Conditions: Advanced Solid Tumor Non-Small Cell Lung Cancer Colorectal Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 5
Healthy volunteers: no

Brief summary:
The reason for this study is to see if the study drug LY3499446 is safe and effective in participants with solid tumors with KRAS G12C mutation.

Detailed description:

Arms:
arm 1: Participants received high dose LY3499446 as oral monotherapy twice daily (BID) in 21-day cycles. arm 2: Participant received mid dose LY3499446 as oral monotherapy once every other day (QOD) in 21-day cycles. arm 3: Participants received low dose LY3499446 as oral monotherapy once daily (QD) in 21-Day cycles. arm 4: LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV).

This trial was terminated prior to initiation of combination therapy cohorts. arm 5: LY3499446 as oral monotherapy and LY3499446 combined with either abemaciclib (orally), erlotinib (orally), or cetuximab (IV).

The trial was terminated prior to initiation of Phase 2 of this study. arm 6: Docetaxel IV infusion.

The trial was terminated prior to initiation of Phase 2 of this study.

Interventions: intervention 1: LY3499446 intervention 2: Abemaciclib intervention 3: Cetuximab intervention 4: Erlotinib intervention 5: Docetaxel
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered IV intervention 4: Administered orally intervention 5: Administered IV

Protocol document:
Prot_000.pdf: 
JZKA Protocol (b) 
 
Phase 1/2 Study of LY3499446 Administered to Patients with Advanced Solid Tumors with 
KRAS G12C mutation 
 
 
NCT04165031 
 
 
Approval Date: 21-Jan-2020 


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
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 9 9 4 4 6, 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/ 2 St u d y  of L Y 3 4 9 9 4 4 6 A d mi nistere d t o Patie nts wit h A d va nce d 
S oli d T u m ors wit h K R A S G 1 2 C m ut atio n
Pr ot oc ol N u m b er: J 2 K-M C -J Z K A
A me n d me nt N u m ber: ( b)
C o m p o u n d N u m ber:
L Y 3 4 9 9 4 4 6
St u d y P h ase: P hase 1/ 2
S h ort Title: A St u d y  of L Y 3 4 9 9 4 4 6 i n Patient s with A d va nce d S oli d T u m ors wi t h K R A S G 1 2 C
m utati o n
Acr o n y m:  J Z K A
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 5
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 o n date pr o vi de d bel o w.
A p pr o v al D at e: 2 1- J a n- 2 0 2 0 G M T


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
2
Protocol Amendment Summary of Changes
DOCUMENT HISTORY
Document
Date
Amendment (a)
07-Oct-2019
Protocol J2K-MC-JZKA
22-Aug-2019
Amendment (b)
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 update the Phase 1 portion of the study as a result of 
observed safety signals in initially enrolled patients, as well as to provide additional safety 
guidance for investigators.
Section # and Name
Description of Change
Brief Rationale
Throughout
Revision of Phase 1 dose escalation 
dosing, cohorts, and schedule
Dose escalation design 
revised for safety
Section 1.3 Schedule of 
Activities
Visits 4, 11, and 18 added; additional 
hematology and chemistry visits 
included on visits 4, 11, and 18 of 
Cycles 1 and 2.
Visits added to monitor for 
safety
Section 1.3 Schedule of 
Activities
Modified baseline and on-treatment 
visit windows for Phase 1 patients
Visit windows modified for 
improved alignment with 
study strategy
Section 1.3 Schedule of 
Activities; Section 6.1 
Study Intervention(s) 
Administered
Removal of 1-week lead-in for 
cetuximab
Revised to align with updated 
study strategy
Section 1.3.1 Sampling 
Schedule for PK and 
ECGs for Participants in 
Phase 1
Time windows added for PK draws; 
additional PK sampling included for
Cycle 1
Time windows added to 
provide flexibility; sampling 
added to align with study 
changes
Section 2.3 Benefit/Risk 
Assessment
Updated benefit/risk description of 
LY3499446 
Section updated to provide
up-to-date safety information
Section 4.3 Justification 
for Dose
Updated justification of starting 
LY3499446 dose
Starting dose updated due to 
observed safety signals


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
3
Section # and Name
Description of Change
Brief Rationale
Section 5.2 Exclusion 
Criteria
New criterion added
Criterion added to align with 
revised dose escalation 
strategy
Section 6.5 Concomitant 
Therapy; Appendix 9
Added CYP2C9 and CYP2C19 
language for LY3499446; Appendix 
added
Cautionary language and 
appendix added as guidance 
for investigators
Section 6.6.1 Dose 
modification of 
LY3499446
Added guidance table and language 
for treatment-emergent adverse events 
suggestive of hemolysis
Additional guidance provided 
for investigators
Section 6.6.2 Dose 
Modification of 
Abemaciclib; Section 
6.6.3 Dose Modification 
of Cetuximab
Addition of dose modification 
guidance for abemaciclib and 
cetuximab
Detailed dose modification 
guidance provided for greater 
clarity
Throughout
Minor editorial and formatting 
changes
Minor, therefore not 
summarized


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
4
Table of Contents
Title Page...................................................................................................................................1
Protocol Amendment Summary of Changes............................................................................2
Table of Contents ......................................................................................................................4
1.
Protocol Summary......................................................................................................8
1.1.
Synopsis.......................................................................................................................8
1.2.
Schema.......................................................................................................................14
1.2.1.
Phase 1 Schema..........................................................................................................14
1.2.2.
Phase 2 Schema..........................................................................................................16
1.3.
Schedule of Activities (SoA) ......................................................................................17
1.3.1.
Sampling Schedule for PK and ECGs for Participants in Phase 1................................29
1.3.2.
Sampling Schedule for PK and ECGs for Participants in Phase 2................................31
2.
Introduction..............................................................................................................32
2.1.
Study Rationale ..........................................................................................................32
2.2.
Background ................................................................................................................32
2.3.
Benefit/Risk Assessment ............................................................................................37
3.
Objectives and Endpoints.........................................................................................40
4.
Study Design .............................................................................................................42
4.1.
Overall Design............................................................................................................42
4.1.1.
Phase 1 .......................................................................................................................42
4.1.1.1.
Dose Escalation Method.................................................................................43
4.1.1.2.
Dose-Limiting Toxicity Determination ...........................................................44
4.1.2.
Phase 2 .......................................................................................................................46
4.2.
Scientific Rationale for Study Design .........................................................................46
4.3.
Justification for Dose..................................................................................................46
4.4.
End of Study Definition..............................................................................................47
5.
Study Population ......................................................................................................48
5.1.
Inclusion Criteria........................................................................................................48
5.2.
Exclusion Criteria.......................................................................................................51
5.3.
Lifestyle Considerations .............................................................................................52
5.4.
Screen Failures...........................................................................................................53
6.
Study Intervention....................................................................................................54
6.1.
Study Intervention(s) Administered ............................................................................54
6.2.
Preparation/Handling/Storage/Accountability.............................................................56
6.3.
Measures to Minimize Bias:  Randomization and Blinding .........................................57
6.4.
Study Intervention Compliance...................................................................................57
6.5.
Concomitant Therapy .................................................................................................57
6.5.1.
Use of Gastric pH Modifying Agents..........................................................................58
6.5.2.
Palliative Medicine and Supportive Care ....................................................................58
6.5.3.
Supportive Management for Diarrhea .........................................................................59
6.6.
Dose Modification......................................................................................................59


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
5
6.6.1.
Dose Modification of LY3499446 ..............................................................................60
6.6.2.
Dose Modification of Abemaciclib .............................................................................63
6.6.3.
Dose Modification of Cetuximab................................................................................65
6.6.3.1.
Treatment Adjustments in Case of Cetuximab 
Allergic/Hypersensitivity Reaction .................................................................66
6.6.4.
Dose Modification of Erlotinib ...................................................................................67
6.6.5.
Dose Modification of Docetaxel .................................................................................67
6.6.6.
Dose Modification for Grade 3 Toxicities Not Clearly Related to 
LY3499446 or Drug Given in Combination................................................................67
6.7.
Intervention after the End of the Study........................................................................68
6.7.1.
Treatment after Study Completion ..............................................................................68
6.7.1.1.
Continued Access...........................................................................................68
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................69
7.1.
Discontinuation of Study Intervention ........................................................................69
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................69
7.2.1.
Discontinuation of Inadvertently Enrolled Patients .....................................................70
7.3.
Lost to Follow-Up ......................................................................................................70
8.
Study Assessments and Procedures .........................................................................71
8.1.
Efficacy Assessments .................................................................................................71
8.2.
Safety Assessments ....................................................................................................73
8.2.1.
Electrocardiograms.....................................................................................................73
8.2.2.
Clinical Safety Laboratory Assessments .....................................................................74
8.2.2.1.
Hepatic Safety Monitoring..............................................................................74
8.2.2.2.
Guidance for Monitoring Renal Function........................................................75
8.2.2.3.
Guidance for ILD/Pneumonitis .......................................................................76
8.3.
Adverse Events and Serious Adverse Events ..............................................................76
Serious Adverse Events.............................................................................................................77
Suspected Unexpected Serious Adverse Reactions............................................................78
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................78
8.3.2.
Follow-Up of AEs and SAEs ......................................................................................78
8.3.3.
Regulatory Reporting Requirements for SAEs............................................................79
8.3.4.
Pregnancy...................................................................................................................79
8.3.5.
Cardiovascular and Death Events................................................................................79
8.3.6.
Complaint Handling ...................................................................................................79
8.4.
Treatment of Overdose ...............................................................................................79
8.5.
Pharmacokinetics........................................................................................................80
8.6.
Pharmacodynamics.....................................................................................................80
8.7.
Genetics .....................................................................................................................81
8.7.1.
Whole Blood Sample for Pharmacogenetic Research..................................................81
8.8.
Biomarkers.................................................................................................................81
8.9.
Medical Resource Utilization and Health Economics..................................................83
9.
Statistical Considerations.........................................................................................84
9.1.
Statistical Hypotheses.................................................................................................84


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
6
9.2.
Sample Size Determination.........................................................................................84
9.3.
Populations for Analyses ............................................................................................85
9.4.
Statistical Analyses.....................................................................................................87
9.4.1.
General Statistical Considerations...............................................................................87
9.4.2.
Treatment Group Comparability .................................................................................87
9.4.2.1.
Participant Disposition....................................................................................87
9.4.2.2.
Participant Characteristics ..............................................................................87
9.4.2.3.
Concomitant Therapy .....................................................................................87
9.4.2.4.
Treatment Compliance....................................................................................87
9.4.3.
Efficacy Analyses.......................................................................................................88
9.4.3.1.
Primary Analyses ...........................................................................................88
9.4.3.2.
Secondary Analyses........................................................................................88
9.4.4.
Safety Analyses ..........................................................................................................90
9.4.5.
PK/Pharmacodynamic Analyses .................................................................................90
9.4.6.
Other Analyses ...........................................................................................................91
9.4.6.1.
Subgroup Analyses.........................................................................................91
9.4.6.2.
Biomarker Analyses .......................................................................................91
9.5.
Interim Analyses.........................................................................................................91
10.
Supporting Documentation and Operational Considerations ................................93
10.1.
Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................93
10.1.1.
Regulatory and Ethical Considerations........................................................................93
10.1.2.
Informed Consent Process ..........................................................................................93
10.1.3.
Data Protection...........................................................................................................94
10.1.4.
Dissemination of Clinical Study Data .........................................................................94
10.1.5.
Data Quality Assurance ..............................................................................................94
10.1.6.
Source Documents......................................................................................................95
10.1.7.
Study and Site Closure................................................................................................95
10.1.7.1.
Discontinuation of the Study...........................................................................95
10.1.7.2.
Discontinuation of Study Sites........................................................................96
10.2.
Appendix 2:  Clinical Laboratory Tests.......................................................................97
10.3.
Appendix 3:  Contraceptive Guidance and Collection of 
Pregnancy Information .............................................................................................100
10.4.
Appendix 4:  Liver Safety:  Suggested Actions and Follow-Up 
Assessments .............................................................................................................103
10.5.
Appendix 5:  Country-Specific Requirements...........................................................104
10.5.1.
Discontinuation of Inadvertently Enrolled Patients in the UK ...................................104
10.6.
Appendix 6:  Inducers and Strong Inhibitors of CYP3A............................................105
10.7.
Appendix 7:  Creatinine Clearance Formula..............................................................106
10.8.
Appendix 8:  Dose-Finding Algorithm of the mTPI-2 Method 
Showing Number of Patients Treated........................................................................107
10.9.
Appendix 9:  Examples of Sensitive and Moderately Sensitive 
CYP2C9 and CYP2C19 Substrates...........................................................................109
10.10.
Appendix 10:  Abbreviations ....................................................................................110
10.11.
Appendix 11:  Protocol Amendment History ............................................................114


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
7
11.
References...............................................................................................................116


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
8
1.
Pr ot oc ol S u m m ar y
1. 1.
S y n o psis
Pr ot oc ol Title:
A P hase 1/ 2 St u d y  of L Y 3 4 9 9 4 4 6 A d mi nistere d t o Patie nts wit h A d va nce d 
S oli d T u m ors wit h K R A S G 1 2 C m ut atio n
S h ort Title: A St u d y  of L Y 3 4 9 9 4 4 6 i n Patient s with S oli d T u m ors wit h K R A S G 1 2 C m ut atio n
R ati o n ale:
M ore t ha n 3 0 % of all ca ncer t y p es p ossess m utati o ns i n R A S .  K R A S m ut atio ns acc o u nt f or 
a p pr o xi matel y 8 5 % of R A S -ass ociate d ca ncers i n h u ma ns a n d ha ve t y picall y bee n ass ociate d 
wi t h w orse o verall s ur vi val a n d i ncrease d resista nce t o treat me nts c o m pare d t o K R A S wil d -t ype 
t u mors ( Di n u et al. 2 0 1 4; Ferrer et al. 2 0 1 8 ; Wi n do n et al . 2 0 1 8).  K R A S m ut atio ns occ ur i n 
a p pr o xi matel y 1 6% t o 4 0 % of n o n-s mall c ell lu n g ca ncer ( N S C L C), a n d G 1 2 C m ut atio ns
re prese nt a p pr o xi matel y 4 0 % of t otal m utati o ns i n N S C L C ( Fer ná n dez -Me dar de a n d Sa nt os 
2 0 1 1).  H o we ver, d ue t o its lac k o f dee p p oc k et s f or bi n di n g of s mall m olec ule i n hi bit ors, R A S is 
t ypicall y  dee me d as “ u n dr u g ga ble.”  Vari o us a nti-R A S t hera pe ut ic strate gies ha ve bee n pr o ve n 
lar gel y ineffect i ve ( Ferrer et al. 2 0 1 8; R o má n et al. 2 0 1 8; O’ Br ya n 2 0 1 9).  Rece nt st u dies ha ve 
bee n f oc usi n g o n K R A S m ut atio n -s pecific t hera pies. 
L Y 3 4 9 9 4 4 6 is a p ote nt a n d orall y a vaila ble s mall m o lec ule i n hi bit or of K R A S G 1 2 C ,
 
 
n d has de m o nstrate d si g nifica nt  acti vity i n precli nical m o dels a gai nst a wi de 
ra n ge of K R A S G 1 2 C m ut a nt t u mors.
St u d y  J 2 K-M C -J Z K A (J Z K A) c o nsists of a P hase 1 , o pe n -label, d ose -escalat i on st u d y  of 
L Y 3 4 9 9 4 4 6 as m o n ot hera p y  or i n c o m bi nati on wi t h a be macicli b, erl oti ni b, or cet u xi ma b i n 
pati e nts wit h a d va nce d s oli d t u m ors wit h K R A S G 1 2 C m ut atio n f oll owe d b y a ra n d o mize d 
c o ntr olle d P hase 2 st u d y of L Y 3 4 9 9 4 4 6 a d mi nistere d as m o n ot hera p y or i n c om bi nat i on wi t h 
a be macicli b or erl oti ni b i n patie nts wit h N S C L C t u m ors har b ori n g K R A S G 1 2 C m ut atio ns, a n d 
of  L Y 3 4 9 9 4 4 6 a d mi nistere d as m o n ot hera p y or in c o m bi nat i on wi t h cet u xi ma b i n patient s wit h 
c olorectal  ca ncer ( C R C) har b ori n g K R A S G 1 2 C m utati o ns, a n d a n e x pa nsi o n o f L Y 3 4 9 9 4 4 6 
m o n ot hera p y  in pat ient s wit h K R A S G 1 2 C m ut a nt s oli d t u m ors, ot her t ha n N S C L C a n d C R C.
C CI


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
9
Objectives and Endpoints
Objectives
Endpoints
Primary
Phase 1 Dose Escalation:
To characterize the RP2D for LY3499446 when administered alone or 
in combination with either abemaciclib, cetuximab, or erlotinib.

DLTs

Assessment of safety including, 
but not limited to, TEAEs, SAEs, 
deaths, and clinical lab 
abnormalities per CTCAE v5.0
Phase 2:
To assess the efficacy of LY3499446 alone or in combination with 
abemaciclib or erlotinib vs. docetaxel in patients with advanced KRAS
G12C-mutant NSCLC.
To evaluate the efficacy of LY3499446 alone or in combination with 
cetuximab in patients with advanced KRAS G12C-mutant CRC.
To evaluate the efficacy of single-agent LY3499446 in patients with 
advanced KRAS G12C-mutant solid tumors (other than NSCLC and 
CRC).

Per RECIST v1.1:
o
ORR (coprimary for 
NSCLC cohorts; 
primary for CRC 
cohorts and Other 
tumors cohort)
o
PFS (coprimary for 
NSCLC cohorts)
Secondary
Phase 1 Dose Escalation:
To characterize the safety and toxicity profile of LY3499446 
administered as monotherapy and in combination with abemaciclib, 
erlotinib (NSCLC), or cetuximab (CRC) to patients with advanced solid 
tumors with KRAS G12C mutation.  
To assess the PK of LY3499446 administered as monotherapy and in 
combination with abemaciclib, erlotinib, or cetuximab in patients with 
advanced solid tumors with KRAS G12C mutation.
To assess any antitumor activity of LY3499446 administered as 
monotherapy and in combination with abemaciclib, erlotinib, or 
cetuximab in patients with advanced solid tumors with KRAS G12C
mutation.

Safety as determined by
(including but not limited to)
TEAEs, SAEs, deaths, and 
clinical laboratory abnormalities 
per CTCAE (Version 5.0)

Plasma concentration of 
LY3499446 administered as 
monotherapy and in combination 
with abemaciclib, erlotinib, or 
cetuximab

Per RECIST v1.1:  ORR, PFS, 
DoR, DCR
Phase 2:
To assess the efficacy of LY3499446 administered as monotherapy or 
in combination with abemaciclib or erlotinib in patients with NSCLC 
tumors harboring KRAS G12C mutations, and of LY3499446 
administered as monotherapy or in combination with cetuximab in 
patients with CRC tumors harboring KRAS G12C mutations, and 
LY3499446 administered as monotherapy in patients with solid tumors, 
other than NSCLC and CRC, harboring KRAS G12C mutations.
To characterize the safety and toxicity profile of LY3499446 
administered as monotherapy and in combination with abemaciclib, 
erlotinib, or cetuximab to patients with advanced solid tumors with 
KRAS G12C mutation.
To assess the PK of LY3499446 administered as monotherapy and in 

Per RECIST v1.1:
o
DoR, DCR, TTR, OS 
(all cohorts)
o
PFS (CRC cohorts and 
Other tumors)

Safety as determined by 
(including but not limited to) 
TEAEs, SAEs, deaths, and 
clinical laboratory abnormalities 
per CTCAE (Version 5.0) 

Plasma concentration of 
LY3499446 administered as 
monotherapy and in combination 
with abemaciclib erlotinib, or 
cetuximab


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
10
combination with abemaciclib, erlotinib, or cetuximab in patients with 
advanced solid tumors with KRAS G12C mutation.
Abbreviations:  CRC = colorectal cancer; CTCAE = Common Terminology Criteria for Adverse Events; 
DCR = disease control rate; DLT = dose-limiting toxicity; DoR = duration of response; NSCLC = nonsmall cell 
lung cancer; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; 
PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid Tumors; RP2D = recommended phase 
2 dose; SAE = serious adverse event; TEAE = treatment-emergent adverse event; TTR = time to response.
Overall Design:
Study JZKA is a first in human, multicenter, open-label dose escalation Phase 1 study, followed 
by a cohort- and disease-specific randomized Phase 2, and a monotherapy Phase 2 expansion in 
patients with solid tumors harboring KRAS G12C mutations other than NSCLC and CRC.
The Phase 1 portion will enroll patients with KRAS G12C mutant solid tumors, where patients 
will be treated with monotherapy, or in combination with abemaciclib, erlotinib, or cetuximab. 
Once a recommended phase 2 dose (RP2D) is established, patients with KRAS G12C mutant 
NSCLC will be randomized across 4 cohorts to evaluate for efficacy and safety to select the 
optimal regimen for further development.  This part is a randomized, controlled, Phase 2 design.
For patients with KRAS G12C mutant CRC, patients will be randomized to either LY3499446 
alone or in combination with cetuximab during the Phase 2 part.
For patients with KRAS G12C mutant solid tumors (other than NSCLC or CRC), an expansion 
cohort of LY3499446 monotherapy will proceed to assess the potential for efficacy once RP2D 
of LY3499446 monotherapy is established. 
Disclosure Statement: This is an open-label, Phase1/2 study that consists of a dose escalation 
followed by a parallel-cohort randomization in patients harboring KRAS G12C mutations.
Number of Participants:
Approximately 111 to 135 (45 monotherapy, 22-30 per combination) patients will be enrolled in 
the Phase 1 portion of the study (including dose-escalation evaluations and backfills).  
Approximately 140 to 280 patients will be enrolled in the Phase 2 portion of the study.

Phase 1:  Total enrollment will be determined by the incidence of dose-limiting toxicities.
o
Monotherapy dose escalation (Part A):  approximately 45 patients will be enrolled
(including 10 patients per cohort as “backfill”)
o
Combination dose escalation (Part B, C, and D):  approximately 22 to 30 patients in 
each part will be enrolled (including 10 patients per cohort as “backfill”)

Phase 2:  Approximately 140 to 280 patients will be enrolled into the Phase 2 portion of this 
study.
o
For patients with NSCLC:  randomized design with docetaxel to establish efficacy 
and safety

Up to 160 patients in total will be enrolled and randomized at a 1:1:1:1 ratio to 
monotherapy (Cohort E1), combination with abemaciclib (Cohort E2), 
combination with erlotinib (Cohort E3), or docetaxel (Cohort E4).  An interim 
data review will be performed based on efficacy, safety, and pharmacokinetics 


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
11
(PK) data. Enrollment will continue while this analysis is being conducted.  A 
final data review will be performed based on safety, efficacy, and PK data.
o
For patients with CRC:  randomized design for relative activity estimation

A total of approximately 40 to 80 patients will be enrolled across Cohorts F1 and 
F2.  Initially, 40 patients will be randomized at a 1:1 ratio to monotherapy (Cohort 
F1) or combination with cetuximab (Cohort F2), and an interim data review will 
be performed based on safety, efficacy, and PK data.

After 40 patients are randomized, an interim analysis of safety and efficacy will 
occur.  If 1 arm meets the criteria for futility, the corresponding arm will close, 
while the open arm may enroll an additional 20 patients.  The “winning” arm 
should have demonstrated better efficacy signal in terms of superior overall 
response rate and comparable safety profile.  A final data review will be 
performed based on safety, efficacy, and PK data.  If no meaningful difference in 
efficacy or safety is observed between the 2 arms, approximately 80 total 
randomized patients (40 in each arm) will be enrolled.
o
Other Tumors with KRAS G12C mutation (other than CRC and NSCLC) with 
monotherapy:  approximately 40 patients will be enrolled in Cohort G, with interim 
data review performed after first 20 patients.  The purpose of this portion is 
signal-finding. 
Intervention Groups and Duration:
Patients enrolled in this study will receive LY3499446 monotherapy or in combination with 
abemaciclib, erlotinib, or cetuximab, as shown in the following table. In addition to the 
LY3499446 dose levels specified in the table below, intermittent dose levels, and/or alternative 
schedules may be explored in accordance with the dose finding rules. Similarly, lower doses or 
alternative schedules of abemaciclib and erlotinib may be explored below the currently approved 
doses based on emerging safety data. The planned duration of treatment is not fixed; participants 
will remain on study until disease progression or unacceptable toxicity occurs.  If participants are 
discontinued from abemaciclib, erlotinib, or cetuximab therapy, they will be allowed to continue 
on LY3499446 treatment if receiving ongoing clinical benefit.  However, if patients are 
discontinued from LY3499446 treatment, they will be allowed to continue on therapy with the 
respective combination drug per the investigator’s discretion, with the exception of patients 
enrolled in the cetuximab cohorts (C1, C2, and F2).


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
1 2
P h ase 1
St u d y Dr u g(s )
( R o ute of 
A d mi nistr ati o n)
C o h ort
Pr o p ose d
D oses
D ose Sc he d ule
M o n ot her a p y/
P art A
L Y 3 4 9 9 4 4 6 ( P O)
A 0 a
Q O D
A 1 b
Q D
A 2
BI D
A- 1 c
Q D
C o m bi n ati o n/
P art B/ C/ D
L Y 3 4 9 9 4 4 6 ( P O)
B 0/ C 0/ D 0
T B D
T B D
B 1/ C 1/ D 1
T B D
T B D
B 2/ C 2/ D 2
T B D
T B D
B 3/ C 3/ D 3
T B D
T B D
B- 1/ C- 1/ D- 1
T B D
T B D
A be macicli b ( P O)
B 0/ B 1/ B 2/ B 3
1 5 0 m g
BI D
B- 1
1 0 0 m g
BI D
Cet u xi ma b (I V)
C 0/ C 1/ C 2/ C 3
4 0 0 m g/ m 2 C 1 D 1;
2 5 0 m g/ m 2
Q W
C- 1
4 0 0 m g/ m 2 C 1 D 1;
2 5 0 m g/ m 2
Q W
Erl oti ni b ( P O)
D 0/ D 1/ D 2/ D 3
1 5 0 m g
Q D
D- 1
1 0 0 m g
Q D
C CI
C CI
C CI
C CI


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
1 3
A b bre viati o ns:  BI D = t wice dail y; I V = i ntra ve n o usl y; P O = orall y; Q D = o nce dail y; Q O D = o nce e ver y ot her 
da y ; T B D = t o be deter mi ne d.
a
I n t he e ve nt t he 
 d osi n g als o lea ds t o 
 or ot her d ose-li miti n g t o xicities, l o wer 
d oses a n d ot her d osi n g fre q ue ncies ma y be e x pl ore d t o e ns ure patie nt safet y a n d s ufficie nt tar get e n ga ge me nt f or 
cli nical be nefit.   T hese ma y i ncl u de, f or e xa m ple, d ose le vel A -1 of 
 or  
.
b
I n t he e ve nt t he  
 d osi n g s h o ul d lea d t o 
 or ot her d ose-li miti n g t o xicities, a d ose of 
 ma y be e x pl ore d t o e ns ure patie nt safet y a n d s ufficie nt tar get e n ga ge me nt f or cli nical be nefit.  As 
warra nte d b y data, a n i nter me diate d ose , f or e xa m ple
 
m a y  be e x pl ore d.
c
In t he e ve nt t he  
 d ose s h o ul d lea d t o 
 or ot her d ose-li miti n g t o xicities, a d ose of 
 
 ma y be e x pl ore d t o e ns ure patie nt safet y a n d s ufficie nt tar get e n ga ge me nt f or cli nical be nefit.
P h ase 2
St u d y Dr u g(s)
( Ro ute of 
A d mi nistr ati o n)
C o h ort
Pr o p ose d
D oses
D ose Sc he d ule
M o n ot her a p y
L Y 3 4 9 9 4 4 6 ( P O)
E 1/ F 1/ G
R P 2 D M
T B D
C o m bi n ati o n wit h 
A be m acicli b
L Y 3 4 9 9 4 4 6 ( P O)
E 2
R P 2 D A
T B D
A be macicli b ( P O )
E 2 
1 5 0 m g
BI D
C o m bi n ati o n wit h 
Erl oti ni b
L Y 3 4 9 9 4 4 6 ( P O)
E 3
R P 2 D E
T B D
Erl oti ni b ( P O)
E 3
1 5 0 m g
Q D
C o m bi n ati o n wit h 
Cet u xi m a b
L Y 3 4 9 9 4 4 6 ( P O)
F 2
R P 2 D C
T B D
Cet u xi ma b (I V )
F 2 
4 0 0 m g/ m 2
C 1 D 1;
2 5 0 m g/ m 2
Q W
Acti ve C o m p ar at or
D oceta xel (I V)
E 4
7 5 m g/ m 2
Q 3 W
A b bre viati o ns:  BI D = t wice dail y; D L = d ose le vel; I V = i ntra ve n o us; P O = orall y; Q D = dail y; Q W = e ver y wee k; 
Q 3 W = e ver y 3 wee ks; R P 2 D A = a be macicli b rec o m me n de d p hase 2 d ose; R P 2 D C = cet u xi ma b rec o m me n de d 
p hase 2 d ose; R P 2 D E = erl oti ni b rec o m me n de d p hase 2 d ose; R P 2 D M = m o n ot hera p y  rec o m me n de d p hase 2 d ose.
N ote:
l ower d oses or al ter nati ve sc he d ules of a be macicli b a n d erl oti ni b ma y be e x pl ore d bel o w 
t he c urre ntl y a p pr o ve d d oses base d o n e mer gi n g safet y data.
D at a M o nit ori n g C o m mittee: N o
C CI
C CI
C CI
C CI
C CI
C CI
C
CI
C CI
C CI
C CI
C CI
C
CI
C CI


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
1 4
1. 2.
Sc he m a
1. 2. 1.
P h ase 1 Sc he m a
C CI
C CI
C CI
C CI


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
1 5
A b bre viati o ns:  BI D = t wice dail y; D L T = d ose -li miti n g t o xicit y; N = n u m ber of patie nts; P K = p har mac o ki netics; P O = orall y ; R P 2 DA = rec o m me n de d p hase 2 
d ose i n c o m bi nati o n wit h a be macicli b; R P 2 D C = rec o m me n de d p hase 2 d ose i n c o m bi nati o n wit h cet u xi ma b; R P 2 D E = rec o m me n de d p hase 2 d ose i n 
c o m bi nati o n w it h erl oti ni b; R P 2 DM = m o n ot hera p y rec o m me n de d p hase 2 d ose.
N ote:   D ose de -escalati o n c o h orts will o nl y occ ur if t he i nitial L Y 3 4 9 9 4 4 6 d oses are deter mi ne d t o be i nt olera ble.   I n a d diti o n t o t he L Y 3 4 9 9 4 4 6 d ose le vels 
s pecifie d i n t his fi g ure, i nter mitte nt d ose le vels, or alter nati ve sc he d ules ma y be e x pl ore d.  Si milarl y , l o wer d oses or alter nati ve sc he d ules of a be macicli b a n d 
erl oti ni b ma y be e x pl ore d bel o w t he c urre ntl y a p pr o ve d d oses base d o n e mer gi n g safet y data. T he t otalit y of data i ncl u di n g safet y, a n d P K e x p os ure a n d t he 
i nci de nce of D L T ma y hel p g ui de e val uati n g alter nati ve d osi n g a n d sc he d ule (e .g. 
 vs.
).
C CI
C CI


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
16
1.2.2.
Phase 2 Schema
Abbreviations:  2L+ = 2 or more lines of therapy; 3L+ = 3 or more lines of therapy; CRC = colorectal cancer; 
N = number of patients; NSCLC = non-small cell lung cancer; R = randomization; RP2DA = recommended phase 
2 dose in combination with abemaciclib; RP2DC = recommended phase 2 dose in combination with cetuximab; 
RP2DE = recommended phase 2 dose in combination with erlotinib; RP2DM = monotherapy recommended phase 
2 dose.
a
An interim analysis will take place after approximately 20 patients have been enrolled within each cohort.  See 
Section 9.5.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
17
1.3.
Schedule of Activities (SoA)
This section contains the following schedules:

Schedule for Participants Enrolled in Phase 1

Schedule for Participants Enrolled in Phase 2

Continued Access Schedule for All Participants

Sampling Schedule for PK and electrocardiograms for All Participants
Schedule for Participants Enrolled in Phase 1
Screening, On-Study, and Posttreatment SoA
Screening
On-Treatment
Cycle = 21 days
Posttreatment
(Day
Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 
3-n
Short-
Term 
Follow-
Upa
Long-
Term 
Follow-
Upb
Instructions
(±1 days)
(±1 days)
(±1
days)
(±3 
days)
(±7 
days)
Visit
28
14
D1
D4
D8
D11
D15
D18
D1
D4
D8
D11
D15
D18
D1
V801
V802-
8XX
Procedure


Informed consent
X
ICF must be signed before any 
protocol-specific procedures are 
performed.
Inclusion/
exclusion criteria
X
Medical history
X
Including assessment of pre-
existing conditions and historical 
illnesses, pre-existing toxicities 
from prior therapies, and habits 
(such as tobacco and alcohol use).
Cancer treatment 
history
X
Record prior anticancer therapy.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
18
Screening, On-Study, and Posttreatment SoA
Screening
On-Treatment
Cycle = 21 days
Posttreatment
(Day
Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 
3-n
Short-
Term 
Follow-
Upa
Long-
Term 
Follow-
Upb
Instructions
(±1 days)
(±1 days)
(±1
days)
(±3 
days)
(±7 
days)
Visit
28
14
D1
D4
D8
D11
D15
D18
D1
D4
D8
D11
D15
D18
D1
V801
V802-
8XX
Procedure


Concomitant 
medication
X
See Instructions
X

At baseline, record prior and 
concurrent medications.

Record all premedication, 
supportive care, and 
concomitant medication 
continuously at every visit and 
throughout the study.
Physical 
examination
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
Measure vital signs (height [at 
baseline], weight, temperature, 
blood pressure, pulse rate, and 
SpO2).
AE collection
X
See Instructions
X

Collect continuously at every 
visit and throughout the study.

CTCAE Version 5.0
ECOG PS
X
X
X
X
X
During study treatment, perform 
3 days prior to treatment.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
19
Screening, On-Study, and Posttreatment SoA
Screening
On-Treatment
Cycle = 21 days
Posttreatment
(Day
Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 
3-n
Short-
Term 
Follow-
Upa
Long-
Term 
Follow-
Upb
Instructions
(±1 days)
(±1 days)
(±1
days)
(±3 
days)
(±7 
days)
Visit
28
14
D1
D4
D8
D11
D15
D18
D1
D4
D8
D11
D15
D18
D1
V801
V802-
8XX
Procedure


ECG
X
See Section 1.3.1
At baseline (screening):  Single 
local ECG with central storage. 
Must be collected before first 
dose and any blood draws.  
Participant should be supine for 5 
to 10 minutes before collection 
and remain supine during ECG.
On-study:  Triplicate ECGs with 
digital data.  Participant should be
supine for 5 to 10 minutes before 
collection and remain supine 
during ECG.  Local testing with 
central storage.
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
May be collected ±1 day from 
scheduled visit.  See Appendix 2
Coagulation
X
See Appendix 2. Perform at 
baseline and as clinically 
indicated
Clinical chemistry 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
May be collected ±1 day from 
scheduled visit.  See Appendix 2
Urine sample
X
Collect urine sample starting at 
the time of dose and completed 
collection at 12 hours.
Urinalysis
X
X
X
X
X
X
X
X
X
See Appendix 2.
Thyroid function
X
May be collected ±3 days from 
scheduled visit.  See Appendix 2.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
20
Screening, On-Study, and Posttreatment SoA
Screening
On-Treatment
Cycle = 21 days
Posttreatment
(Day
Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 
3-n
Short-
Term 
Follow-
Upa
Long-
Term 
Follow-
Upb
Instructions
(±1 days)
(±1 days)
(±1
days)
(±3 
days)
(±7 
days)
Visit
28
14
D1
D4
D8
D11
D15
D18
D1
D4
D8
D11
D15
D18
D1
V801
V802-
8XX
Procedure


Pregnancy test
X
See Instructions
X
Applies only to WOCBP.  See 
Appendix 2.
Note:  during study treatment, 
perform monthly (±3 days) or as 
required per local regulations 
and/or institutional guidelines. 
Radiologic 
imaging and 
measurement of 
palpable or visible 
lesions 
X
See Instructions
X
Perform according to RECIST 
v1.1 criteria, by the same method 
used at baseline, every 6 weeks
(±7 days) for the first 6 months, 
then every 9 weeks (±7 days) 
until radiographic disease 
progression, death, or study 
completion, whichever occurs 
first.
Perform as scheduled, even if 
study treatment is delayed or 
omitted.
Centrally collected and stored.
Brain MRI/CT
X
Only for patients with NSCLC 
and as clinically indicated for 
patients with other tumor types 
Survival 
assessment
X
X
Perform every 3 months (±7 
days).  If an in-person visit is not 
possible, confirm survival by 
contacting the patient directly via 
phone.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
21
Screening, On-Study, and Posttreatment SoA
Screening
On-Treatment
Cycle = 21 days
Posttreatment
(Day
Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 
3-n
Short-
Term 
Follow-
Upa
Long-
Term 
Follow-
Upb
Instructions
(±1 days)
(±1 days)
(±1
days)
(±3 
days)
(±7 
days)
Visit
28
14
D1
D4
D8
D11
D15
D18
D1
D4
D8
D11
D15
D18
D1
V801
V802-
8XX
Procedure


Collection of 
poststudy-
treatment 
anticancer therapy 
information
X
X
Discontinuation from study must 
occur prior to introduction of the
new agent.
Patient diary
See Instructions
Provide patient diary Day 1.  
Completed QD by patient.  
Review at each study visit for 
first 2 cycles.
PK
See Section 1.3.1
Refer to Section 1.3.1 for PK
sampling time points.
Whole blood 
(PGx)
X
Collect once.  Sample can be 
collected at any time if not 
collected on C1D1.
Biomarker plasma
X
Pred
ose
X
X
X
C1D1 sample:  collect prior to 
initiating treatment.  Collect on 
day 1 of every odd cycle starting 
at C3D1.
Administer 
LY3499446
See Instructions
Administer per RP2D. See
Section 6.1.
Administer 
abemaciclib
See Instructions
Administer BID according to 
Section 6.1.
Administer 
cetuximab
See Instructions
Administer by IV QW starting on 
C1D1.According to Section 6.1.
Administer 
erlotinib
See Instructions
Administer 150 mg QD.  See 
Section 6.1.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
22
Abbreviations:  AE = adverse event; BID = twice daily; C = cycle; CR = complete response; CRC = colorectal cancer; CT = computed tomography; CTCAE = 
Common Terminology Criteria for Adverse Events; D = day; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance 
status; ICF = informed consent form; IV = intravenous; MRI = magnetic resonance imaging; NSCLC = nonsmall cell lung cancer; PGx = pharmacogenomics; 
PK = pharmacokinetics; PO = orally; Q3W = every 3 weeks; QD = daily; RECIST = Response Evaluation Criteria in Solid Tumors; SoA = schedule of 
activities; V = visit; V8XX = follow-up visit number; WOCBP = women of childbearing potential.
a
Short-term follow-up begins when the patient and the investigator agree that the patient will no longer continue study treatment and lasts approximately 30 
days.
b
Long-term follow-up occurs every 3 months for the first 2 years and every 6 months thereafter and begins when short-term follow-up period is completed and 
continues until death or study completion.  In all cases, no follow-up procedures will be performed for a patient who withdraws informed consent/assent 
unless he or she has explicitly provided permission and consent/assent.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
23
Schedule for Participants Enrolled in Phase 2
Screening, On-Study, and Posttreatment SoA
Screening
On-Treatment
Cycle = 21 days
Posttreatment
(Day
Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 3-n
Short-
Term 
Follow-
Upa
Long-
Term 
Follow-
Upb
Instructions
(±3 days)
(±3 days)
(±3 days)
(±3 days)
(±7 days)
Visit
28
7
D1
D8
D15
D1
D8
D15
D1
V801
V802-
8XX
Procedure


Informed consent
X
ICF must be signed before any protocol-
specific procedures are performed.
Inclusion/exclusion 
criteria
X
Medical history
X
Including assessment of pre-existing 
conditions and historical illnesses, pre-existing 
toxicities from prior therapies, and habits 
(such as tobacco and alcohol use).
Cancer treatment history
X
Record prior anticancer therapy.
Concomitant medication
X
See Instructions
X

At baseline, record prior and concurrent 
medications.

Record all premedication, supportive care, 
and concomitant medication continuously 
at every visit and throughout the study.
Physical examination
X
X
X
X
X
Vital signs 
X
X
X
X
X
Measure vital signs (height [at baseline], 
weight, temperature, blood pressure, pulse 
rate, and SpO2).
AE collection
X
See Instructions
X

Collect continuously at every visit and 
throughout the study.

CTCAE Version 5.0.
ECOG PS
X
X
X
X
X
During study treatment, perform 3 days prior 
to treatment.
ECG
X
See Section 1.3.1
At baseline (screening):  Single local ECG. 
Must be collected before first dose and any 
blood draws.  Participant should be supine for 


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
24
Screening, On-Study, and Posttreatment SoA
Screening
On-Treatment
Cycle = 21 days
Posttreatment
(Day
Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 3-n
Short-
Term 
Follow-
Upa
Long-
Term 
Follow-
Upb
Instructions
(±3 days)
(±3 days)
(±3 days)
(±3 days)
(±7 days)
Visit
28
7
D1
D8
D15
D1
D8
D15
D1
V801
V802-
8XX
Procedure


5 to 10 minutes before collection and remain
supine during ECG.
On-study:  Single ECGs.  Participant should 
be supine for 5 to 10 minutes before collection 
and remain supine during ECG. Local testing.
Hematology
X
X
X
X
X
May be collected ±3 days from scheduled 
visit.  See Appendix 2.
Coagulation
X
See Appendix 2. Perform at baseline and as 
clinically indicated.
Clinical chemistry 
X
X
X
X
X
May be collected ±3 days from scheduled 
visit.  See Appendix 2.
Urine sample
X
Collect urine sample starting at the time of 
dose and completed collection at 12 hours.
Urinalysis
X
X
X
X
X
See Appendix 2. Perform at baseline and as 
clinically indicated.
Thyroid function
X
May be collected ±3 days from scheduled 
visit.  See Appendix 2.
Pregnancy test
X
See Instructions
X
Applies only to WOCBP.  See Appendix 2.
Note:  during study treatment, perform 
monthly (±3 days) or as required per local 
regulations and/or institutional guidelines. 


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
25
Screening, On-Study, and Posttreatment SoA
Screening
On-Treatment
Cycle = 21 days
Posttreatment
(Day
Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 3-n
Short-
Term 
Follow-
Upa
Long-
Term 
Follow-
Upb
Instructions
(±3 days)
(±3 days)
(±3 days)
(±3 days)
(±7 days)
Visit
28
7
D1
D8
D15
D1
D8
D15
D1
V801
V802-
8XX
Procedure


Radiologic imaging and 
measurement of palpable 
or visible lesions 
X
See Instructions
X
Perform according to RECIST v1.1 criteria, by 
the same method used at baseline, every
6 weeks (±7 days) for the first 6 months, then 
every 9 weeks (±7 days) until radiographic 
disease progression, death, or study 
completion, whichever occurs first.
Perform as scheduled, even if study treatment 
is delayed or omitted.
Centrally collected and stored.
Brain MRI/CT
X
Survival assessment
X
X
Perform every 3 months (±7 days).  If an 
in-person visit is not possible, confirm 
survival by contacting the patient directly via 
phone.
Collection of 
poststudy-treatment 
anticancer therapy 
information
X
X
Discontinuation from study must occur prior 
to introduction of the new agent.
Patient diary
See Instructions
Provide patient diary D1.  Completed QD by 
patient.  Review at each study visit for first 
2 cycles.
PK
See Section 1.3.1
Refer to Section 1.3.1 for PK sampling time 
points.
Whole Blood (PGx)
X
Collect once.  Sample can be collected at any 
time if not collected on C1D1.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
26
Screening, On-Study, and Posttreatment SoA
Screening
On-Treatment
Cycle = 21 days
Posttreatment
(Day
Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 3-n
Short-
Term 
Follow-
Upa
Long-
Term 
Follow-
Upb
Instructions
(±3 days)
(±3 days)
(±3 days)
(±3 days)
(±7 days)
Visit
28
7
D1
D8
D15
D1
D8
D15
D1
V801
V802-
8XX
Procedure


Biomarker plasma
X
(Pred
ose)
X
See 
Instructions
X
C1D1 sample:  collect prior to initiating 
treatment.  Plasma samples from C3D1 
onward to be collected on D1 of each odd 
cycle.
Biomarker serum 
(Cohorts F1 & F2 – CRC 
participants)
X
(Pred
ose)
X
X

C1D1 sample collect prior to initiating 
treatment.
Tumor biopsy (Cohorts 
E1, E2, E3, E4 - NSCLC 
participants)
X
X
Optional
X

Collect at baseline (prior to initiating 
treatment).

Second biopsy collect on C2D1 (±3 days). 

Archival tumor may be requested if new 
baseline insufficient tumor 
quantity/quality.

Optional new tumor biopsy at progression 
for patients on study for at least 6 months 
who have partial or CR.
Tumor biopsy (Cohort 
F1 – CRC monotherapy 
participants)
X
X
Optional
X
Collect at baseline (prior to initiating 
treatment)
Second biopsy collect on C2D1 (±3 days).  
Archival tumor may be requested if new 
baseline biopsy has insufficient tumor 
quantity/quality.
Optional new tumor biopsy at progression 
for patients on study for at least 6 months 
who have partial or CR.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
27
Screening, On-Study, and Posttreatment SoA
Screening
On-Treatment
Cycle = 21 days
Posttreatment
(Day
Relative to 
C1D1)
Cycle 1
Cycle 2
Cycle 3-n
Short-
Term 
Follow-
Upa
Long-
Term 
Follow-
Upb
Instructions
(±3 days)
(±3 days)
(±3 days)
(±3 days)
(±7 days)
Visit
28
7
D1
D8
D15
D1
D8
D15
D1
V801
V802-
8XX
Procedure


Tissue biopsy (Cohort 
F2 - CRC combination 
therapy participants)
See Instructions
Optional
X

Initial biopsy:  collect 1 week post 
monotherapy lead-in (day 5, 6, or 7)

Second biopsy:  collect on C2D1 (±3 days).  

Optional new tumor biopsy at progression 
for patients on study for at least 6 months 
who have partial or CR.
Archival tissue (Cohort 
F2 & G)
X
If archival tissue not available or 
insufficient, new baseline biopsy required.
Administer LY3499446
See Instructions
Administer PO BID according to Section 6.1.
Administer abemaciclib
See Instructions
Administer PO BID according to Section 6.1.
Administer cetuximab
See Instructions
Administer by IV QW according to Section 
6.1.
Administer erlotinib
See Instructions
Administer 150 mg QD.  See Section 6.1.
Administer docetaxel
See Instructions
Administer 75 mg/m2 Q3W.  See Section 6.1.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
28
Abbreviations:  AE = adverse event; BID = twice daily; C = cycle; CR = complete response; CRC = colorectal cancer; CT = computed tomography; CTCAE = 
Common Terminology Criteria for Adverse Events; D = day; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance 
status; ICF = informed consent form; IV = intravenous; MRI = magnetic resonance imaging; NSCLC = non-small cell lung cancer; 
PGx = pharmacogenomics; PK = pharmacokinetics; PO = orally; Q3W = every 3 weeks; QD = daily; QW = every week; RECIST = Response Evaluation 
Criteria in Solid Tumors; SoA = schedule of activities; V = visit; V8XX = follow-up visit number; WOCBP = women of childbearing potential.
a
Short-term follow-up begins when the patient and the investigator agree that the patient will no longer continue study treatment and lasts approximately 30 
days.
b
Long-term follow-up occurs every 3 months for the first 2 years and every 6 months thereafter and begins when short-term follow-up period is completed and 
continues until death or study completion.  In all cases, no follow-up procedures will be performed for a patient who withdraws informed consent/assent 
unless he or she has explicitly provided permission and consent/assent.
Continued Access SoA for All Participants
Visita
Study Treatment
30-Day Follow-Up
Instructions
501-5XX
901
Procedure
AE Collection
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.
Collect throughout the study.
Administer study 
intervention
X
See Section 6.1 for Study Intervention administration details and guidelines.
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; SAE = serious adverse event; SoA = schedule of activities.
a
Continued access follow-up begins when the patient and the investigator agree that the patient will no longer continue treatment in the continued access 
period and lasts approximately 30 days. In all cases, no follow-up procedures will be performed for a patient who withdraws informed consent unless he or 
she has explicitly provided permission and consent.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
29
1.3.1.
Sampling Schedule for PK and ECGs for Participants in Phase 1
Cycle
Day
Dose
Time after Dose 
(hours)a
LY3499446
Combination 
Agentb
Collect 
ECGd
1
1
1
Predose
X
Xe
0.5
X ±5 min
X ±5 min
1
X ±10 min
X ±10 
min
1.5
X ±10 min
2
X ±10 min
3
X ±10 min
4
X ±20 min
Erlotinibc
Cetuximabc
X ±20 
min
8
X ±30 min
Abemaciclibc
X ±30 
min
24 (Predose, if 
applicable)
X ±60 min
8
(±1 day, to 
align with 
LY3499446 
dosing day)
1
Predose
X
Xe
0.5
X ±5 min
X ±5 min
1
X ±10 min
X ±10 
min
1.5
X ±10 min
2
X ±10 min
3
X ±10 min
4
X ±20 min
Erlotinibc
Cetuximabc
X ±20 
min
8
X ±30 min
Abemaciclibc
X ±30 
min


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
30
Cycle
Day
Dose
Time after Dose 
(hours)a
LY3499446
Combination 
Agentb
Collect 
ECGd
2 and every 
other cycle
1
1
Predose
X
Xe
4
X ±20 min
Erlotinibc
Cetuximabc
Abemaciclibc
X ±20
min
Abbreviations:  ECG = electrocardiogram; PK = pharmacokinetics.
a
Time after dose starts after the patient has ingested the full amount of the capsules. 
b
Combination agent samples are to be collected only if the patient is being treated by that agent.
c
PK sample collection timepoint for combination agent is intended to capture Cmax.
d
All ECGs (excluding screening and follow-up ECGs) are to be triplicate ECGs; the 3 replicates of each should be
completed within 5 minutes and preferably 1 minute apart.
e
Predose ECGs should be taken at either 90 (-90) minutes, 60 (-60) minutes, or 30 (-30) minutes.  Predose 
timepoints are flexible for site convenience


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
31
1.3.2.
Sampling Schedule for PK and ECGs for Participants in Phase 2
Phase 2 PK sampling schedule is subject to change based on PK data and analysis results from 
the Phase 1 potion of the study.
Cycle
Day
Dose
Time after Dose 
(hours)a
LY3499446
Combination 
Agentb
Collect ECGd
1
1
1
Predose
X
Xe
1
X
X ±30 min
4
X
Erlotinibc
8
X
Abemaciclibc
2
1
1
Predose
X
Erlotinibc
Cetuximabc
Abemaciclibc
Xe
0.5
X
1
X
X ±30 min
4
X
3 and every 
other cycle
1
1
Predose
X
Cetuximabc
Erlotinibc
Abemaciclibc
Xe
1
X
X ±30 min
Abbreviations:  Cmax = maximum concentration; ECG = electrocardiogram; PK = pharmacokinetics.
a
Time after dose starts after the patient has ingested the full amount of the capsules. 
b
Combination agent samples are to be collected only if the patient is being treated by that agent.
c
PK sample collection timepoint for combination agent is intended to capture Cmax.
d
All ECGs in Phase 2 should be single ECGs
e
Predose ECGs should be taken at either 90 (-90) minutes, 60 (-60) minutes, or 30 (-30) minutes.  Predose 
timepoints are flexible for site convenience.


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
3 2
2.
I ntr o d ucti o n
2. 1.
St u d y R ati o n ale
M ore t ha n 3 0 % of all ca ncer t y pes p ossess m utati o ns i n R A S .  K R A S m ut atio ns acc o u nt f or 
a p pr o xi matel y 8 5 % of R A S-ass o ciate d ca ncers i n h u ma ns a n d ha ve t ypicall y bee n ass oci ate d 
wi t h w orse o verall s ur vi val ( O S) a n d i ncrease d resista nce t o treat me nts c o m pare d t o K R A S
wil d -t yp e t u m ors ( Di n u et al. 2 0 1 4; Ferrer et al. 2 0 1 8 ; Wi n d o n et al. 2 0 1 8 ).  K R A S m ut at i ons 
occ ur i n a p pr o xi matel y  1 6% t o 4 0 % of n o ns mall cell l u n g ca ncer ( N S C L C), a n d G 1 2 C m ut atio ns 
re prese nt a p pr o xi matel y 4 0 % of t otal m utati o ns i n N S C L C ( Fer ná n dez -Me dar de a n d Sa nt os 
2 0 1 1).  H o we ver, d ue t o its lac k o f dee p p oc kets f or bi n di n g of s mall m o lec ule i n hi bit ors, R A S is 
t ypicall y  dee me d as “ u n dr u g ga ble.”  Vari o us a nti-R A S t hera pe ut ic strate gies ha ve bee n pr o ve n 
lar gel y ineffect i ve ( Ferrer et al. 2 0 1 8; Ra m on et al . 2 0 1 8; O’ Br ya n 2 0 1 9).  Rece nt st u dies ha ve 
bee n f oc usi n g o n K R A S m ut atio n -s pecific t hera pies. 
L Y 3 4 9 9 4 4 6 is a p ote nt a n d orall y ( P O) a vaila ble s mall m o lec ule i n hi bit or of K R A S G 1 2 C , 
 
a n d has de m o nstrate d si g nifica nt acti vit y i n precli nical 
m o dels a gai nst a wi de ra n ge o f K R A S G 1 2 C m ut a nt t u m ors.
St u d y J 2 K -M C -J Z K A (J Z K A) c o nsists of a P hase 1 , o pe n -label, d ose -escalat i on st u d y  of 
L Y 3 4 9 9 4 4 6 as m o n ot hera p y  or i n c o m bi nati on wi t h a be macicli b, erl oti ni b, or cet u xi ma b i n 
pati e nts wit h a d va nce d s oli d t u m ors wit h K R A S G 1 2 C m ut atio n f oll owe d b y a ra n d o mize d ,
c o ntr olle d , P hase 2 st u d y  of L Y 3 4 9 9 4 4 6 a d mi nistere d as m o n ot hera p y or i n c o m bi nati on wi t h 
a be macicli b, erloti ni b , or s ta n dar d of care, d oceta xel, i n patie nts wit h N S C L C t u m ors har b ori n g 
K R A S G 1 2 C m ut atio ns ( C o h orts E 1 t hr o u g h E 4), a n d of L Y 3 4 9 9 4 4 6 a d mi nis tere d as 
m o n ot hera p y  or i n c om bi nat i on wi t h cet u xi ma b i n patie nts wit h c olorectal  ca ncer ( C R C) 
har b ori n g K R A S G 1 2 C m ut atio ns (c o h orts F 1 a n d F 2), a n d a n e x pa nsi o n of L Y 3 4 9 9 4 4 6 
a d mi nistere d as m o n ot hera p y in patie nts wit h K R A S G 1 2 C m ut a nt s oli d t u m ors ( C o h ort G), ot her 
t ha n N S C L C a n d C R C.
2. 2.
B ac k gr o u n d
T he R A S famil y of ge nes, i ncl u di n g K R A S , H R A S , a n d N R A S , are t he m ost c o m m on o nc o ge nes 
i n ca ncer ( Li n dsa y et al. 2 0 1 8), wit h a p pr o xi matel y 3 0 % of all hu ma n t u m or t y pes p ossessi n g 
m utati o ns i n R A S ( O’ Br y a n 2 0 1 9).  R A S pr otei ns f u ncti on as a G T Pase a n d ha ve a ce ntral 
c o or di nat i n g r ole c o n necti n g u pstrea m si g nals fr o m cell s urface rece pt ors t o d o w nstrea m 
sig nali n g pat h wa ys ass ociate d wit h ca ncer ( Li n ds a y et al. 2 0 1 8).  T ypicall y , R A S pr otei ns sta y in 
a G D P -b o u n d i nact i ve f or m in q uiesce nt cells.  T he d o w nstrea m si g nali n g is acti vate d w he n 
G D P is release d fr o m R A S via t he acti o n of g ua ni ne e xc ha n ge fact ors a n d s u bse q ue nt l y bi n ds t o 
g ua n osi ne tri p h os p hate ( G T P ) wit h hi g h s pecificit y a n d affi nit y.  T he e xc ha n ge of G D P f or G T P 
lea ds t o c haracteristic c ha n ges i n R A S c o nf or mati o n, res ulti n g i n recr uitme nt  of d o w nstrea m 
effect or pr otei ns, s uc h as R A F a n d PI 3 K, a n d act i vati o n of ke y si g nali n g pat h wa ys.
A m o n g all R A S ge nes, K R A S m ut atio ns acc o u nt f or a p pr o xi matel y  8 5 % of R A S -ass ociate d 
ca ncers i n h u ma ns:  a b o ut 9 0 % of pa ncreat ic ca ncers ( Zeit o u ni et al. 2 0 1 6), 3 5% t o 4 5 % of C R C 
C CI


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
33
(Tan and Du 2012; Wilson et al. 2016), and 25% NSCLC (Román et al. 2018).  KRAS mutations 
are well-characterized oncogenic drivers and have typically been associated with worsened OS 
and increased resistance to treatments than KRAS wild-type tumors (Dinu et al. 2014; Ferrer et 
al. 2018; Windon et al. 2018).  Most KRAS mutations affect exon 2 (codon 12/13) and exon 3 
(codon 61), leading to KRAS remaining in the GTP-bound active form (Román et al. 2018).  
Evidence suggests variability in biological activity across KRAS mutant cancers.  In patients with 
NSCLC, the presence of KRAS G12C mutation in resected tumors was associated with worse 
disease-free survival and OS compared to other KRAS mutations and to KRAS wild-type (Nadal 
et al. 2014).  KRAS G12C accounts for 12% of all KRAS mutations and 40% of KRAS mutations 
in NSCLC (Fernández-Medarde and Santos 2011; Prior et al. 2012).  The overall prevalence of 
KRAS G12C in NSCLC is about 10% to 16%, and 1% to 4% in colorectal and pancreatic 
cancers, respectively (Bailey et al. 2016; Campbell et al. 2016; Giannakis et al. 2016; Jordan 
et al. 2017).
RAS has been a target for therapeutic inhibition for the past 3 decades (Wilson et al. 2016).  
However, due to its lack of deep pockets for binding of small molecule inhibitors, RAS is 
typically deemed as “undruggable” (O’Bryan 2019).  Various therapeutic strategies, including 
targeting KRAS membrane association, targeting downstream effectors of KRAS pathways, and 
inhibition of synthetic lethal targets, have been investigated in both preclinical and clinical 
settings and have, with some notable exceptions, proven ineffective (Ferrer et al. 2018; Román et 
al. 2018; O’Bryan, 2019).  In the SELECT-1 Phase 3 study, adding MEK inhibitor selumetinib to 
docetaxel did not show significant improvement in progression-free survival (PFS) or OS in 
second-line advanced NSCLC patients with KRAS mutations:  median PFS was 3.9 months with 
selumetinib plus docetaxel compared to 2.8 months with docetaxel alone (hazard ratio [HR], 
0.93) with a median OS of 8.7 months and 7.9 months (HR 1) and an overall response rate 
(ORR) of 20.1% and 13.7%, respectively (Jänne et al. 2017).
Despite the efforts over the past 3 decades, there are no therapeutic agents approved by the 
United States Food and Drug Administration (FDA) targeting RAS mutations.  Current 
approaches to treating NSCLC and CRC patients with KRAS mutations include standard 
chemotherapy or immunotherapy, if applicable (Aredo and Padda 2018).  Responses are variable 
across different patient subsets, highlighting the challenges in developing effective therapy for 
patients with KRAS mutant NSCLC, and such therapy is not directed specifically at KRAS
mutations (Kim et al. 2017; Rittmeyer et al. 2017).  For CRC patients with KRAS mutations, 
chemotherapy alone or in combination with antiangiogenic therapy is standard-of-care in first-
and second-line therapy with initially good response to therapy followed universally by 
progression.  Upon progression, therapy with either regorafenib or trifluridine plus tipiracil is 
preferred and represents current standard-of-care in third-line therapy, regardless of RAS
mutation status (Grothey et al. 2013; Mayer et al. 2015).  In the CORRECT study (Grothey et al. 
2013), median OS for all previously treated CRC patients (including about 50% to 60% of 
patients with known KRAS mutations) was 6.4 months in the regorafenib group, with a response 
rate of 1% and median PFS of 1.9 months, indicating the inadequacy of current systemic therapy 
and high unmet medical need.
Nonetheless, a new wave of development of anti-KRAS therapies has been stimulated by recent 
research findings, particularly focusing on KRAS mutation-specific therapies.  These therapies
include molecules targeting the inactive form of KRAS trapped in GDP-bound form and 


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
3 4
d e m o nstrate acti vit y i n precli nical m o dels ( Ostre m et al. 2 0 1 3; Lit o et al. 2 0 1 6; Parti celli et al. 
2 0 1 6; Ja nes et al . 2 0 1 8).
T hese precli nical o bser vat i ons were f urt her s u p p orte d b y  a rece nt discl os ure o n a n o n g oi n g 
P hase 1 st u d y  ( Fa ki h et al. 2 0 1 9) e val uati n g t he safet y a n d t olera bilit y of a K R A S G 1 2 C
i n hi bit or, A M G 5 1 0.  T hirt y-fi ve patient s wit h vari o us lo c al l y a d va nce d or metastatic s oli d 
t u mors wi t h K R A S G 1 2 C m ut atio ns ( 1 4 N S C L C, 1 9 C R C, a n d 2 wit h a p pe n diceal ca ncer) were 
treate d.  The t o xicit y pr ofile was fa v ora ble wit h n o o bser ve d d ose -li miti n g t o xicity ( D L T) at t he 
d ose l e vels ( D Ls) teste d ( 1 8 0 t o 9 6 0 m g, dail y [ Q D ]) a n d preli mi nar y res ults i n dicate d a 
p ote nti al for a nti t u mor acti vit y w he n a d mi nistere d as a m o n ot hera p y  base d o n a 5 0 % ( 5/ 1 0) 
res p o nse rate see n i n N S C L C patie nts ( Fa ki h et al. 2 0 1 9).  Earl y cli nical acti vity i n C R C a p pears 
m o re li mit e d wit h a majori t y ( 1 3/ 1 8) of e val ua ble C R C patie nts s h o wi n g n o o bjecti ve res p o nse, 
al beit wit h o ut o vert disease pr o gressi o n.  T hese fi n di n gs pr o vi de a pr o of of c o nce pt t hat K R A S 
G 1 2 C ca n be tar gete d effect i vel y a n d pr o vi de e vi de nce of p ote ntial cli nical utility o f a K R A S 
G 1 2 C i n hi bit or gi ve n al o ne or i n c om bi nati o n i n t he treat me nt of ca ncers t hat carr y a K R A S
G 1 2 C m ut atio n.
A d dit i onall y , t he de velo p me nt a n d a p pr o val  of se veral tar gete d t hera pies acr oss mul tiple t u m or 
t ypes hi g hli g hte d se veral facts, es peciall y  in t he c o nte xt of tar geti n g t he R A S/ R A F/ M E K
pat h wa y :
1)
t here is p ote ntial f or i n nate a n d ac q uire d resista nce i n m ost patie nts ( Pra halla d et al. 
2 0 1 2; Va n E m b ur g h et al. 2 0 1 6)
2)
t here is varia ble act i vity acr oss differe nt t u mor t ypes base d o n hist ol o g y , w hic h has bee n 
clearl y d e mo n strate d i n t he case of B R A F V 6 0 0 E m utati o ns i n C R C, m ela n o ma a n d 
N S C L C ( S os ma n et al. 2 0 1 2; Be n dell et al. 2 0 1 4 ; Pl a nc har d et al. 2 0 1 6)
3)
c o m bi nat i on t hera pies ma y ha ve t he p ote ntial t o o verc o me i n nate resista nce a n d dela y 
e mer gi n g resistance as e vi de nce d b y data o btai ne d i n rele va nt precli nical m o dels a n d 
cli nical o utc o mes see n b y c o m bi nati o n t hera p y tar geti n g t he R A S/ R A F/ M E K pat h wa y 
( Be n dell et al. 2 0 1 4; L o n g et al. 2 0 1 4; K o petz et al. 2 0 1 5; K o petz et al. 2 0 1 7, E S M O 
2 0 1 9).
M utati o ns i n t h e R A S/R A F pat h wa y  ha ve re mai ne d a c halle n ge f or si n gle a ge nt -base d re gi me ns 
d ue t o a c o m pe nsat or y mec ha nis m lea di n g t o ra pi d e v o l uti on of ac q uire d resista nce ( Villa n ue va 
et al. 2 0 1 0; Pra halla d et al. 2 0 1 2; Wa gle et al. 2 0 1 4; A hr o nia n et al. 2 0 1 5).  T his has bee n 
d e m o nstrate d cli nicall y  wit h B R A F V 6 0 0 E m ut a nt N S C L C w here t he c o m bi nat i on of B R A F a n d 
M E K i n hi bit ors was m ore effect i ve t ha n t he si n gle a ge nt ( Pla nc har d et al. 2 0 16 ).  Si milarl y, a 
triple c o m bi nat i on of e pi der mal gr o wt h fact or rece pt or (E G F R )/ M E K/ B R A F i n hi bit ors was 
s u perior t o sta n dar d -of -care i n B R A F V 6 0 0 E m ut a nt C R C ( K o petz et al. 2 0 1 9).  W hile f urt her 
a n d m ore t h or o u g h st u dies are nee de d, i n pat ient s wit h K R A S G 1 2 C m ut a nt C R C at least, t he 
lac k of o bjecti ve res p o nse see n o n treat me nt wit h A M G 5 1 0 s u g gests t hat c o m bi nati o n t hera p y 
ma y st ill be re q uire d wit h K R A S G 1 2 C tar gete d t hera p y in t his setti n g, a n d p ossi bl y ot hers.
L Y 3 4 9 9 4 4 6 is a p ote nt a n d P O a vaila ble s mall m o lec ule i n hi bit or of K R A S G 1 2 C , 
 
 
C CI


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
35
Abemaciclib is an inhibitor of cyclin-dependent kinase (CDK)4 and CDK6 and was most active 
against cyclin D1/CDK4 in enzymatic assays.  Cyclin-dependent kinases CDK4 and CDK6 
participate in a complex with D type cyclins to initiate the transition through the G1 restriction 
point.  Cyclin-dependent kinase inhibitors p15INK4b and p16INK4a, the retinoblastoma tumor 
suppressor protein, and cyclin D family members are among the major regulatory genes of the 
G1/S transition.  Overexpression of cyclin D1, abnormal RB1 pathway functioning, and mutated 
or aberrant p16INK4a have been reported in lung cancer (Zhou et al. 2001).  In KRAS-positive
NSCLC, constitutive KRAS activity can lead to abnormally increased levels of cyclin D, further 
increasing the pool of cyclin D accumulation (Coleman et al. 2004; Musgrove et al. 2011; 
Dempsey et al. 2013).  Importantly, synthetic lethal interaction between KRAS mutation and 
CDK4 inhibition indicates a potential therapeutic application for CDK4 and CDK6 inhibitors in 
NSCLC (Puyol et al. 2010).  Inhibition of CDK4 and CDK6 kinase activity by abemaciclib 
inhibits growth of human NSCLC tumor xenograft models in vivo (Patnaik et al. 2016).
The phase 3 study JUNIPER compared abemaciclib to erlotinib in previously treated advanced 
NSCLC patients with KRAS mutations (KRAS G12C represented 30%) (Goldman et al. 2018).  
Nearly 50% of patients in this study had tested positive for the presence of a KRAS G12C
mutation. Median OS was 7.4 months with abemaciclib versus 7.8 months with erlotinib (HR 
0.97), while PFS was 3.6 months versus 1.9 months (HR 0.58; p<0.001) with an ORR of 8.9% 
compared to 2.7% (p=0.01) (Goldman et al. 2018).  Notably, the results in the G12C subgroup 
did not significantly differ from the overall or nonG12C subsets. 
While the JUNIPER study did not meet its primary endpoint, additional preclinical mechanistic 
and combination data support the rationale for combining LY3499446 with abemaciclib.  Along 
with our preclinical data demonstrating synergistic activity, Lou and colleagues demonstrated in 
CRISPER screen the possibility of synthetic lethal interaction of CDK4/6 inhibition with KRAS
G12C (Lou et al. 2019).  Additionally, the combination of the KRAS G12C inhibitor ARS-1620 
with CDK4/6i demonstrated activity in pancreatic and lung cancer xenograft models.  This data,
along with our preclinical studies, provides the foundation to re-evaluate abemaciclib in 
combination with LY3499446 in KRAS G12C mutant NSCLC.
Preclinical studies of LY3499446 in combination with abemaciclib in vitro and in vivo in KRAS
G12C mutant models demonstrated that LY3499446 is generally active in a panel of 18 KRAS
G12C mutant cell lines consisting of lung, pancreatic, colorectal, esophageal, and bladder cancer 
cells with a range of the sensitivity in in vitro cell proliferation assay.  In vitro combination of 
LY3499446 and abemaciclib shows synergistic or additive effects on inhibition of cell 
proliferation in such cell panels based on IC50 and combination index results .  The synergistic 
effect was more significant for tumor cells, such as H1792, LXFA-983L and SW1573 less 
sensitive to LY3499446 monotherapy.  In xenograft or patient-derived xenograft models of lung, 
colorectal, and pancreatic cancer, LY3499446 monotherapy demonstrated significant antitumor 
growth activity.  However, the combination of LY3499446 and abemaciclib showed more robust 
antitumor growth activity based on tumor growth inhibition and regression .
Erlotinib is an EGFR small molecule inhibitor that was approved for treatment of patients with 
locally advanced or metastatic NSCLC, and patients with locally advanced, unresectable, or 
metastatic pancreatic cancer.  LY3499446 binds to the GDP-bound and inactive form of KRAS 
protein.  Although the KRAS G12C mutation impairs the GTPase activity of KRAS, the GTPase 
cycle through transition of GDP-bound inactive form to GTP-bound active bound form is still 


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essential for full function of KRAS G12C protein (Lito et al. 2016).  Guanine nucleotide 
exchange factors (GEF), such as SOS, are important components critical for KRAS GDP to 
KRAS GTP transition.  Epidermal growth factor receptor activation was demonstrated to 
enhance GEF activity, regulate KRAS GDP/GTP equilibrium, and thus impact the KRAS 
inhibition by a KRAS G12C inhibitor in KRAS G12C mutant cells (Lito et al. 2016; Lou et al. 
2019).  Additionally, EGFR is often expressed and activated in tumor cells of epithelial origin.  
Therefore, we hypothesize that the combination of EGFR and KRAS G12C inhibition will
improve the efficacy of LY3499446 in KRAS G12C mutant cancers.  Indeed, in vitro 
combination of LY3499446 and EGFR small molecule inhibitor, such as erlotinib, showed 
synergistic or additive effects on inhibition of cell proliferation in a panel of tumor cells with 
KRAS G12C mutation based on IC50 and combination index results.  In a patient-derived 
xenograft model of lung cancer, the combination of LY3499446 with erlotinib or afatinib 
showed better activity than any monotherapy, and robust antitumor regression activity.  
Mechanistically, combining an EGFR inhibitor with LY3499446 increases KRAS G12C target 
occupancy and enhances inhibition of active KRAS GTP activity. 
Cetuximab is an anti-EGFR monoclonal antibody that is approved for the treatment of patients 
with head and neck cancer and in patients with extended RAS wild-type CRC (Price and Cohen 
2012; Goldberg et al. 2018).  Activating mutations in KRAS and BRAF is well-established to 
have implications on therapy (Larki et al. 2017).  Targeting the RAS/RAF pathway in patients 
with CRC has demonstrated significant challenges.  While BRAF V600E is well-established as a 
prognostic marker (associated with worse median OS), it is often associated with the lack of 
response to cetuximab.  Additionally, a decade of preclinical and clinical work has demonstrated 
a lack of efficacy of a single-agent BRAF inhibitor (Kopetz et al. 2015).  An emergent 
compensatory mechanism via EGFR receptor signaling can overcome BRAF inhibition 
(Prahallad et al. 2012), and improved responses are seen when cetuximab is added to 
vemurafenib and irinotecan (Kopetz et al. 2017).  More recently, the combination of encorafenib, 
binimetinib, and cetuximab has demonstrated improved ORR, PFS, and OS over 
standard-of-care (Kopetz et al. 2019). 
Limitations in clinical response observed in KRAS G12C CRC patients treated with AMG510 is 
in line with other data pointing to the complex challenge of inhibiting the MAPK pathway when 
activating mutations are present.  These challenges likely include the compensatory mechanism 
mediated by EGFR and the, to some extent related, control of the equilibrium between 
GTP/GDP-bound KRAS.  Our preclinical data suggest that combining EGFR inhibitors 
including cetuximab with LY3499446 increases KRAS G12C target occupancy and enhances 
inhibition of active KRAS GTP activity.  In a panel of KRAS G12C mutant cell lines consisting 
of lung, pancreatic, colorectal, esophageal, and bladder cancer cells, in vitro combination of 
LY3499446 and cetuximab showed synergistic or additive effects on inhibition of cell 
proliferation based on IC50 and combination index results.  In 2 xenograft models of CRC, 
LY3499446 monotherapy demonstrated significant antitumor growth activity.  However, the 
combination of LY3499446 and cetuximab showed more robust antitumor growth regression in 
both models, suggesting potential benefit of LY3499446 and cetuximab combination for CRC.  
Additionally, LY3499446 and cetuximab combination improved target occupancy and inhibition 
of active RAS activity in a CRC xenograft model.


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
3 7
2. 3.
Be nefit/ Ris k Assess me nt
L Y 3 4 9 9 4 4 6 is a p ote nt i n hi bit or of K R A S G 1 2 C a n d has de m o nstrate d si g nifica nt acti vit y i n 
precli nical m o dels a gai nst a wi de ra n ge of K R A S G 1 2 C m ut a nt t u m ors.  Usi n g L Y 3 4 9 9 4 4 6 i n 
pati e nts wit h K R A S G 1 2 C m ut atio ns is e x pecte d t o pr o vi de cli nical be nefit i n t hese patie nts, 
w hic h ge nerall y  s ho w w o rse O S a n d i ncrease d resista nce t o treat me nts c o m pare d t o K R A S
wil d -t yp e t u m ors a n d ha ve li mite d treat me nt o pti o ns.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.  Base d o n t he o bser ve d P K pr ofile 
a n d t he hi g her t ha n a nt ici pate d e x p os ure, t he re vise d pla n f or d osi n g a n d sc he d ule, c o u ple d wit h 
C CI


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additional PK sampling and closer monitoring for CBC, appears to be an acceptable risk/benefit 
strategy.
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated adverse events (AEs) of LY3499446 are to be found in the 
Investigator’s Brochure (IB).
Abemaciclib is FDA approved for the treatment of women with advanced breast cancer. 
Erlotinib has been commonly used in the treatment of patients with NSCLC. The use of 
LY3499446 with each of these combination therapies is predicted to show promising efficacy 
based on preclinical data reviewed in detail and available on file. The AE profiles of 
abemaciclib and erlotinib are well-documented and predictable.
Cetuximab is commonly used for the treatment of extended RAS wild-type CRC.  Our preclinical 
data suggest that combining cetuximab with LY3499446 increases KRAS G12C target 
occupancy with predicted improved efficacy.
Combination with Erlotinib
Erlotinib has been associated with diarrhea, interstitial lung disease, rash, and risk of 
hepatotoxicity, especially in the light of underlying liver disease.  LY3499446 in nonclinical 
studies has associated with renal and hepatic injury.  There is a risk of overlapping toxicity, 
especially in regard to hepatic injury, and therefore, close monitoring of liver function tests will 
be performed through the first cycle and later on, during the study.  If signs of increased liver 
enzymes or liver injury are observed, recommendations for monitoring and dose modifications 
for LY3499446 should be followed as outlined in Section 6.6.1.  Monitoring and dose 
modifications for erlotinib should follow those provided in the product label or institutional 
guidelines.
Combination with Cetuximab
Cetuximab has been associated with diarrhea, interstitial lung disease, rash, hypomagnesemia, 
and serious infusion reactions.  Sudden death has occurred in 2% of patients with head and neck 
cancer receiving cetuximab with radiation and in 3% of patients receiving cetuximab in 
combination with platinum-based therapy.  While the exact risks of overlapping toxicity with 
cetuximab and LY3499446 remain unknown, nonclinical toxicity studies of monotherapy 
LY3499446 refer to hyperphosphatemia, and potential for secondary hypomagnesemia as an 
overlapping toxicity.  Therefore, the phosphorus and magnesium levels will be monitored closely 
and replaced appropriately during the study.  Recommendations for monitoring and dose 
modifications for LY3499446 should be followed as outlined in Section 6.6.1.  Monitoring and 
dose modifications for cetuximab should follow those provided in the product label or 
institutional guidelines.
Combination with Abemaciclib
Abemaciclib is associated with diarrhea, fatigue, neutropenia, hepatotoxicity, and interstitial lung 
disease.  While the exact risk of overlapping toxicity with abemaciclib and LY3499446 remains 
unknown, nonclinical toxicity studies suggest hepatotoxicity and possible effects on the kidney.  
Patients will be monitored with weekly visits and comprehensive metabolic panel weekly for the 
first 4 weeks and every 3 weeks or as clinically indicated thereafter.  If signs of increased liver 
enzymes/kidney injury, or increased serum creatinine/kidney injury is observed, 


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39
recommendations for monitoring and dose modifications for LY3499446 should be followed as 
outlined in Section 6.6.1.  Monitoring and dose modifications for abemaciclib should follow 
those provided in the product label or institutional guidelines.
Given the potential therapeutic benefit anticipated for LY3499446 administered as monotherapy
and in combination with abemaciclib, erlotinib, or cetuximab, the known risk profile of these 
combination therapies, and the benefit/risk assessment of LY3499446 monotherapy, the
combination in the proposed study is considered acceptable.
More detailed information about the known and expected benefits and risks of cetuximab, 
erlotinib, and abemaciclib may be found in the following:  Patient Information Leaflet, Package 
Insert, and Summary of Product Characteristics.


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3.
Objectives and Endpoints
Objectives
Endpoints
Primary
Phase 1 Dose Escalation:
To characterize the RP2D for LY3499446 when 
administered alone or in combination with either 
abemaciclib, cetuximab, or erlotinib.

DLTs

Assessment of safety including, but not 
limited to, TEAEs, SAEs, deaths, and 
clinical lab abnormalities per CTCAE v5.0
Phase 2:
To assess the efficacy of LY3499446 alone or in 
combination with abemaciclib or erlotinib vs. docetaxel in 
patients with advanced KRAS G12C-mutant NSCLC.
To evaluate the efficacy of LY3499446 alone or in 
combination with cetuximab in patients with advanced
KRAS G12C mutant CRC.
To evaluate the efficacy of single-agent LY3499446 in 
patients with advanced KRAS G12C mutant solid tumors 
(other than NSCLC and CRC).

Per RECIST v1.1:
o
ORR (primary for CRC cohorts 
and Other tumors cohort; 
coprimary for NSCLC cohorts)
o
PFS (coprimary for NSCLC 
cohorts)
Secondary
Phase 1 Dose Escalation:
To characterize the safety and toxicity profile of 
LY3499446 administered as monotherapy and in 
combination with abemaciclib, erlotinib (NSCLC), or 
cetuximab (CRC) to patients with advanced solid tumors 
with KRAS G12C mutation.  
To assess the PK of LY3499446 administered as 
monotherapy and in combination with abemaciclib, 
erlotinib, or cetuximab in patients with advanced solid 
tumors with KRAS G12C mutation.
To assess any antitumor activity of LY3499446 
administered as monotherapy and in combination with 
abemaciclib, erlotinib, or cetuximab in patients with 
advanced solid tumors with KRAS G12C mutation.

Safety as determined by (including but not 
limited to) TEAEs, SAEs, deaths, and 
clinical laboratory abnormalities per 
CTCAE (Version 5.0)

Plasma concentration of LY3499446
administered as monotherapy and in 
combination with abemaciclib, erlotinib, or 
cetuximab

Per RECIST v1.1:  ORR, PFS, DoR, DCR


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Objectives
Endpoints
Phase 2:
To assess the efficacy of LY3499446 administered as 
monotherapy or in combination with abemaciclib or 
erlotinib in patients with NSCLC tumors harboring KRAS
G12C mutations, and of LY3499446 administered as 
monotherapy or in combination with cetuximab in patients 
with CRC tumors harboring KRAS G12C mutations, and 
LY3499446 administered as monotherapy in patients with 
solid tumors, other than NSCLC and CRC, harboring 
KRAS G12C mutation.
To characterize the safety and toxicity profile of 
LY3499446 administered as monotherapy and in 
combination with abemaciclib, erlotinib, or cetuximab to 
patients with advanced solid tumors with KRAS G12C
mutation.
To assess the PK of LY3499446 administered as 
monotherapy and in combination with abemaciclib, 
erlotinib, or cetuximab in patients with advanced solid 
tumors with KRAS G12C mutation.

Per RECIST v1.1:
o
DoR, DCR, TTR, OS (all cohorts)
o
PFS (CRC cohorts and Other 
tumors)

Safety as determined by (including but not 
limited to) TEAEs, SAEs, deaths, and 
clinical laboratory abnormalities per 
CTCAE (Version 5.0)

Plasma concentration of LY3499446
administered as monotherapy and in 
combination with abemaciclib, erlotinib, or 
cetuximab
Tertiary/Exploratory
To explore the association between biomarkers and 
clinical outcomes.

Results of biomarker assessments and 
clinical outcomes
Abbreviations:  CRC = colorectal cancer; CTCAE = Common Terminology Criteria for Adverse Events; 
DCR = disease control rate; DLT = dose-limiting toxicity; DoR = duration of response; NSCLC = nonsmall cell 
lung cancer; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; 
PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid Tumors; RP2D = recommended phase 
2 dose; SAE = serious adverse event; TEAE = treatment-emergent adverse event; TTR = time to response.


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4.
Study Design
4.1.
Overall Design
Study JZKA is a first in human, multicenter, open-label dose escalation Phase 1 study, followed 
by cohort- and disease-specific randomized Phase 2. 
The Phase 1 portion will enroll patients with KRAS G12C mutant solid tumors, where patients 
will be treated with monotherapy LY3499446 or LY3499446 in combination with abemaciclib, 
erlotinib, or cetuximab. 
Once a recommended phase 2 dose (RP2D) for monotherapy and dosing in combination has been 
established, patients with KRAS G12C mutant NSCLC will be randomized across 4 cohorts, 
including docetaxel as an active comparator arm, to evaluate the efficacy and safety of 
LY3499446 alone and in combination.  Depending on the relative benefit/risk assessment of 
different treatment regimens and the level of clinical efficacy seen, efforts will be pursued with 
intent to support a marketing authorization application of the optimal regimen with docetaxel as 
the comparator.  Such efforts may include, as appropriate and upon prior consultation with the 
competent regulatory authorities, expanding enrollment to support a marketing authorization 
application with data obtained from Study JZKA.
For patients with KRAS G12C mutant CRC, patients will be randomized to either LY3499446 
alone or in combination with cetuximab during the Phase 2 part.  The purpose of this part of the 
study is activity estimation and continued assessment of safety. 
For patients with KRAS G12C mutant solid tumors (other than NSCLC or CRC), an expansion 
cohort of LY3499446 given alone is intended to assess the potential for efficacy and to further 
evaluate safety.  The primary purpose of this portion of the study is signal-finding in indications 
other than NSCLC and CRC.
Section 1.2 illustrates the study schema.
4.1.1.
Phase 1
Phase 1 (dose escalation) will assess the safety and tolerability of LY3499446 to identify a 
monotherapy RP2D and the RP2D for each combination (abemaciclib, cetuximab, and erlotinib) 
in patients with advanced solid tumors with a KRAS G12C mutation. 
Patients enrolled in Phase 1 will receive one of the following treatments:

LY3499446 monotherapy (Cohorts A0, A1, A2, and A-1)

LY3499446 in combination with abemaciclib (Cohorts B0, B1, B2, B3, and B-1)

LY3499446 in combination with cetuximab (Cohorts C0, C1, C2, C3, and C-1)

LY3499446 in combination with erlotinib (Cohorts D0, D1, D2, D3, and D-1)
The RP2DM will be determined based on the aggregate analysis of the number of observed DLTs, 
PK, safety, and clinical response data and may fall below the maximum tolerated dose [MTD].
Treatment cycles will consist of 21 days.  A 21-day DLT observation period will apply to all 
cohorts in Phase 1.  Refer to Section 4.1.1.1 for additional details on the dose escalation method.


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In the Combination Dose Escalation cohorts (Parts B, C, and D), multiple DLs of LY3499446 
will initially be explored for each combination based on the final range of dose levels evaluated 
and deemed safe in the monotherapy dose escalation.  Initially, previously registered doses of 
abemaciclib, erlotinib, and cetuximab will be utilized. However, lower doses may be explored as 
warranted based on emerging safety data.  Refer to Section 4.1.1.1 for details on the dose 
escalation method.
Eli Lilly and Company (Lilly) and the investigators will hold a meeting to review safety and 
available PK results after completion of the DLT period for each cohort to ensure it is safe to 
proceed with the next cohort, and determine the next dose level, and schedule. Adverse events 
from non-evaluable patients will also be reviewed throughout the dose escalation process in 
Phase 1.
In the dose escalation of LY3499446 monotherapy and the combination regimens, once a given 
DL is cleared for initial DLT evaluation, and if the PK supports therapeutic index, more patients 
could be enrolled (i.e., backfilled) to that DL while a higher DL is being evaluated for DLT.  
Approximately10 backfill patients may be enrolled for each cohort in Part A.  Likewise, up to 10 
backfill patients may be enrolled to each combination regimen. Those backfilled patients who 
meet the definition of DLT-evaluable population (see Section 4.1.1.1) will be included in making 
decisions on dose escalation.  Dose-limiting toxicity evaluation at a higher DL could be halted, 
and additional patients could be enrolled to a DL that has cleared for initial DLT evaluation (i.e., 
stay) or to a lower DL (i.e., de-escalation), depending on the total number of DLTs observed 
among all DLT-evaluable patients at that DL (initial and backfilled patients).  These aggregate 
safety data will be taken into account in defining the RP2D.
4.1.1.1.
Dose Escalation Method
Dose escalation for monotherapy will utilize the modified toxicity probability interval-2 
(mTPI-2) methodology (Guo et al. 2017) where a precalculated 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).  At the lowest DL1 of 
monotherapy and combinations, at least 2 patients will be tested in a cohort, while at subsequent 
higher DLs, a minimum of 3 patients will be enrolled in a DL cohort to estimate the DLT 
incidence rate.  A given cohort will continue to enroll and follow patients until the observed DLT 
rate is either above or below the specified target incidence range.  If the dose is de-escalated to -1 
DL, the mTPI-2 rule will be followed, except no further de-escalation is allowed, and the study 
will be discontinued if necessary.
The monotherapy RP2D will be determined based on aggregate analysis of the number of 
observed DLTs, PK, safety, tolerability, and clinical response data.
Combination therapies will also be evaluated using the mTPI-2 methodology.  The combination 
cohorts (Part B/C/D) will not open until the monotherapy RP2DM is established in Part A or until 
a monotherapy DL deemed safe by the safety review committee and associated with exposures 
predicted to be efficacious is achieved.  Cohorts B0, C0, and D0 will utilize a LY3499446 dose 
at least 1 DL below the previously established safe monotherapy DL.  If a sufficient number of 
patients experience DLTs at the first DL for a combination to warrant de-escalation, enrollment 
to the dose from the next lower monotherapy DL will be opened.  If the DLT rate at the lowest 


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
4 4
all o we d le vel s u g gests f urt her de- escalat i on, t he n f urt her e nr oll me nt t o t hat c o m bi nat i on will be 
close d. 
Li k e t he 3 + 3 desi g n, t he m T PI - 2 met h o d i nc or p orates pres pecifie d escalat i on r ul es.  H o we ver , 
t he mT PI - 2 met h o d is base d o n q ua nt itati ve m o dels t hat i nc or p orate u ncertai nt y i nt o t he decisi o n 
r ules, t here b y all o wi n g m ore precise R P 2 D selecti o n.  If 3 or 6 patie nts are e nr olle d i n a c o h ort, 
t he escalati o n r ule parallels a tra dit i onal 3 + 3 desi g n. H o we ver, it a ll ows f or a fle xi ble n u m ber of 
pati e nts i n a c o h ort. F or e xa m ple , wit h 2 D L Ts per 6 patie nts e nr olle d, t he m T PI - 2 w o ul d 
rec o m me n d sta yi n g at t he c urre nt d ose, as a nal o g y t o 1 D L T per 3 patie nts e nr olle d i n 3 + 3 
desi g n; t heref ore, it all o ws f or m ore patie nt s f or a m ore precise esti mate of t he D L T rate at t his 
D L.
F o ll owi n g a di sc ussi on bet wee n t he Lill y cli nical researc h p h ysicia n/cli nical researc h scie nt ist 
( C R P/ C R S) a n d t he i n vest i gat ors, a m ore c o nser vati ve d ose sel e ctio n/ de -escalat i on m a y be 
a p plie d t o t he ne xt c o h ort (f or i nsta nce, if P K or ot her data s u g gest t hat f urt her d ose i ncrease 
w o ul d n ot be e x pecte d t o yiel d a d dit i on al  be nefit).  F or 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 c o h ort , e xce pt f or t he c o h ort at 
t he lo west D L i n t he P hase 1 part of t his st u d y, will c o ntai n a mi ni m u m of 3 e val ua ble pati e nts, 
u nless t he e scalati 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 decisi o n was “ D U,” t he d ose ca n n ot be 
r e-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 th a d ose -li miti n g tar get 
t o xicit y r at e 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 ar o u n d t he tar get 
t o xicit y r at e.  F o r t his st u d y, t he e q ui vale nce i nter val is elicite d t o be ( 2 7 %, 3 3 %), i n dicat i n g t hat 
a n y val ues bet wee n ( 2 7 %, 3 3 %) ca n be c o nsi dere d as acce pte d t o xicit y rates for M T D.  T he fi nal 
M T D will be t he d ose f or w hic h t he est i mate d t o xicity rate is t he closest t o t he tar get t o xicit y rate 
of  3 0 % a n d less t ha n 3 3 %.  T he res ulti n g mT PI -2 decisi o n r ul es f or a n y c o h ort size u p t o 2 5 a nd 
a h y p ot hetical e xa m ple f or D L T deter mi nati on after all pat ient s c o mplete D L T e val uat i ons are 
pr o vi de d i n A p pe n di x 8.
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 t he d ose escalat i on decisi o n, P K res ults (f or e xa m ple, Cma x, area u n der 
t he c ur ve [ A U C ], a n d p har mac o d y na mics res ults) will be use d as sec o n dar y/s u p p or ti n g data f or 
d ose escalat i on.
I nter mitte nt d ose le vels or alter nati ve sc he d ules ma y be e x pl ore d.  Si milarl y, l o wer d oses or 
alter nati ve sc he d ules of a be macicli b a n d erl oti ni b ma y be e x pl ore d bel o w t he c urre ntl y a p pr o ve d 
d oses base d o n e mer gi n g safet y data.   T he t otalit y of  data i ncl u di n g safety,  P K e x p os ure, a n d t he 
i nci de nce of D L T ma y hel p g ui de e val uati n g alter nati ve d osi n g a n d sc he d ule (e.g.  
 
vers us
 
)
4. 1. 1. 2.
D ose -Li miti n g T o xicit y Deter mi n ati o n
A D L T is defi ne d as a n y o f t he e ve nts acc or di n g t o t he Nati o nal Ca ncer I nst itut e ( N CI) C o m m o n 
Ter mi n o l og y Cri t eria for A d verse E ve nts ( C T C A E) Versi o n 5. 0 bel o w if b ot h t he f o ll owi n g 
criteria are met:
1.
T he e ve nt occ urs d uri n g t he D L T o bser vati o n peri o d of C ycle 1, bet wee n Da ys 1 a n d 2 1, 
a n d,
C CI
C CI
C C
I
C CI


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2.
The event is clinically significant and not clearly related to disease progression or 
intercurrent illness

Grade 3 nonhematological toxicity according to the NCI CTCAE version 5.0, with the 
exceptions listed below:
o
nausea lasting <72 hours
o
vomiting lasting <72 hours
o
diarrhea lasting <72 hours
o
constipation lasting <72 hours
o
electrolyte disturbance lasting <72 hours
o
rash not attributed to LY3499446

Any Grade 4 nonhematologic toxicity, regardless of duration

Any Grade 3 nausea, vomiting, diarrhea, or constipation lasting >72 hours despite 
adequate supportive care

Any Grade 3 electrolyte disturbances lasting >72 hours despite conventional medical 
interventions.  Grade 3 electrolyte disturbances that require hospitalization should be 
considered a DLT.

Grade 4 hematological toxicity that persists more than 5 days

Grade 3 thrombocytopenia associated with clinically significant bleeding and/or requiring 
platelet transfusion, or Grade 4 thrombocytopenia of any duration

Grade ≥3 febrile neutropenia and/or neutropenia requiring granulocyte 
colony-stimulating factor (G-CSF)

Grade ≥3 anemia requiring a blood transfusion

Total bilirubin > 5× ULN, except for cases clearly related to biliary obstruction

Confirmed Grade 2 or higher ILD during DLT assessment period

Any death not clearly due to the underlying disease or extraneous causes and for any 
toxicity requiring permanent discontinuation of study drug(s).

Any toxicities which require dose omissions of more than 20% of intended dose and 
which are deemed by the primary investigator and Lilly CRP/CRS to be dose limiting.

Grade ≥2 hemolysis of any duration
Patients with normal or near normal alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) at baseline (<1.5× upper limit of normal [ULN]):

ALT or AST ≥8× ULN

ALT or AST ≥3× ULN and total bilirubin (TBL) ≥2× ULN in the absence of significant 
cholestasis (i.e., alkaline phosphatase [ALP] >2× ULN). 
Patients with elevated ALT or AST at baseline (≥1.5× ULN):

ALT or AST ≥5× baselinea. 

ALT or AST ≥3× baselinea and TBL ≥2× ULN in the absence of significant cholestasis 
(i.e., ALP >2× ULN). 


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
4 6
a
M ulti ples of baseli ne pertai n t o t h e  a mi n otra nsferase ( A L T or A S T) w hic h is ele vate d at baseli ne, res pecti vel y.
It s h o ul d be rec o g nize d t hat f or patie nts w h o ha ve recei ve d pri or i m m u ne t hera p y, i ncl u di n g
c hec k p oi nt i n hi bit or s, t here is t he p ote ntial for d el a ye d ma nifestat i on of seri o us i m m u ne-relate d 
a d verse e ve nts (irA Es ) s uc h as c olitis, he patitis, p ne u m o nitis, a n d e n d ocri n o pat hies.  Patie nts 
ma nifest i n g p ote ntial dela ye d i r AEs s h o ul d recei ve pr o m pt e val uat i on a n d treat me nt .
I n vesti gat ors, t o get her wit h t he Lill y C R P/ C R S, ca n declare a D L T if a patie nt is e x perie nci n g
i ncreasi n g t o xicity d uri n g treat m e nt a n d it bec o mes clear t hat it is n ot g oin g t o be p ossi ble t o
c o mplete t he treat m e nt wit ho ut e x p osi n g t he patie nt t o e xcessi ve ris k.
A D L T -e q ui vale nt is defi ne d as a n A E t hat w o ul d ha ve met t he crit eria for D L T if it ha d 
occ urre d d uri n g C ycle 1 f or a patie nt e nr olle d i n t he d ose escalat i on p hase, b ut t hat occ urs a n y  
ti me after C ycle 1.  D ose-li miti n g t o xicity- e q ui vale nt t o xicit ies ma y be co nsi dere d i n 
deter mi ni n g t he R P 2 D. 
4. 1. 2.
P h ase 2
I n t he P hase 2 p orti o n, ra n d o mizati on will be i m ple me nte d t o deter mi ne t he treat me nt f or 
pati e nts wit h N S C L C a n d C R C wit h K R A S G 1 2 C m utati o n.
F or N S C L C c o h orts, u p t o 1 6 0 patie nts i n t otal will  be e nr olle d a n d ran d o mize d at a 1: 1: 1: 1 ratio 
t o mo n ot hera p y  ( C o h ort E 1), i n c o m bi nati on wi t h a be macicli b ( C o h ort E 2), i n c om bi nati o n wit h 
erloti ni b ( C o h ort E 3), or d oceta xel al o ne (act i ve c o ntr ol; C o h ort E 4).  A n i nteri m data re vie w 
will be perf or me d base d o n efficac y, saf et y,  a n d P K data. E nr oll me nt will c o nt i n ue w hile t his 
a nal ysis is bei n g c o n d ucte d.  A fi nal data re vie w will be perf or me d base d o n safet y,  efficac y, a n d 
P K data.
F or C R C c o h orts, a p pr o xi matel y 4 0 patie nts will be e nr olle d i nit iall y a n d will be ra n d omize d at a 
1: 1 rati o t o m o n ot hera p y  ( C o h ort F 1) or i n c om bi nati o n wit h cet u xi ma b ( C o h ort F 2).  A n ot her 
4 0 pati e nts ma y be e nr olle d t o o ne of t he treat me nt ar ms ( F 1 or F 2) base d o n t he i nteri m a nal ysis 
res ults of t he first 4 0 ra n d o mize d patient s.  Cet u xi ma b a d mi nistratio n will  be gi n o n C ycle 1 
D a y 8 af t er a 1-wee k lea d -i n with L Y 3 4 9 9 4 4 6.  A n i nteri m data re vie w will be perf or me d base d 
o n safet y,  efficac y, a n d P K data.
A p pr o xi matel y  4 0 p atie nts wit h ot her t u mor t y pes ass oci ate d wit h K R A S G 1 2 C m ut atio n ( ot her 
t ha n N S C L C a n d C R C) will be e nr o lle d t o recei ve L Y 3 4 9 9 4 4 6 m o n ot hera p y ( C o h ort G).  A n 
i nteri m a nal ysis f or safet y a n d preli mi nar y efficac y will be perf or me d after t he first 2 0 patie nts 
are e nr olle d i nt o t he c o h ort.
4. 2.
Scie ntific R ati o n ale f or St u d y Desi g n
T he o verall rati o nale f or t he st u d y  desi g n is descri be d i n t he I ntr o d ucti o n secti on u n der St u d y
Rati o nale ( Sect i on 2. 1 ) a n d i n t he Statistical C o nsi derati o ns ( Sectio n 9).  D ose sel ect i on a n d 
j ustificati on details ca n be f o u n d i n t he J ustificatio n f or D ose, Secti o n 4. 3.
4. 3.
J u stific ati o n f or D ose
D ue t o t he safet y si g nals o bser ve d i n st u d y J Z K A i n t he 
, a m o difie d 
starti n g d ose of 
 is pr o p ose d as t he ne xt starti n g D L . T he 
P P D
C CI
C CI


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
4 7
pri mar y  g o al of the m o difie d starti n g d ose is t o mi ni mize t he ris k of seei n g A Es o bser ve d s o far 
i n t he first 2 pati e nts. 
T he ori gi nal  starti n g d ose of 
 ac hie ve d e x p os ures 2- t o 6- f ol d hi g her t ha n t he 
a vera ge pre dicte d e x p os ure i n t he 
 treate d wit h L Y 3 4 9 9 4 4 6. P har mac o ki net ic 
data c ollecte d f or b ot h patie nts wit hi n t he first 2 4 h o urs of c y cle 1 are s h o w n i n t he fol l owi n g 
ta ble.   Please n ote, t he a nal ysis o f t he P K data fr o m t he  
 s o far i n st u d y J Z K A is 
base d o n preli mi nar y data wit h n o mi nal t i mes o nl y. Act ual  ti me a n d date of P K sa m ples a n d 
d osi n g t i me a n d dates were n ot a vaila ble at t he ti me of a nal ysis. T here c o ul d be p ote nti al 
di scre pa ncies bet wee n t he preli mi nar y data a n d fi nal data. Alt h o u g h hi g h le vel c o ncl usi o ns fr o m  
t he data are n ot e x pecte d t o c ha n ge, i nter pretati o n of t he a nal ysis res ults s h o ul d be d o ne wit h 
ca utio n.
O bser ve d P h ar m ac o ki netic P ar a meters 
 wit h C o m p aris o n t o 
M o del Pre dicte d V al ues f or T he A ver a ge P atie nt B ase d o n N o ncli nic al D at a.
P art A C o h ort A 1 L Y 3 4 9 9 4 4 6 
Pre dicte d P K
P ar a meter
A b bre viati o ns:  A U C [ 0 -1 2] = area u n der t he c o nce ntrati o n vs. ti me c ur ve fr o m ti me 0 t o 1 2 h o urs, C ma x = o bser ve d ma xi m u m 
ser u m c o nce ntrati o n.
N ote: A nal ysis of t he P K data 
is base d o n preli mi nar y data wit h n o mi nal ti mes o nl y.
Decreasi n g t he d ose t o  
 is reas o na bl y e x pecte d t o res ult i n l o wer plas ma c o nce ntrati o n. 
L o wer d osi n g fre q ue nc y  will decrease t he c u m ulati ve d ose i n a 4 8-hr peri o d b y 8- f ol d a n d res ult 
i n l ower A U C o ver t he d osi n g i nter val.
S h o ul d t he 
 be well t olerate d wit ho ut 
 or ot her d ose-li miti n g 
t o xicities, mor e f re q ue nt d osi n g re gi me ns will be e x pl ore d. I n t he e ve nt t he 
 d osi n g 
als o lea ds t o 
 or ot her d ose-li miti n g t o xicities, lo wer d oses a n d / or ot her d osi n g 
fre q ue ncies will be e x pl ore d t o e ns ure patie nt safet y a n d s ufficie nt tar get e n ga ge me nt f or cli nical 
be nefit.
I n c o nju nct i on t o t he m o difie d starti n g d ose a n d d osi n g i nter val, mor e f re q ue nt P K sa m pli n g a n d 
safety m o nit ori n g will als o be i m ple me nte d t o e ns ure a n y  p ote ntial a d verse e ve nts are ca pt ure d 
earlier a n d treat me nt a djust e d acc or di n gl y. T he c ollect i on of a d dit i on al  P K a n d safet y data will 
aid i n u n dersta n di n g t he 
 t o better i nf or m f ut ure d ose decisi o ns i n t he 
st u d y.
4. 4.
E n d of St u d y Defi niti o n
T he e n d o f t he st u d y is defi ne d as t he date of t he last visit of t h e last partici pa nt i n t he st u d y or 
last sc he d ule d pr oce d ure s h o w n i n t he S o A ( Secti o n 1. 3 ) for t he last partici pa nt i n t he trial 
gl o ball y .
P P D
P P D
P P D
P P D
P P
D
P P D
P P
D
P P D
P P D
P P D
P P D
P P D
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
P P D


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
48
5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be ≥18 years of age at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Participants who have histological or cytological evidence of a diagnosis of a locally 
advanced and/or metastatic solid tumor with an identified KRAS G12C mutation.  For 
patients to be eligible for enrollment in Phase 2 Part E (NSCLC) or Part F (CRC), KRAS 
G12C mutation status must be determined by one of the following methods:

FoundationOne CDx

ThermoFisher Oncomine Dx

MSK -IMPACT
a.
Part A, B, C, and D Dose Escalation Phase:  

Patients must be, in the judgement of the investigator, an appropriate candidate 
for experimental therapy and must have progressed through or be intolerant to all 
therapies known to confer clinical benefit, or have refused such a therapy

Patients are eligible if they have measurable or evaluable disease per Response 
Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
b. Phase 2 Part E (NSCLC): 

Patients must have histological or cytologically proven recurrent/metastatic, 
unresectable NSCLC with KRAS G12C mutation

Patients must be negative for targetable oncogenic driver mutation or alteration, 
such as EGFR, ALK, BRAF, or ROS.

Patients are eligible if they have measurable disease per RECIST v1.1

The patient must be, in the judgment of the investigator, an appropriate candidate 
for experimental therapy after progressing on at least first-line immunotherapy 
and platinum-based treatment, intolerant to available standard therapies, or 
refused such a therapy
c.
Phase 2 Part F (CRC): 

Patients must have histological or cytologically proven recurrent/metastatic, 
unresectable CRC with KRAS G12C mutation

Patients must be, in the judgement of the investigator, an appropriate candidate 
for experimental therapy and must have received at least 2 prior regimens of 
therapy for advanced or metastatic CRC including fluoropyrimidine-, 
oxaliplatin-, and irinotecan-based regimens

Patients are eligible if they have measurable disease per RECIST v1.1
d. Phase 2 Part G (other tumors): 


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
49

Patients must have histological or cytologically proven recurrent/metastatic, 
unresectable solid tumors other than NSCLC and CRC, and with KRAS G12C
mutation

The patient must be, in the judgment of the investigator, an appropriate candidate 
for experimental therapy after progressing or being intolerant to all available 
standard therapies, or have refused such therapy.

Patients are eligible if they have evaluable or measurable disease per RECIST 
v1.1
3. Phase 2 NSCLC and CRC patients (Cohorts E1, E2, E3, E4, F1, and F2) must be able and 
willing to undergo 2 biopsies as specified below.  On-treatment biopsies are required if 
medically feasible.  Cohort F2 and Cohort G patients are required to submit archival 
tissue.  Sites should confirm availability of archival tissue with pathological laboratory 
prior to randomization.
a.
Patients to be enrolled into Phase 1 are not required to provide tissue (archival or 
new biopsy)
b. Patients to be enrolled into Phase 2 Cohort G will be required to submit an 
archival tissue sample to enroll (block or freshly cut slides).  If there is 
insufficient tissue for enrollment, a new biopsy will be required
c.
Patients to be enrolled into Phase 2 Cohorts E1, E2, E3, E4, and F1 must be able 
and willing to undergo pretreatment and on-treatment biopsies
d. Patients to be enrolled into Phase 2 Cohort F2 will be required to submit an 
archival tissue sample to enroll (block or freshly cut slides).  In addition, patients 
must be willing to undergo 2 on-treatment biopsies
4. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group scale 
(Oken et al. 1982).
5. Have adequate organ function prior to enrollment (Phase 1) or randomization (Phase 2), 
as defined in the table below:
System
Laboratory Value
Hematologic
ANC
1.5×109/L
Platelets
100×109/L
Hemoglobin
8 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 prior to enrollment (Phase 1) or randomization (Phase 2).  If a patient receives 
transfusions, erythropoietin, or G-CSF therapy ≥14 days prior to enrollment (Phase 1) or 
randomization (Phase 2), the hematologic criteria listed above must be met following the 
14-day window and prior to enrollment (Phase 1) or randomization (Phase 2).
Hepatic
TBL
1.5× ULN, patients with 
Gilbert’s syndrome with a TBL
≤3.0 times ULN and direct 
bilirubin within normal limits are 
permitted.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
50
System
Laboratory Value

ALT and AST
2.5× ULN OR
5× ULN if the liver has tumor 
involvement.
Renal
Serum creatinine OR
<1.5× ULN OR
Measured creatinine clearance OR
50 mL/min/1.73 m2
Calculated creatinine clearance (See Appendix 7)
Coagulation
International normalized ratio OR 
≤1.5× ULN unless participant is 
receiving anticoagulant therapy as 
long as prothrombin time or 
activated partial thromboplastin 
time is within therapeutic range of 
intended use of anticoagulants.
Prothrombin time OR
Activated partial thromboplastin time
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; G-CSF = granulocyte colony-stimulating factor; TBL = total bilirubin; ULN = upper limit of 
normal.
6. Have discontinued all previous treatments for cancer with resolution of any AEs, with the 
exception of alopecia, and of all clinically significant toxic effects of prior locoregional 
therapy, surgery, radiotherapy, or systemic anticancer therapy to Grade ≤1.  Participants 
must have discontinued from previous treatments, as shown in the table below:
Previous Treatment
Length of Time Prior to Enrollment (Phase 1) or 
Randomization (Phase 2)
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
28 days
Investigational agents
28 days.  If the agent has a long half-life (e.g., >2 weeks), then 
3 months or 5 half-lives (whichever is longer) should have passed
Radiotherapy
Limited-field radiotherapy with 
palliative intent
14 days
Other radiotherapy
28 days
Major surgery, excluding biopsy
28 days
7. Must be able to swallow capsules.
8. Agree and adhere to contraceptive use by men or women that is consistent with local 
regulations regarding the methods of contraception for those participating in clinical 
studies.  See Appendix 3 for guidance on contraceptive use and collection of pregnancy 
information.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
51
9. Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test documented within 7 days prior to enrollment (Phase 1) or randomization 
(Phase 2) (see Appendix 3).
10. Have an estimated life expectancy of ≥12 weeks.
11. Patients are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
Informed Consent
12. Capable of giving signed 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
5.2.
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
13. Disease suitable for local therapy administered with curative intent.
14. Have an active fungal, bacterial, and/or active untreated viral infection, including HIV or 
viral (A, B, or C) hepatitis (screening is not required).
15. The patient has a serious pre-existing medical condition(s) that, in the judgment of the 
investigator, would preclude participation in this study, including interstitial lung disease 
(ILD), severe dyspnea at rest, or requiring oxygen therapy.
16. Have a serious cardiac condition, such as:
a.
congestive heart failure
b. New York Heart Association Class III/IV heart disease
c.
unstable angina pectoris
d. myocardial infarction or cardiovascular event within the last 3 months before 
enrollment (Phase 1) or randomization (Phase 2)
e.
valvulopathy that is severe, moderate, or deemed clinically significant
f.
arrhythmias that are symptomatic or require treatment (not including patients with 
rate-controlled supraventricular tachycardia)
g. have a mean QT interval corrected for heart rate of ≥470 msec on screening 
electrocardiogram (ECG) as calculated using Fridericia’s formula (QTcF) at 
several consecutive days of assessment
h. a history of additional risk factors for Torsades de Pointes (e.g., heart failure, 
hypokalemia, family history of Long QT syndrome).
i.
require the use of concomitant medications that prolong the QT/QTc interval
17. Have a second active primary malignancy prior to enrollment (Phase 1), or diagnosed 
and/or treated for an additional malignancy within 3 years prior to randomization 
(Phase 2) with the exception of curatively-treated basal cell carcinoma of the skin, 
nonmetastatic prostate cancer treated with observation only, squamous cell carcinoma of 
the skin, and/or curatively resected in situ cervical and/or breast cancers.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
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52
18. Have known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously-treated brain metastases may participate 
provided they are radiologically stable, i.e., without evidence of progression for at least 
4 weeks by repeat imaging (note that the repeat imaging should be performed during 
study screening), clinically stable, and without requirement of steroid treatment for at 
least 14 days prior to enrollment (Phase 1) or randomization (Phase 2). 
19. Have prior history of hemolytic anemia
Prior/Concomitant Therapy
20. NSCLC patient otherwise eligible for enrollment in Phase 2 Cohorts E1-E4 that have 
received any prior LY3499446, docetaxel, EGFR inhibitors, or CDK4/6 inhibitors for 
systemic treatment in the Phase 2 randomized portion of the study.  However, such 
therapy is allowed for the combination dose escalation in Phase 1 Cohorts B, C, and D.
21. Have received prior treatment with any KRAS G12C small molecule inhibitor.
Prior/Concurrent Clinical Study Experience
22. Are currently enrolled in any other clinical study involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.
23. Have participated, within the last 30 days; (3 months for studies conducted in the United 
Kingdom [UK]), in a clinical study involving an investigational product. If the previous 
investigational product has a long half-life, 5 half-lives or 30 days (3 months for studies 
conducted in the UK), whichever is longer, should have passed.  Exceptions will be 
considered on a case-by -case basis by the Lilly CRP/CRS.
Other Exclusions
24. Pregnant, breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the screening visit through 180 days after the last dose 
of study medication. 
25. Known allergic reaction against any of the components of the study treatments.
Additional Exclusion for Phase 2 Part E:
27. Patients enrolling into Phase 2 Part E (NSCLC cohorts) will be excluded if:
a.
bilirubin > ULN, or
b. AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × 
ULN
5.3.
Lifestyle Considerations
25. Patients should refrain from consuming grapefruit, grapefruit juice, and 
grapefruit-containing products while on study due to the effect on cytochrome P450 
(CYP)3A4.
26. Patients will not be permitted to use herbal supplements in any form while on study due 
to the unknown (UN) risk of potential drug-drug interaction.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
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53
5.4.
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical study 
but are not subsequently enrolled.  A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities.  
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Individuals may be rescreened up to 2 times if the reason for screen failure is 
anticipated to have been resolved.  The interval between rescreening should be ≥2 weeks.  Each 
time rescreening is performed, the individual and/or the individual’s legally acceptable 
representative, parent(s), or legal guardian (when applicable) must sign a new form (ICF) and 
will be assigned a new identification number.  Repeating of laboratory tests during the screening 
period or repeating screening tests to comply with the protocol-designated screening period does 
not constitute rescreening.


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
5 4
6.
St u d y I nter ve n ti o n
St u d y  int er ve nt i on is defi ne d as a n y i n vesti gati onal i nter ve nt i on(s) or mar kete d pr o d uct(s) 
i nte n de d t o be a d mi nistere d t o a st u d y partici pa nt acc or di n g t o t he st u d y pr ot oc ol.
6. 1.
St u d y I nter ve nti o n(s) A d mi nistere d
T he ta ble bel o w s h o ws t he treat me nt re gime ns f or P hases 1 a n d 2 .  D oses will be a d mi nistere d at 
a p pr o xi matel y t he sa me ti mes o n eac h da y. Treat me nt will be a d mi nistere d i n 2 1- d a y  c ycles f or 
all 3 st u d y dr u gs.
P h ase 1
St u d y Dr u g(s)
( R o ute of 
A d mi nistr ati o n)
C o h ort
Pr o p ose d
D oses
D ose Sc he d ule
M o n ot her a p y/
P art A
L Y 3 4 9 9 4 4 6 ( P O)
A 0 a
Q O D
A 1 b
Q D
A 2
BI D
A- 1 c
Q D
C o m bi n ati o n/
P art B/ C/ D
L Y 3 4 9 9 4 4 6 ( P O)
B 0/ C 0/ D 0
T B D
T B D
B 1/ C 1/ D 1
T B D
T B D
B 2/ C 2/ D 2
T B D
T B D
B 3/ C 3/ D 3
T B D
T B D
B- 1/ C -1/ D - 1
T B D
T B D
A be macicli b ( P O)
B 0/ B 1/ B 2/ B 3
1 5 0 m g
BI D
B- 1
1 0 0 m g
BI D
Cet u xi ma b (I V)
C 0/ C 1/ C 2/ C 3
4 0 0 m g/ m 2 C 1 D 1;
2 5 0 m g/ m 2
Q W
C- 1
4 0 0 m g/ m 2 C 1 D 1;
2 5 0 m g/ m 2
Q W
Erl oti ni b ( P O)
D 0/ D 1/ D 2/ D 3
1 5 0 m g
Q D
D- 1
1 0 0 m g
Q D
C CI
C CI
C CI
C CI


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
5 5
A b bre viati o ns:  BI D = t wice dail y; I V = i ntra ve n o usl y; P O = orall y ; Q D = o nce dail y; Q O D = o nce e very ot her da y;
T B D = t o be deter mi ne d.
a
I n t he e ve nt t he 
 d osi n g als o lea ds t o 
 or ot her d ose-li miti n g t o xicities, l o wer 
d oses a n d ot her d osi n g fre q ue ncies ma y be e x pl ore d t o e ns ure pati e nt safet y a n d s ufficie nt tar get e n ga ge me nt f or 
cli nical be nefit.  T hese ma y i ncl u de, f or e xa m ple, d ose le vel A-1 of 
 or 
b
I n t he e ve nt t he  
 d osi n g s h o ul d lea d t o 
 or ot her d ose-li miti n g t o xicities, a d ose of 
 ma y be e x pl ore d t o e ns ure patie nt safet y a n d s ufficie nt tar get e n ga ge me nt f or cli nical be nefit.  As 
warra nte d b y data, a n i nter me diate d ose of  
 ma y be e x pl ore d.
c
I n t he e ve nt t he  
 d ose s h o ul d lea d t o 
 or ot her d ose-li miti n g t o xicities, a d ose of 
 
 ma y be e x pl ore d t o e ns ure patie nt safet y a n d s ufficie nt tar get e n ga ge me nt f or cli nical be nefit.
P h ase 2
St u d y Dr u g(s)
( Ro ute of 
A d mi nistr ati o n)
C o h ort
Pr o p ose d
D oses
D ose Sc he d ule
M o n ot her a p y
L Y 3 4 9 9 4 4 6 ( P O)
E 1/ F 1/ G
R P 2 D M
T B D
C o m bi n ati o n wit h 
A be m acicli b
L Y 3 4 9 9 4 4 6 ( P O)
E 2
R P 2 D A
T B D
A be macicli b ( P O )
E 2 
1 5 0 m g
BI D
C o m bi n ati o n wit h 
Erl oti ni b
L Y 3 4 9 9 4 4 6 ( P O)
E 3
R P 2 D E
T B D
Erl oti ni b ( P O )
E 3
1 5 0 m g
Q D
C o m bi n ati o n wit h 
Cet u xi m a b
L Y 3 4 9 9 4 4 6 ( P O)
F 2
R P 2 D C
T B D
Cet u xi ma b (I V )
F 2 
4 0 0 m g/ m 2
C 1 D 1;
2 5 0 m g/ m 2
Q W
Acti ve C o m p ar at or
D oceta xel (I V)
E 4
7 5 m g/ m 2
Q 3 W
A b bre viati o ns:  BI D = t wice dail y; D L = d ose le vel; I V = i ntra ve n o us; P O = orall y; Q D = dail y; Q W = e ver y wee k; 
Q 3 W = e ver y 3 wee ks; R P 2 D A = a be macicli b rec o m me n de d p hase 2 d ose; R P 2 D C = cet u xi ma b rec o m me n de d 
p hase 2 d ose; R P 2 D E = erl oti ni b rec o m me n de d p hase 2 d ose; R P 2 D M = m o n ot hera p y  rec o m me n de d p hase 2 d ose.
N ote:
l ower d oses or alter nati ve sc he d ules o f a be macicli b a n d erl oti ni b ma y be e x plore d bel o w 
t he c urre ntl y a p pr o ve d d oses base d o n e mer gi n g safet y data.
I n a d diti on t o t he L Y 3 4 9 9 4 4 6 d ose le vels s pecifie d i n t his secti on , i nter mitte nt d ose le vels, or 
alter nati ve sc he d ules ma y be e x pl ore d.  Si milarl y, l o wer d oses or alter nati ve sc he d ules of 
a be macicli b a n d erl oti ni b ma y be e x plore d bel o w t he c urre nt l y a p pr o ve d d oses base d o n 
e mer gi n g safet y data. T he t otalit y of  data i ncl u di n g safety, t olera bilit y, e x p os ure, a n d t he 
i nci de nce of D L T ma y re q uire e val uat io n of alter nati ve d oses a n d/ or sc he d ule (e.g. 
v er s us
).
E nr olle d pat ient s will recei ve L Y 3 4 9 9 4 4 6 a d mi nistere d P O wi t h a d ose a n d sc he d ule base d o n 
t he c o h ort t he y are e nr olle d i n t he a b o ve ta ble.  Misse d d oses of L Y 3 4 9 9 4 4 6 ma y be ta ke n wit hi n 
3 0 mi n utes o n da y s w he n P K sa m ples are sc he d ule d, or wit hi n 2 h o urs o n ot her da ys.  V o mite d 
C CI
C CI
C CI
C CI
C CI
C CI
C
CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
56
doses of LY3499446 should not be redosed.  Dosing of LY3499446 should occur at least 1 hour 
prior to food intake or at least 2 hours after.  Patients enrolled in combination cohorts will also 
receive abemaciclib, erlotinib, or cetuximab.  Abemaciclib will be administered 150 mg BID PO 
on Days 1 to 21 of a 21-day cycle.  Erlotinib will be administered 150 mg PO QD on Days 1 to 
21 of a 21-day cycle.  Dosing of abemaciclib and erlotinib with respect to food intake should 
follow instructions given on the respective approved label.  Depending on the totality of safety, 
tolerability, PK, and DLT seen in the combination cohorts, lower doses of erlotinib, abemaciclib, 
or cetuximab may be explored.  Docetaxel will be given by intravenous (IV) 75 mg/m2 on Day 1 
of every 21-day cycle.
In Cycle 1, patients enrolled into cetuximab combination cohorts will receive a loading dose of 
400 mg/m2 cetuximab as an approximately 120-minute infusion on Day 1 and then 250 mg/m2 as 
an approximate 60-minute infusion on Day 8 and15 of a 21-day cycle.  In Cycle 2 and beyond, 
patients will receive 250 mg/m2 cetuximab as an approximately 60-minute infusion on 
Days 1, 8, and 15 of a 21-day cycle.  Cetuximab should be administered following institutional-
approved standard-of-care premedication.  All concomitant medications, including 
premedication, should be recorded on the case report form (CRF).  Close monitoring is required 
during the infusion, particularly during the first infusion, and for at least 1 hour after the end of 
the infusion.  Refer to the Package Insert for further details.
The investigator or his/her designee is responsible for the following:
explaining the correct use of the drug(s) and the planned duration of each individual’s 
treatment to the patient and study site personnel
verifying that instructions are followed properly
maintaining accurate records of study drug dispensing and collection
at the end of the study, returning all unused medications to Lilly, or its designee, unless 
Lilly and sites have agreed all unused medications are to be destroyed by the site, as 
allowed by local law
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and 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.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
57
5. Investigators should consult the study drug information provided in the Pharmacy 
Manual or label for the specific administration information (including warnings, 
precautions, contraindications, adverse reactions, and dose modifications).
6.3.
Measures to Minimize Bias:  Randomization and Blinding
This is a Phase 1, open-label, dose escalation study followed by a randomized Phase 2 study.  
The Phase 2 part will implement a randomization design to mitigate the selection bias in 
allocating patients with NSCLC or CRC to either monotherapy or combination therapies.
Patients enrolled into the Phase 2 NSCLC and CRC cohorts will be stratified by the following 
factors:

NSCLC patients
o
Lung only metastases versus others
o
Co-occurring mutations KRAS G12C + P53 (KP) versus KRAS G12C + 
KEAP1 or KRAS G12C + LKB1 (KL) versus others (K)

CRC patients
o
Sidedness of the tumor (right versus left)
o
Sites of metastases (1 versus 2 versus >2)
6.4.
Study Intervention Compliance
Patient compliance with study intervention will be assessed at each visit.  A patient diary will be 
given to the patient in order to help patient compliance with LY3499446, recording food intake 
time relative to LY3499446 administration, and discussion with investigators about tolerability.  
Compliance will be assessed by direct questioning, counting returned capsules/tablets, and 
reviewing patient diaries. Patient diary evaluations will occur only in the first 2 cycles.  Patients 
must receive 80% of assigned doses to be considered compliant with study.
Study intervention that is administered by IV will be administered only at the investigational 
sites by the authorized study site personnel.  As a result, treatment compliance is assured.  
Deviation(s) from the prescribed dosage regimen should be recorded in the electronic case report 
form (eCRF).
6.5.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.
Abemaciclib is extensively metabolized through oxidation by CYP3A.  In clinical drug 
interaction studies, coadministration of clarithromycin, a strong CYP3A inhibitor, increased 


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
58
exposure (AUC) to abemaciclib by 3.4-fold (Study I3Y-MC-JPBE) and coadministration of 
rifampin, a strong CYP3A inducer, decreased exposure to abemaciclib by 95% (Study 
I3Y-MC-JPBF).  Therefore, grapefruit or grapefruit juice as well as inducers and strong or 
moderate inhibitors of CYP3A should be substituted or avoided if possible (see Appendix 6).  
The information in Appendix 6 is provided for guidance to investigators and does not preclude 
the use of these medications if clinically indicated.
Abemaciclib and/or its major metabolites inhibit the efflux transporters P-glycoprotein and 
breast cancer resistance protein and renal transporters organic cation transporter 2, multidrug and 
toxin extrusion protein 1 (MATE1) and MATE2-K at clinically relevant concentrations.  
Therefore, substrates of these transporters such as metformin and those with a narrow therapeutic 
index such as digoxin and dofetilide should be substituted or avoided if possible.
Erlotinib and docetaxel are also metabolized by CYP3A4; therefore, grapefruit juice as well as
inducers (for example, phenytoin or carbamazepine) and strong inhibitors of CYP3A4 should be
substituted or avoided if possible (Appendix 6). Additionally, erlotinib is also metabolized by 
CYP1A2.  Use of combined CYP3A4 and CYP1A2 inhibitors (eg, ciprofloxacin), cigarette 
smoking (CYP1A2 inducer), and concomitant use with moderate CYP1A2 inducers (eg, 
teriflunomide, rifampin, or phenytoin) should be avoided.  For additional instructions, please 
refer to the approved label for erlotinib.  Use of a drug that is listed in Appendix 6 when there is 
no appropriate clinical substitute for that drug will not be considered a protocol violation. After 
the DLT assessment period, close monitoring for toxicity and a dose reduction could be 
considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided.
Investigators are advised to avoid or to use caution in the use of sensitive or moderately sensitive 
substrates of CYP2C9 and CYP2C19 with LY3499446 (refer to Appendix 9).
The Lilly CRP/CRS should be contacted if there are any questions regarding concomitant or 
prior therapy.  No other chemotherapy, immunotherapy, herbal supplements and/or herbal drugs 
intended to treat cancer, or experimental drugs will be permitted while the patients are on this 
study.
6.5.1.
Use of Gastric pH Modifying Agents
Patients receiving erlotinib in combination with LY3499446 should administer H2-receptor 
antagonists and antacids according to the approved label for erlotinib.
6.5.2.
Palliative Medicine and Supportive Care
Palliative radiation therapy is permitted after discussion with and agreement of the Lilly CRP or 
designee for irradiating small areas of painful metastases that cannot be managed adequately 
using systemic or local analgesics. Such areas must not be an identified target lesion and must 
not constitute progressive disease (PD) or meet RECIST criteria for PD. Any symptomatic 
deterioration or clinical disease progression requiring, in the opinion of the investigator, other 
forms of specific antitumor systemic therapy will be cause for discontinuation of study therapy.
In addition, any disease progression requiring other forms of specific antitumor therapy will also 
necessitate early discontinuation from the study. Appropriate documentation for all forms of 
premedications, supportive care, and concomitant medications must be captured on the 
CRF. Replacement hormonal therapy initiated before study entry will be allowed.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
59
Patients should receive full supportive care.  Hematopoietic growth factors (e.g., erythropoietin 
or G-CSFs) may be administered according to institutional guidelines and the local Package 
Insert, except in the DLT observation period. Hematopoietic growth factors will be allowed in 
the DLT observation period if a patient experiences neutropenia that is declared an AE. 
Administration of G-CSFs prior to first occurrence of neutropenia is prohibited. Blood product 
transfusions are permitted throughout the study. If clinically indicated at any time during the 
study, erythropoietin and packed red blood cell transfusions may be used according to American 
Society of Clinical Oncology (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.
6.5.3.
Supportive Management for Diarrhea
Participants should receive instructions on the management of diarrhea.  In the event of diarrhea, 
supportive measures should be initiated as early as possible.  These include the following:

At the first sign of loose stools, the participant should initiate antidiarrheal therapy (for 
example, loperamide) and notify the investigator for further instructions and appropriate 
follow-up.

Participants should also be encouraged to drink fluids (that is, 8 to 10 glasses of clear 
liquids per day).

Site personnel should assess the response within 24 hours.

If diarrhea does not resolve with antidiarrheal therapy within 24 hours to at least Grade 1 
(per CTCAE Version 5.0), dosing of LY3499446 and, as applicable, abemaciclib, 
cetuximab, or erlotinib should both be suspended until diarrhea is resolved to at least 
Grade 1.

When treatment recommences, dosing should be adjusted as outlined in Section 6.6.1.  
For severe cases of diarrhea, the measurement of neutrophil counts and body temperature 
and proactive management of diarrhea with antidiarrheal agents should be considered.  If 
diarrhea is severe (requiring IV hydration) and/or associated with fever or severe 
neutropenia, broad-spectrum antibiotics such as fluoroquinolones should be considered 
and treatment should be suspended and appropriate dose modification should be 
instituted per protocol.
Participants with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be carefully monitored and given IV fluids and electrolyte replacement as clinically 
indicated.  Please refer to Section 6.6 for specific dose-related modifications for diarrhea. 
6.6.
Dose Modification
The sections below detail dose modification and delays of LY3499446, abemaciclib, cetuximab, 
erlotinib, and docetaxel.  If any study drugs are permanently discontinued, dosing could be 
continued with the remaining compound(s) according to the schedule, if clinically indicated.  
Treatment cycles may be delayed up to 7 days due to holidays, weekends, bad weather, or other 
unforeseen circumstances, and will not be deemed as protocol violation.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
60
When a study drug is delayed, if possible and appropriate, patients should resume study 
treatment within 1 treatment cycle and, if not possible, then every effort should be made to start 
on the first day of the next dosing cycle.  In rare circumstances, a delay >21 days may be 
permitted before permanent treatment discontinuation, as long as the patient has clinical benefit 
without objective disease progression and is recovering from the toxicity.  Such circumstances 
must be discussed with the Lilly CRP/CRS.  All dose modifications should be documented, 
including the approach taken and a clear rationale for the need for modification.  Dose reductions 
will not be permitted during the DLT period.
Any patient who requires a dose reduction will continue to receive the reduced dose for the 
remainder of the study.
6.6.1.
Dose Modification of LY3499446
Toxicity Type
Toxicity Profile and 
Severity
Dose Suspension
Dose Reduction
Hematologic toxicity 
Grade 3
Dose MUST be 
suspended until 
toxicity resolves to 
at least Grade 2.
Dose MAY be reduced by 1 
DL – investigator’s 
discretion.
Hematologic toxicity 
Recurrent Grade 3 
Dose MUST be 
suspended until 
toxicity resolves to 
at least Grade 2.
Dose MUST be reduced by 
1 DL. 
Hematologic toxicity 
Grade 4
Dose MUST be 
suspended until 
toxicity resolves to 
at least Grade 2.
Dose MUST be reduced by 
1 DL.
If at lowest DL, then 
discontinue from study.
Hematologic toxicity:  
Patient requires 
administration of 
blood cell growth 
factors
Regardless of severity. 
(growth factors use 
according to ASCO 
guidelines)
Dose MUST be 
suspended for at 
least 48 hours after 
the last dose of 
blood cell growth 
factors was 
administered and 
until toxicity 
resolves to at least 
Grade 2. 
Dose MUST be reduced by 
1 DL unless already 
performed for incidence of 
toxicity that led to the use of 
growth factor.
If at lowest DL, then 
discontinue from study.
Nonhematologic 
toxicity (except 
diarrhea and alopecia)
Persistent or recurrent 
Grade 2 that does not 
resolve with maximal 
supportive measures 
within 7 days to 
baseline or Grade 1
Dose MAY be 
suspended until 
toxicity resolves to 
either baseline or 
Grade 1.
Dose MAY be reduced by 
1 DL – investigator’s 
discretion.
Nonhematologic 
toxicity (except 
alopecia)
Grade 3 or 4 that does 
not resolve with 
maximal supportive 
Dose MUST be 
suspended until 
toxicity resolves to 
Dose MUST be reduced by 
1 DL.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
61
Toxicity Type
Toxicity Profile and 
Severity
Dose Suspension
Dose Reduction
measures within 
72 hours to baseline or 
Grade 1
either baseline or 
Grade 1.
Hepatic toxicity
Grade 3
Dose MUST be 
suspended
Dose MUST be reduced by 
1 DL after toxicity returns to 
Grade ≤1
Grade 4
Dose MUST be 
suspended.
Patient MUST be 
discontinued from study.
Diarrhea
Requires hospitalization 
for Grade 3 or 4
Dose MUST be 
suspended until 
toxicity resolves to 
at least Grade 1.
Dose MUST be reduced by 
1 DL for any Grade 4 and 
for Grade 3 diarrhea lasting 
> 3 days despite maximum 
supportive care
Diarrhea
Persistent or recurrent 
Grade 2 that does not 
resolve with maximal 
supportive measures 
within 24 hours to at 
least Grade 1
Dose MUST be 
suspended until 
toxicity resolves to 
at least Grade 1.
Dose MAY be reduced by 
1 DL – investigator’s 
discretion.
Diarrhea
Persistent or recurrent 
Grade 1 that does not 
resolve with maximal 
supportive measures 
within 24 hours to 
baseline
Patient to be 
followed for 
48 hours to ensure 
grade does not 
worsen.
Dose MAY be maintained 
during monitoring –
investigator’s discretion.
Diarrhea
Grade ≥2 diarrhea 
recurs despite maximal 
supportive measures 
after resuming same DL
after initial Grade 2 
diarrhea
Dose MUST be 
suspended until 
toxicity resolves to 
at least Grade 1.
Dose MUST be reduced by 
1 DL.
Bloody diarrhea
Any grade
Dose MUST be 
suspended until 
bloody diarrhea 
resolves and 
diarrhea resolves 
to at least Grade 1.
Dose MUST be reduced by 
1 DL.
QTcF Prolongation
≤Grade 2 (QTcF average 
of triplicate readings >480 
ms but ≤500 ms)
Continue at current dose level.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
62
Toxicity Type
Toxicity Profile and 
Severity
Dose Suspension
Dose Reduction
Grade 3 (QTcF average of 
triplicate readings >500 
ms)
Withhold treatment; if QTcF returns to within 30 ms of 
baseline or <450 ms within 14 days, treatment may be 
resumed at a reduced dose. If the event recurs a second 
time, treatment will be terminated.
Grade 4 (QTcF average of 
triplicate readings >500 
ms or >60 ms change from 
baseline and TdP or 
polymorphic
ventricular tachycardia or
signs/symptoms of serious 
arrhythmia)
Treatment should be terminated.
Interstitial Lung Disease
Grade 1
Continue to monitor without dose modification.
Confirmed Interstitial 
Lung Disease
Grade 2 to 4
Discontinue and institute appropriate therapy.
Abbreviations:  ASCO = American Society of Clinical Oncology; DL = dose level.
The table below provides additional guidance for responding to treatment-emergent adverse 
events suggestive of hemolysis:
Treatment-Emergent Adverse Event
Action
Hemoglobin decrease of ≥2 grams/dL
OR
Elevated total bilirubin, ≥ Grade 2
OR
Indirect bilirubin ≥ upper limit of normal
Obtain hemolysis workup including:
1.
Peripheral blood smear
2.
Haptoglobin
3.
LDH
4.
Reticulocyte count
5.
Direct Coombs
6.
Indirect Coombs
7.
B12, folate, iron level, ferritin, TIBC
If these laboratory values suggest hemolysis, hold 
drug and institute every other day monitoring of 
hematologic parameters.  Do not resume study 
drug without approval from the Sponsor medical 
monitor.  Decision to resume with dose reduction 
or permanent discontinuation will be based on the 
severity of the event and dose at which it occurred, 
as well as consideration of any clinical benefit the 
patient is achieving related to study drug.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
63
Abbreviations: LDH = lactic dehydrogenase; TIBC = total iron binding capacity.
6.6.2.
Dose Modification of Abemaciclib
Dose adjustments as outlined in the following table are allowed.  Abemaciclib should be reduced 
sequentially by 1 dose level.  For patients requiring dose reduction(s), any re-escalation to a prior 
dose level is permitted only after consultation with the Lilly CRP/CRS.  After re-escalation, 
subsequent dose adjustments should be based on the dose of abemaciclib that the patient is 
currently receiving. 
Dose Adjustments of Abemaciclib
Dose Adjustment
Oral Dose
Frequency
0
150 mg 
Twice Daily with at least 6 hours between 
doses
1
100 mg
Twice Daily with at least 6 hours between 
doses
2
50 mg
Twice Daily with at least 6 hours between 
doses
If a patient receiving the 50-mg twice daily dose of abemaciclib requires further dose reduction, 
the patient must be discontinued from abemaciclib.
Abemaciclib Dose Adjustments for Treatment-Related Adverse Events
Treatment-emergent laboratory abnormalities of neutrophil count decreased and/or ALT/AST 
increased, regardless of clinical significance, must follow the dose adjustment table below.
Toxicity Type
Toxicity Profile and 
Severity
Abemaciclib Dose 
Suspension
Abemaciclib Dose 
Reduction
Hematologic Toxicity
Grade 3
Dose MUST be 
suspended until toxicity 
resolves to at least Grade 
2.
Dose reduction is NOT 
required.
Recurrenta Grade 3 or 
Grade 4
Dose MUST be 
suspended until toxicity 
resolves to at least Grade 
2.
Dose MUST be reduced 
by 1 dose level.
Hematologic Toxicity:  If 
patient requires 
administration of blood 
cell growth factors
Regardless of severity 
(Use of growth factors 
according to ASCO 
guidelines)
Dose MUST be 
suspended for at least 48 
hours after the last dose of 
blood cell growth factors 
was administered and 
until toxicity resolves to 
at least Grade 2.
Dose MUST be reduced 
by 1 dose level unless 
already performed for 
incidence of toxicity that 
led to the use of growth 
factor.


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
64
Toxicity Type
Toxicity Profile and 
Severity
Abemaciclib Dose 
Suspension
Abemaciclib Dose 
Reduction
Nonhematologic 
Toxicityb (except 
diarrhea, ALT increased, 
and ILD/pneumonitis, and 
VTEc)
Persistent or recurrenta
Grade 2 that does not 
resolve with maximal 
supportive measures 
within 7 days to baseline 
or Grade 1
Dose MUST be 
suspended until toxicity 
resolves to either baseline 
or ≤Grade 1.
Dose MUST be reduced 
by 1 dose level.
Grade 3 or 4
Dose MUST be 
suspended until toxicity 
resolves to either baseline 
or ≤Grade 1.
Dose MUST be reduced 
by 1 dose level.
Diarrhea
Grade 2 that does not 
resolve within 24 hours to 
≤Grade 1
Dose MUST be 
suspended until toxicity 
resolves to ≤Grade 1.
Dose MAY be reduced by 
1 dose level.
Grade 2 that persists or 
recurs after resuming the 
same dose despite 
maximal supportive 
measures 
Dose MUST be 
suspended until toxicity 
resolves to ≤Grade 1.
Dose MUST be reduced 
by 1 dose level.
Grade 3 or 4
Dose MUST be 
suspended until toxicity 
resolves to ≤Grade 1.
Dose MUST be reduced 
by 1 dose level.
Any grade that requires 
hospitalization
Dose MUST be 
suspended until toxicity 
resolves to ≤Grade 1.
Dose MUST be reduced 
by 1 dose level.
ALT Increased
Persistent or recurrenta
Grade 2 (>3.0-5.0×ULN), 
or Grade 3 (>5.0-
20.0×ULN)d
Dose MUST be 
suspended until toxicity 
resolves to baseline or 
≤Grade 1.
Dose MUST be reduced 
by 1 dose level.
Grade 4 (>20.0×ULN)
Abemaciclib treatment 
MUST be discontinued
Abemaciclib treatment 
MUST be discontinued
ALT Increased with 
increased total bilirubin, 
in the absence of 
cholestasis
Grade 3 increased ALT 
(>5.0×ULN) with total 
bilirubin >2×ULN
Abemaciclib treatment 
MUST be discontinued.
Abemaciclib treatment 
MUST be discontinued.
ILD / pneumonitis
Grade 2 that persists or 
recurs despite maximal 
supportive measures and 
does not return to baseline 
or Grade 1 within 7 days
Dose MUST be 
suspended until toxicity 
resolves to either baseline 
or ≤Grade 1.
Dose MUST be reduced 
by 1 dose level.
Grade 3 or 4
Abemaciclib treatment 
Abemaciclib treatment 


CONFIDENTIAL
Protocol J2K-MC-JZKA(b)
LY3499446
65
Toxicity Type
Toxicity Profile and 
Severity
Abemaciclib Dose 
Suspension
Abemaciclib Dose 
Reduction
MUST be discontinued.
MUST be discontinued.
Abbreviations:  ALT = alanine transaminase; ASCO = American Society of Clinical Oncology; AST = aspartate 
aminotransferase; ILD = interstitial lung disease; ULN = upper limit of normal; VTE = venous thromboembolic 
event.
a
Determination of persistent events will be at the discretion of the investigator.  Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).
b
Additional guidance for hepatic and renal monitoring is in Section 8.2.1.1 and Section 8.2.1.2.
c    For VTE, dose reduction of abemaciclib will be at the discretion of the investigator.
d  Grade 3 ALT/AST increased is a trigger for additional assessments and possibly hepatic monitoring.
If a patient receiving the 50-mg twice daily dose of abemaciclib requires further dose reduction, 
the patient must be discontinued from abemaciclib.  Patients undergoing surgery: 

For minor surgeries and procedures (for example, ambulatory), investigators should treat 
as clinically indicated and closely monitor any signs of infection or healing 
complications.

For major surgeries, the recommendation is to suspend dosing of abemaciclib for at least 
7 days before and may be resumed as clinically indicated.

Consider monitoring neutrophils and platelets before surgery and before resuming 
abemaciclib. The scars should be aseptic and healing process be reasonable before 
resuming abemaciclib.

Dose suspensions ≥28 days must be discussed with Lilly CRP/CRS.
At the investigator’s discretion with consultation with the Lilly CRP/CRS, patients may continue 
on LY3499446 if they discontinue from abemaciclib.  Based upon the toxicity’s relation to the 
study drug, the investigator may choose to reduce one or both study treatments.
6.6.3.
Dose Modification of Cetuximab
Reduce, delay, or discontinue cetuximab treatment to manage adverse reactions as described in 
the table below:
Reaction
Severity
Dose Modification
Infusion reactions
Grade 1 or 2
Reduce infusion rate by 50%.
Grade 3 or 4
Immediately and permanently 
discontinue cetuximab.


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Reaction
Severity
Dose Modification
Dermatologic toxicities and 
infectious sequelae (eg acneiform 
rash, mucocutaneous disease) 
First occurrence; Grade 3 or 4
Delay infusion 1 to 2 weeks.  If 
condition improves, continue at 250 
mg/m2.  If no improvement, 
discontinue cetuximab.
Second occurrence; Grade 3 or 4
Delay infusion 1 to 2 weeks.  If 
condition improves, continue at 200 
mg/m2.  If no improvement, 
discontinue cetuximab.
Third occurrence; Grade 3 or 4
Delay infusion 1 to 2 weeks.  If 
condition improves, continue at 150 
mg/m2.  If no improvement, 
discontinue cetuximab.
Fourth occurrence; Grade 3 or 4
Discontinue cetuximab.
Pulmonary toxicity
Acute onset or worsening pulmonary 
symptoms
Delay infusion 1 to 2 weeks.  If 
condition improves, continue at the 
dose that was being administered at 
the time of occurrence.
If no improvement in 2 weeks or 
interstitial lung disease/pneumonitis 
is confirmed, discontinue cetuximab.
At the investigator’s discretion with consultation with the Lilly CRP/CRS, patients may continue 
on LY3499446 if they discontinue from cetuximab.  Based upon the toxicity’s relation to the 
study drug, the investigator may choose to reduce one or both study treatments.
6.6.3.1.
Treatment Adjustments in Case of Cetuximab Allergic/Hypersensitivity
Reaction
Treatment adjustments in the event of cetuximab-caused allergic/hypersensitivity reactions 
should follow institutional practice.  The following table is provided as guidance to investigators:


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Grade
Event
Treatment
1
Transient flushing or rash; drug fever <38°C 
(<100.4°F)
Decrease cetuximab infusion rate by 50% 
and monitor closely for any worsening.
The total infusion time for cetuximab should 
not exceed 4 hours.
2
Rash; flushing; urticaria; dyspnea; drug fever 
38°C (100.4°F)
Stop cetuximab infusion.
Administer bronchodilators, oxygen, etc., as 
medically indicated.
Resume infusion at 50% of previous rate 
once allergic/hypersensitivity reaction has 
resolved or decreased to Grade 1 and 
monitor closely for any worsening.
3
Symptomatic bronchospasm, with or without 
urticaria; parenteral medication(s) 
indicated; allergy-related 
edema/angioedema; hypotension
Stop cetuximab infusion immediately and 
disconnect infusion tubing from the patient.
Administer epinephrine, bronchodilators, 
antihistamines, glucocorticoids, intravenous 
fluids, vasopressor agents, oxygen, etc., as 
medically indicated.
Patients have to be withdrawn immediately 
from the treatment and must not receive any 
further cetuximab treatment.
4
Anaphylaxis
Once the cetuximab infusion rate has been decreased due to an allergic/hypersensitivity reaction, 
it will remain decreased for all subsequent infusions.  If the patient has a second 
allergic/hypersensitivity reaction with the slower infusion rate, the infusion should be stopped, 
and cetuximab treatment should be discontinued.  If a patient experiences a Grade 3 or 4 
allergic/hypersensitivity reaction at any time, cetuximab should be discontinued.  If there is any 
question as to whether an observed reaction is an allergic/hypersensitivity reaction of Grade 1 
to 4, Lilly should be contacted immediately to discuss and grade the reaction.
6.6.4.
Dose Modification of Erlotinib
Dose modifications of erlotinib should follow the product label and institutional guidelines.  At 
the investigator’s discretion with consultation with the Lilly CRP/CRS, patients may continue on 
LY3499446 if they discontinue from erlotinib.  Based upon the toxicity’s relation to the study 
drug, the investigator may choose to reduce one or both study treatments.
6.6.5.
Dose Modification of Docetaxel
Dose modifications of docetaxel should follow the product label and institutional guidelines.
6.6.6.
Dose Modification for Grade 3 Toxicities Not Clearly Related to LY3499446 or 
Drug Given in Combination
In the event of Grade 3 toxicity in any of the combination arms, both agents should be held until 
toxicity has resolved or decreased to Grade 1.  At the time of reinitiating therapy, 1 or both of 
these agents MUST be reduced by 1 DL per the investigator’s discretion or after discussion with 
the Lilly CRP/CRS.  For a specific toxicity addressed in Section 6.6.1, the investigators should 
reference the dose modification requirements specific to that particular toxicity.


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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 receiving
study intervention when study completion occurs.  Lilly will notify investigators when the 
continued access period begins.  Lilly may allow patients to enroll in a “rollover” protocol to 
provide long-term continued access for patients enrolled in this study.
The continued access period will begin after study completion and ends at the end of study.  The 
participant’s continued access to study treatment will end when a criterion for discontinuation is 
met (Section 7).  Continued access follow-up will begin when the participant and the investigator 
agree to discontinue study treatment.  Follow-up procedures will be performed as shown in the 
SoA (Section 1.3).
Participants who are in short-term follow-up when the continued access period begins will 
continue in short-term follow-up until the short-term follow-up visit is completed. Long-term 
follow-up does not apply.
Participants who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention 
Possible reasons leading to permanent discontinuation of investigational product:

Subject Decision
o
the participant or the participant’s designee, for example his or her parents or legal 
guardian, requests to discontinue investigational product.
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula [QTcF]) after enrollment, the investigator or 
qualified designee will determine if the participant can continue in the study, and if any change 
in participant management is needed. This review of the ECG printed at the time of collection 
must be documented. Any new clinically relevant finding should be reported as an AE.
In addition, participants will be discontinued from the investigational product in the following 
circumstances:

the patient becomes pregnant during the study

the patient is significantly noncompliant with study procedures and/or treatment

disease progression.  Exceptions for continuing study treatment beyond confirmed 
radiographic progression may be made on a case-by-case basis for patients who are 
believed to be clinically benefiting from study treatment, and the investigator and the 
sponsor agree that continuing study treatment is in the patient’s best interest

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 treatment will occur prior to introduction of the new agent

the investigator decides that the patient should be discontinued from study treatment.
Participants discontinuing from the investigational product prematurely for any reason should 
complete AE and other follow-up procedures per Section 1.3 (SoA), Section 8.3 (AEs and 
SAEs), 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)


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
the patient or the patient’s designee requests to be withdrawn from the study

the patient becomes pregnant during the study.  See Section 8.3 regarding regulatory 
reporting requirements on fetal outcome.
Participants discontinuing from the study prematurely for any reason should complete AE and 
other safety follow-up per Section 1.3 (SoA), Section 8.3 (AEs and SAEs), and Section 8.2
(Safety Assessments) of this protocol.
Participants who withdraw their consent from the study and request to discard their genetic and 
biomarker samples will have their samples destroyed.  Analysis results that are available before 
the consent withdrawal may be published in articles or other disclosures without identifiable 
individual patient information. 
7.2.1.
Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the patient should be discontinued from study treatment, unless 
there are extenuating circumstances that make it medically necessary for the patient to continue 
on study treatment.  If the investigator and the sponsor CRP/CRS agree it is medically 
appropriate to continue, the investigator must obtain documented approval from the sponsor 
CRP/CRS to allow the inadvertently enrolled participant to continue in the study, with or without 
treatment with investigational product. Safety follow-up is as outlined in Section 1.3 (SoA), 
Section 8.3 (AEs and SAEs), and Section 8.2 (Safety Assessments) of the protocol.  Refer to 
Appendix 5 for country-specific requirements related to the discontinuation of inadvertently 
enrolled patients in the UK.
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.
The discontinuation of specific sites or of the study as a whole is handled as part of Section
10.1.7.


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8.
Study Assessments and Procedures
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results. Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
Study procedures and their timing are summarized in the SoA (Section 1.3).  Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention.
Adherence to the study design requirements, including those specified in the SoA (Section 1.3), 
is essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
Procedures conducted as part of the participant’s routine clinical management (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
Tumor assessments will be performed for each patient at the times shown in the SoA (Section 
1.3).
Response Evaluation Criteria in Solid Tumors v1.1 (Eisenhauer et al. 2009) will be applied as 
the primary criteria for assessment of tumor response and date of disease progression.  The 
method of tumor assessment used at baseline must be used consistently throughout the study.  
Local tumor imaging (investigator assessment with site radiological reading) will be used.
Computed tomography (CT) scans, including spiral CT, are the preferred methods of 
measurement (CT scan thickness recommended to be ≤5 mm); however, magnetic resonance 
imaging (MRI) is also acceptable in certain situations, such as when body scans are indicated or 
if there is a concern about radiation exposure associated with CT.  Intravenous and oral contrast 
are required unless medically contraindicated.
The CT portion of a positron emission tomography (PET)-CT scan may be used as a method of 
response assessment if the site can document that the CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast).  A PET scan alone or as part of a PET-CT may be 
performed for additional analyses, but cannot be used to assess response according to RECIST 
v1.1.
Efficacy assessments include tumor evaluation every 6 weeks after treatment initiation through 
Week 24, and then approximately every 9 weeks thereafter.  Patients who discontinue treatment 


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without documented progression should continue to be assessed per the above schedule until 
disease progression is observed or the patient starts subsequent anticancer therapy.
All patients are required to undergo chest/abdomen/pelvis and brain imaging at baseline and 
subsequent serial scans at disease assessment timepoints. All scans will be collected and stored 
at a central facility for central reviewer assessment during the study.  Response will be assessed 
per RECIST v1.1 requirements (Eisenhauer et al. 2009).
Finally, all patients will enter long-term follow-up for confirming disease progression if not 
occurring on treatment, subsequent anticancer therapy(ies), and survival.
Baseline disease assessment with radiographic tumor measurements using CT or MRI of the 
chest, abdomen, pelvis, or any other areas with suspected disease involvement, must occur 
within 28 days of Cycle 1 Day 1. During Phase 2, brain imaging is required at baseline for 
patients with a history of CNS metastases or other patients if clinically indicated, and subsequent 
serial scans if brain metastases are present at baseline (MRI preferred, CT with contrast is 
acceptable if MRI contraindicated).  For each modality, IV and oral contrast should be utilized 
(chest CT does not require IV contrast) unless there is a clear contraindication (e.g., decreased 
renal function or allergy that cannot be addressed with standard prophylactic treatments). In the 
absence of known or suspected disease involvement, head and neck CT/MRI scans are not 
required for malignancies other than those originating in the head and neck region. Other areas 
of scanning may also differ depending on disease type. Postbaseline scans should be performed 
every 6 weeks (±7 days) for 6 months and every 9 weeks (±7 days) thereafter, including imaging 
of the chest, abdomen, and pelvis, using the same modality(ies) as used for baseline imaging 
assessment until PD, withdrawal of consent, or initiation of (a) new anticancer therapy(ies). 
Additionally, any studies performed at baseline that are positive for sites of disease should be 
repeated at all postbaseline assessments. Additional studies can also be performed as clinically 
indicated. In addition, investigators may conduct an initial tumor evaluation on Cycle 2 Day 1 
(±7 days) and a confirmatory tumor evaluation a minimum of 4 weeks (i.e., 28 days) after the 
first tumor evaluation that shows a complete response (CR) or partial response (PR) by RECIST 
v1.1 (or Response Assessment in Neuro-Oncology, as appropriate to tumor type), if consistent 
with local regulatory authority requirements. In addition, an initial postbaseline assessment on 
Cycle 2 Day 1 (±7 days) is encouraged if consistent with regulatory guidelines. If a scan is 
performed on Cycle 2 Day 1, the next scan should continue according to the schedule above 
(beginning at Cycle 3 Day 1). All scans will be collected and stored at a central facility to permit 
central reviewer assessment. A blinded independent data review may be considered in order to 
confirm response rate across the study cohorts.  Please see the Site Imaging Manual for 
guidelines on how the various imaging studies should be performed.
Best Overall Response (BOR)
Subjects’ BOR will be categorized as CR, PR, stable disease (SD), PD, or UN according to 
RECIST v1.1 criteria.  As the phases of the study intended to provide a definitive analysis of 
response are randomized, CR and PR BOR status need not be confirmed.  To qualify as a 
response other than PD or UN, a subject’s BOR must be observed at least 6 weeks postbaseline.  
A PD observed prior to that point will qualify as the subject’s BOR.  Otherwise, if a subject does 
not have an adequate disease assessment, per RECIST v1.1 criteria, a BOR of UN will be 
assigned.


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Overall response rate is the proportion of patients who achieved a CR or PR out of all patients 
treated. Tumor responses will be measured and recorded using RECIST v1.1 guidelines 
(Eisenhauer et al. 2009). To confirm objective responses, all lesions should be radiologically 
assessed, and the same radiologic method used for the initial response determination should be 
repeated at least 4 weeks following the initial observation of an objective response, using the 
sample method that was used at baseline. Disease control rate (DCR), defined as the proportion 
of patients who achieved a CR, PR, or SD out of all patients treated, will also be summarized.
Disease control rate is the proportion of enrolled patients who have a BOR of confirmed CR, 
confirmed PR, or SD.  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 the 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 will be defined as the time from study enrollment to the first 
observation of a PD overall response or death without documented disease progression per 
RECIST v1.1 criteria.  Patients not known to have either of these events will be censored.  A full 
description of censoring rules is provided in Section 9.4.3.2.
Overall Survival
Overall survival will be defined as the time from study enrollment to death from any cause.  
Patients alive at the end of the study, who have withdrawn from the study, or who are lost to 
follow-up will be censored on their last known alive date.
See Section 9.4.3 for further definitions of the efficacy endpoints.
8.2.
Safety Assessments
For each patient, ECGs, vital signs, laboratory tests, and other tests should be collected as shown 
in the SoA (Section 1.3).  Results from any clinical laboratory test analyzed by a central 
laboratory (refer to Appendix 2) will be provided to investigative sites by Lilly or its designee.
Refer to Section 8.3 for details on the recording of AEs.
8.2.1.
Electrocardiograms
On-treatment ECGs in Phase 1 will be 12-lead triplicate assessments obtained at the time points 
indicated in the SoA (Section 1.3).  Patients must be supine for approximately 5 minutes in a 
quiet environment before ECG collection and remain supine but awake during ECG collection.  


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After enrollment, if a clinically significant increase in the QT/QTcF interval from baseline or 
other clinically significant change from baseline is identified, the patient will be assessed by the 
investigator for symptoms (e.g., palpitations, near syncope, or syncope) and to determine 
whether the patient can continue in the study.  The investigator or qualified designee is 
responsible for determining if any change in patient management is needed and must document 
his/her review of the ECG printed at the time of evaluation from at least 1 of the replicate ECGs 
from each time point.
All digital ECGs will be electronically transmitted to a central ECG laboratory designated by 
Lilly for storage.
8.2.2.
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 refer 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 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 801 after the last dose of study intervention should 
be repeated until the values return to normal or baseline, or are no longer considered clinically 
significant by the investigator or medical monitor.

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.

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).
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 nonprotocol-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).
8.2.2.1.
Hepatic Safety Monitoring
In study participants with baseline ALT/AST<1.5× ULN:
If a study participant enrolled with baseline ALT/AST <1.5× ULN, experiences elevated 
ALT/AST ≥5× ULN, or elevated ALT/AST ≥3× ULN and TBL ≥2× ULN, liver testing 


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(Appendix 4) should be repeated within 3 to 5 days including ALT, AST, ALP, TBL, direct 
bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the abnormality and to 
determine if it is increasing or decreasing. If the abnormality persists or worsens, clinical and 
laboratory monitoring and evaluation for possible causes of abnormal liver tests should be 
initiated by the investigator in consultation with the study medical monitor. Monitoring of ALT, 
AST, TBL, and ALP should continue until levels normalize or return to approximate baseline 
levels.  
In study participants with baseline ALT/AST ≥1.5× ULN:
If a study participant enrolled with baseline ALT/AST ≥1.5× ULN, experiences elevated 
ALT/AST ≥3× baseline or ALT/AST ≥2× baseline and TBL ≥2× ULN, liver testing (Appendix 
4) including ALT, AST, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase 
should be repeated within 3 to 5 days to confirm the abnormality and to determine if it is 
increasing or decreasing. If the abnormality persists or worsens, clinical and laboratory 
monitoring and evaluation for possible causes of abnormal liver tests should be initiated by the 
investigator in consultation with the study CRP/CRS. Monitoring of ALT, AST, and TBL 
should continue until levels normalize or return to approximate baseline levels.
8.2.2.1.1. Special Hepatic Safety Data Collection
Additional safety data should be collected via the CRF/electronic data entry/designated data 
transmission methods if 1 or more of the following conditions occur: 
In participants enrolled with baseline ALT/AST <1.5× ULN:

Elevation of serum ALT/AST to ≥5× ULN on 2 or more consecutive blood 
tests

Elevated ALT/AST ≥3× ULN and elevated TBL ≥2× ULN
In participants enrolled with baseline ALT/AST ≥1.5× ULN

Elevated ALT/AST ≥3× baseline on 2 consecutive tests

Elevated ALT/AST ≥2× baseline and elevated TBL ≥2× ULN
In all study participants 

Discontinuation from study treatment due to a hepatic event or abnormality of 
liver tests

Occurrence of a hepatic event considered to be a SAE
8.2.2.2.
Guidance for Monitoring Renal Function
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C-calculated glomerular filtration rate (GFR).  
Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period, and were reversible upon treatment discontinuation.  If 
deterioration of renal function is suspected, serum creatinine should not be the only measurement 
used to assess a patient’s renal function.


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Dose alterations (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function.  Other 
measures of renal function such as cystatin C GFR should be used as an alternative to either 
creatinine or creatinine calculations of GFR since creatinine would not be an accurate method to 
assess renal function.  If deterioration of renal function is suspected per the investigator’s clinical 
assessment, dose alteration should follow the protocol guidance for nonhematological toxicities 
if considered related to abemaciclib.
8.2.2.3.
Guidance for ILD/Pneumonitis
Interstitial lung disease/pneumonitis has been identified as an adverse drug reaction for 
abemaciclib. Additional information is available in the IB.
Investigators should ask patients to report any new or worsening respiratory symptoms, such as 
cough, dyspnea, or fever, and investigate and treat as per your local clinical practice (including 
corticosteroids as appropriate).  If ILD/pneumonitis is suspected, investigations may include 
imaging, such as high resolution computed tomography, bronchoalveolar lavage, and biopsy, as 
clinically indicated.
Refer to Section 6.6.2 for guidance on dose adjustments of abemaciclib for patients.
8.3.
Adverse Events and Serious Adverse Events
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the participant.
The investigator is responsible for the appropriate medical care of participants during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the participant to discontinue the investigational product 
before completing the study.  The participant should be followed until the event resolves, 
stabilizes with appropriate diagnostic evaluation, or is otherwise explained.  The frequency of 
follow-up evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via CRF the occurrence and nature of 
each participant’s pre-existing 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 or investigational product via CRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.


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A “reasonable possibility” means that there is a cause-and-effect relationship among 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 one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or 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.
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.


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Investigators are not obligated to actively seek AEs or SAEs in subjects 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 subject 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.
Serious AEs, including death, caused by disease progression should not be reported unless the 
investigator deems them to be possibly related to LY3499446.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 Code of Federal Regulations 312.32 and European Union Clinical Trial 
Directive 2001/20/EC and the associated detailed guidances or national regulatory requirements 
in participating countries require the reporting of SUSARs. Lilly has procedures that will be 
followed for the identification, recording, and expedited reporting of SUSARs that are consistent 
with global regulations and the associated detailed guidances.
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to Lilly begins after the patient has signed the ICF and has received study drug.  
However, if an SAE occurs after signing the ICF, but prior to receiving LY3499446, it needs to 
be reported ONLY if it is considered reasonably possibly related to study procedures.
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the AE CRF. 
All SAEs will be recorded and reported to the sponsor or designee immediately, and under no 
circumstance should this exceed 24 hours.  The investigator will submit any updated SAE data to 
the sponsor within 24 hours of it being available.  Serious adverse events, including death, 
caused by disease progression should not be reported unless the investigator deems them to be 
possibly related to study treatment.
Investigators are not obligated to actively seek 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 
nonleading verbal questioning of the participant and/or legal guardian is the preferred method to 
inquire about AE occurrences.
8.3.2.
Follow-Up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 


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8.3.3.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities 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/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the Institutional Review 
Board/IEC, if appropriate, according to local requirements.
8.3.4.
Pregnancy

Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 3.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk of inclusion of a woman with an early 
undetected pregnancy.
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.
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.
8.4.
Treatment of Overdose
Refer to the IB and/or Product Label for intervention or comparator for available information on 
the signs, symptoms, and treatment of overdose.


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8.5.
Pharmacokinetics
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
to determine the plasma concentrations of LY3499446, erlotinib, abemaciclib and its metabolites 
(LSN2839567 and LSN3106726), and serum concentrations of cetuximab.
A maximum of 5 samples, in addition to those shown in the SoA (Section 1.3), may be collected
at additional time points during the study if warranted and agreed upon between both the 
investigator and sponsor.  Blood samples will be obtained from a peripheral location and not the 
central line.  Instructions for the collection and handling of blood samples will be provided by 
the sponsor.  The actual date and time (24-hour clock time) of each sampling will be recorded.
Blood samples will be analyzed at a laboratory approved by the sponsor.  Plasma concentrations 
of LY3499446, erlotinib, and abemaciclib and its metabolites will be assayed using a validated 
liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.  Serum concentrations 
of cetuximab will be assayed using a validated enzyme-linked immunosorbent assay method.
Urine samples (collected over approximately 12 hours) will be collected from all patients for 
determination of LY3499446 concentrations in urine on Cycle 1 Day 8. Total urine output for 
the 12 hours post-administration of LY3499446 will be collected, pooled, and 
refrigerated. Urine collection for determination of LY3499446 should cease after the 12-hour 
collection. For the collection period (0-12 hr), the total urine volume will be recorded, and 2 
approximately 10-mL samples will be stored frozen. The remaining urine will be 
discarded. Instructions for the collection and handling of the urine samples will be provided by 
the sponsor.
Urine samples will be analyzed at a laboratory designated by the sponsor. Urine concentrations 
of LY3499446 will be quantified using an LC-MS/MS assay. The remaining urine samples may 
be used for exploratory metabolism work. Results from exploratory metabolism work will not 
be included in the final integrated study report.
Bioanalytical samples collected to measure investigational product concentration and 
metabolism and/or protein binding will be retained for a maximum of 1 year following last 
participant visit for the study.  During this time, blood samples remaining after the bioanalyses
may be analyzed for exploratory drug metabolism work and other PK/pharmacodynamics work,
as deemed appropriate by the sponsor.  The results of such exploratory metabolism work may 
only be included in the clinical study report (CSR) if deemed appropriate by the sponsor or may 
be reported in a separate exploratory metabolism report.
8.6.
Pharmacodynamics
Samples collected to measure pharmacodynamic biomarkers will be identified by the participant 
number (coded) and retained at a facility selected by Lilly or its designee for a maximum of 15 
years following last participant visit for the study at a facility selected by Lilly or its designee.  
See section 8.8 for biomarker information.


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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 LY3499446, to 
investigate genetic variants thought to play a role in cancer, and to determine whether genetic 
alterations identified in tumor samples are somatic or germline variants. Assessment of variable 
response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and/or 
ethical review boards (ERBs)/institutional review boards (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 
LY3499446 or after LY3499446 becomes commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome 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, mechanism of action, 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, and tumor tissue samples for biomarker research will be collected at the times 
specified in the SoA (Section 1.3) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to study 
treatment, pathways associated with study treatment, mechanism of action of study treatment, 
and/or research method in validating diagnostic tools or assays related to cancer.  Additionally, 
samples may be used to confirm the tumor KRAS G12C mutation status.
Collection of the following tumor tissue sample(s) is required for Cohorts E1, E2, E3, E4, and 
F1 patients to participate in this study:

A newly obtained baseline biopsy specimen (archival tissue will be requested if new 
biopsy insufficient)


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
An on-treatment biopsy specimen collected at a time specified in Section 1.3 if medically 
feasible
Collection of the following tumor tissue sample(s) is required for Cohort F2 patients to 
participate in this study:

Archival tumor tissue block or freshly cut slides, sites should confirm the availability of 
tumor tissue with the pathological laboratory prior to randomization 

Two on-treatment biopsy specimens collected at times specified in Section 1.3 if 
medically feasible
Collection of the following tumor tissue sample(s) is required for Cohort G patients to 
participate in this study:

Archival tumor tissue block or freshly cut slides (new baseline biopsy required if 
insufficient archival tissue available), sites should confirm the availability of tumor tissue 
with the pathological laboratory prior to enrollment
Collection of the following tumor tissue sample(s) is optional for Phase 2 cohort E1, E2, E3, F1, 
and F2 patients participating in this study:

New biopsy at progression for patients on treatment for at least 6 months who have had 
PR or CR. 
All samples will be coded with the participant number.  These samples and any data generated 
can be linked back to the participant only by the investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and ERBs 
impose shorter time limits.  This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of LY3499446 or after LY3499446 becomes commercially available.
Technologies are expected to improve during the 15-year storage period and therefore cannot be 
specifically named.  Existing approaches, including mutation profiling, copy number variability 
analysis, gene expression assays, multiplex assays, and/or immunohistochemistry, may be 
performed on these tissue samples to assess potential associations between these biomarkers and 
clinical outcomes.
The pathology report accompanying archival tissue may also be requested.  The pathology report 
must be coded with the patient number.  Personal identifiers, including the patient’s name and 
initials, must be removed from the institutional pathology report prior to submission.  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.
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.  These results may not be disclosed to 
patients because this research is considered exploratory.


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8.9.
Medical Resource Utilization and Health Economics
Health Economics and Medical Resource Utilization parameters will not be evaluated in this 
study.


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
The statistical hypothesis for the dose escalation phase of this study is that at least 1 evaluated 
DL for LY3499446 will have an estimated DLT rate that is within or below the target range of 
27% to 33%, when administered alone or in combination with abemaciclib, erlotinib, or 
cetuximab.
The statistical hypothesis for the Phase 2 part of the study is that durable objective responses will 
occur at a rate indicative of clinically relevant activity within the selected monotherapy and 
combination regimens.
For NSCLC, the statistical hypothesis is LY3499446 alone or in combination with erlotinib or 
abemaciclib will lead to significant and clinically meaningful improvement in ORR and PFS 
when compared to docetaxel.
9.2.
Sample Size Determination
This study will consist of 2 segments, a Phase 1 dose escalation, and a Phase 2 evaluation of 
clinical activity.  The Phases 1 and 2 segments will each evaluate both monotherapy and 
combination regimens.
Phase 1 segment
The dose escalation phase will initially evaluate doses in sequentially opened cohorts, with the 
possibility to explore additional immediate doses or schedules.  Dose escalation will implement 
the mTPI-2 methodology.  While the mTPI-2 algorithm allows for escalation after as few as 1 
patient is evaluated, a minimum of 3 evaluable patients will be enrolled in each cohort for DLT 
evaluations.  Thus, approximately up to 25 patients will be enrolled across monotherapy regimen 
DLs for dose-escalation evaluations, plus 10 patients per cohort as backfills, totaling 
approximately 45 patients in Part A.  With 4 DL cohorts, this will assure a sufficient number of 
patients will be dosed at the MTD to allow adequate characterization of the overall safety profile.
Combinations with abemaciclib, erlotinib, and cetuximab will be independently evaluated using 
the mTPI-2 methodology.  Approximately 22-30 evaluable patients will be enrolled to each
combination regimen (including up to 10 patients enrolled as “backfills” per cohort).
Phase 2 segment
Once an RP2D is established for all 4 regimens, enrollment to the Phase 2 portion for initial 
evaluation of clinical activity will begin.  There will be 7 cohorts opened.
In NSCLC, the treatment arms will be (with corresponding targeted ORR):

LY3499446 monotherapy (targeted ORR = 35%)

LY3499446 in combination with erlotinib (targeted ORR = 55%)

LY3499446 in combination with abemaciclib (targeted ORR = 55%)

Docetaxel (historical ORR = 15%)


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In patients with CRC, the treatment arms will be:

LY3499446 monotherapy (targeted ORR = 15%)

LY3499446 in combination with cetuximab (targeted ORR = 25%)
A cohort of patients with solid tumors other than NSCLC or CRC whose tumors harbor the 
KRAS G12C mutation will be treated with LY3499446 monotherapy.
An interim analysis will be conducted within each cohort once approximately 20 patients have 
been enrolled in each arm and evaluated for response per RECIST v1.1.  Patients who do not 
complete an on-treatment or poststudy treatment assessment will be considered nonresponders 
for analysis purposes and will not be replaced.  After the interim, enrollment will continue in the 
remaining arms until at least 20 additional patients are enrolled in each treatment arm.
With a 1-sided significance level of 0.10, we have 80% statistical power to detect a 20% 
difference in response rate (assuming LY3499446 monotherapy: 35% versus control: 15%) with 
approximately 40 patients per arm.  With the same 1-sided significance level of 0.10, we have 
>99% statistical power to detect a 40% difference in response rate (assuming LY3499446 
combination: 55% versus control: 15%) with approximately 40 patients per arm.
For the single-arm Cohort G, with a 1-sided significance level of 0.10, we have 85% statistical 
power to detect a response rate difference of 10%, assuming a historical control rate of 5% and a 
response rate of 15% under the alternative.
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 1) who either complete 
3 weeks of follow-up and at least 80% of treatment doses or discontinue 
treatment prior to 3 weeks due to a DLT.  Patients enrolled into the cetuximab 
combination cohorts must receive 2 out of 3 cetuximab doses to be considered 
DLT evaluable.
Randomized
(Phase 2 portion only). All patients with either CRC or NSCLC who are 
randomized to a treatment regimen, regardless of whether they take any study 
drug.
PK evaluable
All enrolled patients who have at least 1 postbaseline 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 1
All patients assigned to a treatment cohort during the dose escalation (Phase 1) 
portion of the study.
Phase 2
All patients randomized to treatment during the Phase 2 portion of the trial 
(NSCLC and CRC cohorts), regardless of whether the cohort to which they are 
assigned is closed during or at the end of the Phase 2 portion of the study or 
continues to Phase 3.  All patients enrolled to the “Other Tumors” cohort 


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(nonrandomized).
Abbreviations:  CRC = colorectal carcinoma; DLT = dose-limiting toxicity; NSCLC = nonsmall cell lung cancer; 
PK = pharmacokinetics.


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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 (i.e., safety) patients within each 
phase of the study.  This set includes all data from all enrolled participants within a study phase, 
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 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 
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.  A summary of baseline patient and disease characteristics, 
historical diagnoses, pre-existing conditions, and prior therapies will be reported using 
descriptive statistics.
9.4.2.3.
Concomitant Therapy
A summary of prior and concomitant medications by treatment cohort 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.


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9.4.3.
Efficacy Analyses
9.4.3.1.
Primary Analyses
Phase 1
There is no primary efficacy endpoint for the Phase 1 portion of the study, as the primary 
objective is to determine an RP2D, based on the incidence of DLTs and totality of data 
(including, but not limited to, PK, target occupancy, and clinical response data).
Phase 2
For the Phase 2 portion of the study, the primary analysis will be an evaluation of whether any of 
the treatment regimens are likely to provide a clinically relevant level of activity.  This will be 
based on an evaluation of the ORR within each treatment arm, and evaluation of PFS in the 
NSCLC cohorts.  Primary efficacy assessment will be based on an independent review of 
imaging data.  Comparative analyses will be done for Phase 2, Cohorts E1 through E4 (NSCLC), 
and separately for Phase 2 Cohorts F1 and F2 (CRC).
At the first interim analysis (approximately 20 patients enrolled in each arm), a determination 
will be made whether any of the treatment arms may be dropped due to limited clinical activities.  
An integrated benefit-risk assessment from other data such as DOR, PK, target occupancy, 
tolerability, and safety will also be used to determine if a treatment arm should be stopped early 
due to futility.  Otherwise, approximately 20 additional patients will be randomized or enrolled 
to each of the remaining treatment arms to confirm the efficacy signals.  A final analysis of the 
Phase 2 ORR and PFS will be performed after all patients randomized to an arm have had the 
opportunity of having at least 3 months (for ORR evaluations) or 6 months (for PFS evaluations) 
of follow-up.  See Section 9.5 for details of the interim analyses.
Enrollment may be discontinued due to futility if the response rate in the first 20 patients 
enrolled in any one arm is less than:

20% for arms E1, E2, or E3, and

10% for arms F1 or F2
In addition to ORR, an integrated benefit-risk assessment considering DOR, PK, target 
occupancy, tolerability, and safety will also be used to determine if a treatment arm should be 
stopped early due to futility.
9.4.3.2.
Secondary Analyses
Assessments of PFS (CRC and Other Tumors cohorts) and OS (all cohorts) in Phase 2 will be 
performed as secondary analyses.  Data from Phase 1 subjects will be summarized within each 
treatment cohort, but comparisons between cohorts will not be made.  Data from Phase 2 
subjects will be summarized within treatment arms.  Comparisons between treatment arms will 
be made within tumor type.  Survival rates at various time points (e.g., at 3, 6, 9, and 12 months), 
75%, median, and 25% survival times will be reported, including differences between arms and 
their 95% confidence interval.
Progression-free survival is defined as the time from the date of randomization until the 
first occurrence of documented disease progression per RECIST v1.1 criteria, or death from any 


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cause in the absence of documented PD. Patients known to be alive and without disease 
progression will be censored at the time of the last adequate tumor assessment. Progression-free 
survival will be compared between treatment arms using a stratified log-rank test, stratified 
by the randomization strata. The corresponding HR between treatment arms will be estimated 
using a stratified Cox regression model (Cox 1972), stratified by randomization 
strata. Progression-free survival curves, median PFS, and PFS rates at various time points with 
95% confidence interval for each treatment arm will be estimated using the Kaplan-Meier 
method (Kaplan and Meier 1958). Sensitivity analyses for PFS will be described in the SAP.
Symptomatic deterioration (i.e., symptomatic progression that is not confirmed per RECIST 
v1.1) will not be considered as tumor progression.
PFS Event/Censoring Scheme
Situation
Event/Censor Date of Event or Censor
Tumor progression or death
Event
Earliest date of PD or death
No tumor progression and no death
Censored
Date of last adequate tumor assessment,
per RECIST v1.1 criteria, or date of 
randomization (whichever is later)a
Unless
No baseline radiologic tumor assessment 
available
Censored
Date of randomization
No adequate postbaseline tumor 
assessment available and death reported 
after 2 scan intervals following
randomizationa,b
Censored
Date of randomization
Tumor progression or death documented
immediately after 2 or more scan 
intervals following last adequate tumor 
assessment or randomization (whichever 
is later)a,b
Censored
Date of last adequate tumor assessment, 
per RECIST v1.1 criteria, or date of 
randomization (whichever is later)a
New therapeutic anticancer treatment 
started prior to tumor progression or 
death
Censored
Date of last adequate radiological 
assessment prior to new therapeutic 
anticancer therapya


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Abbreviations: CR = complete response; PD = progressive disease; PFS = progression-free survival; PR = partial 
response; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1; SD = stable disease.
a
Adequate tumor assessment per RECIST v1.1 criteria refers to an assessment with one of the following 
responses: CR, PR, SD, or PD.
b
Refer to the statistical analysis plan for the definition of 2 scan intervals, including any adjustment for scan 
window.
9.4.4.
Safety Analyses
All patients who receive at least 1 dose of any study therapy will be evaluated for safety and 
toxicity.
Safety analyses will include summaries of the following:

DLTs at each DL

AEs, including severity and possible relationship to study drug

DLT-equivalent AEs, including severity and possible relationship to study drug

SAEs, including possible relationship to study drug

AEs leading to dose 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.
PK/Pharmacodynamic Analyses
Pharmacokinetic analyses will be conducted on patients who have received at least 1 dose of the 
study drug and have sufficient samples collected to allow the estimation of LY3499446 PK 
parameters.
Pharmacokinetic parameter estimates for LY3499446 will be calculated using standard 
noncompartmental methods of analysis.  The primary parameters for analysis will be maximum 
concentration and area under the concentration-time curve (AUC[0-tlast], AUC[0-∞]) of
LY3499446.  Other noncompartmental parameters, such as half-life, apparent clearance, and 
apparent volume of distribution, may be reported.
Additional analyses such as population PK analyses may also be conducted if deemed 
appropriate.  Other validated PK software programs (for example, NONMEM) may be used if 
appropriate and approved by Global PK management.  The version of any software used for the 
analysis will be documented and the program will meet the Lilly requirements of software 
validation.
Pharmacokinetic/pharmacodynamic analyses may be conducted to explore exposure-response 
relationships between LY3499446 concentrations in systemic circulation and various 
pharmacodynamic measures or clinical outcomes.
Plasma concentrations of erlotinib, abemaciclib and its metabolites, and serum concentrations of 
cetuximab at different time points will be summarized by descriptive statistics.


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9.4.6.
Other Analyses
9.4.6.1.
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.
9.4.6.2.
Biomarker Analyses
Single-marker and/or multi-marker statistical analysis may be performed to explore the 
association between biomarkers, dose/exposure, and clinical outcomes.
9.5.
Interim Analyses 
In the Phase 1 portion of this study, data will be reviewed for safety on a cohort-by-cohort basis 
during the study, 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.  Before opening of the randomized Phase 2 portion of this study, a formal 
interim analysis including all Phase 1 data will be performed to conclude the safety profiles and 
RP2Ds.
The Phase 2 portion of Study JZKA comprises more than 3 cohorts and may warrant additional 
considerations to ensure patient safety.  
Lilly has systematic and robust internal processes in place that ensure safety surveillance of 
development compounds in line with expectations of Regulatory Agencies.  This includes 
processes with clearly described roles and responsibilities that are owned by Lilly’s Global 
Patient Safety organization. These processes are designed to monitor the evolving safety profile 
(i.e., review of cumulative SAEs and other important safety information) by designated 
crossfunctional teams in a timely manner at predefined intervals or on an ad-hoc basis.  In 
addition, a dedicated process may be used to perform unblinded comparisons of event rates for 
SAEs, as necessary.  
This system ensures that the accumulating safety data derived from individual and multiple trials 
across a development program are reviewed on a regular basis and that important new safety 
information such as the need for protocol modification or other relevant safety-related material is 
identified and communicated to regulators and investigators appropriately and in a timely 
fashion.  An internal review of aggregate safety data occurs on at least a quarterly basis or more 
frequently, as appropriate.  Any serious adverse reactions (SARs) are reported within the 
required timeline for expedited reporting.
In addition to annual periodic safety updates and to further inform investigators, a line listing 
reports of SUSARs is created and distributed to investigators on a biannual (twice yearly) basis.  
Any significant potential risk/safety concerns that are being monitored, as well as any results 
being reported in other periodic reports for the compound, SAC decisions, and other significant 


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safety data (for example, nonclinical, clinical findings, and removal of SARs) are included in the 
report.
In the Phase 2 portion of this study, a safety review will be performed after the first 20 patients 
across all cohorts (NSCLC, CRC, and Other Tumors) are enrolled and treated for 1 cycle, and 
then every 6 months afterward.
In the Phase 2 portion of this study:

For the NSCLC cohorts, an interim analysis of safety and efficacy is planned after 
approximately 20 patients in each cohort are treated and have completed 2 cycles or have 
discontinued before the first postbaseline tumor assessment.  At this first interim analysis, 
the totality of data (including, but not limited to, safety and preliminary efficacy) will be 
used to determine if any of the treatment cohorts (E1, E2, E3) may be dropped due to 
limited clinical activities relative to the active comparator (E4).  After the data cutoff date 
of this interim analysis, approximately 20 additional patients will be randomized to each 
of the remaining treatment arms to confirm the efficacy signals.  Enrollment will be 
paused until the interim analysis has been completed.

For the CRC cohorts, an interim analysis of safety and efficacy is planned after 
approximately 20 patients in each arm are treated and have completed 2 cycles or have 
discontinued before the first postbaseline tumor assessment.  Enrollment will be paused 
until the interim analysis has been completed.  Depending on the preliminary efficacy 
signal and totality of data, 1 arm may be dropped for futility.  An additional 40 patients 
will be enrolled into the remaining arm.  If no meaningful difference in efficacy or safety 
is observed in between the 2 arms, the 40 additional patients may be randomized at a 1:1 
ratio, leading to approximately 80 total randomized patients (40 in each arm).  Depending 
on the magnitude of clinical response observed in terms of durable objective responses, 
Study Protocol JZKA may be amended to provide for a more robust assessment of 
benefit/risk in this setting.  The futility rules will be detailed in the SAP.

For the Other Tumors cohort, an interim of safety and efficacy is planned after 
approximately 20 patients are treated and have completed 2 cycles or have discontinued 
before the first postbaseline tumor assessment.  The trial will continue to enroll an 
additional 20 patients for the final analysis.
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.).


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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
o
Applicable laws and regulations.

The protocol, protocol amendments, ICF, IB, and other relevant documents (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 Code of Federal Regulations (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 


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Insurance Portability and Accountability Act requirements, where applicable, and the 
IRB/IEC or study center.

The medical record must include a statement that written informed consent was obtained 
before the participant was entered in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative and kept on file.
Participants who are rescreened are required to sign a new ICF.
10.1.3.
Data Protection

Participants will be assigned a unique identifier by the investigator.  Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable will 
not be transferred.

The participant and/or legal representative, when applicable, must be informed that 
his/her personal study-related data will be used by the sponsor in accordance with local 
data protection law.  The level of disclosure must also be explained to the participant.

The participant and/or legal representative, when applicable, must be informed that 
his/her medical records may be examined by Clinical Quality Assurance auditors or other 
authorized personnel appointed by the sponsor, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
10.1.4.
Dissemination of Clinical Study Data
Dissemination of study data will be performed according to all applicable Lilly and international 
policies.
10.1.5.
Data Quality Assurance
To ensure accurate, complete, and reliable data, the sponsor or its representatives will do the 
following:

provide instructional material to the study sites, as appropriate

provide sponsor start-up training to instruct the investigators and study coordinators.  
This training will give instruction on the protocol, the completion of the CRFs, and study 
procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and verify data reported to detect potential errors 


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In addition, the sponsor or its representatives will periodically check a sample of the participant 
data recorded against source documents at the study site.  The study may be audited by the 
sponsor or its representatives and/or regulatory agencies at any time.  Investigators will be given 
notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An electronic data capture system will be used in this study for the collection of CRF data.  The 
investigator maintains a separate source for the data entered by the investigator or designee into 
the sponsor-provided electronic data capture system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Data collected via the sponsor-provided data-capture system(s) will be stored by a third-party.  
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s).  Prior to decommissioning, the investigator will 
receive an archival copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system, and results will be provided to the investigator for review 
and retention.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
10.1.6.
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available.
10.1.7.
Study and Site Closure
10.1.7.1.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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10.1.7.2.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.


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


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Clinical Laboratory Tests
Hematologya,b
Clinical Chemistrya,b
Leukocytes (WBC)
Serum Concentrations of:
Neutrophilsc
ALT
Lymphocytes
Albumin
Monocytes
Alkaline phosphatase
Eosinophils
AST
Basophils
Bilirubin, direct
Erythrocytes (RBC)
Bilirubin, total
HGB
BUN or blood urea
HCT
Calcium
PLT
Creatinine 
Creatine kinase
Urinalysisb
Glucose (random)
Blood
Magnesium
Glucose
Phosphorous
Ketones
Potassium
pH
Protein
Protein
Sodium
Specific gravity
Urine leukocyte esterased
Pregnancy Testb,c
Urine or serum pregnancy test
Thyroid Functionb,e
TSH
Coagulationb
FT4
PT/INR
aPTT


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Abbreviations:  ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; CRF = case report form; FT4 = free thyroxine; HCT = hematocrit; 
HGB = hemoglobin; INR = international normalized ratio; PLT = platelets; PT = prothrombin time; RBC = red 
blood cells; TSH = thyroid-stimulating hormone; 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
Local or investigator-designated laboratory.
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.
e
FT4 should only be collected if TSH is not within normal limits.


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10.3.
Appendix 3:  Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Women of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 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 and 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 level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT).  However, in the 
absence of 12 months of amenorrhea, confirmation with more than 1 follicle 
stimulating hormone measurement >40 mIU/mL is required. 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the nonestrogen 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:


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


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spermicides only, and lactational amenorrhea method are not acceptable methods of contraception for this study.  
Male condom and female condom should not be used together (due to risk of failure with friction).
Collection of Pregnancy Information
Male participants with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study.  This
applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy.  The 
female partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to the sponsor.  
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for the procedure. 
Female Participants who become pregnant

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study.  Information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant's pregnancy. 

The participant will be followed to determine the outcome of the pregnancy.  The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor.  Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date.  Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) 
or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE.  A 
spontaneous abortion is always considered to be an SAE and will be reported as such.  
Any poststudy 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 
discontinue study intervention and be withdrawn from the study.


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10.4.
Appendix 4:  Liver Safety:  Suggested Actions and Follow-Up 
Assessments
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with participants in consultation with the Lilly CRP/CRS.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
HGB
HCT
Hepatic Coagulationa
Erythrocytes (RBC)
Prothrombin time
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
PLT
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
TBL
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Recommended Autoimmune Serology
AST
Antinuclear antibodya
GGT
Antismooth muscle antibodya
CPK
Antiactin antibodya
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CRF = case report form; 
CPK = creatinine phosphokinase; GGT = gamma-glutamyl transferase; HCT = hematocrit; HGB = hemoglobin; 
Ig = immunoglobulin; INR = international normalized ratio; PLT = platelets; RBC = red blood cells; TBL = total 
bilirubin; WBC = white blood cells.
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.


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10.5.
Appendix 5:  Country-Specific Requirements
10.5.1.
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 (SoA), Section 8.3 (AEs and 
SAEs), and Section 8.2 (Safety Assessments) of the protocol.


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10.6.
Appendix 6:  Inducers and Strong Inhibitors of CYP3A
The information in this table is provided for guidance to investigators and does not 
preclude the use of these medications if clinically indicated.
Strong Inducers of CYP3A
Carbamazepine
Dexamethasone
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St John’s wort
Moderate Inducers of CYP3A
Bosentan
Lenisurad
Modafinil
Primidone
Telotristat ethyl
Strong Inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin
Conivaptan
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Posaconazole
Troleandomycin
Verapamil
Abbreviation:  CYP = cytochrome P450.


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10.7.
Appendix 7:  Creatinine Clearance Formula
Note:  This formula is to be used for calculating creatinine clearance from local laboratory 
results only.
Cockcroft-Gault prediction of creatinine clearance from serum creatinine (Cockroft and Gault 
1976)
For serum creatinine concentration in mg/dL:
CrCl =
(mL/min)
(140 – age
a) (wt) 0.85 (if female), or 1.0 (if male)
72 serum creatinine (mg/dL)
For serum creatinine concentration in µmol/L:
CrCl =
(mL/min)
(140 – age
a) (wt) 0.85 (if female), or 1.0 (if male)
0.81 serum creatinine (μmol/L)
Abbreviations:  CrCl = creatinine clearance; wt = weight.
a
Age in years, wt in kilograms.
Source:  Cockcroft and Gault 1976.


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10.8.
Appendix 8:  Dose-Finding Algorithm of the mTPI-2 Method 
Showing Number of Patients Treated
Abbreviations:  DLT = dose-limiting toxicity; mTPI-2 = modified toxicity probability interval-2.
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.


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
If 1 of 6 patients experiences a DLT, escalate the dose (see “E” at column 6, row 1).

If 2 of 3 patients experience a DLT the dose to treat the next patient is de-escalated (see 
“D” at column 3, row 2).  If 5 of 7 patients experience a DLT, the dose is determined to 
be unacceptably toxic and will never be used again in the trial (see “DU” at column 7, 
row 5).


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10.9.
Appendix 9:  Examples of Sensitive and Moderately Sensitive 
CYP2C9 and CYP2C19 Substrates
The information in this table is provided for guidance to investigators and does not preclude the 
use of these medications if clinically indicated.
Isoform
Sensitive substrates
Moderately sensitive substrates
CYP2C9
celecoxib
glimepiride, phenytoin, tolbutamide, warfarin
CYP2C19
S-mephenytoin, omeprazole
diazepam, lansoprazole, rabeprazole, voriconazole
Abbreviation: CYP = cytochrome P450.


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10.10.
Appendix 10:  Abbreviations
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the curve
BID
twice daily
BOR
best overall response
CDK
cyclin-dependent kinase
CFR
Code of Federal Regulations
CNS
central nervous system
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety, effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CR
complete response
CRC
colorectal cancer
CRF
case report form
CRP/CRS
clinical research physician/clinical research scientist:  Individual responsible for the 
medical conduct of the study.  Responsibilities of the CRP/CRS may be performed by a 
physician, clinical research scientist, global safety physician, or other medical officer.
CSR
clinical study report
CT
computed tomography
CYP
cytochrome P450


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CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DL
dose level
DLT
dose-limiting toxicity
ECG
electrocardiogram
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
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
FDA
Food and Drug Administration
GCP
good clinical practice
G-CSF
granulocyte colony-stimulating factor
GDP
guanosine diphosphate
GEF
guanine nucleotide exchange factors
GFR
glomerular filtration rate
GTP
guanosine triphosphate
HNSTD
highest nonseverely toxic dose
HR
hazard ratio
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committees
ILD
interstitial lung disease


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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, 
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
Institutional Review Board
IV
intravenous
LC-MS/MS
liquid chromatography-tandem mass spectrometry
MATE
multidrug and toxin extrusion protein
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTPI-2
modified toxicity probability interval-2
NCI
National Cancer Institute
NOAEL
no-observed-adverse-effect-level
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PO
orally
PR
partial response
QD
daily


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QOD
once every other day
QTc
corrected QT interval
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SAR
serious adverse reaction
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
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin
UK
United Kingdom
ULN
upper limit of normal
UN
unknown
WOCBP
women of childbearing potential


C O N FI D E N TI A L
Pr ot oc ol  J 2 K-M C -J Z K A( b)
L Y 3 4 9 9 4 4 6
1 1 4
1 0. 1 1.
A p pe n di x 1 1 :  Pr ot oc ol A me n d me nt Hist or y
A me n d me nt ( a)
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he cri t eria set f ort h i n Art icle 1 0(a) of 
Di recti ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.
O ver all R ati o n ale f or t he A me n d me nt:
T his a me n d me nt i nc or p orates c ha n ges acc or di n g t o re g ulat or y a ge nc y fee d bac k.  A d ditio nall y, 
clarificatio ns were m a de t hr o u g h o ut t he d oc u me nt t o i m pr o ve c o nsiste nc y  a n d rea da bilit y for 
sites a n d i n vestigat ors.
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 1. 1: S y n o psis; 
Secti o n 4. 1. 1. 1 D ose 
Escal at i on Met h o d; 
Secti o n 9. 5: I nteri m 
A nal yses
A d dit i onal la n g ua ge a d de d t o clarif y 
e nr o ll me nt
Per re g ul at or y fee d bac k
Secti o n 1. 2. 1: P hase 1 
Sc he ma; Sect i on 1. 2. 2: 
P hase 2 Sc he ma
M o ve d start of e nr o ll me nt of erl oti ni b 
c o h orts t o matc h ti min g of  
a be macicli b c o h orts i n P hase 1
Per re g ul at or y fee d bac k
Secti o n 1. 3: Sc he d ule of 
Act i vities
A d de d f o ot n otes s pecif yi n g d urati o n 
of  s h ort-t er m a n d lo n g- t er m fol l ow - u p
Per re g ul at or y fee d bac k
Secti o n 2. 3: Be nefit/ Ris k 
Assess me nt
Pr o vi de d a d di tio nal  in f or matio n f or 
erloti ni b, cet u xi ma b, a n d a be macicli b 
c o m bi nat i ons
Per re g ul at or y fee d bac k
Secti o n 3: O bject i ves a n d 
E n d p oi nts; Secti o n 1. 1 
S y n o psis
A d de d se parate sec o n dar y  o bject i ve 
b ullet f or Ot her t u m ors c o h ort
Per re g ul at or y fee d bac k
Secti o n 4. 1. 1. 1: D o se 
Escal at i on met h o d
A d de d c o n dit i onal state me nt for 
starti n g L Y 3 4 9 9 4 4 6 d ose at 
Per re g ul at or y fee d bac k
Secti o n 4. 1. 1. 1: D ose 
Escal at i on Met h o d; 
Secti o n 9. 1: Stati stical 
H y p ot heses; A p pe n di x 8
C ha n ge d e q ui vale nce i nter val t o ( 2 7 %, 
3 3 %); u p date d d ose -fi n di n g al g orit h m 
fi g ure
Per re g ul at or y fee d bac k
Secti o n 4. 1. 1. 2: D ose -
Li mit i n g T o xicit y 
Deter mi nat i on
Re vise d D L T criteria
Per re g ul at or y fee d bac k
Secti o n 5. 1: I ncl usi o n 
Cri teria; Sectio n 5. 2: 
E xcl usi o n Cri t eria
M o difie d i ncl usi o n/e xcl usi o n cri t eria 
2, 1 6, a n d 1 9; A d de d e xcl usi o n 2 7.
Per re g ul at or y fee d bac k
Secti o n 6. 1: St u d y  
I nter ve nti o n(s) 
A d de d d osi n g la n g ua ge relat i ve t o 
Per re g ul at or y fee d bac k
C CI


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Section # and Name
Description of Change
Brief Rationale
Administered
food intake
Section 6.3: Measures to 
Minimize Bias: 
Randomization and 
Blinding
Revised stratification factors
Per regulatory feedback
Section 6.5: Concomitant 
Therapy; Section 6.5.1: 
Use of Gastric pH 
Modifying Agents
Provided additional cautionary 
language for erlotinib 
Per regulatory feedback
Section 6.5.3: Supportive 
Management for Diarrhea
Modified diarrhea management 
language to be applicable for all study 
drugs
Per regulatory feedback
Section 6.6.1: Dose 
Modification of 
LY3499446
Modified diarrhea dose modifications 
and added guidance for interstitial 
lung disease
Per regulatory feedback
Section 6.6.6 Dose 
Modification for Grade 3 
Toxicities Not Clearly 
Related to LY3499446 or 
Drug Given in 
Combination
Guidance added for Grade 3 toxicities 
not related to LY3499446 or 
combination drugs
Per regulatory feedback
Section 9.2: Sample Size 
Determination; 9.4.3.1: 
Primary Analyses
Additional statistical justification 
provided and clarity added to 
descriptions of Phase 2 cohorts
Per regulatory feedback
Section 1.3: Schedule of 
Activities
Moved Phase 2 CRC biomarker serum 
samples on C2D1 and C3D1 to C1D8 
and C1D15
Modified to align samples 
with biopsy time points
Section 1.3: Schedule of 
Activities
Removed docetaxel line from Phase 
1a section
Docetaxel will not be 
administered in Phase 1a
Section 9.3: Populations 
for Analyses
Clarified that 2 of 3 cetuximab doses 
are required for cetuximab 
combination cohorts
Modified for consistency with 
DLT evaluability
Throughout
Minor editorial and formatting 
changes
Minor, therefore not 
summarized


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

SAP_001.pdf: 
JZKA SAP v2  
 
Phase 1/2 Study of LY3499446 Administered to Patients with Advanced Solid Tumors with 
KRAS G12C mutation 
 
 
NCT04165301 
 
Approval Date: 04-Feb-2020 


J 2 K -M C - J Z K A St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 1
L Y 3 4 9 9 4 4 6
1.
St ati sti c al A n al y si s Pl a n:  
J 2 K -M C -J Z K A : A P h a s e 1/ 2 St u d y  of L Y 3 4 9 9 4 4 6 
A d mi ni st er e d t o P ati e nt s wit h A d v a n c e d S oli d T u m or s 
wit h K R A S G 1 2 C m ut ati o n
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 t h e i nf or m ati o n c o nt ai n e d 
wit hi n it m a y n ot b e r e pr 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 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.  
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 me 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 nf or 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 e pr 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.
K R A S G 1 2 C I n hi bit or ( L Y 3 4 9 9 4 4 6)
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I ndi a n a U S A 4 6 2 8 5
Pr ot o c ol J 2 K -M C -J Z K A
P h a s e 1/ 2
St ati sti c al A n al y si s Pl a n V er si o n 1 a p pr o v e d b y Lill y o n 2 4 O ct o b er 2 0 1 9 .
St ati sti c al A n al y si s Pl a n V er si o n 2 el e ctr o ni c all y si g n e d a n d a p pr o v e d b y Lill y o n d at e 
pr o vi d e d b el o w.
A p pr o v al D at e: 0 4- F e b- 2 0 2 0 G M T


J2K-MC-JZKA Statistical Analysis Plan Version 2
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   J2K-MC-JZKA: A Phase 1/2 Study of 
LY3499446 Administered to Patients with Advanced Solid Tumors 
with KRAS G12C mutation..................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................7
4.1.
Primary Objective ..........................................................................................................7
4.2.
Secondary Objectives.....................................................................................................7
5.
Study Design.......................................................................................................................9
5.1.
Summary of Study Design..............................................................................................9
5.1.1.
Phase 1 Study Design.............................................................................................9
5.1.2.
Phase 2 Study Design...........................................................................................12
5.2.
Determination of Sample Size ......................................................................................13
5.3.
Method of Assignment to Treatment ............................................................................15
6.
A Priori Statistical Methods ..............................................................................................16
6.1.
General Considerations ................................................................................................16
6.2.
Adjustments for Covariates (Phase 2 Only) ..................................................................17
6.3.
Handling of Dropouts or Missing Data.........................................................................18
6.4.
Multicenter Studies ......................................................................................................19
6.5.
Multiple Comparisons/Multiplicity...............................................................................19
6.6.
Use of an “Efficacy Subset” of Patients........................................................................19
6.7.
Patient Disposition .......................................................................................................20
6.8.
Patient Characteristics ..................................................................................................20
6.9.
Treatment Compliance .................................................................................................20
6.10. Concomitant Therapy...................................................................................................20
6.11. Efficacy Analyses ........................................................................................................21
6.11.1.
Efficacy Definitions .............................................................................................21
6.11.2.
Efficacy Analyses for Phase 1 ..............................................................................22
6.11.3.
Efficacy Analyses for Phase 2 ..............................................................................23
6.11.3.1.
Primary Analyses ...........................................................................................23
6.11.3.2.
Secondary Analyses........................................................................................23
6.12. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................24
6.13. Safety Analyses............................................................................................................24
6.13.1.
Extent of Exposure...............................................................................................24
6.13.2.
Adverse Events ....................................................................................................25


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6.13.2.1.
Overall Summary of Adverse Events ..............................................................25
6.13.2.2.
Treatment-Emergent Adverse Events..............................................................25
6.13.3.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................26
6.13.4.
Clinical Laboratory Evaluation.............................................................................26
6.13.5.
Vital Signs, Physical Findings, and Other Observations 
Related to Safety..................................................................................................26
6.14. Subgroup Analyses.......................................................................................................27
6.15. Protocol Violations.......................................................................................................27
6.16. Interim Analyses and Data Monitoring.........................................................................27
6.17. Annual Report Analyses...............................................................................................29
6.18. Clinical Trial Registry Analyses...................................................................................29
7.
References ........................................................................................................................31


J2K-MC-JZKA Statistical Analysis Plan Version 2
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Table of Contents
Table
Page
Table JZKA.6.1. Data Handling Conventions and Analysis Populations..................................16


J2K-MC-JZKA Statistical Analysis Plan Version 2
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Table of Contents
Figure
Page
Figure JZKA.5.1 Illustration of Phase 1 study design...............................................................11
Figure JZKA.5.2. Illustration of Phase 2 study design...............................................................13


J 2 K -M C - J Z K A St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 6
L Y 3 4 9 9 4 4 6
3.
R e vi si o n Hi st or y
Stati stical A nal ysis Pl a n ( S A P) Versi o n 1 was a p pr o ve d pri or t o t he first visit w he n a s u bject
recei ves st u d y dr u g or a n y ot her pr ot oc ol i nter ve ntio n. T h e S A P V ersio n 1 is base d o n Pr ot oc ol 
J 2 K-M C -J Z K A(a), a p pr o ve d o n 0 7-Oct -2 0 1 9.
T he S A P Versi o n 2 is base d o n Pr ot o c ol  J2 K -M C -J Z K A( b), a s u bsta ntial a me n d me nt a p pr o ve d 
o n 2 1- Ja n-2 0 2 0. P hase 1 p orti o n of  the st u d y was u p date d as a res ult of  obser ve d safety sig nals 
i n i nitiall y e nr olle d pati e nts. A d dit i onal safety g ui da nce f or i n vesti gat ors was als o pr o vi de d. T he 
S A P Versi o n 2 was a p pr o ve d pri or t o t he patie nt e nr o ll me nt i nt o t he C CI


J2K-MC-JZKA Statistical Analysis Plan Version 2
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4.
Study Objectives
4.1.
Primary Objective
Primary Objectives
Endpoints
Phase 1 Dose Escalation:
To characterize the RP2D for LY3499446 when 
administered alone or in combination with either 
abemaciclib, cetuximab, or erlotinib.

DLTs

Assessment of safety 
including, but not limited 
to, TEAEs, SAEs, deaths, 
and clinical lab 
abnormalities per CTCAE 
v5.0
Phase 2:
To assess the efficacy of LY3499446 alone or in 
combination with abemaciclib or erlotinib vs. docetaxel in 
patients with advanced KRAS G12C-mutant NSCLC.
To evaluate the efficacy of LY3499446 alone or in 
combination with cetuximab in patients with advanced 
KRAS G12C mutant CRC.

To evaluate the efficacy of single-agent LY3499446 in 
patients with advanced KRAS G12C-mutant solid tumors 
(other than NSCLC and CRC).

Per RECIST v1.1:
o
ORR (coprimary 
for NSCLC cohorts; 
primary for CRC 
cohorts and Other 
tumors cohort)
o
PFS (coprimary for 
NSCLC cohorts)
Abbreviations:  CRC = colorectal cancer; CTCAE = Common Terminology Criteria for Adverse Events; DLT = 
dose-limiting toxicity; NSCLC = non-small cell lung cancer; ORR = overall response rate; PFS = progression-
free survival; RECIST = Response Evaluation Criteria in Solid Tumors; RP2D = recommended phase 2 dose; 
SAE = serious adverse event; TEAE = treatment-emergent adverse event.
4.2.
Secondary Objectives
Secondary Objectives
Endpoints
Phase 1 Dose Escalation:
To characterize the safety and toxicity profile of 
LY3499446 administered as monotherapy and in 
combination with abemaciclib, erlotinib (NSCLC), or 
cetuximab (CRC) to patients with advanced solid tumors 
with KRAS G12C mutation.  
To assess the PK of LY3499446 administered as 
monotherapy and in combination with abemaciclib, 
erlotinib, or cetuximab in patients with advanced solid 
tumors with KRAS G12C mutation.
To assess any antitumor activity of LY3499446 
administered as monotherapy and in combination with 
Safety as determined by 
(including but not limited 
to) TEAEs, SAEs, deaths, 
and clinical laboratory 
abnormalities per CTCAE 
(Version 5.0)
Plasma concentration of 
LY3499446 administered 
as monotherapy and in 
combination with 
abemaciclib, erlotinib, or 
cetuximab
Per RECIST v1.1:  ORR, 
PFS, DoR, DCR


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Secondary Objectives
Endpoints
abemaciclib, erlotinib, or cetuximab in patients with 
advanced solid tumors with KRAS G12C mutation.
Phase 2:
To assess the efficacy of LY3499446 administered as 
monotherapy or in combination with abemaciclib or 
erlotinib in patients with NSCLC tumors harboring KRAS
G12C mutations, and of LY3499446 administered as 
monotherapy or in combination with cetuximab in patients 
with CRC tumors harboring KRAS G12C mutations, and 
LY3499446 administered as monotherapy in patients with 
solid tumors, other than NSCLC and CRC, harboring KRAS
G12C mutations.
To characterize the safety and toxicity profile of 
LY3499446 administered as monotherapy and in 
combination with abemaciclib, erlotinib, or cetuximab to 
patients with advanced solid tumors with KRAS G12C 
mutation.
To assess the PK of LY3499446 administered as 
monotherapy and in combination with abemaciclib, 
erlotinib, or cetuximab in patients with advanced solid 
tumors with KRAS G12C mutation.

Per RECIST v1.1:
o
DoR, DCR, TTR, 
OS (all cohorts)
o
PFS (CRC cohorts 
and Other tumors)

Safety as determined by 
(including but not limited 
to) TEAEs, SAEs, deaths, 
and clinical laboratory 
abnormalities per CTCAE 
(Version 5.0) 

Plasma concentration of 
LY3499446 administered 
as monotherapy and in 
combination with 
abemaciclib erlotinib, or 
cetuximab
Abbreviations:  CRC = colorectal cancer; CTCAE = Common Terminology Criteria for Adverse Events; 
DCR = disease control rate; DoR = duration of response; NSCLC = non-small cell lung cancer; ORR = overall 
response rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; RECIST = 
Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; TEAE = treatment-emergent 
adverse event; TTR = time to response.


J2K-MC-JZKA Statistical Analysis Plan Version 2
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5.
Study Design
5.1.
Summary of Study Design
Study JZKA is a first in human, multicenter, open-label dose escalation Phase 1 study, followed 
by a cohort- and disease-specific randomized Phase 2, and a monotherapy Phase 2 expansion in 
patients with solid tumors harboring KRAS G12C mutations other than NSCLC and CRC.
Section 5.1.1 describes the Phase 1 study design, and Section 5.1.2 describes the Phase 2 study 
design.
5.1.1. Phase 1 Study Design
The Phase 1 portion will enroll patients with KRAS G12C mutant solid tumors, where patients 
will be treated with monotherapy, or in combination with abemaciclib, erlotinib, or cetuximab. 
Figure JZKA.5.1 illustrates the Phase 1 study design.


J 2 K -M C -J Z K A St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 1 0
L Y 3 4 9 9 4 4 6
C CI
C CI
C CI
C CI


J 2 K -M C - J Z K A St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 1 1
L Y 3 4 9 9 4 4 6
A b bre viati o ns: BI D = t wice dail y; D L T = d ose -li miti n g t o xicit y; N = n u m ber of patie nts; P K = p har mac o ki netics; P O = orall y; 
R P 2 D A = rec o m me n de d p hase 2 d ose i n c o m bi nati o n wit h a be macicli b; R P 2 D C = rec o m me n de d p hase 2 d ose i n c o m bi nati o n wit h 
cet u xi ma b; R P 2 D E = rec o m me n de d p hase 2 d ose i n c o m bi nati o n wit h erl oti ni b; R P 2 D M = m o n ot hera p y  rec o m me n de d p hase 2 d ose.
N ote: D ose de -escalati on c o h orts will o nl y occ ur if t he i nitial L Y 3 4 9 9 4 4 6 d oses are deter mi ne d t o be i nt olera ble. I n a d diti o n t o t he 
L Y 3 4 9 9 4 4 6 d ose le vels s pecifie d i n t his fi g ure, int e r mitte nt d ose le vels, or alter nati ve sc he d ules ma y be e x pl ore d. Si milarl y, l o wer 
d oses or alter nati ve sc he d ules of a be macicli b a n d er l oti ni b ma y be e x pl ore d bel o w t he c urre ntl y a p pr o ve d d oses base d o n e mer gi n g 
safet y data. T he t otalit y of data i ncl u di n g safet y, a n d P K e x p os ure a n d t he i nci de nce of D L T ma y hel p g ui de e val uati n g alter nati ve 
d osi n g a n d sc he d ule (e. g. 
).
Fi g ur e J Z K A . 5. 1
Ill u str ati o n of P h a s e 1 st u d y d e si g n.
C CI


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LY3499446
5.1.2. Phase 2 Study Design
Once a recommended phase 2 dose (RP2D) is established, patients with KRAS G12C mutant 
NSCLC will be randomized across 4 cohorts to evaluate for efficacy and safety to select the 
optimal regimen for further development.  This part is a randomized, controlled, Phase 2 design.
For patients with KRAS G12C mutant CRC, patients will be randomized to either LY3499446 
alone or in combination with cetuximab during the Phase 2 part.
For patients with KRAS G12C mutant solid tumors (other than NSCLC or CRC), an expansion 
cohort of LY3499446 monotherapy will proceed to assess the potential for efficacy once RP2D 
of LY3499446 monotherapy is established.
Figure JZKA.5.2 illustrates the Phase 2 study design.


J2K-MC-JZKA Statistical Analysis Plan Version 2
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LY3499446
Abbreviations:  2L+ = 2 or more lines of therapy; 3L+ = 3 or more lines of therapy; 
CRC = colorectal cancer; N = number of patients; NSCLC = non-small cell lung 
cancer; R = randomization; RP2DA = recommended phase 2 dose in combination with 
abemaciclib; RP2DC = recommended phase 2 dose in combination with cetuximab; 
RP2DE = recommended phase 2 dose in combination with erlotinib; 
RP2DM = monotherapy recommended phase 2 dose.
a
An interim analysis will take place after approximately 20 patients have been 
enrolled within each cohort.  
Figure JZKA.5.2.
Illustration of Phase 2 study design.
5.2.
Determination of Sample Size
This study will consist of 2 segments, a Phase 1 dose escalation, and a Phase 2 evaluation of 
clinical activity.  The Phases 1 and 2 segments will each evaluate both monotherapy and 
combination regimens.
Phase 1 segment
The dose escalation phase will initially evaluate doses in sequentially opened cohorts, with the 
possibility to explore additional immediate doses or schedules. Dose escalation will implement 


J 2 K -M C -J Z K A St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 1 4
L Y 3 4 9 9 4 4 6
t he m T PI - 2 met h o d ol o g y . W hile t he m T PI - 2 al g ori t h m all o ws f or escalat i on aft er as fe w as 1 
patie nt is e val uate d, a mi ni m u m of  3 eval ua ble pati e nts will be e nr o lle d i n eac h c o h ort f or D L T 
e val uat i ons. T h us, a p pr o xi matel y u p t o 2 5 patie nts will be e nr o lle d acr oss m o n ot hera p y  re gi me n 
D Ls 
f or d ose -escalat i on e val uat i ons, p l us 1 0 patie nts per c o h ort as bac kfills, t otali n g 
a p pr o xi matel y 4 5 pat ient s i n P art A. Wit h 4 D L c o h orts, t his will ass ure a s ufficie nt n u m ber of  
pati e nts will be d ose d at t he M T D t o all o w a de q uate c haracterizat i on of t he o verall safet y pr ofile.
 
 
 
 
 
 
teste d. A h y p ot hetical e xa m ple f or t he M T D deter mi nat i on is s h o w n bel o w . I n t his e xa m ple, 
d ose l e vel 3 
 is t he M T D.
D ose Le vel
1 
2 (
3 
4 
# D L Ts
0
1
1
2
# E val ua ble Pat ient s 
3
4
6
2
I n case m ult i ple d osi n g stre n gt hs of  t he sa me d osi n g sc he me (e. g., Q D or BI D) ar e e val uate d, if 
a p plica ble t he fi nal M T D ma y be deter mi ne d f or eac h d osi n g sc he me i nstea d of  b y a g gre gati n g 
all data t o get her.
C o m bi nat i ons wi t h abe macicli b, erloti ni b, a n d cet u xi ma b will be i n de pe n de ntl y e val uate d usi n g 
t he m T PI - 2 met h o d ol o g y . A p pr o xi matel y  22- 3 0 e val ua ble pat ient s will be e nr o lle d t o eac h 
c o m bi nat i on re gi me n (i ncl u di n g u p t o 1 0 patie nts e nr o lle d as “ bac kfills” per c o h ort).
P h ase 2 se g me nt
O nc e a n R P 2 D is esta blis he d f or all 4 re gi me ns, e nr oll me nt t o t he P hase 2 p orti o n f or i nit ial 
e val uat i on of cli nical act i vity will  be gi n.  T here will be 7 c o h orts o pe ne d.
I n N S C L C, t he treat me nt ar ms will be ( wit h c orres p o n di n g tar gete d O R R):

L Y 3 4 9 9 4 4 6 m o n ot h era p y (tar gete d O R R = 3 5 %)

L Y 3 4 9 9 4 4 6 i n c o m bi nati o n wit h erl oti ni b (tar gete d O R R = 5 5 %)

L Y 3 4 9 9 4 4 6 i n c o m bi nati o n wit h a be macicli b (tar gete d O R R = 5 5 %)

D oceta xel ( hist orical O R R = 1 5 %)
I n patie nts wit h C R C, t he treat me nt ar ms will be:

L Y 3 4 9 9 4 4 6 m o n ot hera p y  (tar gete d O R R = 1 5 %)

L Y 3 4 9 9 4 4 6 i n c o m bi nati o n wit h cet u xi ma b (tar gete d O R R = 2 5 %)
A c o h ort of  patie nts wi t h sol i d t u mors ot her t ha n N S C L C or C R C w h ose t u mors har b or t he 
K R A S G 1 2 C m ut atio n will be treate d wit h L Y 3 4 9 9 4 4 6 m o n ot hera p y .
C CI
C CI
C CI
C CI
C CI
C CI


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An interim analysis will be conducted within each cohort once approximately 20 patients have 
been enrolled in each arm and evaluated for response per RECIST v1.1.  Patients who do not 
complete an on-treatment or poststudy treatment assessment will be considered nonresponders 
for analysis purposes and will not be replaced.  After the interim, enrollment will continue in the 
remaining arms until at least 20 additional patients are enrolled in each treatment arm.
With a 1-sided significance level of 0.10, we have 80% statistical power to detect a 20%
difference in response rate (assuming LY3499446 monotherapy: 35% versus control: 15%) with
approximately 40 patients per arm. With the same 1-sided significance level of 0.10, we have
>99% statistical power to detect a 40% difference in response rate (assuming LY3499446
combination: 55% versus control: 15%) with approximately 40 patients per arm.
For the single-arm Cohort G, with a 1-sided significance level of 0.10, we have 85% statistical
power to detect a response rate difference of 10%, assuming a historical control rate of 5% and a
response rate of 15% under the alternative.
5.3.
Method of Assignment to Treatment
The Phase 2 part of study JZKA will implement a randomization design to mitigate the selection 
bias in allocating patients with NSCLC or CRC to either monotherapy or combination therapies.
Patients enrolled into the Phase 2 NSCLC and CRC cohorts will be stratified by the following
factors:

NSCLC patients
o
Lung only metastases versus others
o
Co-occurring mutations KRAS G12C + P53 (KP) versus KRAS G12C + KEAP1 
or KRAS G12C + LKB1 (KL) versus others (K)

CRC patients
o
Sidedness of the tumor (right versus left)
o
Sites of metastases (1 versus 2 versus >2)
Randomization will occur using an Interactive Web Response System (IWRS). Assignment to
treatment groups will be determined by a computer-generated random sequence. 


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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company. The 
interpretation of the study results will be the responsibility of the investigator with the Lilly CRP 
or CRS, pharmacokineticist, and statistician. The CRP or CRS and statistician will also be 
responsible for the appropriate conduct of an internal review for both the final study report and 
any study-related material to be authorized by Lilly for publication.
Sponsor standard tables, figures, and listings (TFLs) and supporting programs and software (e.g., 
TAFFY, BEACH) will be utilized for all analyses where a suitable standard exists. Data
derivations in this SAP are defined, based upon current Sponsor reporting standards at the time
of writing, and may be updated at the time of analysis in order to maintain accordance with the
most current Sponsor standards at that time.
In general, continuous variables will be presented using the mean, standard deviation, coefficient
of variation, median, minimum, maximum and number of patients with an observation (n). For
categorical variables, the population size (N), the number of patients with events (n) and the
percentage of patients with events are usually reported.
All confidence intervals (CIs) will be given at a 2-sided 95%, unless otherwise stated.
The data handling conventions and analysis populations are outlined in Table JZKA.6.1.
Table JZKA.6.1.
Data Handling Conventions and Analysis Populations
Term
Definition or Rule
Relative Study
Day
The study day of a safety event or assessment will be calculated as:

the difference between the date of the event or assessment and the 
date of first dose plus 1 for all events or assessments occurring on or 
after the day of first dose. For example, if an event occurs on 
08JUN2017 and the date of first dose was 06JUN2017, the study day 
of the event is 3.

the difference between the date of the event or assessment and the 
date of first dose for all events or assessments occurring before the 
day of first dose. For example, if an event occurs on 05JUN2017 and 
the date of first dose was 06JUN2017, the study day of the event is -
1.
The study day of an efficacy event or assessment will be calculated as:

the difference between the date of the event or assessment and the 
date of randomization plus 1 for all events or assessments occurring 
on or after the date of randomization.

the difference between the date of the event or assessment and the 
date of randomization for all events or assessments occurring before 
the date of randomization.
Cycle Day
If assessment is on or after date of first dose in cycle then
(date of assessment) – (date of first study drug dose in cycle) +1
There is no Cycle Day 0. Cycle Day 1 is the date of first dose in that cycle.


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Term
Definition or Rule
Baseline
The baseline value of a safety assessment is the last value observed prior to 
the first dose. This may occur on the day of first dose.
The baseline value of an efficacy assessment is the last value observed prior 
to the date of randomization. If a patient’s first assessment occurs after 
randomization but prior to the first dose, this assessment will be used as the 
baseline.
Entered
All participants who sign informed consent
DLT evaluable
All patients enrolled in the dose escalation phase (Phase 1) who either 
complete 3 weeks of follow-up and at least 80% of treatment doses or 
discontinue treatment prior to 3 weeks due to a DLT.
Randomized (ITT)
(Phase 2 portion only). All patients with either CRC or NSCLC who are 
randomized to a treatment regimen, regardless of whether they take any study 
drug.
PK evaluable
All enrolled patients who have at least 1 postbaseline 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.
Per-Protocol
ITT (randomized) patients who received any study therapy and did not have 
any important protocol deviations that could potentially affect the efficacy 
conclusion.
Phase 1
All patients assigned to a treatment cohort during the dose escalation (Phase 
1) portion of the study.
Phase 2
All patients randomized to treatment during the Phase 2 portion of the trial 
(NSCLC and CRC cohorts), regardless of whether the cohort to which they 
are assigned is closed during or at the end of the Phase 2 portion of the study 
or continues to Phase 3.  All patients enrolled to the “Other Tumors” cohort 
(nonrandomized).
Screen Failures
Patients who have signed informed consent, do not meet eligibility criteria 
and are not enrolled.
Abbreviations:  CRC = colorectal cancer; DLT = dose-limiting toxicity; ITT = intent-to-treat; NSCLC = non-small 
cell lung cancer; PK = pharmacokinetic(s).
Any change to the data analysis methods described in the protocol/SAP will require an 
amendment ONLY if it changes a principal feature of the protocol/SAP. Any other change to the 
data analysis methods described in the protocol/SAP, and the justification for making the change, 
will be described in the clinical study report. Additional exploratory analyses will be conducted 
as deemed appropriate.
6.2.
Adjustments for Covariates (Phase 2 Only)
As supportive analysis, the primary PFS endpoint in Phase 2 will also be analyzed adjusting for 
potential prognostic factors, including all stratification factors and variables identified for 
subgroup analyses. See Section 5.3 for a list of stratification factors for the NSCLC and CRC 
cohorts.


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6.3.
Handling of Dropouts or Missing Data
Missing data, except dates, will not be imputed. Historical data such as historical diagnosis, 
historical illness, preexisting conditions and prior therapies should be collected in a sufficiently 
informative way. For example, in order to be considered as historical illness, events occurring in 
the same year as study entry should have at least a known month and year for the end date, while 
events occurring in previous years should have at least a known year for the end date. The start 
dates and end dates for adverse events and concomitant medications will be imputed following 
the most recent Sponsors’ standards. Partial dates should be reported in all listings and not the 
imputed date.
General rules for imputing dates related to AE or concomitant therapy:

Onset date of an AE or start date of a concomitant therapy:
o
If only the day is missing, the date will be set to:

First day of the month that the event occurred, if the onset yyyy-mm is 
after the yyyy-mm of first study treatment.

The day of the first study treatment, if the onset yyyy-mm is the same as 
yyyy-mm of the first study treatment.
o
If both the day and month are missing, the complete date will be set to:

January 1 of the year of onset, if the onset year is after the year of the first 
study treatment.

The date of the first dose, if the onset year is the same as the year of the
first study treatment.

Resolution date of an AE or end date of a concomitant therapy:
o
If only the day is missing, the date will be set to the last day of the month of the 
occurrence.
o
If both the day and month are missing, the date will be set to December 31 of the 
year of occurrence. If a date is completely missing, then the AE will be 
considered treatment-emergent. In case of additional therapies, the therapy will be 
considered concomitant.
General rule for imputing other dates: If a date variable is needed for an analysis, use the 
following general rule to impute incomplete date:

If the date has no missing year and month but the day is missing, then assign Day 1 to the 
day.

If the date has no missing year, but has missing month, then assign January to the month.
However, after imputation, check if the imputed date is logically consistent with other relevant 
date variable(s) and make appropriate correction if necessary. For example, if a visit start date 


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was May 10, 2008 and a tumor assessment date was May xx, 2008 (missing day) but it was 
known that it occurred after that visit, then after imputation, the tumor assessment date became 
May 01, 2008. In this case, the imputed tumor assessment date should be compared to the visit 
start date and then corrected to be the visit start date, May 10, 2008.
Safety analysis: The following rule for missing data processing will apply for safety analysis:

Missing classifications concerning study medication relationship will be considered as 
related to study medication (both components).

If the AE onset date is missing or partial, the date will be compared as far as possible 
with the date of first dose of study medication when determining whether or not the AE is 
present at baseline. In this case, the AE will be assumed to be treatment-emergent, unless 
there is clear evidence (through comparison of partial dates) to suggest that the AE 
started prior to the first dose of study medication.
Time-to-event analysis: All censored data will be accounted for using appropriate statistical 
methods. See Section 6.11 for details.
6.4.
Multicenter Studies
The Phase 1 portion of study JZKA is multicenter and open-label.
The NSCLC and CRC cohorts in Phase 2 portion of study JZKA is multicenter, open-label and
randomized. Investigative center was not a stratification factor because the large number of 
investigative centers would break down the intended balance within each combined stratification 
level by the stratified randomization method. It will not be included as a covariate in any 
covariate-adjusted analysis because the large number of investigative centers in this study cannot 
be practically incorporated into such analysis.
The “Other Tumors” cohort (other than NSCLC and CRC) in Phase 2 portion of study JZKA is 
multicenter and open-label.
6.5.
Multiple Comparisons/Multiplicity
Comparative analyses will be done for Phase 2, Cohorts E1 through E4 (NSCLC), and separately 
for Phase 2 Cohorts F1 and F2 (CRC). Formal multiple comparison adjustment will be done for
the NSCLC cohorts only relative to the active control arm.
6.6.
Use of an “Efficacy Subset” of Patients
The Phase 1 portion of study JZKA aims to characterize the RP2D for LY3499446 when 
administered alone or in combination with either abemaciclib, cetuximab, or erlotinib. Patients 
that are used for dose recommendation and final MTD determination by the mTPI-2 method 
must be DLT-evaluable (see Table JZKA.6.1 for the population definitions). DLT non-
evaluable patients may be replaced to ensure sufficient number of patients are tested for DLT at 
any given dose level. 
Safety analyses for study JZKA are based on the safety population.


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Efficacy analyses for study JZKA will be done based on the following populations:

For non-randomized cohorts (cohorts in Phase 1 and Cohort G in Phase 2), the safety 
population will be used.

For randomized cohorts (NSCLC and CRC cohorts in Phase 2), the intent-to-treat (ITT) 
population will be used.
Per-protocol analyses for study JZKA will be performed based on the per-protocol population
only if study JZKA is intended for registration.
6.7.
Patient Disposition
A detailed summary of patient disposition will be provided. It will include a summary of the
number and percentage of patients entered into the study, and treated as well as number and
percentage of patients completing the study (Phase 1: patients who receive 1 cycle of study dose 
or are evaluable for DLT; Phase 2: patients who die while on study (either on treatment or during
long-term follow-up), or still on study at study completion), or discontinuing (overall and by 
reason for discontinuation of LY3499446). Reason for discontinuation from both the study 
treatment and the study will be summarized by predetermined categories.
A listing of primary reasons for study treatment and study discontinuation will also be provided.
6.8.
Patient Characteristics
Demographic data are collected and reported to demonstrate that the study population represents 
the target patient population. A summary of baseline patient and disease characteristics, 
historical diagnoses, pre-existing conditions, and prior therapies will be reported using 
descriptive statistics.
6.9.
Treatment Compliance
Study treatment compliance for LY3499446, abemaciclib, and erlotinib 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.
Docetaxel and cetuximab will be intravenously administered only at the investigational sites, so 
patient compliance is ensured.
6.10. Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with:

Reason for use


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
Dates of administration including start and end dates
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.
All medications will be coded to the generic preferred name according to the current World
Health Organization (WHO) drug dictionary. All concomitant medications will be summarized
for the safety population using the preferred name.
6.11. Efficacy Analyses
6.11.1. Efficacy Definitions
The following definitions for efficacy endpoints will be used:
Overall response rate (ORR) is the proportion of patients who achieved a CR or PR out of all 
patients treated.  Tumor responses will be measured and recorded using RECIST v1.1 guidelines 
(Eisenhauer et al. 2009).  To confirm objective responses, all lesions should be radiologically 
assessed, and the same radiologic method used for the initial response determination should be 
repeated at least 4 weeks following the initial observation of an objective response, using the 
sample method that was used at baseline. Confirmation of CR or PR is required per RECIST 
v1.1.
Disease control rate (DCR) is defined as the proportion of patients who achieved a best overall 
response (BOR) of confirmed CR, confirmed PR, or SD out of all patients treated. 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 the 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) will be defined as the time from study enrollment (for non-
randomized cohorts)/the time from randomization (for randomized cohorts) to the first 
observation of a PD overall response or death without documented disease progression per 
RECIST v1.1 criteria.  Patients not known to have either of these events will be censored.  A full 
description of censoring rules is described below:


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PFS Event/Censoring Scheme
Situation
Event/Censor
Date of Event or Censor
Tumor progression or death
Event
Earliest date of PD or death
No tumor progression and no death
Censored
Date of last adequate tumor assessment, per 
RECIST v1.1 criteria, or date of randomization 
(whichever is later)a
Unless
No baseline radiologic tumor assessment 
available
Censored
Date of randomization
No adequate postbaseline tumor assessment 
available and death reported after 2 scan 
intervals following randomizationa,b
Censored
Date of randomization
Tumor progression or death documented
immediately after 2 or more scan intervals 
following last adequate tumor assessment or 
randomization (whichever is later)a,b
Censored
Date of last adequate tumor assessment, 
per RECIST v1.1 criteria, or date of 
randomization (whichever is later)a
New therapeutic anticancer treatment started and 
no tumor progression or death within 14 days
Censored
Date of last adequate radiological assessment 
prior to start of new therapeutic anticancer 
therapy +14 days, or date of randomization, 
whichever is latera
Abbreviations: CR = complete response; PD = progressive disease; PFS = progression-free survival; PR = partial 
response; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1; SD = stable disease.
a
Adequate tumor assessment per RECIST v1.1 criteria refers to an assessment with one of the following 
responses:  CR, PR, SD, or PD.
b
Refer to the statistical analysis plan for the definition of 2 scan intervals, including any adjustment for scan 
window.
Overall survival (OS) is defined as the time from study enrollment (for non-randomized 
cohorts)/the time from randomization (for randomized cohorts) to death from any cause.  Patients 
alive at the end of the study, who have withdrawn from the study, or who are lost to follow up 
will be censored on their last known alive date.
6.11.2. Efficacy Analyses for Phase 1
There is no primary efficacy endpoint for the Phase 1 portion of the study, as the primary 
objective is to determine an RP2D, based on the incidence of DLTs and totality of data 
(including, but not limited to, PK, target occupancy, and clinical response data). Antitumor 
activity of LY3499446 administered as monotherapy and in combination with abemaciclib, 
erlotinib, or cetuximab will be evaluated (secondary objective).


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6.11.3. Efficacy Analyses for Phase 2
6.11.3.1. Primary Analyses
The primary analysis will be an evaluation of whether any of the treatment regimens are likely to 
provide a clinically relevant level of activity.  This will be based on an evaluation of the ORR 
within each treatment arm, and evaluation of PFS in the NSCLC cohorts. Primary efficacy 
assessment will be based on an independent review of imaging data. Comparative analyses will 
be done for Phase 2, Cohorts E1 through E4 (NSCLC), and separately for Phase 2 Cohorts F1 
and F2 (CRC).
At the first interim analysis (approximately 20 patients enrolled in each arm), a determination 
will be made whether any of the treatment arms may be dropped due to limited clinical activities. 
An integrated benefit-risk assessment from other data such as DOR, PK, target occupancy, 
tolerability, and safety will also be used to determine if a treatment arm should be stopped early 
due to futility. Otherwise, approximately 20 additional patients will be randomized or enrolled to 
each of the remaining treatment arms to confirm the efficacy signals. Analysis of the Phase 2 
ORR and PFS will be performed after all patients randomized to an arm have had the opportunity 
of having at least 3 months (for ORR evaluations) or 6 months (for PFS evaluations) of follow-
up. An updated analysis will be performed when DoR and PFS data are mature (e.g., 60% PFS 
events are observed).
Enrollment may be discontinued due to futility if the response rate (confirmed and unconfirmed)
in the first 20 patients enrolled in any one arm is less than:

20% for arms E1, E2, or E3, and

10% for arms F1 or F2
6.11.3.2. Secondary Analyses
Assessments of PFS (CRC and Other Tumors cohorts), DoR, DCR, TTR and OS (all cohorts) in 
Phase 2 will be performed as secondary analyses.  Data from Phase 1 subjects will be 
summarized within each treatment cohort, but comparisons between cohorts will not be made.  
Data from Phase 2 subjects will be summarized within treatment arms.  Comparisons between 
treatment arms will be made within tumor type.  Survival rates at various time points (e.g., at 3, 
6, 9, and 12 months), 75%, median, and 25% survival times will be reported, including 
differences between arms and their 95% confidence interval.
Progression-free survival will be compared between treatment arms using a stratified log-rank 
test, stratified by the randomization strata. The corresponding HR between treatment arms will 
be estimated using a stratified Cox regression model (Cox 1972), stratified by randomization 
strata.  Progression-free survival curves, median PFS, and PFS rates at various time points with 
95% confidence interval for each treatment arm will be estimated using the Kaplan-Meier 
method (Kaplan and Meier 1958).
Symptomatic deterioration (i.e., symptomatic progression that is not confirmed per RECIST 
v1.1) will not be considered as tumor progression.


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6.12. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods
Unless stated otherwise, the Lilly pharmacokineticist will be responsible for the PK/PD analyses.
Pharmacokinetic analyses will be conducted on patients who have received at least 1 dose of the 
study drug and have sufficient samples collected to allow the estimation of LY3499446 PK 
parameters.
Pharmacokinetic parameter estimates for LY3499446 will be calculated using standard 
noncompartmental methods of analysis.  The primary parameters for analysis will be maximum 
concentration and area under the concentration-time curve (AUC[0-tlast], AUC[0-∞]) of
LY3499446.  Other noncompartmental parameters, such as half-life, apparent clearance, and 
apparent volume of distribution, may be reported.
Additional analyses such as population PK analyses may also be conducted if deemed 
appropriate.  Other validated PK software programs (for example, NONMEM) may be used if 
appropriate and approved by Global PK management.  The version of any software used for the 
analysis will be documented and the program will meet the Lilly requirements of software 
validation.
Pharmacokinetic/pharmacodynamic analyses may be conducted to explore exposure-response 
relationships between LY3499446 concentrations in systemic circulation and various 
pharmacodynamic measures or clinical outcomes.
Plasma concentrations of erlotinib, abemaciclib and its metabolites, and serum concentrations of 
cetuximab at different time points will be summarized by descriptive statistics.
6.13. Safety Analyses
All patients who receive at least 1 dose of any study therapy will be evaluated for safety and 
toxicity.
Safety analyses will include summaries of the following:

DLTs at each DL

AEs, including severity and possible relationship to study drug

DLT-equivalent AEs, including severity and possible relationship to study drug

SAEs, including possible relationship to study drug

AEs leading to dose 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
6.13.1. Extent of Exposure
The following exposure-related variables will be reported using summary statistics (number of 
patients, mean, and standard deviation) by treatment group:


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
exposure: duration of treatment; number of cycles received; number of patients 
completing ≥1 cycle, ≥2 cycles, …, ≥6 cycles, and mean, SD; number of patients with 
dose adjustments: dose reduction, dose delay, and dose omission;

reasons for dose adjustments
The following exposure-related variables will be reported using summary statistics (number of 
patients, mean, SD, median, 1st and 3rd quartiles, minimum, and maximum) by treatment group:

dose intensity: cumulative dose; weekly dose intensity; relative dose intensity, overall 
weekly dose intensity, overall relative dose intensity
Details of study drug administration will be included in patient listings.
6.13.2. Adverse Events
The most current version of MedDRA at time of analysis will be used when reporting AEs by
MedDRA terms. Unless otherwise specified, when summarized by PT, AEs will be presented in
decreasing frequency of PT; when summarized by System Organ Class (SOC) and PT, AEs will 
be presented in decreasing frequency of PT within SOC. If more than 1 AE is recorded for a 
patient within any SOC or PT term, the patient will only be counted once on the most severe 
grade and the closest relationship to treatment.
6.13.2.1. Overall Summary of Adverse Events
An overall summary of AEs will be provided to summarize the following categories using 
frequency counts and percentages:

patients with at least 1 TEAE, treatment-emergent serious adverse event (TE-SAE), 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and above

patients with AEs that led to death (on study, within 30 days after treatment 
discontinuation)

patients with AEs that led to discontinuation and SAEs that led to discontinuation
The summary will be provided for regardless of study drug causality, and repeated for events 
deemed by the investigator to be related to study treatment. Comparison between the treatment 
groups will be performed using Fisher’s exact test.
6.13.2.2. Treatment-Emergent Adverse Events
The following summaries of TEAEs will be provided (*repeat for events deemed by the 
investigator to be possibly related to study medication, and repeat for events grade 3 and above;
†include consolidated summary):

by PT*†

>5% in any treatment arm by PT*†

by SOC and PT*

by maximum CTCAE grade and by PT*†


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A patient listing of all AEs will be provided.
6.13.3. Deaths, Other Serious Adverse Events, and Other Notable
Adverse Events
Reasons for deaths (study disease, AE [any study drug-related, investigational drug-related, 
procedural related]) will be summarized separately for 1) all deaths, 2) on study treatment deaths, 
within 30 days after treatment discontinuation, and more than 30 days after treatment 
discontinuation.
Serious adverse events will be summarized by SOC and PT, by PT and repeated for events 
deemed by the investigator to be possibly related to study medication, with consolidated 
summary performed if needed. A listing of SAEs will be produced.
In addition, the following analyses will be performed (*repeated for events deemed by the 
investigator to be possibly related to study medication, †include consolidated summary):

adverse events leading to death by PT†

adverse events leading to study treatment discontinuations by PT†

adverse events leading to study treatment dose modification by PT†

adverse events of special interest by PT* (if applicable)

liver injury/failure

listing of deaths

listing of AESIs
6.13.4. Clinical Laboratory Evaluation
The severity of laboratory results will be classified according to CTCAE Version 5.0. The shifts 
in CTCAE toxicity grading from baseline to worst grade postbaseline (first dose up to 30 days 
after the last dose of study treatment) will be produced.
A patient listing of all laboratory data will be provided with a flag for values outside of the 
laboratory normal range as well as investigator site, patient identifier, age, gender, race, and visit.
6.13.5. Vital Signs, Physical Findings, and Other Observations Related 
to Safety
A summary of ECOG performance status at each scheduled time point will be provided. Actual 
value and change from baseline for vital sign measurements will be summarized at each 
assessment time point using summary statistics. Electrocardiogram (ECG) measurements will be 
summarized at each assessment time point using summary statistics. Listings of ECOG 
performance status, vital signs, ECG data will be provided.


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6.14. Subgroup Analyses
Efficacy analyses will be performed for the following potential prognostic subgroup variables:

All baseline stratification factors

age (<65 years versus ≥65 years)

race (White versus Asian versus Other)

gender (females versus males)

ECOG performance status (0 versus 1)
If a level of a factor consists of fewer than 20% of randomized patients, analysis within that level 
will be omitted. The treatment effect within each subgroup will be summarized, and, separately, 
across subgroups with a test of interactions of subgroups with treatment performed. Estimated 
HRs and CIs for the within subgroup analyses will be presented as a forest plot along with p-
values for tests of interactions between subgroup variables and treatment. 
Other subgroup analyses not specified in the SAP may be performed as deemed appropriate. If 
any safety analyses identify important imbalances between arms, subgroup analyses of these 
endpoints may be performed.
6.15. Protocol Violations
All significant protocol violations will be summarized by pre-determined categories (e.g., 
inclusion/exclusion criteria, noncompliance with protocol procedures, drug dosage/intervention, 
use of excluded treatments, informed consent/assent process, continuing after meeting 
withdrawal criteria, or other). These violations will include deviations which can be identified 
programmatically and those which can only be identified by the clinical research associate 
(CRA) during monitoring.
The Per-Protocol population is a subset of the ITT population and consists of the randomized and 
treated patients who do not have an important protocol deviation (IPD, that is, clinically 
important and potentially impact efficacy evaluations). The Trial Issue Management Plan 
(TIMP) details the IPDs and indicates which deviations are programmable or not.
6.16. Interim Analyses and Data Monitoring
In the Phase 1 portion of this study, data will be reviewed for safety on a cohort-by-cohort basis 
during the study, 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.  Before opening of the randomized Phase 2 portion of this study, a formal 
interim analysis including all Phase 1 data will be performed to conclude the safety profiles and 
RP2Ds.


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The Phase 2 portion of Study JZKA comprises more than 3 cohorts and may warrant additional 
considerations to ensure patient safety.  
Lilly has systematic and robust internal processes in place that ensure safety surveillance of 
development compounds in line with expectations of Regulatory Agencies.  This includes 
processes with clearly described roles and responsibilities that are owned by Lilly’s Global 
Patient Safety organization. These processes are designed to monitor the evolving safety profile 
(i.e., review of cumulative SAEs and other important safety information) by designated cross-
functional teams in a timely manner at predefined intervals or on an ad-hoc basis.  In addition, a 
dedicated process may be used to perform unblinded comparisons of event rates for SAEs, as 
necessary.  
This system ensures that the accumulating safety data derived from individual and multiple trials 
across a development program are reviewed on a regular basis and that important new safety 
information such as the need for protocol modification or other relevant safety-related material is 
identified and communicated to regulators and investigators appropriately and in a timely 
fashion.  An internal review of aggregate safety data occurs on at least a quarterly basis or more 
frequently, as appropriate.  Any serious adverse reactions (SARs) are reported within the 
required timeline for expedited reporting.
In addition to annual periodic safety updates and to further inform investigators, a line listing 
reports of SUSARs is created and distributed to investigators on a biannual (twice yearly) basis.  
Any significant potential risk/safety concerns that are being monitored, as well as any results 
being reported in other periodic reports for the compound, SAC decisions, and other significant 
safety data (for example, nonclinical, clinical findings, and removal of SARs) are included in the 
report.
In the Phase 2 portion of this study, a safety review will be performed after the first 20 patients 
across all cohorts (NSCLC, CRC, and Other Tumors) are enrolled and treated for 1 cycle, and 
then every 6 months afterward.
In the Phase 2 portion of this study:

For the NSCLC cohorts, an interim analysis of safety and efficacy is planned after 
approximately 20 patients in each cohort are treated and have completed 2 cycles or have 
discontinued before the first postbaseline tumor assessment.  At this first interim analysis, 
the totality of data (including, but not limited to, safety and preliminary efficacy) will be 
used to determine if any of the treatment cohorts (E1, E2, E3) may be dropped due to 
limited clinical activities relative to the active comparator (E4).  After the data cutoff date 
of this interim analysis, approximately 20 additional patients will be randomized to each 
of the remaining treatment arms to confirm the efficacy signals.  Enrollment will be 
paused until the interim analysis has been completed.

For the CRC cohorts, an interim analysis of safety and efficacy is planned after 
approximately 20 patients in each arm are treated and have completed 2 cycles or have 
discontinued before the first postbaseline tumor assessment. Enrollment will be paused 
until the interim analysis has been completed. Depending on the preliminary efficacy 


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signal and totality of data, 1 arm may be dropped for futility and an additional 20 patients 
will be enrolled into the remaining arm.  If no meaningful difference in efficacy or safety 
is observed in between the 2 arms, 40 additional patients may be randomized at a 1:1 
ratio, leading to approximately 80 total randomized patients (40 in each arm). Depending 
on the magnitude of clinical response observed in terms of durable objective responses, 
Study Protocol JZKA may be amended to provide for a more robust assessment of 
benefit/risk in this setting.

For the Other Tumors cohort, an interim of safety and efficacy is planned after 
approximately 20 patients are treated and have completed 2 cycles or have discontinued 
before the first postbaseline tumor assessment. The trial will continue to enroll an 
additional 20 patients for the final analysis.
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.).
6.17. Annual Report Analyses
The following reports are needed as requested for annual reporting purposes.
Development Safety Update Report:

Cumulative Subject Exposure by Age Group and Sex

Cumulative Subject Exposure by Racial Group

Estimated Cumulative Subject Exposure

Exposure Information

Listing of Discontinuations Due to AE During the Reporting Period

Listing of Subjects Who Died During the Reporting Period 
Clinical IB: 

Listing and Summary of Serious Adverse Event (SAE)

Listing and Summary of Death

Listing and Summary of TEAE (and by maximum CTCAE grade)

Listing and Summary of Patient Disposition

Listing and Summary of Study Drug Adjustment 
Other reports may be requested if deemed appropriate for the IB.
6.18. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  


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Analyses provided for the CTR requirements include the following:
Summary of adverse events, provided as a dataset which will be converted to an XML file.   
Both Serious Adverse Events and ‘Other’ Adverse Events are summarized: by treatment 
group, by MedDRA preferred term.

An adverse event is considered ‘Serious’ whether or not it is a treatment emergent 
adverse event (TEAE).

An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment group, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 
In addition, a participant flow will be created that will describe how many enrolled patients 
completed the study, and for those who did not, the frequency of each reason for not completing. 
This analysis will be based on study discontinuation, not treatment discontinuation. A patient 
will be identified as having completed the study if the patient is observed until event (PD or 
death) or the patient had discontinued study treatment and is in follow up at the time of the final 
analysis. Patients who withdraw consent or are lost to follow-up before the final analysis, or who 
are still on treatment at the time of the final analysis will be identified as not completing the 
study.


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7.
References
[CTCAE] Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse 
Events, Version 5.0, DCTD, NCI, NIH, DHHS. 2017. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-247.
Guo W, Wang SJ, Yang S, Lynn H, Ji Y. A Bayesian interval dose-finding design addressing
Ockham's razor: mTPI-2. Contemp Clin Trials. 2017;58:23-33.
Iasonos A, O’Quigley J. Design considerations for dose-expansion cohorts in phase I trials. J
Clin Oncol. 2013;31(31):4014-4021.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 
1958;53(282):457-81.


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