A Phase 1a/1b Study of LY3405105 Administered to Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Solid Tumor
Sponsor: Eli Lilly and Company

 
 
 
Protocol J1F-MC-JZFA (c) 
 
 
A Phase 1a/1b Study of LY3405105 Administered to Patients with 
Advanced Solid Tumors 
 
 
NCT03770494    
 
 
Approval Date: 13-Aug-2020 

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 1
LY3405105
Protocol J1F-MC-JZFA (c)
A Phase 1a/1b Study of LY3405105 Administered to 
Patients with Advanced Solid Tumors
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY3405105, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY3405105
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 20 Aug 2018.
Amendment (a) Electronically Signed and Approved by Lilly on 22 Nov 2018.
Amendment (b) Electronically Signed and Approved by Lilly on 02 Jul 2020.
Amendment (c) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 13-Aug-2020 GMT

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 2
LY3405105
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment (b)
02-Jul-2020
Amendment (a)
22-Nov-2018
Original Protocol
20-Aug-2018
Amendment (c)
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:
Section # and Name
Description of Change
Brief Rationale
2. Schedule of Activities
9.5 Pharmacokinetics
9.6. Pharmacodynamics
9.8.3. Other Samples for Biomarker 
Research
Skin biopsies and
peripheral blood 
mononuclear cell 
collections have been 
removed from Phase 1a/1b, 
and urine pharmacokinetics 
(PK) have been removed
from Phase 1a schedule.
There is no further planned 
analysis for additional 
samples.
2. Schedule of Activities
Clarification of mandatory 
versus optional ECG and 
plasma PK samples in 
Phase 1a schedule
PK parameters have been 
characterized; thus, fewer
ECG and PK samples are now 
required, reducing the burden 
on the sites and patients whilst 
maintaining safety.
1. Synopsis
2. Schedule of Activities
5.1. Overall Design
5.1.1. Dose Escalation Phase
7.1.1. Dose Escalation Phase (Phase 1a)
7.1.1.2. Dose Escalation Method
7.2.1. Selection and Timing of Doses
10.1. Sample Size Determination
10.3.2. Safety Analyses
The intermittent dosing 
schedule in Part A2 will no 
longer be pursued in the 
study and was removed.
Available safety and human 
exposure data support 
continuous daily dosing.
Other minor editorial changes were made to add clarity and correct typos

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 3
LY3405105
Table of Contents
Section
Page
Protocol J1F-MC-JZFA (c)  A Phase 1a/1b Study of LY3405105 
Administered to Patients with Advanced Solid Tumors.......................................................1
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................11
2.1.
Provision for Changes in Study Conduct Due to Emergencies ......................................19
3.
Introduction ......................................................................................................................20
3.1.
Study Rationale............................................................................................................20
3.2.
Background..................................................................................................................20
3.2.1.
Role of CDK7......................................................................................................20
3.2.2.
Targeting the SWItch/Sucrose Non-Fermentable (SWI/SNF) 
Complex ..............................................................................................................21
3.3.
Benefit/Risk Assessment..............................................................................................22
4.
Objectives and Endpoints..................................................................................................23
5.
Study Design.....................................................................................................................25
5.1.
Overall Design .............................................................................................................25
5.1.1.
Dose Escalation Phase..........................................................................................26
5.1.2.
Dose Expansion Phase .........................................................................................26
5.1.3.
Study Period Definitions ......................................................................................26
5.2.
Number of Patients.......................................................................................................27
5.3.
End of Study Definition ...............................................................................................27
5.4.
Scientific Rationale for Study Design...........................................................................27
5.5.
Justification for Dose ...................................................................................................28
5.6.
Justification for Enrolling Patients ≥12 Years of Age ...................................................30
6.
Study Population...............................................................................................................31
6.1.
Inclusion Criteria..........................................................................................................31
6.2.
Exclusion Criteria ........................................................................................................33
6.3.
Lifestyle Restrictions....................................................................................................34
6.4.
Screen Failures.............................................................................................................34
7.
Treatment..........................................................................................................................35
7.1.
Treatment Administered...............................................................................................35
7.1.1.
Dose Escalation (Phase 1a) ..................................................................................35
7.1.1.1.
Dose-Limiting Toxicity Determination and Maximum 
Tolerated Dose Definition...............................................................................35
7.1.1.2.
Dose Escalation Method.................................................................................36
7.1.2.
Dose Expansion (Phase 1b)..................................................................................37

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 4
LY3405105
7.1.3.
Packaging and Labeling .......................................................................................38
7.2.
Method of Treatment Assignment ................................................................................38
7.2.1.
Selection and Timing of Doses.............................................................................38
7.3.
Blinding .......................................................................................................................38
7.4.
Dose Modification........................................................................................................39
7.5.
Preparation/Handling/Storage/Accountability...............................................................41
7.6.
Treatment Compliance .................................................................................................41
7.6.1.
Evaluable Patients................................................................................................41
7.7.
Concomitant Therapy...................................................................................................41
7.7.1.
Growth Factors ....................................................................................................42
7.8.
Treatment After the End of Study.................................................................................42
7.8.1.
Treatment After Study Completion.......................................................................42
7.8.1.1.
Continued Access...........................................................................................43
8.
Discontinuation Criteria ....................................................................................................44
8.1.
Discontinuation from Study Treatment.........................................................................44
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................44
8.2.
Discontinuation from the Study....................................................................................45
8.3.
Lost to Follow-Up........................................................................................................45
9.
Study Assessments and Procedures ...................................................................................46
9.1.
Efficacy Assessments...................................................................................................46
9.2.
Adverse Events ............................................................................................................46
9.2.1.
Serious Adverse Events........................................................................................47
9.2.2.
Suspected Unexpected Serious Adverse Reactions ...............................................48
9.2.3.
Complaint Handling.............................................................................................48
9.3.
Treatment of Overdose.................................................................................................49
9.4.
Safety...........................................................................................................................49
9.4.1.
Safety Measures...................................................................................................49
9.4.2.
Safety Monitoring ................................................................................................49
9.4.2.1.
Special Hepatic Safety Data Collection...........................................................49
9.5.
Pharmacokinetics .........................................................................................................49
9.6.
Pharmacodynamics ......................................................................................................50
9.7.
Genetics .......................................................................................................................50
9.7.1.
Whole Blood Sample for Pharmacogenetic Research ...........................................50
9.8.
Biomarkers...................................................................................................................51
9.8.1.
Biomarkers Required for Eligibility .....................................................................51
9.8.2.
Tumor Tissue Samples for Exploratory Biomarker Research................................51
9.8.3.
Other Samples for Biomarker Research................................................................52
9.9.
Health Economics ........................................................................................................53

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 5
LY3405105
10.
Statistical Considerations ..................................................................................................54
10.1. Sample Size Determination ..........................................................................................54
10.2. Populations for Analyses..............................................................................................55
10.3. Statistical Analyses ......................................................................................................55
10.3.1.
Efficacy Analyses ................................................................................................55
10.3.2.
Safety Analyses....................................................................................................56
10.3.3.
Other Analyses.....................................................................................................57
10.3.3.1.
Patient Disposition..........................................................................................57
10.3.3.2.
Patient Characteristics ....................................................................................57
10.3.3.3.
Concomitant Therapy .....................................................................................57
10.3.3.4.
Extent of Exposure/Treatment Compliance.....................................................57
10.3.3.5.
Pharmacokinetic/Pharmacodynamic Analyses ................................................57
10.3.3.6.
Biomarker Analyses .......................................................................................58
10.3.4.
Interim Analyses..................................................................................................58
11.
References ........................................................................................................................59
12.
Appendices .......................................................................................................................62

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 6
LY3405105
List of Tables
Table
Page
Table JZFA.2.1.
Baseline, On-Study Treatment, and Post Treatment 
Schedule of Activities for Phase 1a.........................................................12
Table JZFA.2.2.
Baseline, On-Study Treatment, and Post Treatment 
Schedule of Activities for Phase 1b ........................................................16
Table JZFA.2.3.
Continued Access Schedule of Activities................................................19
Table JZFA.4.1.
Objectives and Endpoints .......................................................................23
Table JZFA.5.1.
Dose and Exposure Multiples for Oral Administration of 
LY3405105 Based on Administered Dose and Predicted 
Human Exposure....................................................................................29
Table JZFA.7.1.
Example Dose Escalation Scheme for Study J1F-MC-
JZFAa ....................................................................................................37
Table JZFA.7.2.
Dose Modifications in Patients due to Toxicity.......................................40
Table JZFA.10.1.
Estimated Incidence Rate and its 2-Sided 95% CI...................................54

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 7
LY3405105
List of Figures
Figure
Page
Figure JZFA.5.1.
Illustration of study design......................................................................25

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 8
LY3405105
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................63
Appendix 2.
Clinical Laboratory Tests........................................................................69
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................70
Appendix 4.
Restricted and Prohibited Concomitant Medications...............................73
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ...........................................................................................74
Appendix 6.
Creatinine Clearance Formula.................................................................75
Appendix 7.
Statistical Details for Dose Escalation.....................................................76
Appendix 8.
Performance Scales ................................................................................77
Appendix 9.
Protocol Amendment History .................................................................78

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 9
LY3405105
1. Synopsis
Protocol Title:
A Phase 1a/1b Study of LY3405105 Administered to Patients with Advanced Solid Tumors
Rationale:
Study J1F-MC-JZFA (JZFA) is designed to investigate the safety and tolerability of LY3405105 
for the treatment of patients with advanced cancers and to evaluate the anti-tumor activity in the 
defined population in the Phase 1b portion.
Objectives and Endpoints:
Objectives
Endpoints
Phase 1a
Primary

To assess the safety and tolerability of LY3405105 
administered as monotherapy, and to determine the 
RP2D and schedule in patients with solid tumors

Safety (including but not limited to):  incidence and 
severity of DLTs, TEAEs, SAEs, deaths, and 
clinical laboratory abnormalities 
Secondary

To assess the PK of LY3405105 administered as 
monotherapy to patients with solid tumors

AUC/Cmax of LY3405105

To document any anti-tumor activity observed with 
LY3405105 when administered as monotherapy to 
patients with solid tumors

Per RECIST v1.1:
o
ORR
o
DCR
o
DoR
o
TTR
o
PFS

OS
Phase 1b
Primary

To assess the efficacy of LY3405105 when 
administered as monotherapy in the defined patient 
population 

ORR (per RECIST v1.1)
Secondary

To evaluate the safety and tolerability of 
LY3405105 when administered as monotherapy to 
patients with solid tumors

Safety, including but not limited to incidence and 
severity of TEAEs, SAEs, deaths, and clinical 
laboratory abnormalities per CTCAE v.4.0

To document any anti-tumor activity observed with 
LY3405105 when administered as monotherapy to 
patients with solid tumors across the defined cohorts

Per RECIST v1.1:
o
DCR
o
DoR
o
PFS
o
TTR

OS

To assess the PK of LY3405105 administered as 
monotherapy to patients with solid tumors across 
the defined cohorts

Plasma concentration of LY3405105

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 10
LY3405105
Abbreviations:  AUC = area under the plasma concentration x time curve; Cmax = maximum concentration;
CTCAE = Common Terminology Criteria for Adverse Events; DCR = disease control rate; DLT = dose-limiting 
toxicity; DoR = duration of response; 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 JZFA is a Phase 1, multicenter, nonrandomized, open-label dose escalation study in 
patients with advanced solid tumors followed by dose expansion of oral LY3405105 in a defined 
patient population with advanced solid tumors. 
Number of Patients:
Dose Escalation:  Phase 1a, approximately 30-64 patients will be enrolled (including up 
to10 patients in the safety expansion at recommended Phase 2 dose [RP2D]).
Dose Expansion:  Phase 1b, approximately 20 patients will be enrolled in each of Cohorts 1-4.  
In the bladder cancer Cohort 5, approximately 30 patients will be enrolled.
Treatment Arms and Duration:
Patients enrolled in the monotherapy dose escalation will receive LY3405105 orally, on a 28-day 
cycle. During the escalation, the investigators and Eli Lilly and Company (Lilly) will consider 
both the Bayesian model-based toxicity band method (N-CRM) recommendation, the observed 
dose-limiting toxicity rate, and the totality of the data (pharmacokinetics, pharmacodynamics, 
and overall safety) at each cohort to determine the next dose level, dose schedule, and determine 
when to stop the escalation.
After the monotherapy RP2D has been determined from Phase 1a, approximately 20 patients will 
be enrolled in each of the Phase 1b Cohorts 1-4.  In the bladder cancer cohort (Cohort 5 in Phase 
1b), approximately 30 patients will be enrolled.  Patients will receive LY3405105 at the RP2D 
orally daily on a 28-day cycle.
Study treatment should be continued until evidence of disease progression or discontinuation 
criteria is met.  Patients with documented progressive disease may be allowed to continue 
LY3405105 if the patient is tolerating treatment and, in the opinion of the investigator, is 
deriving clinical benefit from continuing study treatment and continuation of treatment is 
approved by the Sponsor.
30-Day Safety Follow-Up Visit:  Occurs 30 ±7 days after the decision is made to discontinue 
from study treatment.
Long-Term Follow-Up:  Begins the day after 30-day follow-up visit is completed and ends with 
the patient’s death, lost to follow-up, or overall study completion, whichever is earlier.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 11
LY3405105
2. Schedule of Activities

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 12
LY3405105
Table JZFA.2.1.
Baseline, On-Study Treatment, and Post Treatment Schedule of Activities for Phase 1a
Procedure
Baseline
Post Treatment 
Follow-Up
Instructions
All Remaining Parts on Treatment (Cycle = 28 days )
Days Prior 
to C1D1
Cycle 1
(±3 Days)
Cycle 2
(±3 Days)
Cycle 3-n
(±3 Days)
Short-
Terma
(30 ± 7
Days)
Long-Term
(Every 90 ± 7 
Days)
Day
Day
Day

1
8
15
1
15
1
Visit 801
Visit 802-8XX
Informed consent
X
ICF must be signed before any 
protocol-specific procedures are 
performed. Baseline/screening labs 
or imaging, as part of routine 
patient care, drawn within the 
indicated window of C1D1 may be 
used for both screening/baseline 
and C1D1 labs.
Physical 
examination*
X
X
X
X
X
X
X
Perform prior to 
administration/dispensing of study 
drug.
Vital signs and 
weight*
X
X
X
X
X
X
X
Perform prior to 
administration/dispensing of study 
drug. Include height (only at 
baseline), weight, and vital signs 
(temperature, blood pressure, pulse 
rate)
Medical history
X
Inclusion/Exclusio
n evaluation
X
Concomitant 
medication
X
X
X
X
X
X
AE collection
X
X
X
X
X
X
X
X
CTCAE V4.0. During long-term 
follow-up, only AEs that are related 
to study treatment will be followed 
to resolution.
ECOG 
performance status
X
X
X
X
X
X
X
Radiologic 
imaging and 
measurement of 
palpable or visible 
lesions
X
X
X
X
Perform according to RECIST v1.1 
criterion, by the same method used 
at baseline, q 8 wk (±7 days) for the 
first 6 mo after C1D1 and q 12 wk 
(±7 days) thereafter until 
radiographic disease progression, 
death, or study completion, 
whichever occurs first.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 13
LY3405105
Procedure
Baseline
Post Treatment 
Follow-Up
Instructions
All Remaining Parts on Treatment (Cycle = 28 days )
Days Prior 
to C1D1
Cycle 1
(±3 Days)
Cycle 2
(±3 Days)
Cycle 3-n
(±3 Days)
Short-
Terma
(30 ± 7
Days)
Long-Term
(Every 90 ± 7 
Days)
Day
Day
Day

1
8
15
1
15
1
Visit 801
Visit 802-8XX
Perform as scheduled, even if study 
treatment is delayed or omitted.
ECG
X
X
X
X
X
X
X
ECG collections that are underlined 
and in bold are mandatory. All 
other ECG collections are optional.
Baseline: Single ECG only
Cycle 1 Day 1: collect digital 
ECGs for QT analysis in triplicate 
at predose, 2 hrs postdose. If 
possible, a 24 hr reading should be 
taken.
  
Day 15: Predose (triplicate)
A corresponding PK sample should 
be collected after the ECG reading.
Cycle 2: Single ECGs only 
(predose on D1 and D15)
Cycle 3-n: Single ECG on D1 
(predose).
Perform additional evaluations in 
the setting of cardiac symptoms 
and/or at the discretion of the 
investigator. Perform locally.
Hematology*
X
X
X
X
X
X
X
3 days prior to start of each cycle, 
unless more frequent assessment is 
clinically indicated.
Coagulation
X
Only collected at baseline, unless 
more frequent assessment is 
clinically indicated.
Clinical 
chemistry*
X
X
X
X
X
X
X
3 days prior to start of cycle, 
unless more frequent assessment is 

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 14
LY3405105
Procedure
Baseline
Post Treatment 
Follow-Up
Instructions
All Remaining Parts on Treatment (Cycle = 28 days )
Days Prior 
to C1D1
Cycle 1
(±3 Days)
Cycle 2
(±3 Days)
Cycle 3-n
(±3 Days)
Short-
Terma
(30 ± 7
Days)
Long-Term
(Every 90 ± 7 
Days)
Day
Day
Day

1
8
15
1
15
1
Visit 801
Visit 802-8XX
clinically indicated.
Urinalysis*
X
X
X
X
X
3 days prior to start of cycle, 
unless more frequent assessment is 
clinically indicated
Urine pregnancy 
test
X
X
X
X
Applies only to women of 
childbearing potential. Where
required by local law or regulation, 
perform ≤3 day prior to start of 
every cycle prior to administration 
of study treatment.
Patient diary
X
X
Provide patient diary Day 1. 
Completed daily by patient. Review 
at each study visit during Cycle 1.
Survival 
assessment
X
X
Perform q 3 mo (±7 days). If an in-
person visit is not possible, confirm 
survival by contacting the patient 
directly via phone.
LY3405105
X
Administer orally on Days 1-28 of 
a 28-day cycle. Patients should be 
advised to take dose after PK draw 
on days of PK collection.
Pharmacokinetics
– plasma
1. Predose
2. 1hr±5min
3. 
2hr±10min
4. 
4hr±10min
5. 
6hr±15min
6. 
8hr±15min
7. 24hr±2hr
8. 48hr±2hr
9. 
Predose
10. Predose
11. 1hr±5min
12. 
2hr±10min
13. 
4hr±10min
14. 
6hr±15min
15. 
8hr±15min
16. 24hr±2hr
17. 48hr±2hr
18. 
Predose
Sample collection times that are 
underlined and in bold are 
mandatory; all other plasma PK
samples are optional.
24-hr samples should be drawn 
prior to next dose. 48-hr samples 
are not required as Part A2 is no 
longer being pursued.
Plasma biomarker 
sample
X
X
X
X
Collect predose on D1 of C1, C2, 
C3, C5, C7, and then every third 
cycle (for example, C10).

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 15
LY3405105
Procedure
Baseline
Post Treatment 
Follow-Up
Instructions
All Remaining Parts on Treatment (Cycle = 28 days )
Days Prior 
to C1D1
Cycle 1
(±3 Days)
Cycle 2
(±3 Days)
Cycle 3-n
(±3 Days)
Short-
Terma
(30 ± 7
Days)
Long-Term
(Every 90 ± 7 
Days)
Day
Day
Day

1
8
15
1
15
1
Visit 801
Visit 802-8XX
Pharmacogenetics 
whole blood
X
A pretreatment blood sample is 
preferred; however, the whole blood 
sample for pharmacogenetic 
analysis may be collected at a later 
time point if necessary.
Archived tumor 
tissue
X
Sample should be submitted to the 
central laboratory within 28 days 
after initiation of study treatment.  
See Section 9.8.2.  
Optional tumor 
biopsy
X
X
An optional biopsy specimen after 
treatment with LY3405105 has 
been initiated or after disease 
progression may be allowed.
Abbreviations:  AE = adverse event; C = cycle; CRP/CRS = clinical research physician/clinical research scientist; CTCAE = Common Terminology Criteria for Adverse 
Events; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; hr = hour(s); ICF = informed consent form; min = minute(s); mo = 
month(s); PK = pharmacokinetics; q = every; RECIST v1.1 = Response Criteria in Solid Tumors Version 1.1; wk = week(s).
a
Short-term follow-up begins the day when the patient and the investigator agree that the patient will no longer continue study treatment and lasts approximately 30 days 
(±7 days).  No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has explicitly provided permission and consent.
*
3 days prior to start of cycle, unless more frequent assessment is clinically indicated

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 16
LY3405105
Table JZFA.2.2.
Baseline, On-Study Treatment, and Post Treatment Schedule of Activities for Phase 1b
Procedure
Baseline
All Remaining Parts on Treatment (Cycle = 28 days )
Post Treatment Follow-Up
Instructions
Days 
Prior to 
C1D1
Cycle 1
(±3 Days)
Cycle 2
(±3 Days)
Cycle 3-n
(±3 Days)
Short-
Terma
(30 ±7
Days)
Long-Term 
(Every 90 ±7 
Days)
Day
Day
Day

1
15
1
15
1
Visit 801
Visit 802-8XX
Informed consent
X
ICF must be signed before any protocol-specific 
procedures are performed. Baseline/screening labs or 
imaging, as part of routine patient care, drawn within 
the indicated window of C1D1 may be used for both 
screening/baseline and C1D1 labs.
Physical 
examination*
X
X
X
X
X
X
X
Perform prior to administration/dispensing of study 
drug.
Vital signs and 
weight*
X
X
X
X
X
X
X
Perform prior to administration/dispensing of study 
drug. Include height (only at baseline), weight, and 
vital signs (temperature, blood pressure, pulse rate).
Medical history
X
Inclusion/Exclusion
evaluation
X
Concomitant 
medication
X
X
X
X
X
X
AE collection
X
X
X
X
X
X
X
X
CTCAE V4.0. During long-term follow-up, only AEs 
that are related to study treatment will be followed to 
resolution.
ECOG 
performance status
or LPS
X
X
X
X
X
X
X
Radiologic 
imaging and 
measurement of 
palpable or visible 
lesions 
X
X
X
X
Perform according to RECIST v1.1 criterion, by the 
same method used at baseline, q 8 wk (±7 days) for 
the first 6 mo after C1D1 and q 12 wk (±7 days) 
thereafter until radiographic disease progression, 
death, or study completion, whichever occurs first.
Perform as scheduled, even if study treatment is 
delayed or omitted.
ECG
X
Baseline: Predose (single).
Perform additional evaluations in the setting of 
cardiac symptoms and/or at the discretion of the 
investigator. Perform locally.
Hematology*
X
X
X
X
X
X
X
3 days prior to start of each cycle, unless more 
frequent assessment is clinically indicated.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 17
LY3405105
Procedure
Baseline
All Remaining Parts on Treatment (Cycle = 28 days )
Post Treatment Follow-Up
Instructions
Days 
Prior to 
C1D1
Cycle 1
(±3 Days)
Cycle 2
(±3 Days)
Cycle 3-n
(±3 Days)
Short-
Terma
(30 ±7
Days)
Long-Term 
(Every 90 ±7 
Days)
Day
Day
Day

1
15
1
15
1
Visit 801
Visit 802-8XX
Coagulation
X
Only collected at baseline, unless more frequent 
assessment is clinically indicated.
Clinical 
chemistry*
X
X
X
X
X
X
X
3 days prior to start of cycle, unless more frequent 
assessment is clinically indicated.
Urinalysis*
X
X
X
X
X
3 days prior to start of cycle, unless more frequent 
assessment is clinically indicated
Urine pregnancy 
test
X
X
X
X
Applies only to women of childbearing potential.
Where required by local law or regulation, perform 
≤3 day prior to start of every cycle prior to 
administration of study treatment.
Patient diary
X
X
Provide patient diary Cycle 1, Day 1. Completed 
daily by patient. Review at each study visit in Cycle 
1.
Survival 
assessment
X
X
Perform q 3 mo (±7 days).  If an in-person visit is not 
possible, confirm survival by contacting the patient 
directly via phone.
LY3405105
X
Administer orally once a day based on the established 
RP2D. Patients should be advised to take dose after 
PK draw on C1D15 and C2D1.
Pharmacokinetics
– plasma
1. Predose
2. 1-2hr
3. 3-4hr
4. Predose
Plasma biomarker 
sample
X
X
X
X
Collect predose on D1 of C1, C2, C3, C5, C7, and 
then every third cycle (for example, C10).
Pharmacogenetics 
whole blood
X
A pretreatment blood sample is preferred; however, 
the whole blood sample for pharmacogenetic analysis 
may be collected at a later time point if necessary.
Archived tumor 
tissue
X
Sample should be submitted to the central laboratory 
within 28 days after initiation of study treatment.  
See Section 9.8.2.  
Optional tumor 
biopsy
X
X
An optional biopsy specimen at baseline and/or after 
treatment with LY3405105 has been initiated or after 
disease progression may be allowed.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 18
LY3405105
Abbreviations:  AE = adverse event; C = cycle; CRP/CRS = clinical research physician/clinical research scientist; CTCAE = Common Terminology Criteria for Adverse 
Events; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; hr = hour(s); ICF = informed consent form; LPS = Lansky performance 
status; mo = month(s); PK = pharmacokinetics; q = every; RECIST v1.1 = Response Criteria in Solid Tumors Version 1.1; wk = week(s).
a
Short-term follow-up begins the day when the patient and the investigator agree that the patient will no longer continue study treatment and lasts approximately 30 
days (±7 days).  No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has explicitly provided permission and 
consent.
*
3 days prior to start of cycle, unless more frequent assessment is clinically indicated

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 19
LY3405105
Table JZFA.2.3.
Continued Access Schedule of Activities
Study Treatment
Follow-Upa
Instructions
Visit
501-5XX
901
Procedureb
AE collection
X
X
CTCAE v4.0
Administer/dispense study drug(s)
X
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events.
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.  No follow-up procedures will 
be performed for a patient who withdraws informed consent unless he or she has explicitly provided permission 
and consent.
b
Efficacy assessments will be done at the investigator’s discretion based on the standard of care.
2.1.
Provision for Changes in Study Conduct Due to Emergencies
There may be times due to exceptional circumstances where it may not be feasible for patients to 
come to investigator sites for study-required visits. To mitigate the risk of patients missing visits 
to allow patients to safely continue to receive care and maintain the data integrity of the study, 
the following may be allowed on a case-by-case basis following approval from the Sponsor and 
if permitted by local regulations:

Remote/virtual visits or extended visit windows may be used. Medically qualified 
site personnel may collect study required information (for example, AEs, 
concomitant medications, ECOG status, and study treatment compliance) via 
videoconference (preferred) or phone. Visit or cycle windows as defined in the 
schedule of activities may be extended to facilitate the ability to perform study-
specific assessments at the site, which is preferred to remote/virtual visits. Every 
effort should be made to return to in-clinic visits as soon as reasonably possible 
and safe for the patient and investigator/site staff. 

Labs, ECGs and/or tumor imaging may be obtained at a local (nonstudy) site.  
Laboratory results (including reference ranges), ECGs and/or scans obtained at a
local lab must be filed and reviewed by the study investigator or qualified 
designee in a timely manner. 

For patients that meet the protocol criteria to continue or restart dosing, local 
processes may be leveraged to deliver drug directly to patients.

A remote informed consent process may be implemented.
Site personnel are responsible for documenting in the source records all changes in study 
conduct, relevant communications (patient and Sponsor), and dispensing/shipment records of IP 
and indicating the actions taken as a result of exceptional circumstances mitigation.  If 
mitigations are approved by the Sponsor, additional instructions on the process and 
documentation will be provided to the site.  Additional mitigations may be approved by the 
Sponsor and will be tracked as protocol deviations as required.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 20
LY3405105
3. Introduction
3.1.
Study Rationale
Cyclin-dependent kinases (CDKs) play a critical role in the regulation of cell cycle and global 
transcription.  Within cancer cells, dysregulated transcription enables hallmark capabilities, 
including resistance to cell death, sustenence of proliferative signaling, and evasion of growth 
suppressors (Hanahan and Weinberg 2011).  The selective advantage that favors cancer cells can 
thus become dependent upon the aberrant function of deregulated transcription.  Thus, selective 
modulation of CDK7, a key transcriptional regulator, may provide therapeutic benefit to patients 
with cancer, particularly those with dysregulated transcriptional phenotypes that result in tumor 
cell survival, growth, and progression.
LY3405105 is an orally bioavailable, covalent inhibitor of CDK7.  Nonclinical data have shown 
that LY3405105 inhibits the proliferation of a variety of cancer cell lines.  Cell lines harboring 
loss-of-function mutation in ARID1A, KMT2C, or KMT2D demonstrated enhanced sensitivity to 
LY3405105.  LY3405105 also demonstrated robust anti-tumor efficacy, including durable tumor 
regressions in cell line and patient-derived xenograft tumor models across triple-negative breast 
cancer (TNBC) irrespective of their molecular profile, ARID1A-mutant ovarian histology, and 
those carrying loss-of-function (LOF) mutations in ARID1A or KMT2C independent of tumor 
type.
Study J1F-MC-JZFA (JZFA) is designed to investigate the safety and tolerability of LY3405105, 
establish the RP2D in patients with solid tumors (Phase 1a), and to assess the anti-tumor activity 
in patients with defined advanced solid tumors (Phase 1b).
3.2.
Background
3.2.1.
Role of CDK7
CDK7 is part of the transcription regulating CDKs, which also include CDK9, 12 and 13. CDK7
enacts its function through:
1) phosphorylating RNA polymerase II at the C terminal domain (CTD) to initiate 
transcription, and 
2) regulating CDKs as a CDK activating kinase (CAK) (Fisher 2019; Chou et 
al.2020).
CDK7 biology has been implicated in transcription regulation and enhancing cancer growth 
associated with super-enhancer-linked oncogenes (Chipumuro et al. 2014; Zhang et al. 2017; 
Sharifnia et al. 2019; Zhang et al. 2020). Gene transcription regulation occurs in part by 
modulating H3K4me3 which impacts epigenetic regulation of gene expression (Ebmeier et al. 
2017).  This process involves different aspects of chromatin remodeling including histone 
methyltransferases such as KMT2C and KMT2D, and methyl demethylase (KDM6A) (Valencia 
and Kadoch 2019). Utilizing pharmacologic approaches in preclinical models demonstrated the 
ability of targeting CDK7 with small molecule inhibitors to downregulate gene transcription and

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 21
LY3405105
induce tumor regression in preclinical models (Christensen et al. 2014; Kwiatkowski et al. 2014; 
Wang et al. 2015; Zhang et al. 2017; Lu et al. 2019; Rasool et al. 2019; Zhang et al. 2019; Sun 
et al. 2020).
3.2.2.
Targeting the SWItch/Sucrose Non-Fermentable (SWI/SNF) 
Complex
ARID1A is a tumor suppressor gene that encodes BAF250a and is part of the SWItch/Sucrose 
Non-Fermentable (SWI/SNF) complex, which is frequently mutated in solid tumors (Reisman et 
al. 2009). Somatic mutations have been reported in wide range of solid tumors and have been
linked to an early event in tumorigenesis of clear cell ovarian cancer and endometriosis
associated malignancies (Wiegand et al. 2010). ARID1A, as part of the chromatin remodeling 
machinery, is frequently mutated in bladder cancer along other chromatin regulating genes 
(KDM6A/UTX, KMT2C/MLL3, and KMT2D/MLL2) (Gui et al. 2011; Jones et al. 2011; Guo et al. 
2013). Our preclinical data suggest that LOF mutation in ARID1A leads to activation of super-
enhancers, which are DNA sequences that binds to transcription factors and enhance gene 
transcription. Utilizing LY3405105 in ARID1A mutant cell lines inhibits transcription and 
downregulates MYC and E2F downstream targets.
Mutations in SMARCB1, another subunit of the SWI/SNF complex, lead to unopposed activation 
of polycomb repressive complex 2 (PRC2) (Kim and Roberts 2016), which in turns activates 
Enhancer of Zeste 2 (EZH2).  Epithelioid sarcoma that commonly harbors mutations in 
SMARCB1 or loss of protein expression of INI1 due to epigenetic silencing, might be amenable 
to epigenetic targeted therapy with EZH2 inhibitors (Rothbart and Baylin 2020).  While 
mutations in other subunits of the SWI/SNF complex might have a gene and tissue specific 
context, systems biology-centered studies indicate that mutations in other SWI/SNF subunits, 
such as ARID1A, SMARCE1 or SMARCA4, may exhibit mechanistic convergence with 
SMARCB1 loss, particularly, in generating and maintaining accessibility over enhancer regions 
(Pan et al. 2018). This hypothesis is also supported by the observation that preclinically, 
inhibiting EZH2 appears to have a broader effect against models with mutations in the SWI/SNF 
complex beyond SMARCB1 (Kim et al. 2015). Preclinical activity of LY3405105 in cell lines 
and patient-derived xenografts (PDX) models harboring ARID1A LOF mutations warrant 
exploring its role in treating malignancies driven by LOF mutations in other SWI/SNF complex
subunits such as SMARCB1, SMARCA2, and SMARCA4.
In summary, CDK7 regulates gene transcription in malignancies associated with super-enhancer
activation.  Targeting CDK7 with a covalent bioavailable inhibitor downregulates gene 
transcription and demonstrates activity in TNBC and several models that harbor mutations in 
ARID1A, KMT2C, and KMT2D.
To estimate the prevalence of LOF mutations, data were extracted from the MSK-IMPACT 
Clinical Sequencing Cohort (Zehir et al. 2017) and analyzed. The following lists the prevalence 
of LOF mutations for select tumor types:

ARID1A:  endometrial cancer (30.9%), bladder cancer (23.2%), ovarian cancer (12.5%), 
soft tissue sarcoma (0.3%)

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 22
LY3405105

KMT2C (MLL3):  bladder cancer (7.3%), endometrial cancer (5.3%), ovarian cancer 
(1.0%)

KMT2D (MLL2):  bladder cancer (21.0%), endometrial cancer (12.1%), ovarian cancer 
(1.4%)

KDM6A (UTX):  bladder cancer (29.0%), endometrial cancer (1.0%), ovarian cancer 
(0%)
The nonclinical toxicity profile of LY3405105 has been characterized in good laboratory practice 
(GLP) -compliant studies conducted to support first-in-human dosing in patients with advanced 
cancer, in accordance with International Conference for Harmonization (ICH) S9 guidance.  The 
key studies were oral repeat-dose general toxicology studies in rats and dogs (4 weeks in 
duration with a 4-week recovery period).  These studies evaluated standard toxicological 
endpoints and assessed safety pharmacology endpoints (cardiovascular, central nervous system
[CNS], respiratory) through quantitative and qualitative evaluations of electrocardiograms 
(ECGs), and detailed clinical observations following dosing. The key nonclinical toxicities were 
degenerative changes in the gastrointestinal (GI) tract and bone marrow hypocellularity. These 
findings were expected based on pharmacology, are dose-dependent, are reversible following 
cessation of dose administration, and are anticipated to translate to humans.  All other important 
toxicities (effects on lymphoid tissues, male reproductive tissues, and skin, and decreased heart 
rate) are considered to be clinically monitorable and/or manageable in the intended patient 
population.
Information pertaining to nonclinical efficacy and safety may be found in Section 4.2 of the 
Investigator’s Brochure (IB).  
Information pertaining to nonclinical pharmacokinetics (PK) and metabolism may be found in 
Section 4.1 of the IB. 
3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated adverse events (AEs) of LY3405105 are to be found in the IB.  

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 23
LY3405105
4. Objectives and Endpoints
Table JZFA.4.1 shows the objectives and endpoints of the study.
Table JZFA.4.1.
Objectives and Endpoints
Objectives
Endpoints
Phase 1a
Primary

To assess the safety and tolerability of LY3405105, 
administered as monotherapy to determine the 
RP2D and schedule in patients with solid tumors

Safety (including but not limited to):  incidence and 
severity of DLTs, TEAEs, SAEs, deaths, and 
clinical laboratory abnormalities 
Secondary

To assess the PK of LY3405105 administered as 
monotherapy to patients with solid tumors

AUC/Cmax of LY3405105

To document any anti-tumor activity observed with 
LY3405105 when administered as monotherapy to 
patients with solid tumors

Per RECIST v1.1:
o
ORR
o
DCR
o
DoR
o
TTR
o
PFS

OS
Exploratory

To assess the relationship between biomarkers, 
LY3405105 exposure, and clinical outcomes

Results of biomarker analyses

Clinical outcomes data
Phase 1b
Primary

To assess the efficacy of LY3405105

ORR
Secondary

To evaluate the safety and tolerability of 
LY3405105 when administered as monotherapy to 
patients with solid tumors

Safety, including but not limited to incidence and 
severity of TEAEs, SAEs, deaths, and clinical 
laboratory abnormalities per CTCAE v4.0

To document any anti-tumor activity observed with 
LY3405105 when administered as monotherapy to 
patients with solid tumors across the defined cohorts

DCR

DoR

PFS

OS

TTR

To assess the PK of LY3405105 administered as 
monotherapy to patients with solid tumors across 
the defined cohorts

Plasma concentration of LY3405105
Tertiary/exploratory

To correlate the clinical activity with molecular 
subtypes as defined in the protocol

ORR in relation to molecular subtypes 

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 24
LY3405105
Abbreviations:  AUC = area under the plasma concentration x time curve; Cmax = maximum concentration;
CTCAE = Common Terminology Criteria for Adverse Events; DCR = disease control rate; DLT = dose-limiting 
toxicity; DoR = duration of response; 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.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 25
LY3405105
5. Study Design
5.1.
Overall Design
Study JZFA is a Phase 1, multicenter, nonrandomized, open-label dose escalation study in 
patients with advanced solid tumors, followed by dose expansion of oral LY3405105 in patients 
with advanced selected solid tumors.  
This initial Phase 1 study of LY3405105 consists of a once daily (QD) continuous (Phase 1a)
dose escalation phase and an expansion phase (Phase 1b) of LY3405105 given as a monotherapy 
in 5 tumor expansion cohorts (Cohorts 1-5) as shown in Figure JZFA.5.1.  The dose escalation 
will determine the maximum tolerated dose (MTD) as well as the RP2D.
Figure JZFA.5.1 illustrates the overall study design, Section 5.1.1 describes the dose escalation 
phase and Section 5.1.2 describes the dose expansion phase.
Abbreviations:  ARID1A = AT-rich interactive domain-containing protein 1A; BRG1 = Brahma-related gene 1; 
BRM = Brahma; DL = dose level; DLT = dose-limiting toxicity; ICH = International Conference on 
Harmonization; INI1 = integrase interactor 1; KDM6A (UTX) = lysine demethylase 6A; 
KMT2C (MLL3) gene = lysine methyltransferase 2C; KMT2D (MLL2) gene = histone-lysine-methyltransferase 
2D; LOF = loss of function; MTD = maximum tolerated dose; n = approximate number of patients per group; 
pts = patients; QD = once daily; SMARCA2 = SWI/SNF related, matrix associated, actin dependent regulator of 
chromatin, subfamily a, member 2; SMARCA4 = SWI/SNF related, matrix associated, actin dependent regulator 
of chromatin, subfamily a, member 4; SMARCB1 = SWI/SNF related, matrix associated, actin dependent 
regulator of chromatin, subfamily b, member 1; SS18 = SS18 subunit of BAF chromatin remodeling complex; 
SSX = SSX family member; TNBC = triple-negative breast cancer.
Figure JZFA.5.1.
Illustration of study design.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 26
LY3405105
5.1.1. Dose Escalation Phase
Monotherapy dose escalation (Phase 1a) started, with a starting dose of LY3405105 1 mg orally 
(PO) QD (Part A1) and 2 mg PO intermittently every Monday, Wednesday, and Friday (MWF)
or Tuesday, Thursday, and Saturday (TTS) (Part A2) on a 28-day cycle.  Based on available
human PK exposure data, the intermittent dosing schedule (Part A2) will no longer be pursued in 
the study.  The Bayesian model-based toxicity method called N-CRM will be used to inform the 
dose levels in each cohort.  The dose escalation method is further described in Section 7.1.1.2.
Each dose level will enroll a minimum of 3 patients (but no more than approximately 6 patients 
per dose level).  At the RP2D, up to 10 patients may be enrolled in selected cohorts to further 
assess the safety and tolerability of the dose selected prior to advancing to the Phase 1b of the 
study. Subsequent dose levels will enroll patients based on the safety from the previous dose 
level, any available PK and pharmacodynamic (PD) data, and discussion with investigators
without sentinel dosing.  This decision is made between the investigators and the Lilly clinical 
research physician/clinical research scientist (CRP/CRS).
Lilly and the investigators will discuss safety and available PK/PD results after each dose level
for Phase 1a of the study, and dose escalation decisions will be made prior to starting enrollment 
to the next dose level. Lilly will send written notification to the investigator site to specify the 
dose and dosing schedule before patients may be enrolled in the next dose level.  Intermediate 
and/or higher dose levels, as well as alternative schedules of administration, will be explored if 
deemed necessary after discussion between Lilly and investigators, taking into account patient 
safety and PK/PD data.
5.1.2. Dose Expansion Phase
After all patients in the dose escalation phase (Phase 1a) have completed the dose-limiting 
toxicity (DLT) evaluation period or discontinued, an interim safety and PK/PD analysis will be 
conducted before opening the dose expansions (Phase 1b).  The N-CRM method along with 
PK/PD analysis will be used to identify a monotherapy RP2D for investigation in the dose
expansion phase.  The monotherapy RP2D may be below the MTD.
Phase 1b dose expansion will include LY3405105 monotherapy in patients with multiple tumor
types and will enroll approximately 20 patients in each of Cohorts 1-4.  Cohort 5 will enroll 
approximately 30 patients.  Patients in Cohorts 2-5 will be identified by the treating investigator 
based on local immunohistochemistry or molecular testing results.
5.1.3. Study Period Definitions
Baseline/Screening: Begins when the informed consent form (ICF) is signed and ends at the 
first study treatment (defined as receiving any study drug); if no study treatment is given, 
baseline/screening ends with the decision not to enroll.  This period lasts up to 28 days.  
Study Period:  The overall study period for Study JZFA begins the day of the first patient’s first 
dose of study treatment and ends at overall study completion (as defined in Section 5.3). 

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 27
LY3405105

Study Treatment Period: Begins with the day of the patient’s first study 
treatment and ends the day the patient and investigator agree that the patient will 
discontinue study treatment (discontinuation of assigned study drug; Section 8.1).  
Individual patients who enroll in Study JZFA may continue treatment until they 
have confirmed progressive disease or discontinue study treatment for any other 
reason (Section 8).

Post Study Treatment Follow-Up Period: Begins the day the patient and 
investigator agree that the patient will discontinue study treatment and ends the 
day of the patient’s death, lost to follow-up, or overall study completion, 
whichever is earlier.  It includes one 30-day safety follow-up visit and a long-term 
follow-up, as follows:
o
30-Day Safety Follow-Up Visit:  Occurs 30 ±7 days after the decision is 
made to discontinue from study treatment.
o
Long-Term Follow-Up:  Begins the day after 30-day follow-up visit is 
completed and ends with the patient’s death, lost to follow-up, or overall 
study completion, whichever is earlier.
5.2.
Number of Patients
Dose Escalation:  Phase 1a, approximately 30-64 patients will be enrolled (including up to 
10 patients in safety expansion at RP2D).
Dose Expansion:  Phase 1b, approximately 20 patients will be enrolled in each of Cohorts 1-4.  
In the bladder cancer Cohort 5, approximately 30 patients will be enrolled.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
The general rationale for the study is described in Section 3 and statistical considerations are 
described in Section 10. 
The purpose of the dose escalation is to determine a RP2D and dosing schedule that will be used 
in the subsequent dose expansion part of the study.  The dose escalation method is described in 
Section 7.1.1.2.
The patient populations in the dose expansion cohorts have been chosen based on preclinical 
data, in vivo efficacy studies, and tumor histology. TNBC and ovarian tumor histology is
broadly addicted to aberrant oncogenic transcription and may demonstrate enhanced sensitivity 
to selective CDK7 inhibition (Wang et al. 2015; Zhang et al. 2017). Preclinically, TNBC and 
ovarian tumor models demonstrate broad sensitivity to LY3405105 in vitro and in vivo.
Molecular biomarker selection in gynecological malignancies and in bladder cancer were 
selected based on the internal preclinical data across cell lines and PDX models (LY3405105
Investigator’s Brochure 2019, Section 4.2.2.1). Additionally, other molecular alterations in the 

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 28
LY3405105
SWI/SNF complex may lead to activation of super-enhancer regions where inhibiting CDK7 
could yield clinical activity (Chipumuro et al. 2014; Wang et al. 2015).
5.5.
Justification for Dose
A starting daily oral dose of 1 mg (Part A1) and 2 mg (Part A2) of LY3405105 was selected 
based on data from GLP-compliant, 4-week oral, daily repeat-dose toxicity studies in rats and 
dogs, and PK/PD data modeling.  Human clearance was predicted using mechanistic approaches
from screening in vitro and nonclinical PK data. 
 
 
 
 
In 
rats, 6 mg/kg LY3405105, administered daily for 4 weeks, was the MTD, and in dogs the highest 
non-severely toxic dose (HNSTD) was 2 mg/kg.  Key pathology findings in both species were 
degenerative changes in the GI tract (with correlative clinical chemistry changes and associated 
abnormal feces) and bone marrow hypocellularity (with correlative hematologic changes).  These 
target organ toxicities in GI and bone marrow were expected based on pharmacology, were dose-
dependent, and were reversible following cessation of dose administration.  When normalizing 
mg/kg to body surface area, the rat MTD (6 mg/kg = 36 mg/m
2), when divided by 10 (that is, 
3.6 mg/m2) is lower than the dog HNSTD (2 mg/kg = 40 mg/m2).  Therefore, the rat is the 
appropriate (more sensitive) species from which to calculate a safe human starting dose.  Based 
on body surface area, 1/10 of 6 mg/kg (that is, 3.6 mg/m2) in rats is approximately equivalent to 
a dose of 6 mg daily in humans and would be considered a safe starting dose (DeGeorge et al. 
1998).  An additional safety factor of 6 was applied to the 6-mg dose to arrive at the human 
starting dose of 1 mg daily (QD). A safety factor of 3 applied to the 6 mg dose, along with the 
decrease in frequency of dosing, supports 2 mg QOD, TIW as a safe starting dose regimen.
Additional details may be found in the IB.
CCI

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 29
LY3405105
Table JZFA.5.1.
Dose and Exposure Multiples for Oral Administration of LY3405105 
Based on Administered Dose and Predicted Human Exposure
Species
Dose Designation
Dose
(mg/m2)
Dose
Multiplea
Average Plasma 
Concentration 
(ng/mL)
Exposure 
Multipleb
Human
Starting dose (1 mg, QD)
0.6
–
2.4c,d
–
Rat 
MTDe (6 mg/kg/day)
36
60×
22d
9.2×
Dog 
HNSTDf (2 mg/kg/day)
40
67×
10d
4.2×
Human
Starting dose (2 mg, QOD, TIW)
3.7g
–
2.3c,h
–
Rat 
MTDe (6 mg/kg/day)
252i
68×
22d
9.6×
Dog 
HNSTDf (2 mg/kg/day)
280i
76×
10d
4.3×
Human
Predicted efficacious dose (7 mg, QD)
4.3
–
17c,d
–
Rat 
MTDe (6 mg/kg/day)
36
8.4×
22d
1.3×
Dog 
HNSTDf (2 mg/kg/day)
40
9.3×
10d
0.6×
Human
Predicted efficacious dose (15 mg, QOD, TIW)
28j
–
17c,d
–
Rat 
MTDe (6 mg/kg/day)
252i
9.0×
22d
1.3×
Dog 
HNSTDf (2 mg/kg/day)
280i
10×
10d
0.6×
Abbreviations:  AUC = area under the plasma concentration × time curve; HNSTD = highest non-severely toxic 
dose; MTD = maximum tolerated dose; TIW = 3 times per week; QD = once daily; QOD = every other day.
a
Dose multiple is the dose in animals divided by the dose in humans based on mg/m2. Doses were converted from 
mg/kg to mg/m2 using a km conversion factor of 6 for the rat, 20 for the dog, and 37 for a 60-kg human.
b
Exposure multiple is the calculated average plasma concentration in animals, divided by the predicted average 
plasma concentration in humans.
c
Plasma pharmacokinetic values shown are steady-state values estimated using mechanistic approaches based on 
screening in-vitro and in vivo data.
d
Value obtained by dividing steady-state AUC (0-24hr) (nghr/mL) by 24 hours.
e
MTD (and associated exposure at steady state) determined in a 4-week repeat-dose toxicity study (8383678).
f
HNSTD (and associated exposure at steady state) determined in a 4-week repeat-dose toxicity study (8383679).
g
Value represents mg/m2 over 1 week of dosing, calculated by multiplying daily value of 1.23 mg/m2 by 3 days.
h
Value obtained by dividing predicted AUC (0-48hr)ss (nghr/mL) by 48 hours.
i
Value represents mg/m2 over 1 week of dosing, calculated by multiplying daily mg/m2 value by 7 days.
j
Value represents mg/m2 over 1 week of dosing, calculated by multiplying daily value of 9.25 mg/m2 by 3 days.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 30
LY3405105
5.6.
Justification for Enrolling Patients ≥12 Years of Age
Soft tissue sarcomas including Epithelioid Sarcoma (ES) and Synovial Sarcoma (SS) are rare 
tumors that affect adolescents, young adults alongside adults with median age of incidence for 
ES of 26 years of age (Weiss and Goldblum 2001), and for SS of 34 years of age of which (17% 
are children or adolescents) (Sultan et al. 2009).  Metastatic sarcoma that progressed beyond 
curative local therapy or standard systemic therapy carry poor prognosis and represent a 
significant unmet medical need. Based on preliminary data from LY3405105 PK exposure, no 
significant difference in exposure was observed in relation to body weight over a range of 44 kg
to 111 kg. Additionally, we anticipate metabolic organ maturity by 12 years of age; therefore, no 
weight dose adjustment is necessary.
Besides safety review that is summarized in Section 10.3.2, additionally, the first patient 
12-18 years of age enrolled into Phase 1b will be monitored through Cycle 1 prior to enrolling 
additional patients in the same age group. The safety review committee will review the safety 
data from the first 3 patients age 12-18 years who are evaluable for safety upon completing the 
first cycle. Similar reviews will take place after each 5 patients of this age group treated to
evaluate for any safety signal in this population. 

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 31
LY3405105
6. Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
have histological or cytological evidence of a diagnosis of a solid tumor
(American Joint Committee on Cancer Staging Criteria) (Amin et al. 2017)
that is advanced and/or metastatic.  
Patients must have received therapies known to confer clinical benefit, must 
not be a candidate for such therapies in the opinion of the investigator, must 
have declined such therapy, or have a tumor type for which no standard of 
care exists.
Patients enrolled to the dose escalation may have any tumor histology. 
Patients enrolled to the dose expansion must have one of the following:
a)
Cohort 1:  Triple-negative breast cancer (TNBC).
b)
Cohort 2:  Clear cell ovarian cancer, endometrioid ovarian cancer, or 
endometrioid endometrial carcinoma with a LOF mutation in one or more of 
the following genes:  ARID1A, KMT2C (MLL3), KMT2D (MLL2), or KDM6A 
(UTX).
c)
Cohort 3: Soft tissue sarcoma or sarcomatoid/rhabdoid malignancy with loss 
of expression of INI1, BRG1, or BRM by immunohistochemistry or a LOF
mutation in one or more of the following genes: ARID1A, SMARCA2, 
SMARCA4, or SMARCB1. Patients with synovial sarcoma and a confirmed 
SS18-SSX gene fusion are also eligible.
d)
Cohort 4:  Epithelioid sarcoma with INI1 loss of expression by 
immunohistochemistry or SMARCB1 LOF mutation.
e)
Cohort 5:  Bladder cancer with a LOF mutation in one or more of the 
following genes:  ARID1A, KMT2C (MLL3), KMT2D (MLL2), or KDM6A 
(UTX).
For Cohorts 2-5, qualifying genomic alterations as defined in Section 9.8.1 or 
immunohistochemistry results will be established on the basis of local testing
performed as part of routine care at each participating site on a previously 
collected tumor biopsy or blood sample and established prior to consideration 
and consent to the study. The result should be generated by a laboratory with 
CLIA, ISO/IEC, CAP, or other similar certification. The presence of an 
eligible genomic alteration must be confirmed upon review of the redacted 
molecular pathology report by the Lilly CRP/CRS prior to enrollment.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 32
LY3405105
[2]
must provide archived formalin-fixed paraffin-embedded (FFPE) tumor tissue 
for exploratory biomarker analysis. If archived tumor tissue is not available, 
the patient may be eligible with prior Sponsor approval. 
Note:  Sites should confirm the availability of tumor tissue for exploratory 
analysis (Section 9.8.2) with the pathology laboratory prior to enrollment.
[3]
have the presence of measurable (Phase 1b) or non-measurable but evaluable 
(Phase 1a) disease as defined by the Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST v1.1) (Eisenhauer et al. 2009).
[4]
are of an acceptable age to provide informed consent according to the local 
regulations and are at least 18 years of age at the time of screening for Cohorts
1, 2, and 5 or are ≥12 years of age with a body weight of ≥40 kg for Cohorts 3 
and 4.  Adolescents between 12 and 18 years are not eligible for participation 
in the Phase 1a dose escalation.
[5]
have given written informed consent prior to any study-specific procedures.  
For minors, consent from the parent or legal guardian and assent from the 
patient is required.
[6]
have adequate organ function as defined in the table below:
System
Laboratory Value
Hematologic
ANC
1.5 × 109 cells/L
Platelets
100 × 109/L
Hemoglobin
Note:  Transfusions to increase a patient’s hemoglobin level or initiation of 
erythropoietin or G-CSF therapy to meet enrollment criteria are not 
allowed in the 14 days preceding the first dose of study drug.
9 g/dL
Hepatic
Total bilirubin
1.5 × ULN
Serum albumin
≥3 g/dL
ALT and AST
2.5 × ULN
Renal
Serum creatinine or
Calculated creatinine clearance (see Appendix 6)
1.5 × ULN or
50 mL/min
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
G-CSF = granulocyte colony-stimulating factor; ULN = upper limit of normal.
[7]
Eastern Cooperative Oncology Group (ECOG) performance status score of 
0-1 (age ≥16 years) or Lansky Performance Score (LPS) ≥40% (age <16 
years) with no sudden deterioration 2 weeks prior to the first dose of study 
treatment (Appendix 8).

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 33
LY3405105
[8]
have discontinued previous treatments for cancer and recovered from the 
acute effects of therapy other than alopecia.  Patients must have discontinued 
from previous treatments at least 21 days prior to first dose of study treatment.
Patients must have discontinued any other investigational agents ≥4 weeks 
prior to enrollment or ≥5 half-lives, whichever is shorter, since completion of 
previous investigational agent.
a)
Patients must have discontinued from mitomycin-C or nitrosoureas at 
least 42 days prior to first dose of study treatment.
[9]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[10] if a male or female of reproductive potential, must agree to use highly 
effective methods of birth control during the study and for at least 12 weeks 
following the last dose of study drug(s), or for the duration specified in 
country requirements, whichever is longer.  Women of childbearing potential 
must test negative for pregnancy based on a urine pregnancy test within 3
days of enrollment.  
[11] have an estimated life expectancy of ≥3 months.
[12] are able to swallow capsules/tablets.
6.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[13] are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[14] have known symptomatic CNS metastasis (screening not required). 
Patients with treated CNS metastases are eligible for this study if they are not 
currently receiving corticosteroids and/or anticonvulsants, and their disease is 
asymptomatic and radiographically stable for at least 90 days prior to consent.
[15] have a serious concomitant systemic disorder (for example, active infection, 
or a GI disorder causing clinically significant symptoms such as nausea, 
vomiting or diarrhea, or profound immune suppression) that, in the opinion of 
the investigator, would compromise the patient’s ability to adhere to the 
protocol.
[16] have a symptomatic human immunodeficiency virus infection or symptomatic 
activated/reactivated hepatitis A, B, or C (screening is not required).
[17] have a serious cardiac condition, such as

congestive heart failure

New York Heart Association Class III/IV heart disease

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 34
LY3405105

unstable angina pectoris

myocardial infarction within the last 3 months

valvulopathy that is severe or moderate 

or arrhythmias that are symptomatic or require treatment (not including 
patients with rate-controlled atrial fibrillation)

cerebrovascular accident (stroke) within the last 3 months

have a mean QT interval corrected for heart rate of ≥470 msec on screening 
ECG as calculated using the Bazett’s formula at several consecutive days 
of assessment.
[18] have a second primary malignancy that in the judgment of the investigator and 
Lilly may affect the interpretation of results (consult with Lilly CRP/CRS).
[19] are currently taking or have taken within 2 weeks prior to start of LY3405105,
strong inhibitors and inducers of CYP3A4 as outlined in Appendix 4.
[20] prior treatment with any CDK 7 inhibitor.
[21] are breastfeeding.
[22] are unwilling or unable to participate in, or do not have tissue adequate for 
participation in, the genetic/biomarker portion of the study.
6.3.
Lifestyle Restrictions
Patients should refrain from consuming grapefruit, grapefruit juice, and grapefruit-containing 
products while on study due to the effect on CYP3A4.
Due to the Phase 1 PK testing and possible unknown interactions, all herbal supplements will not 
be allowed while on study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened one additional time.  If re-screening is performed, the individual must sign a new 
ICF and be assigned a new identification number.
If laboratory tests are repeated during the screening period, this does not constitute re-screening.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 35
LY3405105
7. Treatment
The investigator or his/her designee is responsible for the following:

explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the study site personnel

verifying that instructions are followed properly 

maintaining accurate records of study drug dispensing and collection

returning all unused medication to Lilly, or its designee, at the end of the study, 
unless the site is authorized by Lilly to destroy unused medication, as allowed by
local law.
7.1.
Treatment Administered
7.1.1.
Dose Escalation (Phase 1a)
In the monotherapy dose escalation (Phase 1a), approximately 30-64 patients will start with a 
starting dose of LY3405105 1 mg PO QD (Part A1) on a 28-day cycle.  The dose escalation 
method is described in Section 7.1.1.2. 
Safety data, in particular AEs, will be the primary criteria for the dose escalation.  In addition, if 
available at the time of dose escalation decision, PK and PD results will be used for dose 
escalation.  No dose escalation can occur without prior discussion and agreement between Lilly 
and the investigators.
7.1.1.1.
Dose-Limiting Toxicity Determination and Maximum Tolerated Dose 
Definition
Dose-limiting toxicity is defined as a clinically significant AE during Cycle 1 of the dose
escalation phase that is possibly related to LY3405105 during Phase 1a and fulfills any one of 
the following criteria using the National Cancer Institute’s Common Terminology Criteria for 
Adverse Events (CTCAE) v4.0:

CTCAE Grade 3 non-hematological toxicity.  Exceptions will be made for:
o
Grade 3 nausea or constipation that lasts for <72 hours and can be 
controlled with treatment 
o
Grade 3 diarrhea, vomiting, or electrolyte disturbance that lasts for <72 hours and 
can be controlled with treatment
o
fatigue or anorexia. Grade 3 or Grade 4 fatigue should be considered a 
DLT if persisting >5 days
o
Transient Grade 3 elevations of alanine aminotransferase (ALT) and/or 
aspartate aminotransferase (AST), without evidence of other hepatic 
injury, in the setting of preexisting hepatic metastasis and baseline 
elevation of these values may not be considered a DLT if agreed by the 
study investigator and Lilly CRP/CRS.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 36
LY3405105

Total bilirubin >2 × upper limit of normal (ULN) with ALT/AST >3 × ULN in 
the absence of cholestasis (alkaline phosphatase <2 × ULN)

Grade 4 neutropenia >5 days duration

any febrile neutropenia

Grade 4 thrombocytopenia of any duration

Grade 3 thrombocytopenia with clinically significant bleeding

Grade 3/4 anemia

any other significant toxicity deemed by the primary investigator and Lilly to be 
dose limiting (for example, any toxicity that is possibly related to the study 
medication that requires the withdrawal of the patient from the study during 
Cycle 1 or certain Grade 2 AEs affecting vital organs)
o
A DLT-equivalent toxicity is defined as an AE occurring after Cycle 1 for 
a patient enrolled in Phase 1a.  It will also apply to patients treated in any 
cycle in Phase 1b (including Cycle 1) that would have met the criteria for 
DLT.
Potential DLTs that are AEs which are reasonably anticipated AEs for concomitant medication 
should be reviewed by the treating investigator and Lilly before final determination as a DLT.  
Review and discussion may include additional participating investigators.  Such review may 
determine that confounding factors render the case to be not evaluable for the purposes of dose 
selection.  For the purpose of this study, the MTD is defined as the highest tested dose that has 
less than 33% probability of causing a DLT.  
7.1.1.2.
Dose Escalation Method
In the dose escalation part of the study, data will be evaluated on an ongoing basis until the MTD
is determined. The Bayesian model-based toxicity band method (N-CRM) (Neuenschwander 
et al. 2008) that incorporates prior expectations about the dose-toxicity relationship will be fitted 
to the data at the end of each dose level to recommend a dose for the next dose level.  The 
recommendation is based on the model-based posterior probability of a DLT at each dose and the 
overdose control criteria. Details regarding the toxicity band model and design are provided in 
Appendix 7.
During the escalation, the investigators and Lilly will consider both the Bayesian model-based 
toxicity band method (N-CRM) recommendation and the observed DLT rate at each dose level to 
determine the next dose level and determine when to stop the escalation.
Dose levels will not exceed those recommended by the toxicity band model. Dose escalation 
will take into account all available PK and PD information. Additional patients may therefore be 
enrolled at a specific dose level to better characterize PK/PD.
The starting dose of LY3405105 will be 1 mg QD in Part A1.  If the starting dose exceeds the 
MTD, a lower LY3405105 dose level may be explored.  The maximum increment of escalation 
will be no more than 100%.  Each dose level will have a minimum of 3 patients enrolled to it.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 37
LY3405105
Subsequent dose levels will enroll patients based on the safety from the previous dose level, any 
available PK and PD data, and discussion with investigators.  This decision is made between the 
investigators and the Lilly CRP/CRS. Table JZFA.7.1 shows example dose levels for 
LY3405105.  It should be noted that although an example escalation table is shown below, 
alternate doses may be selected.
Intermediate, alternate, or higher dose levels will be explored if deemed necessary after 
discussion between Lilly and the investigators. The toxicity band model accommodates such 
additional dose levels naturally.
Table JZFA.7.1.
Example Dose Escalation Scheme for Study J1F-MC-JZFAa
Dose Level
LY3405105 Part A1 Dose
1
1 mg QD
2
2 mg QD
3
4 mg QD
4
8 mg QD
5
15 mg QD
6
30 mg QD
7
45 mg QD
Abbreviations:  QD = once daily.
a
Dose levels will start at 1 mg QD (Part A1) and maximum increase will be no more than 100% from previous 
level.  Table lists example dose levels which may be used.
7.1.2. Dose Expansion (Phase 1b)
After the monotherapy RP2D has been determined from Phase 1a, approximately 20 patients will 
be enrolled in each of Phase 1b Cohorts 1-4.  In Cohort 5, approximately 30 patients will be 
enrolled.  Patients will receive LY3405105 at the RP2D orally daily for a 28-day cycle. 
Study treatment should be continued until evidence of disease progression or discontinuation 
criteria is met. Patients with documented progressive disease may be allowed to continue 
LY3405105 if the patient is tolerating treatment and, in the opinion of the investigator, is 
deriving clinical benefit from continuing study treatment and continuation of treatment is 
approved by the Sponsor.
If DLT-equivalent toxicities occur in 33% or more of patients within a tumor-specific cohort 
expansion, then investigators and the Lilly CRP/CRS will assess the nature and severity of these 
toxicities.  If a treatment-related death or Grade 4 toxicity not clearly due to underlying disease 
or extraneous occur, then the investigators and the Lilly CRP/CRS will assess the nature and 
severity of the toxicities and whether the trial should be stopped due to unacceptable toxicity.  
No additional patients will be accrued until this safety review is completed and a decision is 
made either to continue at the current dose or to de-escalate the dose and define a new dose for 
the expansion phase.  The safety review and decision will be documented in writing.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 38
LY3405105
7.1.3.
Packaging and Labeling
All study drug will be provided by Lilly. Clinical study materials will be labeled according to 
the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be assigned to receive LY3405105 in this study. 
The Sponsor will confirm the dose and identification number assignment and dose level for each 
patient.  No dose escalations (that is, to the next dose level) can occur without prior discussion 
and agreement with Lilly. 
If investigators have eligible patients who have consented concurrently, more than the assigned 
number of patients may be entered at a particular dose level provided that accrual has not ceased 
due to excessive toxicity.  This enrollment procedure is allowed because of the advanced disease 
state of this patient population and the screening involved in defining eligibility.  This event 
should be approved by the Sponsor following discussions with the investigators.
7.2.1.
Selection and Timing of Doses
The dosing cycle is defined as an interval of 28 days.  During the monotherapy dose escalation, 
patients will receive doses once daily starting on Day 1 through Day 28 of a 28-day cycle. For 
visits where PK samples will be collected, patients are required to take the morning dose of 
LY3405105 at the hospital/clinic (not at home) after the predose PK sample collection has 
occurred.  
LY3405105 will be administered on an empty stomach (meals should not be consumed within 
1 hour either side of dosing).  Doses should be taken approximately the same time each day 
(±2 hours) as much as possible.  If a patient misses or vomits a dose, that dose should be omitted.  
Patients must record the time and amount of each dose taken (or alternatively, the time and 
amount of the dose missed or vomited) in a daily diary.
A delay of a cycle due to holiday, weekend, bad weather, or other unforeseen circumstances will 
be permitted for a maximum of 7 days and not counted as a protocol deviation. The reason for 
interruption should be documented on the electronic case report form (eCRF).
A patient may continue to receive study treatment until confirmed progressive disease 
(Section 9.1), unacceptable toxicity, or discontinuation for any other reason (Section 8). Patients 
with documented progressive disease may be allowed to continue LY3405105 if the patient is 
tolerating treatment and, in the opinion of the investigator, is deriving clinical benefit from 
continuing study treatment and continuation of treatment is approved by the Sponsor.
7.3.
Blinding
This is an open-label study.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 39
LY3405105
7.4.
Dose Modification
Doses of the study drugs may need to be delayed, reduced, or discontinued to manage specific 
AEs or other toxicities.  Investigators should review the relationship of an AE to the study drug 
to determine if study drug requires dose adjustment or delay (Table JZFA.7.2).  
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 >28 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 Lilly.  All dose modifications should be documented, including the 
approach taken, and a clear rationale for the need for modification.
Any patient who requires a dose reduction will continue to receive the reduced dose for the 
remainder of the study.  Any patient who has had 2 dose reductions and who experiences a 
toxicity that would cause a third dose reduction must be discontinued from study treatment.
If the patient is in Cycle 6 or beyond and is continuing to receive benefit from therapy, additional 
delays may be acceptable if agreed upon by both the investigator and the Sponsor.  If a patient 
has a non-drug-related AE (for example, pneumonia or prolonged flu) requiring a delay of more 
than 1 week, the patient may continue on therapy if, in the opinion of the investigator, he/she is 
showing benefit from therapy and has recovered sufficiently from the AE.  Additional 
procedures may be required for delayed patients before resuming treatment. 

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 40
LY3405105
Table JZFA.7.2.
Dose Modifications in Patients due to Toxicity
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 dose level at the 
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 dose level. 
Hematologic toxicity 
Grade 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced by 
1 dose level.
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 dose level unless already 
performed for incidence of 
toxicity that lead to the use 
of growth factor.
Nonhematologic toxicity (except 
diarrhea)
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 dose level – investigator’s 
discretion.
Nonhematologic toxicity 
Grade 3 or 4 that does not resolve with 
maximal supportive measures within 
72 hours 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.
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 dose level.
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 dose level – 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
Diarrhea recurs despite maximal 
supportive measures after resuming 
same dose level after initial Grade 2 
diarrhea
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced by 
1 dose level.
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 dose level.
Nonhematologic toxicity 
(laboratory)
Total bilirubin >2 × ULN with 
ALT/AST >3 × ULN in the absence of 
cholestasis
Dose MUST be 
permanently suspended.
Dose MUST be 
permanently suspended.
Nonhematologic toxicity (vital 
organs of clinical concern, for 
example cardiotoxicity, 
pneumonitis, neurotoxicity)
Grade 2
Dose MUST be suspended 
until toxicity resolves to either 
baseline or Grade 1. If not 
resolved to Grade 1 within 
around 14 days, discussion 
between the investigator and 
Lilly CRP is recommended. 
Dose MAY be reduced by 
1 dose level – investigator’s 
discretion.
Abbreviation:  ALT = alanine aminotransferase; ASCO = American Society of Clinical Oncology; AST = aspartate 
aminotransferase; MAY = per the investigator’s clinical judgment; MUST = mandatory; ULN = upper limit of 
normal

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 41
LY3405105
7.5.
Preparation/Handling/Storage/Accountability
LY3405105 capsules/tablets for oral consumption will be supplied by Lilly and labeled 
according to country regulation requirements.  All study treatment should be stored according to 
their associated product label and taken as directed.  Patients should store all study treatment in 
the original package provided according to the product label and be instructed to keep all 
medications out of reach from children.  Capsules/tablets should not be opened, crushed, or 
dissolved.
7.6.
Treatment Compliance
Patient compliance with study drug will be assessed at each visit.  LY3405105 compliance will 
be assessed by direct questioning, counting returned capsules/tablets/packages, and reviewing 
patient diaries.  Deviations from the prescribed dosage regimen should be recorded on the CRF.
A patient will be considered significantly noncompliant if he/she misses more than 20% 
cumulative days of study medication (full doses) during each cycle. A patient may be considered 
significantly noncompliant if he or she is judged by the investigator to have intentionally or 
repeatedly taken more than the prescribed amount of medication.
7.6.1. Evaluable Patients
Patients who withdraw from the study before receiving study drug(s) will be replaced and will 
not be included in the safety or efficacy assessments.  Safety analyses will be conducted on all 
patients who have received at least 1 dose of study drug, regardless of whether they are deemed 
evaluable for the assessment of a dose level.
Any patient who is discontinued from the study before receiving at least 80% of LY3405105
planned doses in Cycle 1 will be deemed non-evaluable for assessment of safety at that dose 
level and may be replaced unless they experience a DLT or dose omission/reduction due to 
toxicity prior to withdrawal. A patient may be deemed non-evaluable for assessment of a dose 
level in the event the patient experiences an AE which would meet DLT criteria, and furthermore 
has been determined through discussion between investigator and Lilly CRP/CRS to most likely 
be related to a concomitant medication or a prior line of immune therapy (in the case of immune-
related AEs) due to previously established linkage.
If the patient is noncompliant during Cycle 1 due to reasons other than drug-related toxicity, he 
or she will be considered non-evaluable and may be replaced.
Non-evaluable patients may be replaced to ensure that at least 3 patients complete 1 cycle of 
therapy at each dose level, unless accrual to that dose level has stopped due to a DLT.
Patients who are not evaluable for PK, but who complete 1 cycle of therapy, may be replaced 
upon consultation with the investigator(s) and the Lilly CRP/CRS to ensure adequate PK data, 
unless accrual to that dose level has stopped due to a DLT.
7.7.
Concomitant Therapy
The list of excluded medications and procedures is provided in Appendix 4.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 42
LY3405105
No other chemotherapy, radiotherapy, immunotherapy, cancer-related hormone therapy, 
experimental drugs, or herbal supplements will be permitted while the patients are on this study.  
The need for any form of radiotherapy (including palliative) will be cause for early 
discontinuation from the study. 
Patients should refrain from consuming grapefruit, grapefruit juice, and grapefruit-containing 
products while on study.
In addition, any disease progression requiring other forms of specific anti-tumor therapy will also 
necessitate early discontinuation from the study.  Appropriate documentation for all forms of 
premedication, supportive care, and concomitant medications must be captured on the case report 
form.  Replacement hormonal therapy initiated before study entry will be allowed.
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).
Patients on stable doses of bisphosphonates or denosumab are allowed to continue.  These agents 
should not be initiated within the 2 weeks prior to study enrollment or at any point while on the 
study.
All concomitant medications should be recorded throughout the patient’s participation in the 
study.
7.7.1. Growth Factors
Growth factors should not be administered to enable a patient to satisfy study inclusion criteria. 
Granulocyte colony-stimulating factor (G-CSF) or similar agents are not permitted as primary 
prophylaxis.
The use of G-CSF is permitted at the discretion of the investigator based on ASCO (Smith 
et al. 2015) and European Society for Medical Oncology (Crawford et al. 2009) guidelines. If 
the administration of growth factors is clinically indicated, dosing of LY3405105 must be 
suspended and must not be recommenced within 48 hours of the last dose of growth factors 
being administered. The dose of LY3405105 must be reduced by 1 dose level following the 
administration of growth factors.
7.8.
Treatment After the End of Study
The end of study definition is defined in Section 5.3.  Investigators will continue to follow the 
schedule of activities provided in Section 2 until notified by Lilly that end of study has occurred.
7.8.1.
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 Schedule of Activities (Section 2) for 
all patients until notified by Lilly that study completion has occurred.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 43
LY3405105
7.8.1.1.
Continued Access
Patients who are still on study treatment at the time of study completion may continue to receive 
study treatment if they are experiencing clinical benefit and no undue risks.  
The continued access period will apply to this study only if at least 1 patient is still on study 
treatment when study completion occurs.  Lilly will notify investigators when the continued 
access period begins.
Patients who are in short-term follow-up when the continued access period begins will continue 
in short-term follow-up until the 30-day short-term follow-up visit is completed.  Long-term 
follow-up does not apply.
Patients who are in long-term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 44
LY3405105
8. Discontinuation Criteria
The reason for discontinuation and the date of discontinuation will be collected for all patients.
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
8.1.
Discontinuation from Study Treatment
Patients will be discontinued from study treatment in the following circumstances:

the patient is enrolled in any other clinical study involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

the patient becomes pregnant during the study

the patient is significantly noncompliant with study procedures and/or treatment
as described in Section 7.6

the patient has confirmed progressive disease
Exception: Patients with documented progressive disease may be allowed to 
continue LY3405105 if the patient is tolerating treatment and, in the opinion of 
the investigator, is deriving clinical benefit from continuing study treatment and 
continuation of treatment is approved by the Sponsor.

the patient experiences unacceptable toxicity

the patient has had 2 dose reductions and experiences an AE that would cause a 
third dose reduction

the investigator decides that the patient should be discontinued from study 
treatment

the patient requests to be discontinued from study treatment

the patient’s legal representative requests that the patient be discontinued from 
study treatment.
Patients who are discontinued from study treatment will have follow-up procedures performed as 
shown in the Schedule of Activities (Section 2).
8.1.1.
Discontinuation of Inadvertently Enrolled Patients
If Lilly or the investigator site identifies a patient who did not meet enrollment criteria and who 
was inadvertently enrolled, a discussion must occur between the Lilly CRP/CRS and the 
investigator to determine if the patient may continue in the study.  If both agree that it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
Lilly CRP/CRS to allow the inadvertently enrolled patient to continue in the study with or 

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 45
LY3405105
without study treatment.  Safety follow-up is as outlined in the Schedule of Activities 
(Section 2).
8.2.
Discontinuation from the Study
Patients will be discontinued from the study (including follow-up procedures) in the following 
circumstances:

participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP)

the patient becomes pregnant during the study.  See Section 9.2 regarding 
regulatory reporting requirements on fetal outcome and breastfeeding

the investigator decides that the patient should be discontinued from the study

the patient requests to be discontinued from the study

the patient’s legal representative requests that the patient be discontinued from the 
study.
Patients who discontinue from the study early will have end-of-study procedures performed as 
shown in the Schedule of Activities (Section 2).
8.3.
Lost to Follow-Up
A patient would be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  Study site personnel are 
expected to make diligent attempts to contact patients who fail to return for a scheduled visit or 
who the site is otherwise unable to follow-up.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 46
LY3405105
9. Study Assessments and Procedures
Section 2 provides the Schedule of Activities for this study. 
Appendix 2 provides a list of the laboratory tests that will be performed for this study.
Section 2 provides the schedule for collection of samples in this study.
Unless otherwise stated in the following subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days of receipt of confirmed test results.  Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards.
9.1.
Efficacy Assessments
Tumor assessments will be performed for each patient at the times shown in the Schedule of 
Activities (Section 2).
The RECIST 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 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 is
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 intravenous 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.
See Section 10.3.1 for definitions of the efficacy endpoints.
9.2.
Adverse Events
The investigator will use CTCAE Version [4.0] (NCI 2009) to assign AE terms and severity 
grades.
Investigators are responsible for:

monitoring the safety of patients who have entered into this study and for alerting 
Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient

providing appropriate medical care of the patient during the study (including 
review of laboratory data and examination results)

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 47
LY3405105

following, through an appropriate health care option, AEs that are serious or 
otherwise medically important, considered related to study treatment or the study, 
or that caused the patient to discontinue study treatment before completing the 
study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  Frequency of 
follow-up evaluation is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish safety and toxicity.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  Study site personnel will record via eCRF any change in 
preexisting conditions and any new conditions as AEs.  Investigators should record their 
assessment of the potential relatedness of each AE to study treatment via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatment, or pathologies.  A “reasonable possibility” means that there is a cause 
and effect relationship between the study treatment and/or study procedure and the AE.
Adverse Event grading of toxicities related to estimated Glomerular Filtration Rate (GFR) should 
be evaluated based on the Cockcroft-Gault method or measured GFR.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
Study site personnel must report any dose modifications or treatment discontinuation that results 
from AEs to Lilly or its designee via eCRF, clarifying, if possible, the circumstances leading to 
dose modification or discontinuation of treatment.
9.2.1.
Serious Adverse Events
An SAE is any AE during this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization 

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or require hospitalization, may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 48
LY3405105
Although all AEs after signing the ICF are recorded in the eCRF, SAE reporting to Lilly begins 
after the patient has signed the ICF and has received study treatment.  However, if an SAE 
occurs after signing the ICF, but prior to receiving study treatment, it needs to be reported ONLY 
if it is considered reasonably possibly related to study procedure.
Study site personnel must notify Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a Lilly-approved method.  If alerts are issued via telephone, they are 
to be immediately followed with official notification on study-specific SAE forms.  This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE information.
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE but should be reported.  To fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient 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.
Planned hospitalizations or procedures for preexisting conditions that were recorded in the 
patient’s medical history at the time of study enrollment should not be considered SAEs.  
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.
Serious adverse events, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to study treatment.
9.2.2.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to study treatment or study procedure.  The 
United States 21 CFR 312.32, the Regulation (EU) No 536/2014 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 recording and expedited reporting of 
SUSARs that are consistent with global regulatory regulations and the associated detailed 
guidances.
9.2.3.
Complaint Handling
Lilly collects complaints on study drugs and drug delivery systems used in clinical studies to 
ensure the safety of study participants, monitor quality, and facilitate process and product 
improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 49
LY3405105
9.3.
Treatment of Overdose
The investigator should notify the Lilly CRP/CRS and a decision on next steps will be 
determined in consultation with Lilly.  Refer to the specific IB Section 7.3.9.
9.4.
Safety
9.4.1.
Safety Measures
For each patient, ECGs, vital signs, laboratory tests or other tests should be collected as shown in 
the Schedule of Activities (Section 2). Electrocardiograms should be recorded according to the 
study-specific recommendations that will be provided separately. 
Any clinically significant findings that result in a diagnosis and that occur after the patient 
receives the first dose of LY3405105 should be reported to Lilly or its designee as an AE via 
designated data transmission methods.
9.4.2.
Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods. 
If a study patient experiences elevated alanine aminotransferase (ALT) >5 × ULN and elevated 
total bilirubin (TBL) >2 × ULN, or ALT ≥8 × ULN, liver tests (Appendix 5) should be repeated 
within 3 to 5 days including ALT, AST, TBL, direct bilirubin (D.TBL), gamma-glutamyl 
transferase (GGT) and creatine phosphokinase (CPK) to confirm the abnormality and to 
determine if it is increasing or decreasing.  If the abnormality persists or worsens, clinical and 
laboratory monitoring should be initiated by the investigator based on the hepatic monitoring tests
(Appendix 5) and in consultation with the Lilly CRP. Monitoring of ALT, AST, and TBL should 
continue until levels normalize or return to approximate baseline levels.
9.4.2.1.
Special Hepatic Safety Data Collection
Hepatic data should be collected in the event that a patient meets one of the following conditions 
during the course of the study: 

elevation of serum ALT to ≥10 × ULN

patients without liver tumors or liver metastasis: ALT ≥5 × ULN and TBL ≥2 × ULN

patients with liver tumors or liver metastasis:  ALT ≥8 × ULN and TBL ≥2 × ULN

discontinuation from treatment due to a hepatic event or abnormality of liver tests

occurrence of a hepatic event considered to be a SAE.
9.5.
Pharmacokinetics
Pharmacokinetic samples will be collected as shown in Section 2.
Plasma samples will be used to determine the concentrations of LY3405105.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 50
LY3405105
A maximum of 5 samples may be added at additional time points or removed during the study if 
warranted and agreed upon by the investigator and Lilly. Plasma concentrations of LY3405105 
will be quantified using validated liquid chromatography-tandem mass spectrometry 
(LC-MS/MS) assay in a laboratory designated by the Sponsor. All bioanalytical samples will be 
stored in the United States. The remaining plasma samples collected for PK evaluation may be 
used for exploratory studies to assess the metabolism of LY3405105, which may involve sample 
pooling. Results from exploratory metabolism work will not be included in the final integrated 
study report.
Bioanalytical samples collected to measure LY3405105 concentration and metabolism and/or 
protein binding will be retained for a maximum of 2 years following last patient visit for the 
study.
9.6.
Pharmacodynamics
Samples collected to measure PD biomarkers will be identified by the patient number (coded) 
and retained at a facility selected by Lilly for a maximum of 15 years following last patient visit 
for the study.  Plasma samples will be collected as specified in Section 2, where local regulations 
allow, for biomarker research described in Section 9.8.
9.7.
Genetics
9.7.1.
Whole Blood Sample for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in Section 2, 
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 study treatment
and to investigate genetic variants thought to play a role in cancer.  Assessment of variable 
response may include evaluation of AEs or differences in efficacy.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.  Samples will be retained at a 
facility selected by Lilly for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ethical review boards/institutional review boards
(ERBs/IRBs) impose shorter time limits.  This retention period enables use of new technologies, 
response to questions from regulatory agencies, and investigation of variable response that may 
not be observed until later in the development of LY3405105 or after LY3405105 becomes 
commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing technologies include whole genome and exome 
sequencing, genome-wide association studies, multiplex assays, candidate gene studies, and 
epigenetic analyses.  Regardless of the technology utilized, data generated will be used only for 
the specific research scope described in this section.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 51
LY3405105
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA, RNA, proteins, lipids, 
and other cellular elements.  
This study will analyze biomarkers relevant to study treatment, the mechanism of action of 
LY3405105, variable response to study drug(s), immune function, tumor microenvironment, and 
pathways associated with cancer. These samples may also be used to develop related research 
methods or to validate diagnostic tools or assays.
Samples for biomarker research will be collected as specified in Section 2, where local 
regulations allow.  It is possible that biomarker data for patients in the study has already been 
generated from samples that were collected and analyzed prior to enrolling in this study.  This 
may include data generated from genetic analyses.  If available, these data may be requested 
from medical records for use in the research described in Sections 9.7.1 and 9.8.
9.8.1. Biomarkers Required for Eligibility
For patients enrolled to Cohorts 2-5 on the basis of the genomic alterations outlined in
Section 6.1, LOF mutations are defined as potentially deleterious frameshift mutations, nonsense 
mutations, deletions, or splice site alterations.  The presence of any such defined genomic 
alteration identified in tumor or blood will be based on available test results collected outside of 
Study JZFA as part of prior medical care (local testing).
For patients enrolled to Cohorts 2-5 based on a local laboratory test, the report containing 
evidence of an eligible genomic alteration or IHC result must be sent to the Sponsor or designee.
9.8.2.
Tumor Tissue Samples for Exploratory Biomarker Research
Tissue samples for biomarker research will be collected for the purposes described in 
Section 9.8.
The following samples for biomarker research will be collected as specified in Section 2, where 
local regulations allow.
Collection of the following tumor tissue sample is required for all patients to participate in this 
study:

To meet study eligibility criteria, and therefore, mandatory for study participation, 
patients must provide archived FFPE tumor tissue for exploratory biomarker analysis. 
While the tissue can be from either initial diagnosis or later, the sample should be the 
most recent available specimen containing adequate material.  If archived tumor tissue is 
not available, the patient may be eligible with Sponsor approval.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 52
LY3405105

Sites should confirm the availability of tumor tissue with the pathology laboratory during 
screening and prior to enrollment.  Tumor tissue should be submitted within 28 days 
following enrollment, unless this has been discussed with the Lilly CRP/CRS. 
Collection of the following tumor tissue sample(s) is optional for all patients participating in this 
study:

Optional biopsy samples may be requested if warranted and agreed upon by the 
investigator and Lilly.  If these additional samples are requested, they will be used to 
further investigate biomarkers that may help further characterize treatment response and 
resistance mechanisms, particularly in patients that have experienced clinical benefit 
from LY3405105 as a monotherapy or in combination.
Archived FFPE tumor tissue obtained from the primary tumor or metastatic site should be 
provided as a block (preferred) or unstained slides.  Due diligence should be used to make sure 
that tumor sample (not a normal adjacent or a tumor margin sample) is provided.  
The pathology report accompanying tissue will also be requested. The pathology report must be 
coded with the patient number. Personal identifiers, including the patient’s name and initials, 
must be removed from the institutional pathology report prior to submission.  Archived blocks 
will be sectioned and returned to the study site. Slides and tissue samples collected on study will
not be returned.
Samples will be retained at a facility selected by Lilly for a maximum of 15 years after the last 
patient visit for the study, or for a shorter period if local regulations and/or ERBs/IRBs impose 
shorter time limits.  This retention period enables the use of new technologies, response to 
questions from regulatory agencies, and investigation of variable response that may not be 
observed until later in the development of LY3405105 or after LY3405105 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, and/or immunohistochemistry may be performed on these 
tissue samples to assess potential associations between these biomarkers and clinical outcomes.
9.8.3.
Other Samples for Biomarker Research
The following samples for biomarker research will be collected as specified in Section 2, where 
local regulations allow:

plasma

a maximum of 5 samples may be collected at additional time points during the 
study if warranted and agreed upon by the investigator and Lilly.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.  

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 53
LY3405105
Samples will be retained at a facility selected by Lilly for a maximum of 15 years after the last 
patient visit for the study, or for a shorter period if local regulations and/or ERBs/IRBs impose 
shorter time limits.  This retention period enables use of new technologies, response to questions 
from regulatory agencies, and investigation of variable response that may not be observed until 
later in the development of LY3405105 or after LY3405105 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, and/or gene expression assays may be performed on these samples to assess potential 
associations between these biomarkers and clinical outcomes.
9.9.
Health Economics
Health economics and medical resource utilization parameters will not be evaluated in this study.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 54
LY3405105
10.
Statistical Considerations
10.1. Sample Size Determination
For the dose escalation phase, approximately 30-64 patients will be enrolled (including 10 
patients in safety expansion at RP2D).  The total sample size will be determined by the incidence 
of DLTs. For the Phase 1b expansion Cohorts 1-4, approximately 20 patients will be enrolled in 
each cohort. For bladder cancer cohort (Cohort 5) approximately 30 patients will be enrolled. 
Considering the overlap of different biomarker subgroups among patients with bladder cancer, 
the main rationale for a larger sample size in Cohort 5 (n=30) is to provide reasonable number of 
patients per subgroup, thus allowing for descriptive summaries of the bladder cancer patient
subpopulations.
To confirm the RP2D of LY3405105 as monotherapy and determine the preliminary efficacy of 
LY3405105 as monotherapy, an adequate sample size is required. A sufficient sample size will 
allow for an accurate evaluation of the relationship between exposure and toxicity, as well as an 
evaluation of the relationship between exposure and pharmacological effects using descriptive 
statistics and appropriate modeling techniques, if data warrant. A total of 20 patients with a 
given tumor type treated at the RP2D in dose confirmation can provide adequate precision for 
the estimated incidence rate of the following quantities of interest: 1) patients having a specified 
AE, or 2) patients showing a response (partial response/complete response [PR/CR]) to 
treatment. With a total sample size of n=20, the 95% confidence interval (CI) is approximately 
equal to the observed incidence rate ±12% to 24%. Example point estimates of incidence rates 
and corresponding 2-sided 95% CIs are summarized in Table JZFA.10.1, for n=20 and n=30. 
The values are provided as a reference for estimation rather than a basis of any decision criteria.
Table JZFA.10.1.
Estimated Incidence Rate and its 2-Sided 95% CI
Num of Cases
N
Est Rate
95% CIa
N
Est Rate
95% CIb
Lower Limit
Upper Limit
Lower Limit Upper Limit
0
20
0.0
0.0
0.17
30
0.0
0.0
0.12
3
20
0.15
0.03
0.38
30
0.10
0.02
0.27
5
20
0.25
0.09
0.49
30
0.17
0.06
0.35
10
20
0.50
0.27
0.73
30
0.33
0.17
0.53
15
20
0.75
0.51
0.91
30
0.50
0.31
0.69
Abbreviations:  CI = confidence interval; Est = estimated; Num = number.
a
95% Clopper-Pearson interval for binomial distribution with sample size (N) of 20 patients.
b
95% Clopper-Pearson interval for binomial distribution with sample size (N) of 30 patients.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 55
LY3405105
10.2. Populations for Analyses
The following analysis sets will be defined for this study:
Safety population will include all enrolled patients who received any quantity of study 
treatment, regardless of their eligibility for the study. The safety evaluation will be performed 
based on the first dose of study treatment a patient actually received. The safety population will 
be used for all dosing/exposure, safety, and efficacy analyses.
Pharmacokinetic population will include all treated patients who received at least 1 dose of 
study treatment and have at least 1 postbaseline evaluable PK sample.
Biomarker population will include the subset of patients from the safety population from whom 
a valid assay result has been obtained.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee.
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) and the clinical study report (CSR).  Additional exploratory 
analyses of the data will be conducted as deemed appropriate.
The primary analysis of primary and secondary endpoints will be performed no more than 1 year 
after the last patient is enrolled in the trial. An updated analysis of efficacy may be performed at 
a later time if deemed appropriate.
10.3.1. Efficacy Analyses
Tumor response data will be tabulated, and further exploratory analyses will be conducted as 
warranted, grouping patients by tumor type, for the safety population.
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 the appropriate
guidelines (RECIST v1.1 [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 same method that was used at baseline. 
Disease control rate (DCR) is defined as the proportion of patients who achieved a CR or PR or 
stable disease (SD) out of all patients treated.
Duration of response (DoR) will be calculated only for responders. It is measured from the 
date of first evidence of a confirmed response to the date of first progression of disease or the 
date of death due to any cause, whichever is earlier. For patients who are not known to have 
died or to have had a progression of disease as of the data-inclusion cutoff date, DoR will be 
censored at the date of last objective response assessment prior to the date of any subsequent 
systemic anticancer therapy.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 56
LY3405105
Progression-free survival (PFS) is defined as the time from the date of start of treatment to the 
first date of radiologically documented progressive disease or the date of death due to any cause, 
whichever occurs first. For patients who are not known to have died or progressed as of the 
data-inclusion cutoff date, PFS time will be censored at the date of the last objective progression-
free disease assessment prior to the date of any subsequent systemic anticancer therapy.
Time to response (TTR) is defined as the time from the date of start of treatment to the date 
measurement criteria for confirmed CR or PR (whichever is first recorded) are first met. For 
patients who are not known to have achieved CR or PR as of the data-inclusion cutoff date, TTR 
will be censored at the date of the last objective disease assessment prior the date of any 
subsequent systematic anticancer therapy.
Overall survival (OS) is defined as the time from the date of start of treatment to the date of 
death due to any cause. For patients who are alive, lost to follow-up, or withdrawn from the 
study at the time of analysis, OS will be censored at the last date the patient is known to be alive.
10.3.2. Safety Analyses
All patients in the safety analysis set will be evaluated for safety and toxicity.
The Medical Dictionary for Regulatory Activities (MedDRA) Version 21.0 (or higher) will be 
used when reporting AEs by MedDRA terms.  The MedDRA Lower Level Term will be used in 
the treatment-emergent computation.  Treatment-emergent adverse events (TEAEs) will be 
summarized by System Organ Class (SOC) and by decreasing frequency of Preferred Term 
within SOC.
Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drug

SAEs, including possible relationship to study drug

AEs leading to dose adjustments

DLTs and dose-limiting equivalent toxicities

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.
For dose escalation phase, the model-based recommendation (as detailed in Appendix 7) and the 
observed DLT rate, will provide guidance on the RP2D.  Results will be presented in terms of 
the posterior probability of under (DLT rate <0.16), target (DLT rate 0.16-0.33), excessive (DLT 
rate 0.33-0.6), or unacceptable (DLT rate >0.6) dosing for each dose level tested.  The final 
RP2D of LY3405105 will be determined by review of all DLTs, TEAEs, PK, and PD data.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 57
LY3405105
10.3.3. Other Analyses
10.3.3.1. Patient Disposition
A detailed description of patient disposition will be provided, including a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients completing the study, as defined in the SAP, or 
discontinuing (overall and by reason for discontinuation).  A summary of all-important protocol 
deviations will be provided.
10.3.3.2. Patient Characteristics
Demographic data are collected and reported to demonstrate that the study population represents 
the target patient population considered for regulatory approval.
A summary of baseline patient and disease characteristics, historical diagnoses, preexisting 
conditions, and prior therapies will be reported using descriptive statistics. 
10.3.3.3. Concomitant Therapy
A summary of prior and concomitant medications will be reported.
10.3.3.4. Extent of Exposure/Treatment Compliance
The number of cycles received, dose omissions, dose reductions, dose delays, and dose intensity 
will be summarized for all treated patients by treatment arm.
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 pills dispensed 
and returned over the course of the patient’s treatment.
10.3.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic parameter estimates for LY3405105 will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be maximum concentration (Cmax) and area under the 
concentration-time curve (AUC0-tlast, AUC0-∞).  Other noncompartmental parameters, such as 
half-life (t1/2), apparent clearance (CL/F), apparent volume of distribution (V/F), and renal 
clearance of LY3405105 may be reported.  Additional exploratory analyses will be performed if 
warranted by data and other validated PK software programs (for example, NONMEM) may be 
used if appropriate.  The version of any software used for the analysis will be documented and 
the program will meet the Lilly requirements of software validation.
Pharmacokinetic parameter estimates will be evaluated to delineate effects of dose 
proportionality.  Log-transformed Cmax and AUC estimates will be assessed to estimate ratios of 
geometric means and the corresponding 90% CIs.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 58
LY3405105
10.3.3.6. Biomarker Analyses
Biomarkers related to treatment, immune response, mechanism of action, and/or cancer will be 
measured and analyzed. The association of biomarker and clinical outcome will be assessed via 
single-marker and/or multi-marker analysis.  
10.3.4. Interim Analyses
Because this is a dose-finding study, data will be reviewed on a dose level-by-dose level basis 
during the dose escalation, until the MTDs are determined.  The purpose of these dose level-by-
dose level reviews is to evaluate the safety data at each dose level 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 (and PK/PD data were available) as described in this protocol.  
For Phase 1a, after all patients who are deemed evaluable for the assessment of dose levels 
complete DLT evaluation period or MTD is determined, an interim analysis for safety and PK 
will be conducted.
For Phase 1b, a safety review will be performed after the first 20 patients across all cohorts are 
enrolled and treated for 1 cycle, and then every 6 months afterward. The purpose of this safety 
review is to evaluate the safety and tolerability for each expansion cohort and determine if a 
dose-limiting equivalent toxicity (DLET) has been observed. For the first 20 patients enrolled 
into Phase 1b, if in 7 patients or more DLETs are observed, accrual may be temporarily paused, 
and the available data from Phase 1a and Phase 1b will be analyzed to potentially modify the 
RP2D, or the study. Considerations for stopping recruitment should be given after discussion 
with the investigator and the Sponsor. 
Continued monitoring for safety and efficacy will occur in Phase 1b and if aggregate data 
suggest that continued enrollment is unlikely to alter the outcome or present an unreasonable risk 
to patients, enrollment into any one or all Cohorts 1-5 may be stopped.
If it is deemed that enough data are obtained to assess the primary objective and the secondary 
objectives, a CSR might be created before the last patient visit.  In this case, all data until the 
data-cutoff date will be used for the analysis of safety, efficacy, PK, and PD biomarkers.  All 
data defined in the protocol will continue to be collected from patients on treatment after the 
data-cutoff date. These data may be reported separately and the analyses on all patients 
including these data may not be performed.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 59
LY3405105
11.
References
Amin MB, Edge SB, Greene FL, Compton CC, Gershenwald JE, Brookland RK, Meyer L, Gress 
DM, Byrd DR, Winchester DP, editors. AJCC Cancer Staging Manual. 8th ed. Switzerland: 
Springer International; 2017.
Chipumuro E, Marco E, Christensen CL, et al. CDK7 inhibition suppresses super-enhancer-
linked oncogenic transcription in MYCN-driven cancer. Cell. 2014;159(5):1126-1139.
Chou J, Quigley DA, Robinson TM, et al. Transcription- associated cyclin-dependent kinases as 
targets and biomarkers for cancer therapy. Cancer Discov. 2020;10(3):351-370. 
Christensen CL, Kwiatkowski N, Abraham BJ, et al. Targeting transcriptional addictions in small 
cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell. 2014;26(6):909-922. Erratum 
in: Cancer Cell. 2015;27(1):149. 
Cockcroft DW, Gault MD. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16:31-41.
Crawford J, Armitage J, Balducci L, et al; National Comprehensive Cancer Network. Myeloid 
growth factors. J Natl Compr Cancer Netw. 2009;7(1):64-83.
DeGeorge JJ, Ahn CH, Andrews PA, et al. Regulatory considerations for preclinical 
development of anticancer drugs. Cancer Chemother Pharmacol. 1998;41(3):173-185.
Ebmeier CC, Erickson B, Allen BL, et al. Human TFIIH kinase CDK7 regulates transcription-
associated chromatin modifications. Cell Rep. 2017;20(5):1173-1186. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2) 228-247.
Fisher RP. Cdk7: a kinase at the core of transcription and in the crosshairs of cancer drug 
discovery. Transcription. 2019;10(2):47-56. 
Flowers CR, Seidnefled J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management 
of fever and neutropenia in adults treated for malignancy: American Society of Clinical 
Oncology Clinical Practice Guideline. J Clin Oncol. 2013;31(6):794-810.
Gui Y, Guo G, Huang Y, et al. Frequent mutations of chromatin remodeling genes in transitional 
cell carcinoma of the bladder. Nat Genet. 2011;43(9):875-878. 
Guo G, Sun X, Chen C, et al. Whole-genome and whole-exome sequencing of bladder cancer 
identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. 
Nat Genet. 2013;45(12):1459-1463. 
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
Jones S, Li M, Parsons DW, et al. Somatic mutations in the chromatin remodeling gene ARID1A 
occur in several tumor types. Version 2. Hum Mutat. 2011;33(1):100-103.
Kim KH, Kim W, Howard TP, et al. SWI/SNF-mutant cancers depend on catalytic and non-
catalytic activity of EZH2. Nat Med. 2015;21(12):1491-1496. 
Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016;22(2):128-134. 

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 60
LY3405105
Kwiatkowski N, Zhang T, Rahl PB, et al. Targeting transcription regulation in cancer with a 
covalent CDK7 inhibitor. Nature. 2014;511(7511):616-620. 
Lansky SB, List MA, Lansky LL, et al. The measurement of performance in childhood cancer 
patients. Cancer. 1987;60(7):1651-1656. 
Lu P, Geng J, Zhang L, et al. THZ1 reveals CDK7-dependent transcriptional addictions in 
pancreatic cancer. Oncogene. 2019;38(20):3932-3945. 
[NCI] National Cancer Institute. Cancer Therapy Evaluation Program, Common Terminology 
Criteria for Adverse Events, Version 4.0, DCTD, NCI, NIH, DHHS. Available 
at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
Published: 29 May 2009.
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I 
cancer trials. Stat Med. 2008;27:2420-2439.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655.
Pan J, Meyers RM, Michel BC, et al. Interrogation of mammalian protein complex structure, 
function, and membership using genome-scale fitness screens. Cell Syst. 2018;6(5):555-
568.e7. 
Rasool RU, Natesan R, Deng Q, et al. CDK7 inhibition suppresses castration-resistant prostate 
cancer through MED1 inactivation. Cancer Discov. 2019;9(11):1538-1555. 
Reisman D, Glaros S, Thompson EA. The SWI/SNF complex and cancer. Oncogene. 
2009;28(14):1653-1668.
Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with 
cancer: 2007 American Society of Clinical Oncology/American Society of Hematology 
Clinical Practice Guideline Update. J Clin Oncol. 2008;26(1):132-149. Erratum in: J Clin 
Oncol. 2008;26(7):1192.
Rothbart SB, Baylin SB. Epigenetic therapy for epithelioid sarcoma. Cell. 2020;181(2):211. 
Sharifnia T, Wawer MJ, Chen T, et al. Small-molecule targeting of brachyury transcription 
factor addiction in chordoma. Nat Med. 2019;25(2):292-300. 
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: 
American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol.
2015;33(28):3199-3122.
Sultan I, Rodriguez-Galindo C, Saab R, et al. Comparing children and adults with synovial 
sarcoma in the Surveillance, Epidemiology, and End Results program, 1983 to 2005: an 
analysis of 1268 patients. Cancer. 2009;115(15):3537-3547. 
Sun B, Mason S, Wilson RC, et al. Inhibition of the transcriptional kinase CDK7 overcomes 
therapeutic resistance in HER2-positive breast cancers. Oncogene. 2020;39(1):50-63. 
Valencia AM, Kadoch C. Chromatin regulatory mechanisms and therapeutic opportunities in 
cancer. Nat Cell Biol. 2019;21(2):152-161. 
Wang Y, Zhang T, Kwiatkowski N, et al. CDK7-dependent transcriptional addiction in triple-
negative breast cancer. Cell. 2015;163(1):174-186.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 61
LY3405105
Weiss S, Goldblum J. Malignant soft tissue tumors of uncertain type. In: Weiss S, Goldblum J, 
eds. Enzinger and Weiss's Soft Tissue Tumors. St Louis, Missouri: CV Mosby; 
2001:p 1483‐1571.
Wiegand KC, Shah SP, Al-Agha, et al. ARID1A mutations in endometriosis-associated ovarian 
carcinomas. N Engl J Med. 2010;363(16):1532-1543. 
Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from 
prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703-713.
Zhang Z, Peng H, Wang X, et al. Preclinical efficacy and molecular mechanism of targeting 
CDK7-dependent transcriptional addiction in ovarian cancer. Mol Cancer Ther. 
2017;16(9):1739-1750.
Zhang Y, Zhou L, Bandyopadhyay D, et al. The covalent CDK7 inhibitor THZ1 potently induces 
apoptosis in multiple myeloma cells in vitro and in vivo. Clin Cancer Res. 2019;25(20):6195-
6205. 
Zhang J, Liu W, Zou C, et al. Targeting super-enhancer-associated oncogenes in osteosarcoma 
with THZ2, a covalent CDK7 inhibitor. Clin Cancer Res. 2020;26(11):2681-2692.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 62
LY3405105
12.
Appendices

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 63
LY3405105
Appendix 1.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  any untoward medical occurrence in a patient or clinical 
investigation patient administered a pharmaceutical product and does not 
necessarily have a causal relationship with this treatment.  An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal 
(investigational) product, whether or not related to the medicinal (investigational) 
product.
ALT
alanine aminotransferase
ARID1A
AT-rich interactive domain-containing protein 1A
AST
aspartate aminotransferase
ASCO
American Society of Clinical Oncology
AUC
area under the plasma concentration × time curve
BOR
best overall response
BRG1
Brahma-related gene 1
BRM
Brahma
CAP
College of American Pathologists
CDK
cyclin-dependent kinases
CI
confidence interval
CL/F
apparent clearance
CLIA
clinical laboratory improvement amendments
Cmax
maximum concentration
CNS
central nervous system
collection database
A computer database where clinical study data are entered and validated.
CR
complete response
CrCI
creatinine clearance (CrCl)
CrI
credible interval

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 64
LY3405105
CRP
Clinical research physician:  individual responsible for the medical conduct of the 
study.  Responsibilities of the CRP may be performed by a physician, clinical 
research scientist, global safety physician, or other medical officer.
CRS
clinical research scientist
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTD
C terminal domain
DCR
disease control rate:  the percentage of patients with a best response of CR, PR, or 
SD.
DL
dose level
DLET
dose-limiting equivalent toxicity
DLT
dose-limiting toxicity
DoR
duration of response: the time from the date measurement criteria for CR or PR 
(whichever is first recorded) are first met until the first date that disease is 
recurrent or objective progression is observed, per RECIST v1.1 criteria, or the 
date of death from any cause in the absence of objectively determined disease 
progression or recurrence.
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
effective method of 
contraception
Male condom with spermicide, female condom with spermicide, diaphragm with 
spermicide, cervical sponge, or cervical cap with spermicide.
Also see the definition of highly effective method of contraception.
Enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the 
study are those who have been assigned to a treatment and have received at least 1
dose of study treatment. 
Enter
Patients entered in the study are those who have signed the ICF directly or 
through their legally acceptable representatives.
ERB
ethical review board
ES
epithelioid sarcoma
EU
European Union

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 65
LY3405105
EZH2
Enhancer of Zeste 2
FFPE
formalin-fixed paraffin-embedded
GCP
good clinical practice
G-CSF
granulocyte colony-stimulating factors
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GI
gastrointestinal
GLP
good laboratory practice
highly effective method 
of contraception
Combined oral contraceptive pill and mini-pill, NuvaRing®, implantable 
contraceptives, injectable contraceptives (such as Depo-Provera®), intrauterine 
device (such as Mirena® and ParaGard®), contraceptive patch for women <90 kg 
(<198 pounds), total abstinence, or vasectomy.
Also see the definition of effective method of contraception.
HNSTD
highest non-severely toxic dose
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference for Harmonization
Ig
immunoglobulin
INI1
integrase interactor 1
interim analysis
An analysis of clinical study data that is conducted before the final reporting 
database is authorized for data lock.
Investigational product 
A pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study including products already on the market when used 
or assembled (formulated or packaged) in a way different from the authorized 
form, marketed products used for an unauthorized indication or marketed 
products used to gain further information about the authorized form.
IRB
institutional review board
ISO/IEC
International Organization for Standardization / International Electrotechnical 
Commission
KDM6A (UTX)
lysine demethylase 6A
KMT2C (MLL3) gene
lysine methyltransferase 2C
KMT2D (MLL2) gene
histone-lysine-methyltransferase 2D

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 66
LY3405105
LC-MS/MS
liquid chromatography-tandem mass spectrometry
Lilly
Eli Lilly and Company
LOF
loss of function
LPS
Lansky performance score
MedDRA
Medical Dictionary for Regulatory Activities
MSK-IMPACT
Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer 
Targets
MTD
maximum tolerated dose
MWF
Monday, Wednesday, and Friday
NGS
next-generation sequencing
N-CRM
Bayesian model-based toxicity method
open label
A study in which there are no restrictions on knowledge of treatment allocation;
therefore, the investigator and the study participants are aware of the drug therapy 
received during the study.
ORR
overall response rate: the percentage of patients who achieve a BOR of CR or PR 
OS
overall survival 
PD
pharmacodynamic(s)
PDX
patient-derived xenografts
PET
positron emission tomography
PFS
progression-free survival: the time from the date of start of treatment until the 
first radiographic documentation of progression or death from any cause in the 
absence in progressive disease.  
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PO
orally
PR
partial response
PRC2
polycomb repressive complex 2
PR/CR
partial response/complete response
QD
once daily
QOD
every other day

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 67
LY3405105
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is 
used to produce the analyses and output reports for interim or final analyses of 
data.
re-screen
To screen a patient who was previously declared a screen failure for the same 
study.
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirement to become 
part of a pool of potential candidates for participation in a clinical study.
screen failure
A patient who does not meet one or more criteria required for participation in a 
study.
SD
stable disease
SMARCA2 (BRM)
SWI/SNF related, matrix associated, actin dependent regulator of chromatin, 
subfamily a, member 2
SMARCA4 (BRG1)
SWI/SNF related, matrix associated, actin dependent regulator of chromatin, 
subfamily a, member 4
SMARCB1 (INI1)
SWI/SNF related, matrix associated, actin dependent regulator of chromatin, 
subfamily b, member 1
SNF
sucrose non-fermentable
SOC
system organ class
SS
synovial sarcoma
SS18
SS18 subunit of BAF chromatin remodeling complex
SSX
SSX family member
SUSAR
suspected unexpected serious adverse reactions
SWI/SNF
SWItch/Sucrose Non-Fermentable complex
TBL
total bilirubin
TEAE
treatment-emergent adverse event:  an untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens 
relative to the pretreatment state, and does not necessarily have to have a causal 
relationship with this treatment.
TIW
3 times per week

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 68
LY3405105
TNBC
triple-negative breast cancer
TTR
time to response 
TTS
Tuesday, Thursday, and Saturday
ULN
upper limit of normal

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 69
LY3405105
Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology – Laboratorya
Local
Central
Leukocytes (WBC)
X
Neutrophilsb
X
Lymphocytes
X
Monocytes
X
Eosinophils
X
Basophils
X
Erythrocytes (RBC)
X
Hemoglobin (HGB)
X
Hematocrit (HCT)
X
Mean corpuscular volume (MCV)
X
Mean corpuscular hemoglobin concentration (MCHC)
X
Platelets (PLT)
X
Coagulation – Laboratory
Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT)
X
International normalized ratio (INR) or prothrombin time (PT) 
X
Clinical Chemistry – Laboratory
Serum Concentrations of:
Alanine aminotransferase (ALT)
X
Albumin
X
Alkaline phosphatase
X
Aspartate aminotransferase (AST)
X
Bilirubin, direct
X
Bilirubin, total
X
Blood urea nitrogen (BUN) or blood urea
X
Calcium
X
Creatinine
X
Glucose (random)
X
Magnesium
X
Potassium
X
Protein
X
Sodium
X
Urinalysis – Laboratory
Blood
X
Glucose
X
Ketones
X
pH
X
Protein
X
Specific gravity
X
Urine leukocyte esterase
X
Pregnancy Test (for Female Patients of Childbearing Potential) –Laboratory
Urine pregnancy test
X
Abbreviations:  CRF = case report form; Intl = international; RBC = red blood cells; WBC = white blood cells.
a
Treatment decision will be based on local laboratory results.
b
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.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 70
LY3405105
Appendix 3.
Study Governance, Regulatory, and Ethical 
Considerations 
Informed Consent
The investigator is responsible for: 

ensuring that the patient understands the nature of the study, the potential risks 
and benefits of participating in the study, and that their participation is voluntary 

ensuring that informed consent is given by each patient. This includes obtaining 
the appropriate signatures and dates on the ICF prior to the performance of any 
study protocol procedures and prior to the administration of study treatment.

answering any questions, the patient may have throughout the study and sharing 
in a timely manner any new information that may be relevant to the patient’s 
willingness to continue the patient’s participation in the study.

providing a copy of the ICF to the patient and retaining a copy of the signed ICF 
in the site file.
Ethical Review
Documentation of ERB/IRB approval of the protocol and the ICF must be provided to Lilly 
before the study may begin at the investigative site(s).  Lilly or its representatives must approve 
all ICFs, including any changes made by the ERBs/IRBs, before it is used at the investigative 
site(s).  All ICFs must be compliant with the ICH guideline on GCP.
The study site’s ERB/IRB should be provided with the following:

The protocol, protocol amendments, relevant protocol addenda, the current IB,
and updates during the course of the study

ICF

Other relevant documents (for example, curricula vitae, advertisements).
Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines 

the ICH GCP guideline 

applicable laws and regulations
The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of Lilly will be assigned to a third-party organization.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 71
LY3405105
Investigator Information
Physicians with a specialty in oncology will participate as investigators in this clinical study.
Protocol Signatures
Lilly’s responsible medical officer will approve the protocol, confirming that, to the best of his 
or her knowledge, the protocol accurately describes the planned design and conduct of the study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
The investigator with the most participation will serve as the final CSR coordinating investigator.  
If this investigator is unable to fulfill this function, another investigator will be chosen by Lilly to 
serve as the CSR coordinating investigator.
Lilly’s responsible medical officer and statistician will approve the final CSR for this study, 
confirming that, to the best of his or her knowledge, the report accurately describes the conduct 
and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

provide Sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the CRFs, and study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and verify data reported to detect potential errors. 
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes. If requested, the investigator will provide Lilly, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 72
LY3405105
Data Capture Systems
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the Sponsor.
An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the Sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Data collected via the Sponsor-provided data capture system(s) will be stored at third parties.
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s).  Prior to decommissioning, the investigator will 
receive an archival copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports/electronic transfers will be provided to the 
investigator for review and retention.  Data will subsequently be transferred from the central 
vendor to the Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Study and Site Closures
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the
ERB/IRB of the study site judges it necessary for medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 73
LY3405105
Appendix 4.
Restricted and Prohibited Concomitant 
Medications
The table below describes the drug class and associated medications that will be restricted during 
the study treatment period.  Patients who, in the assessment by the investigator, require the use of 
any of the prohibited treatments for clinical management should be removed from the study.  
This is not an all-inclusive list.  In general, strong CYP3A4 inhibitors, strong inducers of 
CYP3A4, or P-gp, are restricted during the study treatment period.
Strong Inhibitors of CYP3A4
All HIV protease inhibitors
Boceprevir
Clarithromycin
Conivaptan
Danoprevir and ritonavir
Diltiazem
Elvitegravir and ritonavir
Idelalisib
Itraconazole
Ketoconazole
Nefazodone
Paritaprevir and ritonavir and (ombitasvir and/or dasabuvir)
Posaconazole
Telaprevir
Troleandomycin
Voriconazole
Strong Inducers of CYP3A4
Aminoglutethimide
Apalutamide
Avasimibe
Carbamazepine
Enzalutamide
Fosphenytoin
Lumacaftor
Mitotane
Phenobarbital
Phenytoin
Rifabutin
Rifampicin (rifampin)
Rifapentine
St. John's wort
Abbreviation:  HIV = human immunodeficiency virus.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 74
LY3405105
Appendix 5.
Hepatic Monitoring Tests for
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin (HGB)
Hematocrit (HCT)
Hepatic Coagulationa
Erythrocytes (RBC)
Prothrombin time (PT)
Leukocytes (WBC)
Prothrombin time, INR
Neutrophilsb
Lymphocytes
Hepatic Serologiesa,c
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets (PLT)
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine aminotransferase (ALT)
Recommended Autoimmune Serology:
Aspartate aminotransferase (AST)
Anti-nuclear antibodya
Gamma-glutamyl transferase (GGT)
Anti-smooth muscle antibodya
Creatine phosphokinase (CPK)
Anti-actin antibodya
Abbreviations:  Ig = immunoglobulin; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ratio; RBC = red blood cells; 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.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 75
LY3405105
Appendix 6.
Creatinine Clearance Formula
Note:  This formula is to be used for calculating creatinine clearance (CrCl) from local 
laboratory results only.  
For serum creatinine concentration in mg/dL:
CrCl =
(140 – agea) (wt)    0.85 (if female), or 1.0 (if male)
(mL/min) 
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(140 – agea) (wt)  0.85 (if female), or 1.0 (if male)
(mL/min)
0.81 x serum creatinine (mo/L)
a Age in years, weight (wt) in kilograms.
Source:  Cockcroft and Gault (1976).

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 76
LY3405105
Appendix 7.
Statistical Details for Dose Escalation
Dose escalation will be driven by safety.  A model-based method that incorporates prior 
expectations about the dose-toxicity curve and controls for over-dosing probability will be 
applied to the data at the end of each dose level, which will provide quantitative guidance to the 
investigators and Lilly CRP to help determine the next dose level.
The model to be utilized is a two-parameter logistic model (Neuenschwander et al. 2008).  For 
example, the 2 parameters follow a bivariate normal distribution with minimally informative 
prior distribution, μ1=-3.88, μ2=-0.11, σ1=2.85, σ2=0.17, ρ=-0.88 if the prior parameters are set 
such that the median probability of DLT at the 1 mg dose is 0.01 (95% CrI 0.0 to 0.85), and the 
median probability of DLT at the 30 mg dose is 0.28 (95% CrI 0.0 to 0.95).  In the logistic 
model, the reference dose is set at dose level 1 (1 mg).
The posterior probability of a DLT at each dose level will be categorized to 4 bands, defined as:

Under-dosing:  the probability of a DLT at a given dose level in (0, 0.20)

Targeted toxicity:  the probability of a DLT at a given dose level in (0.20, 0.33)

Excessive toxicity:  the probability of a DLT at a given dose level in (0.33, 0.60)

Unacceptable toxicity:  the probability of a DLT at a given dose level in (0.60, 
1.00)
The model aims to recommend a dose which maximizes the probability of targeted toxicity, 
while controlling the probability of excessive or unacceptable toxicity to less than 25% and 
controlling the probability of unacceptable toxicity to less than 5%.  The probability of excessive 
or unacceptable toxicity is changed to 40% after Cohort 8. The maximum increment of 
escalation will be no more than 100%.  The exact increment will be determined by the 
investigators and Lilly CRP/CRS and may be less than the model prediction or <100%. 
Simulations were conducted using FACTs v6.0 to verify the operating characteristics of the 
model-based dose escalation.  Three scenarios were considered with varying DLT rates across 
the dose range, representing 3 different toxicity profiles, where Scenario 2 is the same as the 
prior probabilities used to derive the bivariate normal distribution used in the 2-parameter 
logistic model.
The proportion of simulated trials for which the selected MTD was truly in the target range (DLT 
rate 0.20-0.33) was approximately 63%, 49%, 32%, for each scenario, respectively.  The 
proportions of simulated trials for which the selected MTD is truly in the excessive and 
unacceptable range (DLT rate 0.33-1) were 10%, 16%, 13% for each scenario respectively.  
Overall, the method performs well in selecting the target dose(s) and controlling 
excessive/unacceptable doses based on the simulation results.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 77
LY3405105
Appendix 8.
Performance Scales
Eastern Cooperative Oncology Group (ECOG) Performance Scale
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature, for example, light housework, office work
2
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up 
and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking
hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Source:  Oken et al. 1982.
Lansky Performance Status (16 years old)
Score
Lansky Description
100%
Fully active, normal
90%
Minor restrictions in strenuous physical activity
80%
Active, but tired more quickly
70%
Greater restriction of play and less time spent in play activity
60%
Up and around, but active play minimal; keeps busy by being involved in quieter activities
50%
Lying around much of the day, but gets dressed; no active playing, participates in all quiet 
play and activities
40%
Mainly in bed; participates in quiet activities
30%
Bed bound; needing assistance even for quiet play
20%
Sleeping often; play entirely limited to very passive activities
10%
Does not play; does not get out of bed
0%
Unresponsive
Source:  Lansky et al. 1987.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 78
LY3405105
Appendix 9.
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment (b): (02 July 2020)
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, Amendment (b) is considered substantial.
Section # and Name
Description of Change
Brief Rationale
1. Synopsis
3.1. Study Rationale
4. Objectives and Endpoints
Objectives for Part 1b were 
added and updated.
Evaluation of the anti-tumor activity 
in the defined population in the Phase 
1b portion was added.
1. Synopsis
5.1. Overall Design
7.1.1. Dose Escalation Phase 
(Phase 1a)
The intermittent dosing 
schedule in Part A2 will no 
longer be pursued in the study 
and was deleted.
Available safety and human exposure 
data support continuous daily dosing.
1. Synopsis
7.1.2. Dose Expansion 
Phase (Phase 1b)
Cohorts 6 and 7 have been 
deleted.
Updated study cohorts based on 
biologic rationale and to evaluate 
proof of concept in focused cohorts 
with a smaller number of patients.
1. Synopsis
7.1.2. Dose Expansion 
Phase (Phase 1b)
7.2.1. Selection and Timing 
of Doses
8.1. Discontinuation from 
Study Treatment
Patients with documented 
progressive disease may be 
allowed to continue 
LY3405105.
To allow patients with clinical benefit 
to remain on study if deemed 
appropriate by the treating physician.
1. Synopsis and subsequent 
sections
10.1. Sample Size 
Determination
Number of patients in Cohorts 
1-4 was reduced in Phase 1b.
Study was revised as a focused signal 
finding study and a smaller number of 
patients will suffice to establish proof 
of concept.
1. Synopsis and subsequent 
sections
10.1. Sample Size 
Determination
Number of patients in Cohort 5 
was increased in Phase 1b.
Due to the marker subgroups among 
bladder cancer patients, an increase in 
sample size to 30 in Cohort 5 provides 
sufficient number of patients in each 
subgroup.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 79
LY3405105
Section # and Name
Description of Change
Brief Rationale
1. Synopsis
5.2. Number of Patients
10.1. Sample Size 
Determination
At the recommended Phase 2 
dose (RP2D) in Phase 1a, up to 
10 backfill patients may be 
enrolled, which increased the 
approximate overall number of 
patients from 54 to 64. 
To further assess the safety and 
tolerability of the dose selected prior 
to advancing to the Phase 1b part of 
the study
1. Synopsis
2. Schedule of Activities
Schedule of activities was 
divided in Phase 1a and Phase 
1b and updated to reflect less 
visits needed.
After establishing safety in Phase 1a, 
less frequent monitoring is adequate 
to maintain safety while balancing 
burden of patients and sites during 
Phase 1b dose expansion.
2. Schedule of Activities
9.6. Pharmacodynamics
9.8.3. Other Samples for 
Biomarker Research
Skin biopsies, peripheral blood 
mononuclear cell (PBMC) and 
urine pharmacokinetics (PK) 
have been deleted from 
Phase 1a schedule
There is no further planned analysis 
for additional samples.
1. Synopsis
9.8.2. Tumor Tissue 
Samples for Exploratory 
Biomarker Research
Archived tumor tissue samples 
should be sent to central 
laboratory within 28 instead of 
45 days.
To avoid delays and missing samples 
available, samples will be required to 
be provided within Cycle 1.
1. Synopsis
6.1. Inclusion Criteria
Appendix 8
Lansky Performance Status 
was added for patients ≤16 
years old.
Better functional representation for 
patients <16 years of age.
6.1. Inclusion Criteria
Biomarker specifics have been 
updated to reflect reduced 
number of cohorts in Part 1b.
To align with the study population.
6.1. Inclusion Criteria [4]
5.6. Justification for 
Enrolling Patients ≥12 Years 
of Age
The age for patients in Cohorts 
3 and 4 was lowered to ≥12 
years of age with a body 
weight of ≥40 kg
Patient age was lowered to expand 
enrollment to young patients with 
sarcoma to evaluate LY3405105 
efficacy.
6.1. Inclusion Criteria [6]
Calculated creatinine clearance 
as adequate renal function 
reduced from ≥60 mL/min to 
≥50 mL/min.
Based on renal clearance observed in 
clinic, a lower cutoff for inclusion 
criteria is appropriate without 
impacting the safety of patients.
6.2. Exclusion Criteria [19]
Appendix 4
Removed restriction for co-
administer with P-glycoprotein 
(P-gp) inhibitor and strong 
inhibitors of active renal 
secretion.
Remove of P-gp inhibitor is based on 
human exposure variability and the 
potential saturation of P-gp at the 
potential RP2D.  Remove of active 
renal secretion inhibitor is based on 
the observed renal clearance in clinic.

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 80
LY3405105
Section # and Name
Description of Change
Brief Rationale
7.1.1.1. Dose-Limiting 
Toxicity Determination and 
Maximum Tolerated Dose 
Definition
Grade 3/4 anemia was added to 
the DLT determination section.
To clarify the DLT definition in 
relation to anemia
7.1.1.2. Dose Escalation 
Method
The dose escalation scheme for 
Part A1 was modified.
Removing combination therapies 
throughout dose escalation and 
expansion.
9.8.1. Biomarkers Required 
for Eligibility
Appendix 2
Central next generation 
sequencing testing for 
enrollment is no longer 
offered. Only local laboratory 
results will be used.
To avoid enrollment delays for 
patients or a high rate of screen 
failures.
10.3.1. Efficacy Analyses
Best overall response (BOR) 
and change in tumor size have 
been deleted.
The definition for ORR replaced BOR 
definition to refine or standardize the 
definition of endpoints.
Change in tumor size is not part of the 
end point listed in the objective table, 
so there is no need to define it.
10.3.4. Interim Analyses
Interim analysis for Phase 1b 
was deleted.
Due to the reduction in sample size, 
an interim analysis is not expected to 
allow for appropriate decision 
making.  Instead, safety and clinical 
response will be monitored on an 
ongoing basis without formal 
enrollment hold and interim analysis.
10.3.4. Interim Analyses
Interim analysis plan has been 
revised according to the 
revised study design.
Interim analysis plan has been revised 
to provide more details on monitoring 
the trial progress (both safety and 
efficacy).
Other minor editorial changes were made to add clarity and correct typos

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 81
LY3405105
Amendment (a): (22 November 2018)
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, Amendment (a) is considered substantial.
Overall Rationale for the Amendment
Protocol J1F-MC-JZFA (a) Phase 1a/1b Study of LY3405105 Administered to Patients with 
Advanced Solid Tumors has been amended.  The new protocol is indicated by Amendment (a)
and will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

An addition to Section 3.2 adding more background information for ARID1A, KMT2C, 
KMT2D, and RB1. 

A clarification was made to inclusion Criteria 1, further clarifying that patients should 
have no available therapies known to confer a clinical benefit for their disease.

A clarification was made to inclusion Criteria 8 to include patients who have 
discontinued any other investigational agents ≥4 weeks prior to enrollment or ≥5 half-
lives since completion of previous investigational agent.

A clarification was made to exclusion Criteria 13 further excluding patients recently 
enrolled in a clinical study involving an investigational product if the half-life of the 
investigational agent and time since receiving the agent are not medically compatible 
with the study.

A correction was made to exclusion Criteria 17, excluding patients with a mean QT 
interval corrected for heart rate of ≥470 msec on screening ECG.

An addition to exclusion Criteria 19 and Appendix 4, further excluding patients who have 
discontinued both strong inhibitors and inducers of CYP3A4 and
P-glycoprotein.

A clarification was made to the lifestyle restrictions restricting patients from all herbal 
supplements while on study.

An addition to the DLT and MTD determination Section 7.1.1.1 adding total bilirubin 
>2 × ULN with ALT/AST >3 × ULN in the absence of cholestasis (alkaline phosphatase 
<2 × ULN).

An addition to the DLT and MTD determination Section 7.1.1.1 adding certain Grade 2 
AEs affecting vital organs.

An addition to Table JZFA.7.2 adding further dose modifications in patients due to 
toxicities. 

A justification for skin biopsies was added to Sections 9.6 and 9.8.3. 

J1F-MC-JZFA Phase 1 Oncology Protocol (c)
Page 82
LY3405105

A clarification to Section 9.8.1.2 was added to clarify the anatomical site from which the 
specimen was collected cannot be specified, as Cohorts 3-7 are tumor agnostic and the 
archival specimen may be from a primary or metastatic site.

Other minor editorial changes were made to add clarity.