o llecte d via t he C R F/electr o nic data e ntr y/ desi g nate d data 
tra ns missi on met h o ds if 1 or m ore of t he f o ll owi n g c o n di tio ns occ ur: 
I n p artici p a nts e nr olle d wit h b aseli ne A L T/ A S T < 1. 5× U L N:

Ele vat i on of ser u m A L T/ A S T t o ≥5 × U L N o n 2 or m ore c o nsec ut i ve bl o o d tests

Ele vate d A L T/ A S T ≥3 × U L N a n d ele vate d T B L ≥2 × U L N
I n p artici p a nts e nr olle d wit h b aseli ne A L T/ A S T ≥1. 5 × U L N

Ele vate d A L T/ A S T ≥3 × baseli ne o n 2 c o nsec ut i ve tests

Ele vate d A L T/ A S T ≥2 × baseli ne a n d ele vate d T B L ≥2 × U L N
I n all st u d y p artici p a nts 

Di sc o nti n uatio n f r o m st u d y treat me nt d ue t o a he patic e ve nt or a b n or malit y of 
li ver tests

Occ urre nce of a he pat ic e ve nt c o nsi dere d t o be a S A E
8. 2. 1. 2.
Aller gic re acti o n a n d H y perse nsiti vit y
F or s us pecte d h y perse nsi tivit y react i on, lab or at or y tests ma y be o btai ne d at t he f oll o wi n g t i me 
p oi nts:

I n t he prese nce of ge neralize d urticaria or if a na p h yla xis is s us pecte d.

After t he s u bject has bee n sta bilize d, o btai n a sa m ple wit hi n 1 t o 2 h o urs of t he e ve nt, 
h o we ver, sa m ples ma y  be o btai ne d as late as 1 2 h o urs after t he e ve nt as a nal ytes ca n 
r e mai n altere d f or a n e xte n de d peri o d of ti me.  Rec or d t he ti me at w hic h t he sa m ple was 
c ollecte d.
O btai n a f o ll ow- u p sa m ple at t he ne xt re g ularl y sc he d ule d visit or after 4 wee ks, w hic he ver is 
later.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
78
All biologic agents carry the risk of systemic allergic/hypersensitivity reactions. Clinical 
manifestations of these reactions may include but are not limited to:

Skin rash

Pruritus (itching)

Dyspnea

Urticarial (hives)

Angioedema (for example, swelling of the lips and/or tongue)

Hypotension

Anaphylactic reaction
Participants with clinical manifestations of systemic allergic/hypersensitivity reactions should be 
treated per local standard of care.  Additional data describing each symptom should be provided 
to the sponsor in the CRF.  
In case of anaphylaxis or generalized urticaria, additional blood samples should be collected as 
close as possible to the onset of the event (see Section 8.2.1 Clinical Safety Laboratory 
Assessments).  Follow-up samples should be obtained at the next regularly scheduled visit or 
4 weeks after the event, whichever is later.  The lab results are provided to the sponsor via the 
central laboratory or via CRF.
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 should provide AE verbatim terms and then the terms will be mapped by Lilly 
or its designee to corresponding terminology within the Medical Dictionary for Regulatory 
Activities (MedDRA) Lower Level Term (LLT) dictionary.  The investigator will use Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 to assign AE severity grades.
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.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
79
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.
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 one 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.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
80
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.
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 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 
treatment.  However, if an SAE occurs after signing the ICF, but prior to receiving study 
treatment, it needs to be reported ONLY if it is considered reasonably possibly related to study 
procedures.  
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be reported on the adverse events 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 AEs or SAEs 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 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
81
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). 
8.3.3.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards 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 Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for SUSAR according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., 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

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study intervention and until the 
completion of Visit 803.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 3.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.

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
Events leading to the clinical outcome of death due to study disease that are part of the efficacy 
analyses for this study will not be reported to Lilly or its designee as SAEs unless the 
investigator believes the event may have been caused by the investigational product.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
82
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 to 
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.
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
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.  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 of 
approximately 2 mL will be collected to determine the plasma concentrations of LY3475070.
Aberrations to specified sampling times in the SoA (Section 1.3) will not be considered protocol 
deviations as long as the samples are taken and the actual sampling time is recorded.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
83
Prior to dosing, patient should void bladder.  Following administration of LY3475070, the total 
urine output from 0 (post dose) to 8 hours will be collected, pooled, and refrigerated (Section 
1.3). Urine should not be fractionated unless scientifically justified. From the time period, 1
aliquot will be used to measure LY3475070 for urinary creatinine concentration and 2 aliquots of 
approximately 10 mL each will be stored frozen until further analysis. The total volume of urine 
will be recorded and the remaining urine will be discarded.  Serum samples for creatinine 
measurement should be collected as specified in the study SoA in Section 1.3 (Clinical 
Chemistry).
Blood and urine samples will be analyzed at a laboratory approved by the sponsor.  Plasma and 
urine concentrations of LY3475070 will be assayed using a validated liquid
chromatography-tandem mass spectrometry (LC-MS/MS) method. 
Bioanalytical samples collected to measure investigational product concentrations and 
metabolism and/or protein binding will be retained for a maximum of 2 years following last 
participant visit for the study.  During this time, blood and urine samples remaining after the 
bioanalyses will be analyzed for exploratory metabolite identification, as deemed appropriate by 
the sponsor. The results of such exploratory metabolism work may only be included in the 
clinical study report if deemed appropriate by the sponsor or may be reported in a separate 
exploratory metabolism report.
8.6.
Pharmacodynamics
See Section 1.3.1 for a schedule of serum collection for CD73 inhibition ex vivo 
pharmacodynamic assay 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 LY3475070 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 identification 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 LY3475070 or after LY3475070 become(s) commercially 
available.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
84
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or 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, pharmacodynamics, MOA, variability of participant response (including safety), 
and clinical outcome.  Sample collection is incorporated into clinical studies to enable 
examination of these questions through measurement of biomolecules including 
deoxyribonucleic acid, ribonucleic acid, proteins, lipids, and other cellular elements.
Serum, plasma, tumor tissue, and whole blood for biomarker research will be collected at the 
times specified in the SoA (Section 1.3) where local regulations allow. A 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 
LY3475070, pathways associated with cancer, MOA of LY3475070, 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 patients to participate in this 
study:

Phase 1a:
o
A mandatory archival FFPE tumor tissue sample.  While the tissue can be from 
either initial diagnosis or later, the sample should be the most recent available 
specimen containing adequate material.  Sites should confirm the availability of 
archival tumor tissue with the pathology laboratory during screening and prior to 
enrollment.  Tumor tissue should be submitted within 30 days following 
enrollment. 
o
If an archival sample is unavailable, then a pretreatment biopsy (core or 
excisional) of a tumor lesion from a primary or metastatic site may be submitted 
to meet eligibility requirements.  

Phase 1b:
o
A newly obtained core or excisional baseline biopsy of a tumor lesion from a 
primary or metastatic site. Archived tissue obtained from a recent biopsy may be 
permitted in lieu of the baseline biopsy after discussion between the Lilly 
CRP/CRS and investigator if a patient has not received any therapies for the 
disease between the time the archived tissue was collected to the start of 
LY345070 treatment; the decision to use an archived tissue sample will be 
documented.
o
A tumor tissue sample from a newly obtained core or excisional biopsy specimen 
collected during the study treatment period as shown in the SoA (Section 1.3).

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
85
Patients must be willing to undergo baseline and on-study biopsies that should not put patients at 
undue risk greater than that which comes with a core biopsy.
Collection of biopsies, as outlined above, is mandatory for patients enrolled in Cohorts D1 and 
D2 only in cases in which these patients present with accessible soft tissue metastasis that can be 
safely biopsied. Exceptions will be made in all other cases.
Collection of the following tumor tissue sample(s) is optional for patients participating in this 
study:   

Phase 1a:
o
If archival tissue is submitted to meet eligibility requirements, a newly obtained 
core or excisional pretreatment biopsy of a tumor lesion from a primary or 
metastatic site.
o
A tumor tissue sample from a newly obtained core or excisional biopsy specimen 
collected during the study treatment period as shown in the SoA (Section 1.3).

Phase 1b:
o
An archival FFPE 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 above and in the SoA (section 1.3).

All patients:
o
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 as part of 
clinical care 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.
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 may be acceptable for NSCLC patients upon 
discussion with the Lilly CRP/CRS, but are not acceptable for other cancer types.  An attempt to 
obtain up to 4 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 lesion progressed after radiation).  See the Laboratory Manual for details regarding sample 
collection and 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 pre-treatment sample does not contain adequate tissue for 
analysis, the patient may be replaced.  Lilly may replace up to 10% of the total patients who are
unable to submit an adequate tumor sample.  The pathology report accompanying archival tissue 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
86
may also be requested.  The pathology report must be coded with the patient number.  Personal 
identifiers, including the patient’s name and initials, must be removed from the institutional 
pathology report prior to submission.  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 identification 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 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 LY3475070 or after LY3475070 become(s) 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 Determination of CD73 Expression
Patients must submit all samples from the pretreatment biopsy and be positive for CD73 
expression as determined at a central laboratory to confirm study eligibility into Phase 1b Cohort 
C.  Patients that are not positive for CD73 expression, despite meeting all other eligibility 
criteria, will be screen failures.  Unused tissue from screen failures will be returned to the sites.  
Samples from patients that are positive for CD73 expression and proceed to enroll into the study 
will be retained for biomarker testing.
8.9.
Medical Resource Utilization and Health Economics
Health economics and medical resource utilization parameters will not be evaluated in this study.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
87
9.
Statistical Considerations
9.1.
Statistical Hypotheses
In the dose escalation phase, our hypothesis is that there is a tolerable DL for LY3475070 in both 
monotherapy and in combination treatment with pembrolizumab. 
In the dose expansion phase, the objective is to assess the safety and tolerability, as well as 
clinical activity of LY3475070 as monotherapy and in combination with pembrolizumab.  No 
formal hypothesis testing will be performed to demonstrate any statistically significant 
improvement in objective response rate. Therefore, specification of alternative hypothesis on the 
objective response rate does not apply. 
9.2.
Sample Size Determination
The primary objective of this study is to assess the safety and tolerability of LY3475070, thereby 
identifying and confirming the RP2D of LY3475070, to be administered as monotherapy and in 
combination with pembrolizumab, in patients with advanced solid malignancies.  The primary 
objective of the Phase 1b portion of this study also includes preliminary clinical activity 
evaluation by overall response rate (ORR) per RECIST v1.1, as monotherapy and in combination 
with pembrolizumab. The secondary objective is to evaluate PK and any observed evidence of 
clinical efficacy.  
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 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% CI
a
Number 
of Cases
Estimated
Rate
95% CI
a
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
0.12
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. 
In the dose escalation phase, once a given DL is cleared for DLT evaluation and is deemed safe, 
the dose cohort may be expanded with backfill patients to further investigate the safety, PK, 
pharmacodynamic, and clinical activity of LY3475070 and the combination with 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
88
pembrolizumab.  There will be up to 20 backfill patients enrolled across all DLs in Cohorts A 
and B combined in the phase 1a study.  Enrollment of patients to the dose cohort for DLT 
evaluation/dose escalation decision will take precedent. A Bayesian toxicity monitoring rule will 
be implemented to ensure continuous safety monitoring, assuming DLT or DLT-equivalent 
events arise from a beta-binomial model. Specifically, if the Prob(true DLT or DLT-equivalent 
rate >35%) >55% in any given cohort, the enrollment to that cohort will be halted.  A 35% rate
is targeted to be consistent with the mTPI-2 equivalence interval upper bound. A Beta(1, 1) prior 
for the true rate is utilized. The stopping boundaries for this safety monitoring rule based on the 
aggregated data is listed in the following table. 
Bayesian Toxicity Monitoring Rules
Number of Patients
Pause if Number of Patients with DLT or DLT Equivalent
4-5
≥2
6-8
≥3
9-11
≥4
12-14
≥5
15-16
≥6
17-19
≥7
20
stop
Abbreviations:  DLT = dose-limiting toxicity.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
89
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Entered 
All participants who sign informed consent
DLT evaluable 
All patients enrolled in the dose escalation phase (phase 1a) who either complete 
3 weeks of follow-up and treatment or discontinue treatment prior to 3 weeks 
due to a DLT.
PK Evaluable
All enrolled patients who have at least 1 post baseline evaluable PK sample
Safety
All participants who take at least 1 dose of study treatment.  Participants will be 
included in the treatment group corresponding to their initial dose of study 
treatment, even if it is not the treatment to which they were assigned.  In the 
event of a treatment error, participants will be analyzed according to the 
treatment they actually received.
“Enrolled” population also refers to the “Safety” population in this study.
Phase 1a
All patients assigned to a treatment cohort during the dose escalation portion of 
the study.
Phase 1b
All patients assigned to a treatment cohort during the dose expansion portion of 
the study.
CD73+
CD73+ by IHC
Abbreviations:  DLT = dose-limiting toxicity; IHC = immuno-histochemistry; 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.
Efficacy analyses will be conducted on the set of all enrolled patients. 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.
All tests of treatment effects will be conducted at a 1-sided 0.05 alpha level, as appropriate for 
the comparison, 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 participant disposition will be provided at the end of the study,
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 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
90
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
Study treatment compliance will be assessed as the proportion of treatment that is actually taken, 
relative to what is expected, after accounting for protocol-defined dose adjustments.  Study 
treatment taken will be derived from the difference between the total number of capsules/tablets 
dispensed and returned over the course of the patient’s treatment. The number of cycles 
received, dose omissions, dose reductions, dose delays, and dose intensity will be summarized 
for all treated patients by treatment arm.
9.4.3. Efficacy Analyses
9.4.3.1.
Primary Analyses
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 (DCR), defined as the proportion of patients who achieved a CR or PR 
or 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 before progression, 
but not qualifying for a CR, are required for a best response of PR.
Duration of response (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 that disease is recurrent or 
objective progression is observed, per RECIST v1.1 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.
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 PD or death due to any cause, 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
91
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.
PFS Event/Censoring Scheme
Situationa
Event/Censor
Date of Event or Censor
Tumor progression or death
Event
Earliest date of PD or death
No tumor progression and no death
Censored
Date of last adequate tumor 
assessment per RECIST v1.1, 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 v1.1, 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; PD = progressive disease; PFS = progression-free survival; PR = partial
response; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors; SD = stable disease.
a
Symptomatic deterioration (i.e., symptomatic progression that is not confirmed per RECIST v1.1) will not be
considered as tumor progression.
b
Adequate tumor assessment per RECIST v1.1 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.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
92
9.4.3.3.
Tertiary/Exploratory Analyses 
Overall survival (OS), as well as the efficacy parameters based on iRECIST will also be 
analyzed as the exploratory objectives. The definition of efficacy endpoints based on iRECIST 
will be described in the SAP.
Overall survival is defined as the time from the first start of study treatments until death from 
any cause. If the patient is alive, lost to follow-up, or withdrawn from study at the time of data 
analysis, OS data will be censored on the last date the patient is known to be alive. 
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 MedDRA Version 22.0 (or higher) will be used when reporting AEs by MedDRA terms. 
The MedDRA Lower Level Term (LLT) 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 (PT) within SOC.
Safety analyses will include summaries of the following:

DLTs at each DL in the dose escalation phase and DLT-equivalent AEs for expansion 
cohorts;

AEs, including severity and possible relationship to study drug;

SAEs, including possible relationship to study drug;

AEs leading to dose adjustments;

discontinuations from study treatment due to AEs or death;

treatment emergent abnormal changes in laboratory values;

treatment emergent abnormal changes in vital signs and ECGs.
9.4.5. Pharmacokinetic/Pharmacodynamic Analyses
Selected PK descriptors for LY3475070 (based on actual sampling times), including Cmax, 
approximate time of Cmax (tmax), and AUC will be calculated by noncompartmental analysis 
methods and/or model simulations. As an exploratory analysis, PK descriptor estimates for 
trough concentrations (Cmin) at steady state following repeated dose may be evaluated.  
In addition, PK parameter estimates for LY3475070 as single agent and in combination with 
pembrolizumab may be calculated, 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/pharmacodynamics management.
PK/pharmacodynamics analyses may be conducted to explore exposure-response relationships
between LY3475070 concentrations in systemic circulation and various pharmacodynamic
measures as second step if dose-response relationship is positively assessed.
Renal clearance of LY3475070 will be calculated as the ratio of amount excreted/AUC from 
time 0 to time t (AUC0-t), and will be compared with unbound glomerular filtration rate, 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
93
estimated using creatinine renal clearance and plasma unbound fraction (Fu) (Fu × amount of 
creatinine excreted/creatinine AUC0-t).
9.4.6. Other Analyses
Subgroup Analyses A prespecified list of subgroups will be identified in the SAP.  The treatment 
effect within each subgroup will be summarized.  Other subgroup analyses not specified in the 
SAP may be performed as deemed appropriate.  These subgroups will be based on important 
characteristics, for example, prognostic significance.
9.4.6.1.
Biomarker Analyses
Single-marker and/or multi-marker statistical analysis may be performed to explore the 
association between biomarkers, dose/exposure, and clinical outcomes. For an example, an 
association analysis between CD73 expression and clinical benefit may be triggered after data in 
Phase 1b Cohort C is collected. 
9.5.
Interim Analyses 
In the Phase 1a portion of this study, dose-escalation data (monotherapy and combination) will 
be reviewed for safety on a cohort-by-cohort basis, until the MTDs (or the highest DLs 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 DL and determine if a DLT has been observed that 
would suggest MTD has been met or exceeded.  The investigators and the Lilly study team will 
make the determination regarding dose escalation based upon their review of the safety and 
tolerability data as described in this protocol.
In the Phase 1b portion of this study, a safety review will be performed after the first 20 patients 
across all dose-expansion cohorts are enrolled and treated for 1 cycle, and then every 6 months 
afterward. For preliminary efficacy evaluations, the following interim analyses are planned:

Cohort C (patients with CD73+ tumors) and Cohort D (castrate resistant prostate cancer): 
for each cohort, an interim analysis of safety and efficacy is planned after 10 patients in 
the monotherapy arm are treated and completed 2 cycles or have discontinued before the 
first postbaseline tumor assessment. Per 2:1 randomization ratio, at this interim analysis 
approximately 20 patients in the combination arm are treated. Preliminary efficacy will 
be evaluated on these 20 patients in the combination arm and on these 10 patients in the 
monotherapy arm, and the combination arm may be expanded with additional 20 patients 
if the totality of efficacy, safety, and PK/pharmacodynamics data warrant expansion.  If 
no objective responses are observed, both as monotherapy or combination therapy, the 
combination arm(s) will not continue enrollment.

Cohort E (TNBC): an interim of safety and efficacy is planned after approximately 20 
patients are treated and completed 2 cycles or have discontinued before the first 
postbaseline tumor assessment. The trial may continue to enroll 20 additional patients for 
the final analysis if the totality of efficacy, safety, and PK/pharmacodynamics data 
supports the addition of patients.  If no objective responses are observed, additional 
patient enrollment to Cohort E will be terminated.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
94
The interim analyses may be combined if they are expected to occur within a similar timeframe; 
interim analyses may also be combined with any prespecified safety review or annual reporting 
(such as an update to the IB or Development Safety Update Review, etc.).
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-cutoff date will be used for the analysis of safety, efficacy, PK, and pharmacodynamic
biomarkers. All data defined in the protocol will continue to be collected from patients on 
treatment after the data-cutoff date. These data may be reported separately and the analyses on 
all patients including these data may not be performed.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
95
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:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
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, 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 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
96

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.

Participants otherwise eligible for Phase 1b Cohort C will sign the Cohort C informed 
consent prior to collection of the fresh tissue sample for determination of CD73 
expression and potentially retained for biomarker testing.

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.
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A separate signature will be required to document a participant's agreement to 
allow any remaining specimens to be used for exploratory research. Participants who decline to 
participate in this optional research will not provide this separate signature.
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 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 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
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

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
97

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and verify data reported to detect potential errors 
In addition, 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 system (EDC) will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Additionally, clinical outcome assessment (COA) data will be collected by the subject, via a 
paper source document and will be transcribed by the investigator site personnel into the EDC 
system.
Data collected via the sponsor-provided data capture system will be stored at third party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system.  Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and the 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.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
98
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.
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.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
99
10.2. Appendix 2: Clinical Laboratory Tests

The tests detailed below will be performed as indicated in the table below.  

Local laboratory results are required for inclusion/exclusion determination, study 
intervention administration, and/or response evaluation. If a local sample is required, it is 
important that the sample for central analysis is obtained at the same time. Additionally, 
if the local laboratory results are used to make either a study intervention decision or 
response evaluation, the clinically significant abnormalities must be entered into the AE 
CRF.  If there is an abnormal laboratory value or abnormal value for any other diagnostic 
or screening test (for example, blood pressure increased, neutrophils decreased, etc.) and 
it is known to be related to a diagnosis (for example, hypertension, neutropenia, etc.) this 
should be reported in the CRF as an AE.  Do not enter the test abnormality; enter the 
disease diagnosis or categorical term.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations and clinically significant findings 
should be recorded reported in the CRF as an AE.  
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.

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
1 0 0
Cli nic al L a b or at or y Tests
He m at ol o g y a -l oc al l a b or at or y
Le u k oc ytes ( W B C)
Bas o p hils
Ne utr o p hils
Er y t hr oc ytes ( R B C)
L y m p h oc ytes
He m o gl o bi n ( H G B)
M o n oc ytes
He mat ocrit ( H C T)
E osi n o p hils
Platelets ( P L T)
C o a g ul ati o n -l oc al l a b or at or y
P T/I N R
P T T/a P T T
Cli nic al c he mistr y a -l oc al l a b or at or y
Ser u m c o nce ntrati o ns of: 
Ala ni ne a mi n otra nsferase ( A L T)
Calci u m
Al b u mi n
Creati ni ne
Al kali ne p h os p hatase
Gl uc ose (ra n d o m)
A m ylase
Li pase
As partate a mi n otra nsferase ( A S T)
P otassi u m
Bilir u bi n, direct
Pr otei n
Bilir u bi n, t otal
S o di u m
Bl o o d urea nitr o ge n ( B U N) or bl o o d urea
Uri n al ysis -l oc al l a b or at or y
Bl o o d
Pr otei n
Gl uc ose
S pecific gra vit y
Ket o nes
Uri ne le u k oc yte esterase d
p H
Pre g n a nc y Test c --l oc al l a b or at or y
Uri ne pre g na nc y test
Ser u m pre g na nc y test
N ote : Uri ne pre g na nc y test at a mi ni m u m se nsiti vit y of 2 5 I U/ L or e q ui vale nt u nits of β- h C G .  If uri ne pre g na nc y res ults ca n n ot 
be c o nfir me d as ne gati ve, a ser u m pre g na nc y test will be re q uire d
T h yr oi d p a nel -l oc al l a b or at or y
Trii o d ot h yr o ni ne ( T 3) or Free Trii o d ot h yr o ni ne ( F T 3)
T h yr oi d -sti m ulati n g h or m o ne ( T S H)
Free T h yr o xi ne ( F T 4)
T u m or m ar kers -l oc al l a b or at or y
P S A
C A - 1 2 5
C E A
C A 1 9 - 9
C CI

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
101
IHC - Central laboratory
CD73 expression for Phase 1b Cohort C
Selected tests may be obtained in the event of anaphylaxis or generalized urticaria.
Hypersensitivity Testsb – Central laboratory
Anti-LY antibodies (immunogenicity)
Basophil Activation Test
LY concentration (PK)
Complements
Tryptase
Cytokine Panel
N-methylhistamine
Abbreviations:  aPTT = activated partial thromboplastin time; CA-125 = cancer antigen 125; CA 19-9 = cancer 
antigen 19-9; CEA = carcinoembryonic antigen; CRF = case report form; hCG = human chorionic gonadotropin; 
HCT = hematocrit; HGB = hemoglobin; INR = international normalized ratio; MB = muscle and brain; PLT = 
platelets; PK = pharmacokinetics; PT = prothrombin time; PTT = partial thromboplastin time; PSA = prostate 
specific antigen; RBC = red blood cells; WBC = white blood cells.
a
Treatment and enrollment decisions will be based on local laboratory results.
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.
b
Central laboratory.  In addition, local labs may be collected at investigator’s discretion.
c
For female patients of childbearing potential.
d
Urine microscopy may be used in place of the urine leukocyte esterase assessment to test for the presence of 
WBC.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
102
10.3. Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:
a.
Documented hysterectomy
b. Documented bilateral salpingectomy
c.
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the above,
(e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry.
Note:  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. 

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 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.
Contraception Guidance:
1. Women of child-bearing potential who are abstinent (if this is complete abstinence, as their 
preferred and usual lifestyle) or in a same sex relationship (as part of their preferred and 
usual lifestyle) must agree to either remain abstinent or stay in a same sex relationship 
without sexual relationships with males. Periodic abstinence methods (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration 
of a trial, and withdrawal) are not acceptable methods of contraception. 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
103
2. Women of child-bearing potential must use 2 effective methods of contraception for the 
entirety of the study. Abstinence or contraception must continue following completion of
study drug administration, LY3475070 and pembrolizumab, for at least 120 days following 
the last dose of study drugs or country requirements, whichever is longer.  For patients 
receiving LY3475070 only, contraception should be maintained for 5 half-lives or until 
plasma concentrations are equal to 1/25th of the nonclinical NOAEL exposure, (NOAEL/25)
predicted to be 7 days.
a.
Women of child-bearing potential participating must test negative for pregnancy prior to 
initiation of treatment as indicated by a negative urine pregnancy test at the screening 
visit followed by a negative serum pregnancy test within 24 hours prior to study drug 
exposure. Pregnancy testing is conducted at monthly intervals during study treatment in 
both treatment arms, and up to 120 days after study discontinuation for patients receiving 
LY3475070 and pembrolizumab, and at 7 days after study discontinuation for patients 
receiving LY3475070 monotherapy.
b. Two effective methods of contraception, such as male or female condoms with 
spermicide, diaphragms with spermicide or cervical sponges, will be used. The subject 
may choose to use a double barrier method of contraception. Barrier protection methods 
without concomitant use of a spermicide are not a reliable or acceptable method. Thus, 
each barrier method must include use of a spermicide. It should be noted that the use of 
male and female condoms as a double barrier method is not considered acceptable due to 
the high failure rate when these methods are combined. 
i.
One of the 2 methods of contraception must be a highly effective (less than 1% 
failure rate) method of contraception, such as combination oral contraceptives, 
implanted contraceptives or intrauterine devices.
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.

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 obtaining informed consent from the pregnant 
female partner. 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 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
104
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 8.3.2. 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 be 
discontinued from study treatment.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
105
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, or its designee,
CRP/CRS.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin (HGB)
Hematocrit (HCT)
Hepatic Coagulationa
Erythrocytes (RBC)
Prothrombin time (PT)
Leukocytes (WBC)
Prothrombin time, INR
Neutrophilsb
Lymphocytes
Hepatic Serologiesa,c
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets (PLT)
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine aminotransferase (ALT)
Antinuclear Antibodya
Aspartate aminotransferase (AST)
Gamma-glutamyl transferase (GGT)
Anti-smooth Muscle Antibody a
Creatine phosphokinase (CPK)
Anti-actin Antibodya
Abbreviations:  IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international normalized ratio.
a
Assayed by local laboratory.
b
Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. Whenever 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.
c
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
1 0 6
1 0. 5. A p pe n di x 5: C CI
C CI

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
1 0 7
C CI

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
108
10.6. Appendix 6: Creatinine Clearance Formula
Note:  This formula is to be used for calculating creatinine clearance (CrCl) from local 
laboratory results only.  
For serum creatinine concentration in mg/dL:
CrCl =
(140 – agea) (wt)    0.85 (if female), or 1.0 (if male)
(mL/min) 
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(140 – agea) (wt)  0.85 (if female), or 1.0 (if male)
(mL/min)
               0.81 x serum creatinine (µmo/L)
a
age in years, weight (wt) in kilograms.
Reference:  Cockcroft and Gault 1976.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
109
10.7. Appendix 7: Country-specific Requirements
10.7.1.
Discontinuation of Inadvertently Enrolled Patients in the UK
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should be discontinued from study treatment and 
safety follow up should be performed 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.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
110
10.8. Appendix 8: Dose-Finding Algorithm of the Modified Toxicity 
Probability Interval-2 Method Showing Number of Patients Treated
The number of patients dosed at a given DL 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 
DL 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 DL at a future point in the escalation.
For example, within a cohort:

If 1 of 3 patients experiences a DLT, stay at the same dose (see “S” in column 3, row 1).  
The fourth patient must be treated at the same DL.

If 1 of 6 patients experiences a DLT, escalate the dose (see “E” at column 6, row 1).

If 2 of 3 patients experience a DLT the dose to treat the next patient is de-escalated (see 
“D” at column 3, row 2).

If 5 of 7 patients experience a DLT, the dose is determined to be unacceptably toxic, and 
the previous dose is defined as the MTD.

C O N FI D E N TI A L
Pr ot oc ol  J 2I-M C -J Z M A(d)
L Y 3 4 7 5 0 7 0
1 1 1
1 0. 9. A p pe n di x 9 : A b bre vi ati o ns
T er m
D efi niti o n
9 9 mT c M D P
9 9 mT c -met h y le ne di p h os p h onate
A 1 AR
a de n osi ne 1 A rece pt or
A 2 AR
a de n osi ne 2 A rece pt or
A 2 B R
a de n osi ne 2 B rece pt or
A 3 R
a de n osi ne 3 rece pt or
A E
a d verse e ve nt:  A n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n 
s u bject a d mi nistere d a p har mace utical pr o d uct t hat d oes n ot necessaril y ha ve a ca usal 
relati ons hi p wit h t his treat me nt.  A n a d verse e ve nt ca n t heref ore be a n y u nfa v ora ble a n d 
u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease 
te m p orall y ass ociate d wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct, w het her or
n ot relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct.
AI D S
ac q uire d i m m u n o deficie nc y s y n dr o me
A L P
a l kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase
A M P
a de n osi ne m o n o p h os p hate
A S C O/ C A P
A merica n S ociet y of Cli nical O nc ol o g y/ C olle ge of A merica n Pat h ol o gists
A S T
as partate a mi n otra nsferase
A T P
a de n osi ne tri p h os p hate
A U C
Area u n der t he c ur ve
BI D
t w o ti mes a da y
B O R
best o verall res ults
C D 7 3
ect o- 5′-n ucle oti dase
CI O M S
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical
Scie nces
C M
c uta ne o us mela n o ma
C N S
ce ntral ner v o us s yste m
C O A
cli nical o utc o me assess me nt
C CI

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
112
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.
CRF/eCRF
case report form/electronic 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
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DCR
disease control rate
DL
dose level
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture system
EGFR
epidermal growth factor receptor
EI
equivalence interval
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
FFPE
formalin-fixed paraffin-embedded
FSH
follicle stimulating hormone
GCP
good clinical practice

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
113
G-CSF
granulocyte-colony stimulating factor
HER2
human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus 
HRT
hormonal replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICI
immune checkpoint inhibitor
ICH
International Council for Harmonisation
IHC
immunohistochemistry
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.
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.
irAE
immune-related adverse event
IRB/IEC
Institutional Review Board/Independent Ethics Committee
ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a participant (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that participant allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IV
intravenous
IVRS/IWRS
interactive voice-response system/interactive web-response system
LLT
lower level term
mAb
monoclonal antibody
mCRPC
metastatic castrate resistant prostate cancer

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
114
MedDRA
Medical Dictionary for Regulatory Activities
MOA
mechanism of action
MRI
magnetic resonance imaging
mTNBC
metastatic triple negative breast cancer
MN
micronucleus
MSI-H
microsatellite instability-high
MTD
maximum tolerated dose
mTPI-2
modified toxicity probability interval
NL-NT
new lesion-non-target
NL-T
new lesion-target
NOAEL
no observed adverse effect level
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
PBPK
physiologically-based pharmacokinetics
PD
progressive disease
PD-1
programmed cell death protein 1
PD-1/L1
programmed cell death protein 1/ligand 1
PD-L2
programmed cell death protein/ligand 2
PFS
progression-free survival
PK
pharmacokinetics
PPS
per-protocol set:  The set of data generated by the subset of participant who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model.
PS
performance status
PSA
prostate-specific antigen
PT
preferred term
Q2W
every 2 weeks

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
115
Q3W
every 3 weeks
QD
once a day
QTc
corrected QT interval
RCC
renal cell carcinoma
RECIST/iRECIST
Response Evaluation Criteria in Solid Tumors/immune Response Evaluation Criteria in 
Solid Tumors
RP1D
recommended phase 1 dose
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. 
SoA
schedule of activities
SOC
System Organ Class
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin
TEAE
treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TME
tumor microenvironment
TNBC
triple negative breast cancer
TTR
time to response

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
116
10.10.Appendix 10: 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 (02-Oct-2019)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
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 6.6.1 Dose 
Modification and Toxicity 
Management 
Addition of monitoring and 
management guidelines for 
infusion-related reactions
Based on regulatory agency 
feedback
Section 5.1 Inclusion 
Criteria
Amended criteria to specify 
minimum treatments patients 
should have received for phase 1a
Based on regulatory agency 
feedback
Section 5.1 Inclusion 
Criteria
Amended criteria to specify 
minimum treatments patients 
should have received for 
phase 1b
Based on regulatory agency 
feedback
Section 1.3.1 Sampling 
Schedule for 
Pharmacokinetics and 
Biomarkers
Revised ECG monitoring plan to 
add an ECG collection
Based on regulatory agency 
feedback
Section 6.1.1 Definition of 
DLT and DLT-ET
Modification of dose limiting 
toxicity criteria and clarification 
of definition of DLT-ET
Based on regulatory agency 
feedback
Section 5.2 Exclusion 
Criteria
Separated exclusion criteria a 
through j from Criterion 17 into 
numbered criteria
Based on regulatory agency 
feedback
Section 8.1.2 iRECIST for 
Confirmation of PD in 
Clinically Stable Patients 
and Radiologic PD per 
RECIST v1.1
Modification of management 
guidelines for patients who have 
radiologic evidence of 
progressive disease by 
RECIST v1.1
Based on regulatory agency 
feedback
Section 4.1 Overall Design
Clarification regarding dose 
escalation timeline
Based on regulatory agency 
feedback
Section 1.1 Synopsis,
Resolved inconsistencies 
Based on regulatory agency 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
117
Section # and Name
Description of Change
Brief Rationale
Section 1.2 Schema,
Section 4.1 Overall Design,
Section 6.1 Study 
Intervention(s) 
Administered
regarding naming of 
recommended dose
feedback
Section 6.1 Study 
Intervention(s) 
Administered
Added instruction on how to 
administer LY3475070 with 
regards to food intake
Based on regulatory agency 
feedback
Section 5.1 Inclusion 
Criteria
Removed duplicate inclusion 
criteria related to informed 
consent
Duplication
Section 1.3 Schedule of 
Activities
Specification of requirements 
related to short- and long-term 
follow-up visits
Clarification for sites
Throughout protocol
Minor formatting and editorial 
changes
Minor, therefore not detailed
Amendment b (24-Feb-2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The purpose of this amendment is to add updated informative language for pembrolizumab and 
address regulatory concerns.
Section # and Name
Description of Change
Brief Rationale
Throughout
Addition of pembrolizumab-
specific language
Language added as a result of 
pembrolizumab language 
requirements 
Section 1.3 SoA
Added language regarding 
iRECIST evaluation
Clarification
Section 1.3 SoA
Amended language regarding 
urinalysis collection
Clarification
Section 1.3 SoA, Section 
5.1 Inclusion Criteria, 
Section 5.2 Exclusion 
Criteria, Section 6.5 
Concomitant Therapy, 
Appendix 3:  Contraceptive 
Guidance and Collection of 
Pregnancy Information
Added and amended 
pregnancy/contraception 
language
Per regulatory feedback

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
118
Section 5.1 Inclusion 
Criteria
Amended hepatic inclusion 
language
Per regulatory feedback
Section 5.1 Inclusion 
Criteria
For Inclusion Criteria 2 and 5, 
revised requirements for prior 
lines of therapy for all indications 
Per investigator feedback
Section 10.2 Appendix 2: 
Clinical Laboratory Tests
Amended language regarding 
local laboratory results
Clarification
Throughout protocol
Minor formatting and editorial 
changes
Minor, therefore not detailed.
Amendment c (22-Mar-2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The purpose of this amendment is to add updated informative language for pembrolizumab and 
address regulatory concerns.
Section # and Name
Description of Change
Brief Rationale
Section 1.3. Schedule of 
Activities
Removal of stool sample 
collection
Clarification; site/investigator 
feedback
Section 1.3.1 Sampling 
Schedule for 
Pharmacokinetics and 
Biomarkers
Change of mandatory biopsies to 
optional for Phase 1a patients; 
removal of collection of stool 
samples
Updated for enrollment and 
study participation purposes
Section 5.1 Inclusion 
Criteria
Addition of inclusion criterion 2 
for archival sample collection; 
changed mandatory biopsies to 
optional for Phase 1a patients 
Updated for enrollment and 
study participation purposes
Section 5.1 Inclusion 
Criteria
Removed language regarding 
intervening treatment for PD-1 
indications in Phase 1a for 
inclusion criterion 3; amended 
language of “activating EGFR 
mutations” to “targetable 
mutations”
Updated for enrollment and 
study participation purposes
Section 5.1 Inclusion 
Criteria
Moved inclusion criterion 9 to 
criterion 6 and amended language
Updated for enrollment and 
study participation purposes
Section 5.1 Inclusion 
Criteria
Addition of language for 
inclusion criterion 13; amended 
language regarding wash-out 
period for prior therapy
Clarification; site/investigator 
feedback

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
119
Section 5.1 Inclusion 
Criteria
Updated platelet lab value in 
inclusion criterion 14 to 
100×109/L
Clarification; site/investigator 
feedback
Section 5.2 Exclusion 
Criteria
Amended language for exclusion 
criterion 26
Clarification
Section 5.2 Exclusion 
Criteria
Deletion of exclusion criterion 37 
regarding prior participation in a 
clinical trial
Clarification; site/investigator 
feedback
Section 8.8 Biomarkers
Amended language regarding the 
collection of tumor tissue 
sample(s) and stool collection
Updated for enrollment and 
study participation purposes
Throughout protocol
Minor formatting and editorial 
changes
Minor, therefore not detailed.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
120
11.
References
Allard B, Turcotte M, Stagg J. CD73-generated adenosine: orchestrating the tumor-stroma 
interplay to promote cancer growth. J Biomed Biotechnol. 2012;2012:485156.
Allard D, Chrobak P, Allard B, Messaoudi N, Stagg J. Targeting the CD73-adenosine axis in 
immuno-oncology. Immunol Lett. 2019;205:31-39.
Bendell J, Bauer T, Patel M, Falchook G, Karlix JL, Lim E, Mugundu G, Mitchell PD, Pouliot 
GP, Moorthy G, Linghu B, McGrath L, Harrop B, Shao W, Drake CG, Sachsenmeier K, 
Merchant MS. Evidence of immune activation in the first-in human Phase 1a dose escalation 
study of the adenosine 2a receptor antagonist, AZD4635, in patients with advanced solid 
tumors[abstract]. In: Proceedings of the American Association for Cancer Research Annual 
Meeting 2019; 2019 Mar 29-Apr 3:Atlanta, GA. Philadelphia (PA): AACR; Cancer Res. 
2019;79(13 Suppl):Abstract nr CT026.
Brahmer JR, Pardoll DM. Immune checkpoint inhibitors: making immunotherapy a reality for 
the treatment of lung cancer. Cancer Immunol Res. 2013;1(2):85-91.
Chiappori A, Williams CC, Creelan BC, Tanvetyanon T, Gray JE, Haura EB, Thapa R, Chen 
DT, Beg AA, Boyle TA, Bendiske J, Morris E, Tao A, Hurtado FK, Manenti L, Castro J, 
Antonia SJ. Phase I/II study of the A2AR antagonist NIR178 (PBF-509), an oral 
immunotherapy, in patients with advanced NSCLC. J Clin Oncol. 2018;36(15 Suppl):9089-
9089.
Cockcroft DW, Gault MD. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41.
Crawford J, Caserta C, Roila F; ESMO Guidelines Working Group. Hematopoietic growth 
factors: ESMO recommendations for the applications. Ann Oncol. 2009;20 Suppl 4:162-165.
De Bono JS, Goh JCH, Ojamaa K, Rodriguez JMP, Drake CG, Hoimes CJ, Wu H, Poehlein CH, 
Antonarakis ES. KEYNOTE-199: Pembrolizumab (pembro) for docetaxel-refractory 
metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 
2018;36(15 Suppl):5007-5007.
Dubyak GR, el-Moatassim C. Signal transduction via P2-purinergic receptors for extracellular 
ATP and other nucleotides. Am J Physiol. 1993;265(3 Pt 1):C577-606.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur 
J Cancer. 2009;45(2):228-247.
Fishman P, Bar-Yehuda S, Synowitz M, Powell JD, Klotz KN, Gessi S, Borea PA. 
Adenosine receptors and cancer. Handb Exp Pharmacol. 2009;(193):399-441.
Flowers CR, Seidenfeld J, Bow EJ, Karten C, Gleason C, Hawley DK, Kuderer NM, Langston 
AA, Marr KA, Rolston KV, Ramsey SD. Antimicrobial prophylaxis and outpatient 
management of fever and neutropenia in adults treated for malignancy: American Society of 
Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31(6):794-810.

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
121
Fong L, Forde PM, Powderly JD, Goldman JW, Nemunaitis JJ, Luke JJ, Hellman MD, Kummar 
S, Doebele RC, Mahadevan D, Gadgeel SM, Hughes BGM, Markman B, Riese MJ, Brody J, 
Emens LA, McCaffrey I, Miller RA, Laport G. Safety and clinical activity of adenosine A2a 
receptor (A2aR) antagonist, CPI-444, in anti-PD1/PDL1 treatment-refractory renal cell (RCC) 
and non-small cell lung cancer (NSCLC) patients. J Clin Oncol. 2017;35(15 Suppl):3004-
3004.
Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy 
using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15(5):325-340.
Guo W, Wang SJ, Yang S, Lynn H, Ji Y. A Bayesian interval dose-finding design addressing
Ockham's razor: mTPI-2. Contemporary Clin Trials. 2017;58:23-33.
Hauser RA, Olanow CW, Kieburtz KD, Pourcher E, Docu-Axelerad A, Lew M, Kozyolkin O, 
Neale A, Resburg C, Meya U, Kenney C, Bandak S. Tozadenant (SYN115) in patients with 
Parkinson’s disease who have motor fluctuations on levodopa: a phase 2b, double-blind, 
randomized trial. Lancet Neurol. 2014;13(8):767-776.
Higgs BW, Morehouse CA, Streicher K, Brohawn PZ, Pilataxi F, Gupta A, Ranade K. Interferon 
Gamma Messenger RNA Signature in Tumor Biopsies Predicts Outcomes in Patients with 
Non–Small Cell Lung Carcinoma or Urothelial Cancer Treated with Durvalumab. Clin Cancer 
Res. 2018; (24(16):3857-3866.
Horenstein AL, Bracci C, Morandi F, Malavasi F. CD38 in Adenosinergic Pathways and 
Metabolic Re-programming in Human Multiple Myeloma Cells: In-tandem Insights From 
Basic Science to Therapy. Front Immunol. 2019;10:760.
Hotson D, Powderly J, Emens L, Forde P, Hellman M, Fong L, Markman B, Hughes B, 
Goldman J, Sznol M, Mahadevan D, Kummar S, Brody J, Bonomi P, Luke J, Riese M, 
Owonikoko T, Loi S, Wiese A, Doebele R, Lee J, Gu C, Willingham S, Laport G, Miller R, 
McCaffery I. Clinical activity of adenosine A2A receptor (A2aR) inhibitor CPI-444 is 
associated with tumor expression of adenosine pathway genes and tumor immune modulation. 
J ImmunoTherapy of Cancer. 2017;5(Suppl 2; abstract O4):86.
Iasonos A, O'Quigley J. Design considerations for dose-expansion cohorts in phase I trials. J 
Clin Oncol. 2013;31(31):4014-4021.
Leclerc BG, Charlebois R, Chouinard G, Allard B, Pommey S, Saad F, Stagg J. CD73 
Expression is an independent prognostic factor in prostate cancer. Clin Cancer Res. 
2016;22(1):158-166.
Leone RD, Horton MR, Powell JD. Something in the air: hyperoxic conditioning of the 
tumor microenvironment for enhanced immunotherapy. Cancer Cell. 2015;27(4):435-436.
Leone RD, Emens LA. Targeting adenosine for cancer immunotherapy. J Immunother 
Cancer. 2018;6(1):57.
Loi S, Pommey S, Haibe-Kains B, Beavis PA, Darcy PK, Smyth MJ, Stagg J. CD73 promotes 
anthracycline resistance and poor prognosis in triple negative breast cancer. Proc Natl Acad 
Sci USA. 2013;110(27):11091-11096.
Luke J, Powderly JD, Merchan JR, Barve MA, Hotson AN, Mobasher M, Kwei L, Luciano G, 
Buggy JJ, Piccione E, Miller RA. Immunobiology, preliminary safety, and efficacy of CPI-

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
122
006, an anti-CD73 antibody with immune modulating activity, in a phase 1 trial in advanced 
cancers. J Clin Oncol. 2019;37(suppl; abstract 2505).
Monteiro I, Vigano S, Faouzi M, Treilleux I, Michielin O, Ménétrier-Caux C, Caux C, Romero 
P, de Leval L. CD73 expression and clinical significance in human metastatic melanoma.
Oncotarget. 2018;9(42):26659-26669.
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a 
common language for tumor response to immunotherapy: immune-related response criteria 
using unidimensional measurements. Clin Cancer Res. 2013;15;19(14):3936-3943.
O’Donnell JS, Smyth MJ, Teng MW. Acquired resistance to anti-PD1 therapy: checkmate to 
checkpoint blockage? Genome Med. 2016;8(1):111.
Ohta A, Sitkovsky M. Role of G-protein-coupled adenosine receptors in downregulation of 
inflammation and protection from tissue damage. Nature. 2001;414(6866):916-920.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-655.
Pembrolizumab [Summary of product characteristics]. Whitehouse Station, NJ: Merck & Co., 
Inc.; 2014.
Pembrolizumab [US package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2014.
Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, Cella DF, 
Djulbegovic B, Goode MJ, Jakubowski AA, Rarick MU, Regan DH, Lichtin AE; American 
Society of Clinical Oncology; American Society of Hematology. Use of epoetin and 
darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American 
Society of Hematology clinical practice guideline update. J Clin Oncol. 2008;26(1):132-49.
Robeva AS, Woodard R, Luthin DR, Taylor HE, Linden J. Double tagging recombinant A1 and 
A2A-adenosine receptors with hexahistidine and the FLAG epitope. Development of an 
efficient generic protein purification procedure. Biochem Pharmacol. 1996;51(4):545-555.
Salazar R, Solorzano J, Solis L, Behrens C, Mino B, Parra E, Zhang J, Vaporciyan A, Rice D, 
Kalhor N, Moran C, Gibbons D, Weissferdt A, Sepesi B, Wistuba I. CD73 
Immunohistochemical expression in malignant cells and correlation with immune infiltrate in 
non-small cell lung carcinoma (NSCLC). J Thoracic Oncol. 2018;13(10),Supplement:S533-
S543.
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, Antonarakis ES, Beer TM, 
Carducci MA, Chi KN, Corn PG, de Bono JS, Dreicer R, George DJ, Heath EI, Hussain M, 
Kelly WK, Liu G, Logothetis C, Nanus D, Stein MN, Rathkopf DE, Slovin SF, Ryan CJ, 
Sartor O, Small EJ, Smith MR, Sternberg CN, Taplin ME, Wilding G, Nelson PS, Schwartz 
LH, Halabi S, Kantoff PW, Armstrong AJ; Prostate Cancer Clinical Trials Working Group 3. 
Trial design and objectives for castration-resistant prostate cancer: updated recommendations 
from the prostate cancer clinical trials working group 3. J Clin Oncol. 2016;34(12): 1402-
1418.
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litière S, 
Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger 

CONFIDENTIAL
Protocol J2I-MC-JZMA(d)
LY3475070
123
M, Caramella C, de Vries EG; RECIST Working Group. iRECIST: guidelines for response 
criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152.
Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, Goldberg JM, 
Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO; 
American Society of Clinical Oncology. Recommendations for the use of WBC growth 
factors: American Society of Clinical Oncology clinical practice guideline update. J Clin 
Oncol. 2015;33(28):3199-3212.
Streicher K, Higgs BW, Wu S, Coffman K, Damera G, Durham N, Greenlees L, Lazdun Y, 
Cheng L, Cooper Z, Ranade K. Increased CD73 and reduced IFNG signature expression in 
relation to response rates to anti-PD-1(L1) therapies in EGFR-mutant NSCLC. J Clin Oncol. 
2017;35(15 Suppl):11505-11505.
Sui H, Ma N, Wang Y, Li H, Liu X, Su Y, Yang J. Anti-PD-1/PD-L1 therapy for non-small-cell 
lung cancer: toward personalized medicine and combination strategies. J Immun Res.
2018;2018:6984948.
Tripathi S, Xie W, Flaifel A, Steinharter JA, Stern Gatof A, Jennings RB, Bouchard G, Fleischer
J, Chanza NM, Gray C, Mantia C, Wei XX, Giannakis M, McGregor BA, Choueiri TK,
McDermott DF, Signoretti S, Harshman LC. Prognostic significance of CD73 expression in 
localized renal cell carcinoma (RCC). J Clin Oncol. 2019;37:(15 Suppl),4582-4582.
van der Putten C, Veth J, Sukurova L, Zuiderwijk-Sick EA, Simonetti E, Koenen HJPM, Burm 
SM, van Noort JM, IJzerman AP, van Hijum Saft, Diavatopoulos D, Bajramovic JJ. TLR-
Induced IL-12 and CCL2 Production by Myeloid Cells Is Dependent on Adenosine
A3 Receptor-Mediated Signaling. J Immunol. 2019;202(8):2421-2430.
Willingham SB, Ho PY, Hotson A, Hill C, Piccione EC, Hsieh J, Liu L, Buggy JJ, McCaffery 
I, Miller RA. A2AR antagonism with CPI-444 induces antitumor responses and augments 
efficacy to anti-PD-(L)1 and anti-CTLA4 in preclinical models. Cancer Immunol Res. 
2018;6(10):1136-1149.
Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, 
Smylie M, Guthrie T Jr, Grob JJ, Chesney J, Chin K, Chen K, Hoos A, O'Day SJ, Lebbé C.
Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, 
double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155-164.

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