Conditions: Small Cell Lung Cancer
Keywords: SCLC LY2606368 CHK1
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 133
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of prexasertib when given to participants with extensive stage disease small cell lung cancer (ED-SCLC). The study will evaluate how the body processes the drug and how the drug affects the body. The study will also evaluate the association between tumor response and the participant's perceived quality of life.

Detailed description:

Arms:
arm 1: 105 mg/m\^2 Intravenous (IV) prexasertib administered of every 14 days with extensive stage disease small cell lung cancer (ED-SCLC) who had platinum-sensitive disease (has prior platinum based therapy with subsequent progression greater or less than 90 days after last dose of platinum based therapy). arm 2: 105 mg/m\^2 IV prexasertib administered of every 14 days with extensive stage disease small cell lung cancer (ED-SCLC) who had resistant/refractory disease (did not have an objective response to platinum-based therapy or had progression greater than 90 days after the last dose of platinum). arm 3: 40 mg/m\^2 IV prexasertib Day 1, 2, and Day 3 of a 14 day cycle in participants with ED-SCLC platinum sensitive disease.

Interventions: intervention 1: Prexasertib
Intervention descriptions: intervention 1: Administered IV

Protocol document:
Prot_000.pdf: 
Protocol 14D-MC-JTJH A Phase 2 Study of LY2606368 in Patients with Extensive Stage Disease Small Cell 
Lung Cancer 
 
NCT# NCT02735980 
 
Approval Date: 15-Mar-2016 


I4D-MC-JTJH(a) Clinical Protocol
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Protocol I4D-MC-JTJH(a)
A Phase 2 Study of LY2606368 in Patients with Extensive 
Stage Disease Small Cell Lung Cancer
Confidential Information
The information contained in this protocol 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 
LY2606368, 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.
LY2606368
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly:  01 December 2015
Amendment (a) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 15-Mar-2016 GMT


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Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................16
3.1.
Study Rationale............................................................................................................16
3.2.
Background..................................................................................................................17
3.2.1.
Prior Clinical Experience with LY2606368 as a 
Monotherapy:  Study JTJA...................................................................................18
3.3.
Benefit/Risk Assessment..............................................................................................18
3.4.
Rationale for JTJH Amendment (a)..............................................................................18
4.
Objectives and Endpoints..................................................................................................20
5.
Study Design.....................................................................................................................22
5.1.
Overall Design .............................................................................................................22
5.2.
Number of Patients.......................................................................................................22
5.3.
End of Study Definition ...............................................................................................22
5.4.
Scientific Rationale for Study Design...........................................................................22
5.5.
Justification for Dose ...................................................................................................22
6.
Study Population...............................................................................................................23
6.1.
Inclusion Criteria..........................................................................................................23
6.2.
Exclusion Criteria ........................................................................................................25
6.3.
Lifestyle Restrictions....................................................................................................26
6.4.
Screen Failures.............................................................................................................26
7.
Treatments........................................................................................................................27
7.1.
Treatments Administered .............................................................................................27
7.1.1.
Packaging and Labelling ......................................................................................27
7.2.
Method of Treatment Assignment ................................................................................27
7.2.1.
Selection and Timing of Doses.............................................................................28
7.3.
Blinding .......................................................................................................................28
7.4.
Dosage Modification....................................................................................................28
7.5.
Preparation/Handling/Storage/Accountability...............................................................29
7.5.1.
LY2606368 Mesylate Monohydrate .....................................................................29
7.5.2.
LY2606368 Lactate Monohydrate........................................................................29
7.6.
Treatment Compliance .................................................................................................30
7.7.
Concomitant Therapy...................................................................................................30
7.8.
Treatment after the End of the Study............................................................................31
7.8.1.
Continued Access.................................................................................................31


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8.
Discontinuation Criteria ....................................................................................................33
8.1.
Discontinuation from Study Treatment.........................................................................33
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................33
8.2.
Discontinuation from the Study....................................................................................33
8.3.
Lost to Follow-Up........................................................................................................33
9.
Study Assessments and Procedures ...................................................................................35
9.1.
Efficacy Assessments...................................................................................................35
9.1.1.
Appropriateness of Assessments ..........................................................................35
9.2.
Adverse Events ............................................................................................................35
9.2.1.
Serious Adverse Events........................................................................................36
9.2.2.
Suspected Unexpected Serious Adverse Reactions ...............................................37
9.2.3.
Complaint Handling.............................................................................................38
9.3.
Treatment of Overdose.................................................................................................38
9.4.
Safety...........................................................................................................................38
9.4.1.
Other Safety Measures .........................................................................................38
9.4.2.
Safety Monitoring ................................................................................................39
9.5.
Pharmacokinetics .........................................................................................................39
9.6.
Pharmacodynamics ......................................................................................................39
9.7.
Pharmacogenomics ......................................................................................................39
9.7.1.
Whole Blood Sample for Pharmacogenetic Research ...........................................39
9.8.
Biomarkers...................................................................................................................40
9.8.1.
Blood Samples .....................................................................................................40
9.8.2.
Tissue Samples ....................................................................................................41
9.9.
Health Economics ........................................................................................................42
10.
Statistical Considerations ..................................................................................................43
10.1. Sample Size Determination ..........................................................................................43
10.2. Populations for Analyses..............................................................................................43
10.3. Statistical Analyses ......................................................................................................44
10.3.1.
Efficacy Analyses ................................................................................................44
10.3.2.
Safety Analyses....................................................................................................45
10.3.3.
Other Analyses.....................................................................................................45
10.3.3.1.
Patient Disposition..........................................................................................45
10.3.3.2.
Patient Characteristics ....................................................................................45
10.3.3.3.
Concomitant Therapy .....................................................................................45
10.3.3.4.
Poststudy-Treatment-Discontinuation Therapy ...............................................45
10.3.3.5.
Treatment Compliance....................................................................................46
10.3.3.6.
Pharmacokinetic/Pharmacodynamic Analyses ................................................46
10.3.3.7.
Biomarker Analyses .......................................................................................46


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10.3.3.8.
Health Outcome/Quality of Life Analyses ......................................................47
10.3.4.
Interim Analyses..................................................................................................47
11.
References ........................................................................................................................49


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List of Tables
Table
Page
Table JTJH.2.1.
Schedule of Screening Activities ............................................................10
Table JTJH.2.2.
On-Study-Treatment Schedule of Activities............................................12
Table JTJH.2.3.
Post-Treatment Follow-Up Schedule of Activities ..................................14
Table JTJH.2.4.
Continued Access Schedule of Activities................................................15
Table JTJH.4.1.
Objectives and Endpoints .......................................................................21
Table JTJH.7.1.
LY2606368 for Injection Strengths.........................................................27
Table JTJH.7.2.
Hematologic Parameters Required for the Start of Each Cycle................28
Table JTJH.7.3.
LY2606368 Dose Reductions .................................................................29


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List of Figures
Figure
Page
Figure JTJH.7.1.
Continued access diagram.......................................................................31


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................52
Appendix 2.
Study Governance, Regulatory, and Ethical Considerations....................55
Appendix 3.
Clinical Laboratory Tests........................................................................58
Appendix 4.
Sampling Schedule for Pharmacokinetics ...............................................59
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............60
Appendix 6.
Creatinine Clearance Formula.................................................................61
Appendix 7.
Protocol Amendment I4D-MC-JTJH(a) Summary 
A Phase 2 Study of LY2606368 in Patients with Extensive Stage 
Disease Small Cell Lung Cancer.............................................................62


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1.
Synopsis
Protocol Title:  A Phase 2 Study of LY2606368 in Patients with Extensive Stage Disease Small Cell Lung Cancer
Rationale:
Small-cell lung cancer patients with extensive stage disease (ED-SCLC) are commonly treated with cisplatin or 
carboplatin in combination with etoposide.  While a majority of patients respond to initial treatment, nearly all 
patients relapse and die from their disease.  Consequently, new agents are needed to improve clinical outcomes for 
ED-SCLC patients.  Study I4D-MC-JTJH (Study JTJH) will evaluate the efficacy of LY2606368 in both 
platinum-sensitive and platinum-resistant/refractory patients.
Objectives and Endpoints:
Objectives
Endpoints
Primary

Cohort 1: To estimate the ORR when a dose of 
105 mg/m2 LY2606368 every 14 days is 
administered to patients with ED-SCLC that have 
platinum-sensitive disease

Cohort 2: To estimate the ORR when a dose of 
105 mg/m2 LY2606368 every 14 days is 
administered to in patients with ED-SCLC that 
have platinum resistant/refractory disease

Best overall response (PR+CR) as determined per 
RECIST version 1.1
Secondary

To characterize the safety and toxicity profile of 
LY2606368

The safety endpoints evaluated will include but are not 
limited to the following: AEs, SAEs, clinical laboratory 
tests, ECGs vital signs, and physical examinations

To characterize the PK of LY2606368

LY2606368 concentration in plasma

To estimate secondary efficacy measures 
including DCR, DoR, PFS, and OS

DCR: best overall  response (CR, PR) and SD as 
determined per RECIST, version 1.1

DoR: time from the date of an objective response until 
PD, per RECIST 1.1 or the date of death from any cause
in the absence of PD

PFS: time from enrollment until the first radiographic 
documentation of progression or death from any cause in 
the absence of PD

OS: time from enrollment until death from any cause

To evaluate the association between best tumor 
response and change from baseline in lung 
cancer-specific symptoms, symptomatic distress, 
activity status, overall quality of life, total LCSS
score, and ASBI for patients who have platinum-
sensitive or platinum-resistant/refractory SCLC

Lung cancer symptoms (appetite loss, fatigue, cough, 
dyspnea, hemoptysis, and pain), summation items 
(symptomatic distress, activity level, and global quality of 
life), total LCSS, and ASBI
Abbreviations:  AEs = adverse events; ASBI = Average Symptom Burden Index; CR = complete response; 
DCR = disease control rate; DoR = duration of response; ECG = electrocardiogram; ED-SCLC = extensive-stage 
disease small cell lung cancer; LCSS = Lung Cancer Symptom Scale; ORR = overall response rate; OS = overall 
survival; PD = progressive disease; PFS = progression-free survival; PK = pharmacokinetics; PR = partial response; 
RECIST = Response Evaluation Criteria In Solid Tumors; SAEs = severe adverse events; SD = stable disease.


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Overall Design:
Study I4D-MC-JTJH (JTJH) is a multicenter, Phase 2 study of LY2606368 in patients with ED-SCLC who have 
either platinum-sensitive or platinum-resistant/refractory disease.  Cohort 1 will include patients with objective 
response to prior platinum-based therapy with subsequent progression ≥90 days after the last dose of platinum.  
Cohort 2 will include patients that either did not have an objective response to prior platinum-based therapy or had 
progression <90 days after the last dose of platinum.  Patients cannot have received more than 2 prior therapies for 
ED-SCLC.
Number of Patients:
Approximately 134 patients will be entered into Study JTJH, and 116 patients will be enrolled and complete the 
trial.
Treatment Arms and Duration:
Dose and Schedule (q 14 Days)
Cohort
LY2606368 D1
Number of Cycles
1 and 2
105 mg/m2
Treatment will continue until a discontinuation 
criterion is met.
Abbreviations:  D = day; q = every.


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2.
Schedule of Activities
Table JTJH.2.1.
Schedule of Screening Activities
Study Period
Baseline
Cycle
BL
Visit
0
Duration
Up to 28 days
Relative Day 
≤28
≤14
≤7
Procedure 
Category
Procedure
Comments
Study 
Entry/Enrollment
Informed Consent Form signed 
(prior to conducting any protocol specific 
tests/procedures)
X
Inclusion/Exclusion evaluation
X
Medical History
Initial history/preexisting conditions
X
Historical illness
X
Habits assessment
X
Includes smoking history.
Physical 
Examination
Physical examination
X
Includes height and weight.
ECOG performance status
X
Vital signs
X
Tumor 
Assessment
Radiologic imaging according to 
RECIST 1.1
X
Baseline radiological tumor assessment per RECIST 
version 1.1 should be done (see Section 9.1). 
Radiologic assessments obtained previously as part of 
routine clinical care may be used as the baseline 
assessment provided that they were done no more than 
28 days before the first dose of study drug.
Tumor measurement (palpable or visible)
X
Performed at the same time as radiologic imaging.
Adverse Events Collection/CTCAE Grading
X
Concomitant Medication Notation
X
Laboratory/
Diagnostic Tests
Hematology
X
Chemistry
X
Urinalysis
X
Coagulation
X
Pregnancy test
X
Women of childbearing potential must have negative 
serum pregnancy tests at their baseline visits and have 
negative urine pregnancy tests within 7 days before 
their first doses of  LY2606368 (see Section 6.1).  
ECG
X
Single local ECG
Confirm availability of pretreatment 
tumor tissue
X
If archived tissue is not available, a fresh tumor biopsy 
should be obtained after all other study entry criteria 
have been confirmed, unless the sponsor and 
investigator document that the patient may be enrolled 
without pre-treatment tissue.
Exploratory blood sample for biomarkers
X
Optional pretreatment biopsy
X
Optional and may be performed at any time before
starting treatment with LY2606368.  See Section 9.8.2.
Health Outcome 
Measure
Lung Cancer Symptom Scale
X
The LCSS should be administered prior to extensive 
interaction with site personnel.


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Schedule of Screening Activities 
Abbreviations:  BL = baseline; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2009); 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); LCSS = Lung 
Cancer Symptom Scale; RECIST 1.1 = Response Evaluation Criteria In Solid Tumors Version 1.1 (Eisenhauer 
et al. 2009).


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Table JTJH.2.2.
On-Study-Treatment Schedule of Activities
Study Period
Study Treatment Period
Cycle/Visit
1
2
3-na
Duration
14 days
14 days
14 days
Relative Day within Dosing Cycle
1
8
1
8
1
8
Procedure 
Category
Procedure
Comments
Physical 
Examination
Physical Exam
X
X
X
Includes weight and calculated BSA.  May be completed up to 7 days prior to treatment 
infusion.  In Cycle 4 and beyond may be completed every other cycle (for example,
Cycle 4, 6, 8, etc.).
Vital signs
X
X
X
Includes blood pressure, pulse, and temperature.  Complete before treatment infusion.
ECOG performance status
X
X
X
Complete before treatment infusion.
Laboratory/ 
Diagnostic Tests
Hematology
X
X
X
X
X
X
May be drawn up to 3 days before the planned assessment.  In Cycles 4-n, the Day-8 
sample may be collected at the discretion of the investigator.  
Chemistry
X
X
X
May be drawn up to 3 days before the planned assessment.
Urinalysis
X
May be collected up to 3 days before the planned assessment.
Urine pregnancy test
X
Day 1 of every other cycle.  Only to be performed on women of childbearing potential.
PK sampling
X
X
X
X
X
See PK Schedule for collection information.
Stored sample for pharmacogenetics
X
Collect once.  Sample can be collected at any time if not collected on Day 1 of Cycle 1.
Exploratory blood sample for biomarkers
X
Only to be collected on the same day when the CT scan is obtained (every 3 cycles 
starting with Cycle 3).
Plasma biomarker sample 
X
X
Collect prior to dosing on Day 1 of Cycles 1 and 3 only.
ECG
X
X
X
Single local ECG collected at each time point.  Day 1:  predose, 10 min after EOI 
(±5 min), 30 min after EOI (±10 min), and >1 hour after EOI.
Cycle 2-X:  predose.  However, if QTcF >480 msec is observed on Day 1, then 10 min 
after EOI (±5 min), 30 min after EOI (±10 min), and >1 hour after EOI should also be 
collected in subsequent cycles.
Optional Tumor Biopsy
X
Can occur at any time during patient's treatment.


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Study Period
Study Treatment Period
Cycle/Visit
1
2
3-na
Duration
14 days
14 days
14 days
Relative Day within Dosing Cycle
1
8
1
8
1
8
Tumor 
Assessment
Radiologic imaging according to 
RECIST 1.1
X
For the first 52 weeks following enrollment, perform approximately every 6 weeks 
starting at the end of Cycle 3 (eg, Days 8-14).  Thereafter, perform approximately every 
12 weeks. The scanning interval (6 or 12 weeks [±1 week]) should be maintained even if 
cycles are delayed.  As a result, after Cycle 3, the scans may not always occur at the end 
of a cycle.  The same method of imaging used at baseline should be used for each 
subsequent assessment.  Scans should also be obtained as clinically indicated.
Tumor 
Assessment
Tumor measurement (palpable or visible)
X
Perform at least every 6 weeks starting in Cycle 3 on the same day as the radiologic 
imaging.
Adverse Events Collection/ CTCAE Grading
X
X
X
Concomitant Medication Notation
X
X
X
Lung Cancer Symptom Scale
X
X
X
The LCSS is to be administered prior to extensive interaction with site personnel and prior 
to administration of study drug.
Study 
Treatment
LY2606368
X
X
X
IV over approximately 60 (+10) min
Abbreviations:  BSA = body surface area; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2009); 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group (Oken et al. 1982); EOI = end of infusion; IV = intravenous; min = minute; 
LCSS = Lung Cancer Symptom Scale; PK = pharmacokinetic; QTcF = QT interval using Fridericia’s correction; RECIST 1.1 = Response Criteria In Solid 
Tumors Version 1.1 (Eisenhauer et al. 2009).


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Table JTJH.2.3.
Post-Treatment Follow-Up Schedule of Activities
Study Period
Post-discontinuation Follow-Up
Short-term Follow-Up
Long-term Follow-Up
Duration
30 ± 5 days
60 ± 14 days
Visit
801
802-X
Relative day within a cycle
Period begins the day 
after stopping of study 
treatment and lasts 
approximately 30 days
Period begins 1 day after 
short-term follow-up period is 
completed and continues until 
death, study withdrawal, or the 
patient is lost to follow-up
Procedure 
Category
Procedure
Comments
Physical 
Examination
Physical examination (including  weight)
X
Vital signs
X
Includes blood pressure, pulse, and temperature.
ECOG performance status
X
Tumor 
Assessment
Radiologic imaging according to RECIST 1.1
X
The same method of imaging (CT scan, spiral CT, etc.) used at 
baseline should be used for each subsequent assessment.  Not 
required if progressive disease is documented while on treatment or 
if there are clear signs of clinical progression.
Tumor measurement (palpable or visible)
X
Performed at the same time as radiologic imaging.
Adverse Events Collection/CTCAE Grading
X
X
After Visit 801, only study treatment-related serious events are 
reported.
Concomitant Medication Notation
X
Lab/Diagnostic 
Tests
Hematology
X
Chemistry
X
ECG
X
Exploratory blood sample for biomarkers
X
Plasma biomarker sample
X
Optional posttreatment biopsy
X
See Section 9.8.2.
Health Outcome 
Measure
Lung Cancer Symptom Scale
X
The LCSS will need to be administered prior to extensive 
interaction with site personnel.
Follow-Up
Survival Assessment
X
Approximately every 60 (±14) days (telephone assessment is 
acceptable).
Abbreviations:  CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events (NCI 2009); ECOG = Eastern Cooperative Oncology 
Group (Oken et al. 1982); LCSS = Lung Cancer Symptom Scale; RECIST 1.1 = Response Criteria In Solid Tumors Version 1.1 (Eisenhauer et al. 2009).


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Table JTJH.2.4.
Continued Access Schedule of Activities
Study Treatment
Follow-Upa
Visit
501-5XX
901
Procedureb
Comments
AE collection
X
X
Administer LY2606368
X
IV over approximately 60 (+10) minutes once every 14 days.
Abbreviations:  AE = adverse event; IV = intravenously.
a
Continued access follow-up begins 1 day after 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.


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3.
Introduction
3.1.
Study Rationale
Lung cancer is the leading cause of cancer mortality worldwide, with an estimated rate of 
1.8 million new cases per year, and is responsible for the majority of deaths due to cancer 
(1.59 million) (GLOBOCAN Population Fact Sheets page [WWW]).  Small-cell lung cancer 
(SCLC) is a rapidly growing tumor, with approximately 60% to 70% of patients presenting with 
metastatic disease at diagnosis that accounts for 12% of new lung cancer cases (Wakuda et al. 
2015). Approximately two-thirds of patients with SCLC present with extensive stage disease 
(ED-SCLC), which has traditionally been defined as disease beyond the ipsilateral hemithorax 
and may include malignant pleural effusion, pericardial effusion, or hematogenous metastases
(Micke et al. 2002).
SCLC is highly sensitive to chemotherapy, with combination chemotherapy remaining the focus 
of treatment for patients with ED-SCLC.  About 60% to 80% of patients with extensive stage 
disease respond to combination chemotherapy (Hann and Rudin 2008).  Cisplatin or carboplatin 
in combination with etoposide are commonly used regimens in the first-line treatment of SCLC.  
After an initial response, however, nearly all patients with extensive disease will relapse and the 
majority of patients will eventually die from their disease (Sundstrom et al. 2002).  
Platinum-refractory disease shows progression during therapy or within <90 days of the last dose 
of platinum.  Platinum-sensitive disease shows progression ≥90 days after the last dose of 
platinum.  Patients with platinum-sensitive disease have a higher likelihood of response to 
second-line treatment. Their response rate is approximately 20% to 25% (Fruh et al. 2013; 
Kalemkerian et al. 2013).  In contrast, patients with platinum-refractory disease have a ≤10% 
chance of response to a second-line treatment (Kalemkerian et al. 2013).  If left untreated, a 
relapsed patient will typically live 2 months to 4 months (Wakuda et al. 2015).
Several other agents have been shown to have activity in SCLC, and many studies have 
compared 3-drug regimens to the standard 2-drug regimens with no improvement in efficacy.  
Topotecan is approved for patients that have ED-SCLC that have failed or relapsed after first line 
chemotherapy (Demedts et al. 2010). Patients receiving topotecan (1.5 mg/m2 daily for 5 days 
every 21 days) had an overall response rate of 24.3% (von Pawel et al. 1999).  The median time 
to progression was 13.3 weeks and median survival was 25.0 weeks (von Pawel et al. 1999).  
Adverse events (AEs) associated with this treatment included Grade 4 neutropenia (70.2%), 
Grade 3/4 anemia (42.3%), Grade 4 thrombocytopenia (28.8%), and documented infection 
within 2 days of Grade 4 neutropenia (28%) (von Pawel et al. 1999).  Other agents, including
paclitaxel, irinotecan, vinorelbine, and gemcitabine, have been tested in the second-line setting in 
an effort to improve on the efficacy and tolerability of topotecan.  Despite the modest benefit of 
topotecan, they have not increased efficacy over topotecan (Chan and Coward 2013), 
demonstrating the clear need for new agents to improve outcomes for patients with ED-SCLC.
Checkpoint kinase 1 (CHK1), a multifunctional protein kinase, is a regulator of the 
deoxyribonucleic acid (DNA) damage response (Dai and Grant 2010). CHK1 is a key 
component of the checkpoint response following DNA damage and is essential for homologous 


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recombination repair of DNA double strand breaks. It also affects the initiation of DNA 
replication origin firing, stabilization of replication forks, resolution of replication stress, and 
coordination of mitosis, even in the absence of exogenous DNA damage (McNeely et al. 2014).  
Although CHK1 inhibitors previously have been developed as chemopotentiators, given the 
integral role that CHK1 plays in DNA replication and the regulation of the cell cycle, inhibitors 
of CHK1 may also have single-agent activity.  In particular, replication stress is emerging as a 
factor that may play a sensitizing role for response to monotherapy with CHK1 inhibitors 
(Lecona and Fernandez-Capetillo 2014).
SCLC is a tumor associated with replication stress and may be sensitive to the effects of a CHK1 
inhibitor (Byers et al. 2012; Thompson et al. 2012). Furthermore, tumors with MYC alterations, 
which occur in approximately 20% of patients with SCLC (Byers and Rudin 2015), may have 
increased replication stress and higher sensitivity to CHK1 inhibition (Cole et al. 2011; Hoglund 
et al. 2011).  Short hairpin ribonucleic acid (shRNA)-mediated targeted CHK1 knockdown 
significantly decreased the proliferation of SCLC lines and increased the level of pH2AX, a 
marker of DNA damage (Sen et al. 2015), providing further evidence that CHK1 may be an 
attractive target for this disease.
3.2.
Background
LY2606368 is an adenosine-5'-triphosphate-competitive inhibitor of CHK1. LY2606368 
inhibits the enzymatic activity of CHK1 with a half-maximal inhibitory concentration (IC50) of 
<1 nM and CHK2 with an IC50 of 8 nM in in vitro assays (King et al. 2015). In nonclinical 
studies, LY2606368 induced DNA damage as measured by pH2A.X, a marker of double-
stranded DNA breaks, and replication catastrophe. LY2606368 inhibited tumor growth in cancer 
xenografts, including SCLC models, as monotherapy and in combination with other agents (Wu 
et al. 2012; McNeely et al. 2014; King et al. 2015; Sen et al. 2015).  In vitro data from cell 
viability screens across a large panel of tumor lines representing different tumor histologies 
demonstrated increased sensitivity to growth inhibition by LY2606368 in SCLC compared to 
other lung subtypes as well as generally increased sensitivity in tumor cell lines that were MYC 
amplified (data on file).  In a panel of 39 SCLC lines, proteomic analysis revealed that sensitivity 
to LY2606368 was associated with elevated basal expression of total and phosphor cMYC 
(p=.01) (Sen et al. 2015).
LY2606368 has been evaluated in human clinical trials as a monotherapy for patients with solid 
tumors (Study I4D-MC-JTJA [JTJA], NCT01115790) and in combination with either 
chemotherapy or targeted agents (I4D-MC-JTJF, NCT02124148).  In these Phase 1 studies, 
LY2606368 has shown an acceptable safety/tolerability profile.


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3.2.1. Prior Clinical Experience with LY2606368 as a Monotherapy:  
Study JTJA
LY2606368 was assessed as a monotherapy for patients with solid tumors and demonstrated an 
acceptable safety/tolerability profile, with transient neutropenia being the primary toxicity.
As of 27 August 2015, data were available from 146 patients who were treated with LY2606368 
on Days 1, 2, and 3, or on Day 1 only of a 14-day schedule.  The maximum tolerated dose 
(MTD) of LY2606368 administered on Days 1, 2, and 3 every 14 days was determined to be 
40 mg/m2, and the MTD of LY2606368 when administered on Day 1 every 14 days was 
determined to be 105 mg/m2.  A dose of 105 mg/m2 once every 14 days was selected as the 
recommended Phase 2 dose for monotherapy.
In patients who have received 105 mg/m2 of LY2606368, neutropenia was the most frequent and 
severe toxicity following treatment with LY2606368.  Grade 4 decreases in neutrophils deemed 
related to LY2606368 treatment were observed in 71% of these patients.  In general, neutrophil 
counts nadir on Day 8 and Grade 4 decreases were often less than 5 days.  Grade 4 decreases in 
platelets were observed in 5.7% of patients.  Grade 4 anemia was not observed.  Nonhematologic 
toxicity occurred at a lower frequency than hematologic toxicity and was predominantly Grade 1 
in severity.
In the 105 patients who received LY2606368 at a dose of 105 mg/m2 once every 2 weeks, the 
treatment-related AEs most frequently reported following LY2606368 treatment in Study JTJA 
include neutrophil count decreased (93%), platelet count decreased (46%), anemia (33%), white 
blood cell decreased (30%), fatigue (28%), nausea (14%), febrile neutropenia (11%), and 
headache (11%).
Please see the Investigator’s Brochure (IB) for additional information on the nonclinical and 
clinical experience with LY2606368.
3.3.
Benefit/Risk Assessment
Given the high unmet need for additional therapies for patients with previously treated 
ED-SCLC, the mechanistic rationale that supports a role for CHK1 inhibition in improving 
outcomes for patients with SCLC, the nonclinical data with LY2606368 as a monotherapy in 
nonclinical models (including SCLC), and the clinical safety profile of LY2606368, the 
risk/benefit assessment supports assessing LY2606368 monotherapy in the proposed patient 
population.
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated AEs of LY2606368 are to be found in the IB.
3.4.
Rationale for JTJH Amendment (a)
Amendment (a) was developed to address requests resulting from member states participating in 
the Voluntary Harmonisation Procedure during the assessment of the initial clinical trial 
application for Study JTJH in the European Union.  At the member states’ request, the protocol 
was modified to incorporate those states’ recommendations in the inclusion and exclusion 


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criteria and to establish the actions to be taken in case of prolongation of the QT/QTc interval 
>480 msec.  Because a protocol amendment was required, the opportunity was taken to also 
include several other minor protocol improvements and clarifications.


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4.
Objectives and Endpoints
Table JTJH.4.1 shows the objectives and endpoints of the study.


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Table JTJH.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

Cohort 1: To estimate the ORR when a dose of 
105 mg/m2 LY2606368 every 14 days is 
administered to patients with ED-SCLC that have 
platinum-sensitive disease

Cohort 2: To estimate the ORR when a dose of 
105 mg/m2 LY2606368 every 14 days is 
administered to in patients with ED-SCLC that have 
platinum resistant/refractory disease

Best overall response (PR+CR) as determined per 
RECIST version 1.1
Secondary

To characterize the safety and toxicity profile of 
LY2606368

The safety endpoints evaluated will include but are not 
limited to the following: AEs, SAEs, clinical 
laboratory tests, ECGs, vital signs, and physical 
examinations.

To characterize the PK of LY2606368

LY2606368 concentration in plasma

To estimate secondary efficacy measures including
DCR, DoR, PFS, and OS

DCR: best overall response (CR, PR) and SD as 
determined per RECIST, version 1.1

DoR: time from the date of an objective response until 
PD, per RECIST 1.1 or the date of death from any 
cause in the absence of PD

PFS: time from enrollment until the first radiographic 
documentation of progression or death from any cause
in the absence of PD

OS: time from enrollment until death from any cause

To evaluate the association between best tumor 
response and change from baseline in lung cancer 
specific-symptoms, symptomatic distress, activity 
status, overall quality of life, total LCSS score, and 
ASBI for patients who have platinum-sensitive or 
platinum resistant/refractory SCLC

Lung cancer symptoms (appetite loss, fatigue, cough, 
dyspnea, hemoptysis, and pain), summation items 
(symptomatic distress, activity level, and global quality 
of life), total LCSS, and ASBI
Tertiary/Exploratory

To explore biomarkers associated with the efficacy 
and safety of LY2606368, the exposure (PK) of 
LY2606368, the mechanism of action of CHK1, 
DNA damage response pathways or downstream 
effects, cell cycle markers, immune function, or 
cancer pathobiology

Biomarker research on genetic and circulating factors 
may be assessed from tumor tissue, whole blood, and 
plasma samples, unless precluded by local regulations.

To explore whether ongoing measurement of tumor 
shrinkage (such as changes in tumor size) correlate 
with efficacy measures

Tumor measurements
Abbreviations:  AEs = adverse events; ASBI = Average Symptom Burden Index; CHK1 = checkpoint kinase 1; 
CR = complete response; DCR = disease control rate; DoR = duration of response; ECG = electrocardiogram; 
ED-SCLC = extensive-stage disease small cell lung cancer; LCSS = Lung Cancer Symptom Scale; 
ORR = overall response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; 
PK = pharmacokinetics; PR = partial response; RECIST = Response Evaluation Criteria In Solid Tumors; 
SAEs = severe adverse events; SD = stable disease.


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5.
Study Design
5.1.
Overall Design
Study I4D-MC-JTJH (JTJH) is a multicenter, nonrandomized, parallel-cohort Phase 2 study of 
LY2606368 in patients with ED-SCLC who have either platinum-sensitive or platinum-
resistant/refractory disease.
5.2.
Number of Patients
Approximately 116 patients (58 platinum-sensitive patients and 58 platinum-refractory/resistant 
patients) will be enrolled to receive LY2606368.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure for the last patient.
5.4.
Scientific Rationale for Study Design
An open-label, single-arm, nonrandomized study without concurrent controls is appropriate for 
patients with second-line or greater ED-SCLC.  There is not currently a uniform standard of 
treatment for patients with resistant/refractory disease, and clinical trials are recommended (Fruh 
et al. 2013; Kalemkerian et al. 2013).  Historical response rates are reported to be approximately 
10%, and so large improvements on these options can be detected using a single-arm design.  
Although topotecan is the standard for patients with platinum-sensitive disease, the response 
rates (approximately 20%-25%) are well established from historical controls (von Pawel et al. 
1999; Fruh et al. 2013; Kalemkerian et al. 2013).
5.5.
Justification for Dose
The LY2606368 monotherapy MTD when administered once every 14 days was determined to 
be 105 mg/m2.  This dose and schedule was selected as the recommended Phase 2 dose for 
monotherapy based on several factors including: the nonclinical LY2606368 monotherapy 
pharmacokinetic (PK)/pharmacodynamic model predicted exposure range for maximum tumor 
response coinciding with the observed clinical PK data; human pharmacodynamics simulations
indicating a pharmacodynamic profile in a predicted efficacious range; and an acceptable safety 
profile. Please see the IB for additional details.


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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is 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 diagnosis of ED-SCLC (Edge et al. 2010) and 
have received a prior platinum-based regimen

Cohort 1:  had an objective response to prior platinum-based therapy with 
subsequent progression ≥90 days after the last dose of platinum

Cohort 2: either did not have an objective response to prior platinum 
based therapy or had progression <90 days after the last dose of platinum
If a patient has had more than one line of platinum therapy, the platinum sensitivity 
should be determined from the last exposure to platinum.
[2]
have a performance status of 0 to 1 on the Eastern Cooperative Oncology 
Group scale (Oken et al. 1982)
[3]
have discontinued all previous treatments for cancer and recovered from the 
acute effects of therapy.  Patients must have discontinued from previous 
treatments, as shown below:
Previous Treatment
Length of Time Prior to First Dose of LY2606368
Cytotoxic therapies or targeted agents that are 
small molecule inhibitors
14 days
Biologic agents
14 days
Immunotherapy
14 days
Radiotherapy
14 days
Major surgery, excluding biopsy
14 days
[4]
have at least 1 measurable lesion using standard techniques by Response 
Evaluation Criteria In Solid Tumors (RECIST) 1.1 (Eisenhauer et al. 2009)
[5]
have given written informed consent/assent prior to any study-specific 
procedures
[6]
are of an acceptable age to provide informed consent according to the local 
regulations and are at least 18 years of age


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[7]
have adequate organ function, as defined below:
System
Laboratory Value
Hematologic
ANC
1.5 × 109/L
Platelets
100 × 109/L
Hemoglobin
8 g/dL or 5 mmol
Transfusions to increase the patient’s hemoglobin level to
meet enrollment criteria are not allowed in the 14 days 
preceding the first dose of study drug.
Hepatic
Direct bilirubin
1.5 × ULN
ALT and AST
2.5 × ULN OR
5 × ULN if the liver has tumor involvement
Renal
Serum creatinine OR
Measured creatinine clearance OR
Calculated creatinine clearance
(using the CKP-EPI equation - see 
Appendix 6)
<1.5 × ULN OR
50 mL/min/1.73 m2
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; CKP-EPI = Chronic Kidney Disease Epidemiology Collaboration; ULN = upper 
limit of normal.
[8]
men must be sterile or agree to use an effective method of contraception or a 
highly effective method of contraception during the study and for at least 
12 weeks following the last dose of LY2606368
Refer to Appendix 1 for definitions of fertile men, effective method of contraception,
and highly effective method of contraception.
[9]
women of childbearing potential must:
a.
have a negative serum pregnancy test at the baseline visit
b. have a negative urine pregnancy test within 7 days prior to the first dose of 
LY2606368 
c.
agree to use a highly effective method of contraception (Appendix 1) during the 
study and for 12 weeks following the last dose of LY2606368
d. not be breast-feeding
Refer to Appendix 1 for definitions of women of childbearing potential and
postmenopausal women.


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6.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[10] have received more than 2 prior therapies for ED-SCLC (including 
immunotherapy, targeted therapies, or chemotherapy)
Each line of therapy is preceded by disease progression. Discontinuation of a 
regimen without progression (for example, due to toxicity) or a switch of an agent 
within the same drug class (for example, cisplatin to carboplatin) within a regimen to 
manage toxicity does not define the start of a new line of therapy. Similarly, 
maintenance therapy (continuation maintenance or switch maintenance) will not be 
considered a new line of treatment.
[11] have symptomatic central nervous system (CNS) malignancy or metastasis. 
Asymptomatic patients with treated CNS metastases are eligible for this study 
if they are not currently receiving corticosteroids to treat CNS metastases.  
CNS metastases should be stable for at least 14 days by clinical assessment,
and patients should not have received corticosteroids to treat CNS metastases 
within 14 days of the first dose of study drug.
[12] have a second primary malignancy that in the judgment of the investigator and 
Lilly may affect the interpretation of results
[13] are currently enrolled in a clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically 
compatible with this study
[14] have previously completed or withdrawn from this study or any other study 
investigating LY2606368 or a CHK1 inhibitor or have shown hypersensitivity 
to any of the components of the LY2606368 formulation
[15] have a known serious concomitant systemic disorder (for example, active 
infection or cardiac disease) 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 (HIV) infection or 
symptomatic activated/reactivated hepatitis A, B, or C (screening is not 
required).  If the medical history, symptoms, and/or laboratory values suggest 
that the patient may have HIV or hepatitis A, B, or C, appropriate assessment 
should be conducted to determine whether the patient should be excluded.
[17] have a serious cardiac condition, such as:

symptomatic congestive heart failure

New York Heart Association Class III/IV heart disease

unstable angina pectoris

symptomatic or poorly controlled cardiac arrhythmia

myocardial infarction within the last 3 months


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
have a QT interval using Fridericia’s correction (QTcF) of >470 msec on more 
than one screening electrocardiogram (ECG)

a family history of long-QT syndrome
6.3.
Lifestyle Restrictions
There are no specific lifestyle restrictions for this protocol.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened.  Individuals may be re-screened a maximum of 2 times.  The interval between 
re-screenings should be at least 2 weeks.  Each time re-screening is performed, the individual 
must sign a new informed consent form (ICF) and will be assigned a new identification number.
Repeating of laboratory tests during the 28-day screening period does not constitute re-screening.


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7.
Treatments
7.1.
Treatments Administered
Patients in both cohorts will receive 105 mg/m2 LY2606368 as an approximately 
60 (+10) minute intravenous (IV) infusion on Day 1 of a 14-day cycle.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the drug and planned duration of each individual’s 
treatment to the patient/study site personnel/legal representative

verifying that instructions are followed properly

maintaining accurate records of LY2606368 dispensing and collection

at the end of the study returning all unused medication to Lilly, or its designee, 
unless Lilly and sites have agreed all unused medication is to be destroyed by the 
site, as allowed by local law
7.1.1. Packaging and Labelling
The drug product, LY2606368 for injection, is supplied for clinical trial use as a lyophilized, 
yellow to white solid, in glass vials and is composed of either LY2606368 mesylate 
monohydrate and the inactive ingredient sulfobutyl ether beta-cyclodextrin sodium (Captisol®)
or LY2606368 lactate monohydrate and the inactive ingredients trehalose and mannitol.  
Table JTJH.7.1 below gives the available strengths for these 2 formulations. At the start of the 
study, only the mesylate monohydrate formulation will be available. However, during the study 
the formulation may be switched to the lactate monohydrate formulation.  Sites will be notified 
in writing prior to this occurring. Please see the IB for additional information on these 
formulations.
Clinical trial materials will be labeled according to the country’s regulatory requirements.
Table JTJH.7.1.
LY2606368 for Injection Strengths
Formulation API
Primary Packaging 
(Nominal Vial size, mL)
Strength mg/vial 
(as free base)
LY2606368 mesylate monohydrate
50
40
LY2606368 lactate monohydrate
50
67
Abbreviation:  API = active pharmaceutical ingredient.
7.2.
Method of Treatment Assignment
Upon obtaining informed consent, the site will register the patient via the Interactive Web 
Response System (IWRS), which is accessible 24 hours a day, to assign a patient number. 
Patients who meet all criteria for enrollment will be assigned to receive LY2606368 in this study. 
The IWRS will be used to dispense LY2606368 to each patient.


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7.2.1. Selection and Timing of Doses
A cycle is defined as an interval of 14 days.  A delay of a cycle (Day 1) due to holiday, weekend, 
inclement weather, or other unforeseen circumstances will be permitted for a maximum of 7 days 
and not counted as a protocol deviation.  An interval of at least 14 days must be maintained 
between LY2606368 doses, and if there is a delay the cycle length should be extended to 
accommodate the delay.
The actual doses of LY2606368 to be administered will be determined by calculating the 
patient’s body surface area (BSA) at the beginning of each cycle.  If the patient’s weight does not 
fluctuate by more than 10% from the weight used to calculate the prior dose, the BSA will not 
need to be recalculated.  A 10% variance in the calculated total dose will be allowed for ease of 
dose administration.
A patient may continue to receive LY2606368 until he or she meets 1 or more of the specified 
reasons for discontinuation (as described in Section 8).
7.3.
Blinding
This is an open-label study.
7.4.
Dosage Modification
Before the start of each cycle:

Nonhematologic toxicities must resolve to Grade 0 or 1 or baseline, except AEs with no 
immediate medical consequence or those that can be controlled with adequate treatment 
(for example, alopecia, fatigue, nausea, vomiting, diarrhea, or asymptomatic changes in 
electrolytes).

Neutropenia, thrombocytopenia, and anemia must resolve to Grade 0, 1, or 2, as shown in 
Table JTJH.7.2.
Table JTJH.7.2.
Hematologic Parameters Required for the Start of Each Cycle
Dose
Neutrophils
≥1000/mm3
Platelets
≥75/mm3
Hemoglobin
≥8 g/dL
Treatment may be delayed for a maximum of 14 days to allow a patient sufficient time for 
recovery from LY2606368-related toxicity.  If a patient does not recover from the toxicity within 
28 days from the time of last treatment, the patient should be discontinued from LY2606368. In 
exceptional circumstances, a longer delay is permitted upon agreement between the investigator 
and the Lilly clinical research physician (CRP).
If a patient, in the investigator’s opinion, experiences a toxicity warranting a dose reduction, 
LY2606368 should be reduced as shown in Table JTJH.7.3.


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Table JTJH.7.3.
LY2606368 Dose Reductions
Reduction
Dose
1st LY2606368 dose reduction
80 mg/m2
2nd LY2606368 dose reduction
60 mg/m2
3rd LY2606368 dose reduction
Discontinue from LY2606368
Following a dose reduction, re-escalation is acceptable.  If a subsequent LY2606368 dose 
reduction is again required, the patient’s dose may not be re-escalated a second time.
7.5.
Preparation/Handling/Storage/Accountability
LY2606368 will be administered as an IV infusion using a central or peripheral IV line and will 
be filtered through an in-line filter. LY2606368 should be handled according to standard 
procedures and precautions consistent with a cytotoxic anticancer drug.  For the most current 
detailed formulation information and preparation instructions, refer to the IB and Pharmacy 
Binder.
7.5.1. LY2606368 Mesylate Monohydrate
The LY2606368 mesylate monohydrate drug product contains 40 mg/vial of the base compound 
LY2606368.  The vial contains a 3% excess to facilitate the withdrawal of the label amount
40 mg/vial for use with an appropriate device, such as an infusion set. The drug product is stable 
when stored at room temperature.
Reconstituting the vial contents with 19 mL of water for injection yields a clear yellow solution 
with a concentration of 2 mg/mL of LY2606368 and an osmotic pressure ratio of 344 mOsm.  
The reconstituted formulation is stable for at least 24 hours at room temperature; however, since 
the reconstituted drug product does not contain a preservative, the unused solution must be 
discarded after 12 hours. The reconstituted solution may be diluted with dextrose 5% injection 
(D5W) prior to administration. LY2606368 is incompatible with solutions containing saline or 
lactated Ringer’s and must NOT be mixed or administered simultaneously with other drugs 
through the same infusion line. The infusion line should be flushed with D5W before and after 
LY2606368 administration.
7.5.2. LY2606368 Lactate Monohydrate
A 67-mg strength of LY2606368 lactate monohydrate drug product is in development and may 
be used in Study JTJH.  The vial will contain a slight excess to facilitate the withdrawal of the 
label amount 67 mg/vial for use with an appropriate device, such as an infusion set.  
Reconstituting the vial contents with water for injection yields a clear yellow solution with a 
concentration of 3.35 mg/mL of LY2606368.  For the most current detailed information on this 
strength refer to the IB and Pharmacy Binder.


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7.6.
Treatment Compliance
The study medication will be administered only at the investigational sites by the authorized 
study site personnel.  As a result, treatment compliance is ensured.
7.7.
Concomitant Therapy
No other chemotherapy, immunotherapy, cancer-related hormone therapy, herbal drugs intended 
to treat cancer, or experimental drugs will be permitted while the patients are on this study.  
Radiotherapy (including palliative radiotherapy) will only be permitted if it is agreed upon by the 
both investigator and Lilly.  If the lesion that is to be treated is a target lesion, the lesion will be 
censored at the time of treatment.  However, the patient may be eligible to remain on study drug 
treatment provided there are other lesions that can be followed for progression.  Treatment 
delays of LY2606368 may be required if radiotherapy is administered.  In addition, any disease 
progression requiring other forms of specific antitumor therapy will also necessitate early 
discontinuation from the study.  Replacement hormonal therapy initiated before study entry will 
be allowed.
Patients should receive full supportive care during the trial. American Society of Clinical 
Oncology (ASCO) guidelines (Smith et al. 2015) should be followed for patients requiring 
support with granulocyte-colony stimulating factor (G-CSF).  Primary or secondary prophylactic 
G-CSF support is permitted at the discretion of the investigator.  Per the National 
Comprehensive Cancer Network (NCCN) guidelines, Phase 2 data support the use of 
pegfilgrastim in regimens with a 2-week cycle, and there is uniform consensus that this is 
appropriate (Category 2A) (NCCN guidelines for myeloid growth factors [WWW]).  As a result, 
filgrastim, filgrastim biosimilars, or pegfilgrastim may be used.
Prophylactic antibiotics should be considered for use in patients that have experienced 
neutropenic fever or patients deemed at higher risk for neutropenic fever by the investigators.  
The treatment should be consistent with ASCO guidelines (Flowers et al. 2013).
Transfusion of packed red blood cells (RBCs) within 14 days of study entry is not permitted.  
The initiation of erythropoietin therapy to meet eligibility criteria is not permitted.  Patients who 
are stable on erythropoietin for >1 month before study entry may continue their treatment.  
Erythropoietin and packed RBC transfusion may be used according to ASCO guidelines 
(Rizzo et al. 2008) if clinically indicated at any time during the study.
In Study JTJA, no prolongations in average QTcF interval (Fridericia’s formula) >480 msec or 
of ≥60 msec from baseline were observed with LY2606368 monotherapy (n=101) at any 
time point. A thorough corrected QT (QTc) study has not yet been conducted.  On days when 
LY2606368 is administered, patients should avoid taking multiple concomitant medications that 
are known or suspected to cause prolonged QTc or Torsades de Points and, if possible, 
alternative agents should be considered.


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7.8.
Treatment after the End of the Study
Study completion will occur no more than 1 year after the last patient enrolls in the trial, 
following the final analyses of progression-free survival (PFS) and overall survival (OS).  
Investigators will continue to follow Schedule of Activities (Section 2) for all patients until 
notified by Lilly that study completion has occurred.
7.8.1. Continued Access
Patients who are still on LY2606368 at the time of study completion may continue to receive 
LY2606368 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 LY2606368 when study 
completion occurs.  Lilly will notify investigators when the continued access period begins.
Lilly may allow patients to enroll in a LY2606368 “rollover” protocol to provide long-term 
continued access for patients enrolled in this study. The continued access period is shown in
Figure JTJH.7.1.
The patient’s continued access to LY2606368 will end when a criterion for discontinuation is 
met (Section 8).  Continued access follow-up will begin the day after the patient and the 
investigator agree to discontinue LY2606368 and lasts approximately 30 (±7) days.  Follow-up 
procedures will be performed as shown in the Continued Access Schedule of Activities 
(Table JTJH.2.4).
Figure JTJH.7.1.
Continued access diagram.
Study Treatment Period
a Lilly will notify sites when the continued access period begins and ends. 
b Final analysis of overall survival.  Lilly will notify sites when study completion occurs.
c End of trial occurs at the last visit or last scheduled procedure for the last patient.
Study Completionb
Patient and investigator 
agree to discontinue  
study treatment
Study treatment
Continued access 
follow-up
(approximately 30 days)
Continued Access Perioda
End of Trialc


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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.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Patients will be discontinued from study treatment in the fo llowing circumstances:

the patient is enrolled in any other clinical trial 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

the patient has evidence of progressive disease

the patient experiences unacceptable toxicity

the patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication.  Discontinuation 
from study treatment will occur prior to introduction of the new agent.

the investigator decides that the patient should be discontinued from LY2606368

the patient requests to be discontinued from LY2606368
Patients who are discontinued from LY2606368 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 identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CRP and the investigator to 
determine if the patient may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CRP to allow the 
inadvertently enrolled patient to continue in the study with or without LY2606368.
8.2.
Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

the investigator decides that the patient should be discontinued from the study

the patient requests to be discontinued from the study
Patients who discontinue from the study early will have end-of-study procedures performed as 
shown in the Schedule of Activities (Section 2).
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Study site personnel are expected to make
diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow-up.


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Study site personnel, or an independent third party, will attempt to collect the survival status for 
all enrolled patients who are lost to follow-up, within legal and ethical boundaries.  Public 
sources may be searched for survival status information.  If the patient’s survival status is 
determined, the survival status will be documented, and the patient will not be considered lost to 
follow-up.
Lilly personnel will not be involved in any attempts to collect survival status information.


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9.
Study Assessments and Procedures
Section 2 provides the Schedule of Activities for this study.
Appendix 3 provides a list of the laboratory tests that will be performed for this study.
Appendix 4 provides the schedule for collection of samples in this study.
Unless otherwise stated in the following subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days after 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).
Computed tomography (CT) scans, including spiral CT, are the preferred methods of 
measurement (CT scan thickness recommended to be 5 mm); however, magnetic resonance 
imaging (MRI) is also acceptable in certain situations, such as when body scans are indicated or 
if there is a concern about radiation exposure associated with CT.  Intravenous and oral contrast 
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 CT is of identical diagnostic quality to a diagnostic CT (with IV and 
oral contrast). A PET scan alone or as part of a PET-CT may be performed for additional 
analyses but cannot be used to assess response according to RECIST v.1.1 (Eisenhauer et al. 
2009).
Radiologic scans of the thorax and abdomen are required.  A baseline intracranial evaluation 
with CT or MRI should be conducted.  Scans of the pelvis or bone scans should be performed if 
clinically indicated. Copies of the scans may be requested by the sponsor for central review.
See Section 10.3.1 for definitions of the efficacy endpoints.
9.1.1. Appropriateness of Assessments
The measures used to assess safety and efficacy in this study are consistent with those used in 
most conventional oncology trials.
9.2.
Adverse Events
The investigator will use Common Terminology Criteria for Adverse Events Version 4.0 (NCI 
2009) to assign AE terms and severity grades.


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Investigators are responsible for:

monitoring the safety of patients in 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

the appropriate medical care of patients during the study

documenting their review of each laboratory safety report

following, through an appropriate health care option, AEs that are serious or otherwise 
medically important, considered related to study treatment or the study, or that caused 
the patient to discontinue LY2606368 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 treatment effect.
After the ICF is signed, study site personnel will record via case report form (CRF)/electronic 
data entry/designated data transmission methods the occurrence and nature of each patient’s 
preexisting conditions, including clinically significant signs and symptoms of the disease under 
treatment in the study.  In addition, study site personnel will record via CRF/electronic data 
entry/designated data transmission methods any change in the preexisting conditions and any 
new conditions as AEs.  Investigators should record their assessment of the potential relatedness 
of each AE to study procedure or LY2606368 via CRF/electronic data entry/designated data 
transmission methods.
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 treatments, 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.
Planned surgeries and nonsurgical interventions 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 discontinuations that result 
from AEs to Lilly or its designee via CRF/electronic data entry/designated data transmission 
methods, clarifying, if possible, the circumstances leading to the dose modification or 
discontinuation of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity


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
congenital anomaly/birth defect

considered significant by the investigator for any other reason:  important medical events 
that may not result in death, be life-threatening, or require hospitalization may be 
considered serious, based upon appropriate medical judgment.
Although all AEs after signing the ICF are recorded in the CRF/electronic data entry/designated 
data transmission methods, SAE reporting begins after the patient has signed the ICF and has
received LY2606368.  However, if an SAE occurs after signing the ICF, but prior to receiving 
LY2606368, 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 LY2606368) does not meet the definition of 
an AE but should be reported.  However, to fulfill regulatory requirements, any pregnancy 
should be reported following the SAE process to collect data on the outcome for both mother and 
fetus.
Investigators are not obligated to actively seek AEs or SAEs in 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 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 an SAE.
Serious adverse events, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to LY2606368.
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.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulations and associated 
detailed guidances.


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9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to
facilitate process and product improvements.
Patients should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Refer to the IB for the current guidance on overdose.
9.4.
Safety
9.4.1. Other Safety Measures
For each patient, safety assessments, including ECGs, vital signs, and laboratory tests, should be 
collected as shown in the Schedule of Activities (Section 2).  ECGs should be recorded 
according to the study-specific recommendations that will be provided separately.
As of 27 August 2015, no patients treated with LY2606368 monotherapy have had an average 
QTcF interval >480 msec at any time point. However, if a patient experiences a QTcF interval 
>480 msec, the patient should be monitored for signs of life -threatening arrhythmias such as 
torsades de pointes. It should be confirmed that the measurement is correct by repeating the 
ECG and ruling out other causes such as atrial fibrillation or the presence of a pacemaker. If the 
result is confirmed, institutional guidelines or standard of care measures for management of 
QTcF interval >480 msec and/or associated arrhythmias should be initiated. These actions may 
include the administration of IV magnesium sulfate and the assessment of clinical chemistry. If 
electrolytes are abnormal, they should be repeated as indicated. The QTcF value should be 
monitored until the interval has returned to <480 msec or at least to predose levels. It is 
recommended that the patient be assessed by a cardiologist before leaving the treating facility.  
For all subsequent doses, an ECG must be obtained at 10 minutes after the end of infusion (EOI) 
(±5 minutes), 30 minutes after EOI (±10 minutes), and >1 hour after EOI.
If a patient experiences a QTcF interval >500 msec and has an associated life-threatening 
arrhythmia, he/she should be discontinued from study treatment.  If a patient experiences a QTcF 
interval >500 msec without an associated life-threatening arrhythmia and if the investigator 
deems it in the best interest of the patient, the patient may continue treatment with LY2606368. 
If a patient has a second occurrence of QTcF interval >500 msec, he/she should be discontinued 
from study treatment.  
Any clinically significant findings that result in a diagnosis and that occur after the patient 
receives the first dose of LY2606368 should be reported to Lilly or its designee as an AE via 
CRF/electronic data entry/designated data transmission methods.


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9.4.2. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities. To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP regarding collection of specific recommended 
clinical information and follow-up laboratory tests.  See Appendix 5.

If a patient experiences elevated alanine aminotransferase (ALT) 5 × upper limit of 
normal (ULN) and elevated total bilirubin 2 × ULN, clinical and laboratory monitoring 
should be initiated by the investigator.

For patients entering the study with ALT >3X ULN, monitoring should be triggered at 
ALT >2X baseline and elevated total bilirubin 2 × ULN.
9.5.
Pharmacokinetics
Pharmacokinetic samples will be collected as specified in the Pharmacokinetic Sampling 
Schedule (Appendix 4).
At the visits and times specified in the Study Schedule, venous blood samples will be collected 
to determine the plasma concentrations of LY2606368.  A maximum of 5 samples may be added 
or removed during the study if warranted and agreed upon between both the investigator and 
Lilly.  Instructions for the collection and handling of blood samples will be provided by the 
sponsor.  The actual date and time (24-hour clock time) of each sampling will be recorded.
These samples will be analyzed at a laboratory designated by the sponsor by using a validated 
liquid chromatography–mass spectrometry/mass spectrometry (LC-MS/MS) method.
The PK samples will be stored at a facility designated by the sponsor.  Bioanalytical samples 
collected to measure LY2606368 concentrations will be retained for a maximum of 1 year 
following last patient visit for the study.
9.6.
Pharmacodynamics
Pharmacodynamics samples will not be collected for this trial.
9.7.
Pharmacogenomics
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 LY2606368 and to 
investigate genetic variants thought to play a role in SCLC.  Assessment of variable response 
may include evaluation of AEs or differences in efficacy.


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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 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 (ERBs)/institutional review boards (IRBs) impose 
shorter time limits, at a facility selected by Lilly or its designee.  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 LY2606368 or after 
LY2606368 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.
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, mechanism of action, variability of patient response (including safety), and clinical 
outcome.  Sample collection is incorporated into clinical studies to enable examination of these 
questions through measurement of biomolecules including DNA, RNA, proteins, lipids, and 
other cellular elements.
As part of Lilly’s ongoing efforts to understand the relationship between cancer, genetics, and 
response to therapy, this study will analyze biomarkers relevant to the mechanism of action of 
CHK1, DNA damage response pathways or downstream effects, cell cycle markers, immune 
function, and cancer pathobiology and/or for related research methods or validation of 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 have already been 
generated from samples that were collected and analyzed before the patients’ enrollment in this 
trial.  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 9.8.1 and 9.8.2.  
Samples for biomarker research will be collected as specified Section 2, where local regulations 
allow.
9.8.1. Blood Samples
Plasma samples for biomarker research will be collected as specified in Section 2 where local 
regulations allow.
Samples will be examined for biomarkers related to SCLC, variable response to LY2606368, the 
mechanism of action of LY2606368, and/or for research-related methods or validating diagnostic 
tools or assays.


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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 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, at a facility 
selected by Lilly.  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 LY2606368 or after LY2606368 becomes commercially available.
9.8.2. Tissue Samples
Tumor tissue will be examined for biomarkers related to the mechanism of action of CHK1, 
DNA damage response pathways or downstream effects, cell cycle markers, immune function, 
and cancer pathobiology. These markers may also be evaluated to assess any potential 
correlation with response to LY2606368.
Collection of the following tumor tissue sample(s) is required for all patients:

an archived tumor sample (a block or slides) or a newly obtained biopsy specimen 
collected prior to treatment with LY2606368, if an archived tumor sample is not 
available, if not restricted by local regulations

for patients who do not have archived tissue available and who have disease in 
technically challenging sites to obtain a fresh biopsy, the investigator and sponsor may 
agree to enroll the patient without tumor tissue.  The joint decision must be documented 
in writing before the patient receives the first dose of LY2606368 and will not constitute 
a protocol violation.
Collection of the following tumor tissue sample(s) is optional for all patients:

patients that have archived tumor tissue to meet the inclusion criteria for Study JTJH may 
also have an optional pre-treatment biopsy

following treatment with LY2606368, patients may be asked to undergo collection of 
additional optional on-study, post-treatment, and/or post-progression biopsies for 
biomarker research from patients willing to consent. In particular, biopsies from lesions 
in patients who have received clinical benefit and subsequently progress may help 
identify molecular features that may explain treatment response and resistance 
mechanisms.  Post-progression biopsies should be performed prior to the start of 
subsequent cancer treatment. However, the procedure should not impede or delay the 
planned cancer treatment.
Formalin-fixed paraffin-embedded tumor tissue obtained from the primary tumor or metastatic 
site should be provided as a block 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.  Pathology 
notes/report accompanying archival tissue may also be requested. The notes/report should be 
coded with the patient number. Personal identifiers, including the patient’s name and initials, 
must be removed from the institutional pathology notes/report prior to submission.  Archival 


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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 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, at a facility 
selected by Lilly or its designee.  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 LY2606368 or after LY2606368 becomes
commercially available.
Technologies are expected to improve during the 15-year storage period and therefore cannot be 
specifically named. However, existing technologies, including mutation profiling, copy number 
variability, gene expression, multiplex assays, and/or immunohisto chemistry, may be performed 
on these tissue samples to assess potential associations with these biomarkers and clinical 
outcomes.
9.9.
Health Economics
The primary health outcomes research goal is to evaluate the association between best tumor 
response and change from baseline in lung cancer-specific symptoms, symptomatic distress, 
activity status, overall quality of life, total Lung Cancer Symptom Scale (LCSS) score, and 
Average Symptom Burden Index (ASBI) for patients who have platinum-sensitive or 
platinum-resistant/refractory SCLC. Patient-reported outcomes and symptoms will be assessed 
by the LCSS patient scale. The LCSS is a validated tool that has been broadly used in lung 
cancer research and is available in over 30 different languages.
The LCSS (Hollen et al. 1994) consists of 9 total items, each with a 100-mm line depicting the 
visual analog scale (VAS). Scores equal the length of line as marked by patient and range from 
0 (for best outcome) to 100 (for worst outcome). Six items are symptom-specific measures for 
lung cancer (appetite loss, fatigue, cough, dyspnea, hemoptysis, and pain) that address 
2 dimensions: physical and functional. There are also 3 summation items that describe 
symptomatic distress, activity status, and overall quality of life.
The LCSS will be administered as shown in the Schedule of Activities (Section 2). The LCSS
will be completed by patients when a language translation is available in which the patient is 
fluent or literate.  The recall period is 24 hours and the typical completion time is 8 minutes 
initially for demonstration of VAS; 3 to 5 minutes for subsequent administrations. To avoid 
biased responses, the questionnaires should be administered prior to extensive contact with study 
personnel and clinicians and prior to study drug administration.


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10. Statistical Considerations
10.1. Sample Size Determination
The study will enroll approximately 116 patients (58 platinum-sensitive patients, 58 platinum-
refractory/resistant patients).
For the platinum-sensitive cohort, it is assumed that a true overall response rate (ORR) of less 
than 20% indicates inadequate antitumor activity.  Given that a futility interim analysis will be 
conducted on the first 29 patients’ response data, then with a one-sided significance level of 0.1, 
a sample size of 58 patients will provide approximately 90% power to detect a true ORR of at 
least 35%, i.e. 16 or more confirmed overall responses (complete response [CR] or partial 
response [PR]) are observed in all 58 patients.
For the platinum-refractory/resistant cohort, it is assumed that a true ORR of less than 5% 
indicates inadequate anti-tumor activity.  Given that a futility interim analysis will be conducted 
on the first 29 patients’ response data, then with a one-sided significance level of 0.1, a sample 
size of 58 patients will provide approximately 90% power to detect a true ORR of at least 15%, 
i.e. 6 or more confirmed overall responses (CR or PR) are observed in all 58 patients.
For each cohort, the overall type II error rate, i.e. the probability of terminating an effective 
cohort, will be controlled using a Lan-DeMets spending function (Lan and DeMets 1983), which 
generates boundaries that are very similar, though not identical, to the classical stopping 
boundaries of O’Brien and Fleming (1979).  The type II error rate spent at interim analysis after 
the first 29 patients for each cohort is approximately 2%; the cumulative type II error rates spent 
at final analysis for platinum-sensitive cohort and platinum-refractory/resistant cohort are 9.9% 
and 9.4%, respectively.
10.2. Populations for Analyses
The following populations will be defined for this study:
Intention-to-Treat (ITT) population:  will include all enrolled patients.  This population will 
be used for all baseline, efficacy, and health economics analyses. All patients in the ITT 
population will be considered to have completed the study.
Per-protocol population:  will include all enrolled patients who receive at least one dose of 
study treatment and do not have any major protocol violations that could potentially affect the 
efficacy conclusions of the study.  This population will be defined in detail in the statistical 
analysis plan (SAP) prior to database lock.
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, and safety analyses.
Pharmacokinetic population:  will include all enrolled patients who received at least 1 full
infusion of LY2606368 and have evaluable PK samples collected.


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Biomarker population:  will include the subset of patients from the ITT 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.
All tests of treatment effects will be conducted at a 1-sided alpha level of 0.1, unless otherwise 
stated.  Unless otherwise stated, all confidence intervals (CIs) will be given at a 2-sided 95%
level.
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP and the clinical study report.  Additional exploratory analyses of the data will be 
conducted as deemed appropriate.
10.3.1. Efficacy Analyses
Overall response rate (ORR) is defined as the number of patients who achieve a best overall 
response of CR or PR, divided by the total number of patients enrolled to the corresponding 
cohort (ITT population).  Complete or partial responses may be claimed only if the criteria for 
each are met at a subsequent time point (greater than 4 weeks).  The ORR, with 95% and 80% 
CIs, will be summarized for each cohort using the Clopper-Pearson method.
Disease control rate (DCR) is defined as the number of patients who achieve a best overall 
response of CR, PR, or stable disease (SD) divided by the total number of patients enrolled to the 
corresponding cohort (ITT population).  The confirmation of CR and PR is required.  In the case 
of SD, measurements must have met the SD criteria at least once after study entry at a minimum 
interval (in general not less than 6 weeks).  The DCR, with 95% CI, will be summarized for each 
cohort using the Clopper-Pearson method.
Duration of response is defined as the time from the date measurement criteria for CR or PR 
(whichever is first recorded) are first met until the first date that disease is recurrent or objective 
progression is observed, per RECIST 1.1 criteria, or the date of death from any cause in the 
absence of objectively determined disease progression or recurrence.
Overall survival is defined as the time from enrollment until death from any cause.  If the patient 
is alive or lost to follow-up at the time of data analysis, OS data will be censored on the last date 
the patient is known to be alive.  Overall survival curves, the median and survival rates at various 
time points with 95% CI, for each cohort will be estimated using the Kaplan-Meier method 
(Kaplan and Meier 1958).
Progression-free survival is defined as the time from enrollment until the first radiographic 
documentation of progression or death from any cause in the absence of PD. Patients known to 
be alive and without disease progression will be censored at the time of the last adequate tumor 
assessment prior to study completion (a detailed PFS event/censoring scheme is provided in 
SAP).  Progression-free survival curves, median PFS, and PFS rates at various time points with 


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95% CI for each cohort will be estimated using the Kaplan-Meier method (Kaplan and Meier 
1958).
Exploratory sensitivity analyses on efficacy endpoints may be conducted as described in the 
SAP.
10.3.2. Safety Analyses
All patients who receive at least 1 dose of any study therapy will be evaluated for safety and 
toxicity.
The Medical Dictionary for Regulatory Activities (MedDRA™) Version 18.0 (or higher) will be 
used when reporting AEs by MedDRA terms.  The MedDRA Lower Level Term will be used in 
the treatment-emergent computation.  Treatment-emergent adverse events will be summarized by 
System Organ Class (SOC) and by decreasing frequency of Preferred Term within SOC.
Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drug

SAEs, including possible relationship to study drug

AEs leading to dose adjustments

discontinuations from study treatment due to AEs or death

treatment-emergent abnormal changes in laboratory values

treatment-emergent abnormal changes in vital signs and ECGs
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 and enrolled in the study, 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 by treatment cohort will be reported.
10.3.3.4. Poststudy-Treatment-Discontinuation Therapy
The numbers and percentages of patients receiving post study-treatment-discontinuation 
anticancer therapies will be provided by type of therapy (surgery, radiotherapy, or systemic 
therapy), and by drug class and/or name, overall and by line of therapy.


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10.3.3.5. 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 cohort.
Study treatment will be administered at the investigator site, therefore treatment compliance is 
assured.
10.3.3.6. Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic parameter estimates for LY2606368 will be estimated by standard population 
PK methods of analysis using validated PK software programs (for example, NONMEM) and 
that is approved for use by Global PK/pharmacodynamic management.  The version of any 
software used for the analysis will be documented, and the program will meet the Lilly 
requirements of software validation.
Sparse LY2606368 PK data obtained from patients who receive at least 1 dose of LY2606368 
and have had samples collected for PK analysis will be pooled with PK data from a previous 
study investigating LY2606368 as monotherapy (Study JTJA) and analyzed by population-based 
PK analysis methods to characterize the observed intra- and interpatient PK variability and 
identify the patient-specific covariates that contribute to the observed PK variability of 
LY2606368.  Post-hoc LY2606368 PK parameters estimates will be calculated for each patient 
in this study and will include the maximum plasma concentration (Cmax), area under the plasma 
concentration versus time curve (for example, AUC[0-72], AUC[0-∞]), terminal elimination half-
life (t1/2), systemic clearance, and the multi-compartmental volumes of distributions (for 
example, V1, V2, and Vss]). A descriptive summary of LY2606368 plasma concentration data 
will also be provided for the LY2606368 Cmax, minimum plasma concentration (Cmin), and 
accumulation ratio across multiple cycles of treatment.
Additional exploratory analyses, such as population-based analyses that examine the relationship 
between LY2606368 exposure (PK) and response and/or safety, may be performed (if the data 
warrant).
Interim review of the clinical PK data after the first 29 patients enrolled in both Cohorts 1 and 2
may be conducted.
10.3.3.7. Biomarker Analyses
Descriptive summaries and statistical analyses results will be provided to support the biomarker 
research objectives outlined in Section 9.8.
Appropriate descriptive statistics for biomarker results based on pre-treatment, on-treatment, or 
post-progression samples will be reported. Each biomarker will be described using summary 
statistics at the study, treatment arm, and at the level of other patient subgrouping of interest.
Any correlations or associations between the biomarkers measured on the same patient will also 
be looked at.
In particular, descriptive summaries of biomarkers obtained from biopsies done on lesions that 
regressed after treatment will be provided. Provided a sufficient number of patients with such 


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biopsies are available, additional analyses may be undertaken to investigate the correlation 
between the change in the status/level of the biomarker and the change in the size of the lesion.
All biomarkers deemed relevant may be specifically investigated with the aim of understanding 
the genetic profile of patients who receive the greatest clinical benefit from LY2606368. These 
investigations will look at the correlation/association between the baseline (archival or 
pre-treatment) status/level of the biomarker(s) and measures of clinical benefit such as objective 
clinical response status (CR/PR or no-CR/PR) or disease control status (CR/PR/SD or no-
CR/PR/SD). Where a change in the status/level of a biomarker over time can be ascertained, 
additional exploratory analyses may be undertaken to assess the effect of the change or its 
magnitude on the same clinical efficacy endpoints. For secondary efficacy measures of PFS and 
OS, parametric and semi-parametric survival analysis will be undertaken to quantify the 
association between the biomarker status and the time-to-event efficacy measure.
For serially measured plasma-based biomarkers, change from baseline to subsequent time points 
may be associated with clinical response outcomes. In addition, the time-course relationship of
these biomarkers with safety and/or PK outcomes may also be investigated.
Biomarker results may also be analyzed to elucidate the associations between the baseline 
status/level, or change in status/level and including, but not limited to, the mechanism of action 
of LY2606368, sensitivity to CHK1 inhibition, and sensitivity or resistance to platinum-based 
therapies.
10.3.3.8. Health Outcome/Quality of Life Analyses
For the LCSS, the compliance rate by cohort will be calculated as the number of completed 
assessments divided by the number of expected assessments (that is, patients still on study).  
Compliance rates, reasons for noncompliance, and data collected will be summarized by cohort. 
Descriptive statistics for each of the domain scores/items of interest by category of best overall 
response (that is, CR, PR, SD, PD) will be summarized and a linear model will be fitted for each
cohort in order to evaluate the association between best overall response and change from 
baseline/the maximum improvement from baseline in lung cancer-specific symptoms, 
symptomatic distress, activity status, overall quality of life , total LCSS score, and ASBI for 
patients who have platinum-sensitive or platinum- resistant/refractory SCLC. The model will 
include change from baseline/maximum change from baseline as the response variable and 
category of best overall response as an independent variable.  The ASBI will be calculated as the 
mean of 6 symptom-specific questions; the total LCSS score will be calculated as the mean of 
9 questions from the LCSS. For a given assessment, if any of the 6 symptom-specific questions 
have not been completed, the ASBI will not be calculated. Similarly, if any of the 9 LCSS 
questions have not been completed, the total LCSS score will not be calculated.
10.3.4. Interim Analyses
For each cohort, one interim analysis of futility will be conducted after the 29th patient in the 
cohort has completed Cycle 3, and, if required, the response is confirmed.  The interim analysis 
will be conducted to assess whether the respective cohort is unlikely to achieve statistical 


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significance on its primary endpoint and may also include PK data in order to confirm that 
patients are in the expected exposure range.
The stopping rule for interim analysis is defined as follows:

Platinum-sensitive cohort:
o
If 4 or fewer confirmed overall responses (CR or PR) are observed in the first 
29 patients, then the cohort will be terminated; otherwise, the cohort will continue.

Platinum-refractory/resistant cohort:
o
If 0 confirmed overall responses (CR or PR) are observed in the first 29 patients, then 
the cohort will be terminated; otherwise, the cohort will continue.


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11. References
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Diao L, Masrorpour F, Shen L, Liu W, Duchemann B, Tumula P, Bhardwaj V, Welsh J, 
Weber S, Glisson BS, Kalhor N, Wistuba, II, Girard L, Lippman SM, Mills GB, Coombes KR, 
Weinstein JN, Minna JD, Heymach JV. Proteomic profiling identifies dysregulated pathways 
in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov. 
2012;2(9):798-811.
Byers LA, Rudin CM. Small cell lung cancer: where do we go from here? Cancer. 
2015;121(5):664-672.
Chan BA, Coward JI. Chemotherapy advances in small-cell lung cancer. J Thorac Dis. 
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Sennett R, Norris G, Laudenslager M, Wood AC, Mayes PA, Jagannathan J, Winter C, 
Mosse YP, Maris JM. RNAi screen of the protein kinome identifies checkpoint kinase 1 
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Dai Y, Grant S. New insights into checkpoint kinase 1 in the DNA damage response signaling 
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carcinoma: current status and future prospects. Eur Respir J. 2010;35(1):202-215.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging
Handbook: from the AJCC Cancer Staging Manual. 7th ed. NY: Springer; 2010.
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
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Langston AA, Marr KA, Rolston KV, Ramsey SD. Antimicrobial prophylaxis and outpatient 
management of fever and neutropenia in adults treated for malignancy: American Society of 
Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31(6):794-810.
Fruh M, De Ruysscher D, Popat S, Crino L, Peters S, Felip E. Small-cell lung cancer (SCLC): 
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GLOBOCAN Population Facts Sheet page. GLOBOCAN website. Available at: 
http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed on November 13, 2015.
Hann CL, Rudin CM. Management of small-cell lung cancer: incremental changes but hope for 
the future. Oncology (Williston Park). 2008;22(13):1486-1492.
Hoglund A, Stromvall K, Li Y, Forshell LP, Nilsson JA. Chk2 deficiency in Myc overexpressing 
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Hollen PJ, Gralla RJ, Kris MG, Cox C. Quality of life during clinical trials: conceptual model for 
the Lung Cancer Symptom Scale (LCSS). Support Care Cancer. 1994;2(4):213-222.
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Loo BW, Jr., Merritt RE, Moran CA, Niell HB, O'Malley J, Patel JD, Ready N, Rudin CM, 
Williams CC, Jr., Gregory K, Hughes M. Small cell lung cancer. J Natl Compr Canc Netw. 
2013;11(1):78-98.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
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King C, Diaz HB, McNeely S, Barnard D, Dempsey J, Blosser W, Beckmann R, Barda D, 
Marshall MS. LY2606368 Causes Replication Catastrophe and Antitumor Effects through 
CHK1-Dependent Mechanisms. Mol Cancer Ther. 2015;14(9):2004-2013.
Lan KKG, DeMets DL. Discrete Sequential Boundaries for Clinical Trials. Biometrika. 1983; 
70:659 ts DL.
Lecona E, Fernandez-Capetillo O. Replication stress and cancer: it takes two to tango. Exp Cell 
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Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, Kusek JW, 
Eggers P, Van Lente F, Greene T, Coresh J. A new equation to estimate glomerular filtration 
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McNeely S, Beckmann R, Bence Lin AK. CHEK again: revisiting the development of CHK1 
inhibitors for cancer therapy. Pharmacol Ther. 2014;142(1):1-10.
Micke P, Faldum A, Metz T, Beeh KM, Bittinger F, Hengstler JG, Buhl R. Staging small cell 
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http://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf. Accessed 
November 13, 2015.
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Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 
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Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, Cella DF, 
Djulbegovic B, Goode MJ, Jakubowski AA, Rarick MU, Regan DH, Lichtin AE; American 
Society of Clinical Oncology; American Society of Hematology. Use of epoetin and 
darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American 
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Sen T, Tong P, Stewart CA, Hong-Fan Y, Feng Y, Wang J, Byers L. Investigation of Chk1 as a 
novel therapeutic target for small cell lung cancer (SCLC) [abstract].  In: Proceedings of the 
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Vigander T, Vilsvik J, Skovlund E, Hannisdal E, Aamdal S. Cisplatin and etoposide regimen is 
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Thompson R, Meuth M, Woll P, Zhu Y, Danson S. Treatment with the Chk1 inhibitor Go6976 
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Wu W, Chen B, Bence A, Um S, Yan B, Starling J, Marshall S, Beckmann, R. Antitumor 
activity of Chk1 inhibitor LY2606368 as a single agent in SW1990 human pancreas orthotopic 
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AACR; Cancer Res 2012;72(8 suppl). Abstract nr 1776.


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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 that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
ALT
alanine aminotransferase
ASBI
Average Symptom Burden Index
AUC(0-72)
area under the plasma concentration-time curve from time zero to 72 hours (3 days)
AUC(0-∞)
area under the plasma concentration-time curve from time zero to infinity
BSA
body surface area
CHK1
checkpoint kinase 1
CI
confidence interval
Cmax
maximum plasma concentration
collection 
database
a computer database where clinical trial data are entered and validated.
CR
complete response
CRF
case report form
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.
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DoR
duration of response
ECG
electrocardiogram
ED-SCLC
extensive stage disease small cell lung cancer
effective method 
of contraception
Effective method of contraception means male condom with spermicide, female condom with 
spermicide, diaphragm with spermicide, cervical sponge, or cervical cap with spermicide.


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Enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are those 
who have been assigned to a treatment and have received at least one dose of study treatment
Enter
Patients entered into a trial are those who sign the informed consent form directly or through 
their legally acceptable representatives.
ERB/IRB
ethical review board / institutional review board
fertile men
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy.
GCP
good clinical practice
G-CSF
granulocyte-colony stimulating factor
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.
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
interim analysis
An interim analysis is an analysis of clinical trial data conducted before the final reporting 
database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial.
ITT
intent-to-treat
LCSS
Lung Cancer Symptom Scale
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
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
OS
overall survival
PD
pharmacodynamics
PFS
progression-free survival


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PK
pharmacokinetic
PR
partial response
QTc 
corrected QT interval
QTcF
corrected QT interval (Fridericia’s formula)
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
SAE
serious adverse event
SAP
Statistical Analysis Plan
Screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
SUSARs
Suspected unexpected serious adverse reactions 
t1/2
half-life
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.
ULN
upper limit of normal
V1
volume of distribution of the central compartment
V2
volume of distribution of the peripheral compartment
Vss
volume of distribution at steady state
women of 
childbearing 
potential 
A woman is considered of childbearing potential (ie, fertile) after menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle-stimulating hormone level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy; however, in the absence of 12 months of amenorrhea, a single follicle-
stimulating hormone measurement is insufficient.


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Appendix 2.
Study Governance, Regulatory, and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the potential risks and benefits of participating in 
the study

ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any study procedures and prior to the administration of LY2606368.

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 his or her participation in the trial
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 
the ICF, 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
ERBs/IRBs should be provided with the following:

the current IB and updates during the course of the study

the ICF

relevant curricula vitae
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 

applicable ICH GCP Guidelines

applicable laws and regulations.
Some obligations of Lilly may be assigned to a third-party organization.
Investigator Information
Physicians with a specialty in oncology will participate as investigators in this clinical trial.


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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 clinical study report coordinating investigator will sign the final clinical study report 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 enrolled patients will serve as the clinical study report 
coordinating investigator.  If this investigator is unable to fulfill this function, another 
investigator will be chosen by Lilly to serve as the clinical study report coordinating investigator.
The Lilly responsible medical officer and statistician will approve the final clinical study report 
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

sponsor start-up training to instruct the investigators and study coordinators.  This session 
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 evaluate CRF data and use standard computer edits to detect errors in data 
collection

conduct a quality review of the database
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 Li lly 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/IRBs with direct access to original source 
documents.


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Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the Lilly provided electronic data capture system.
Electronic patient-reported outcome (ePRO) measures (LCSS) are entered into an ePRO 
instrument (tablet) at the time that the information is obtained.  In these instances where there is 
no prior written or electronic source data at the site, the ePRO instrument record will serve as the 
source.
ePRO records are stored at a third-party site; therefore, investigator sites will have continuous 
access to the source documents during the study and will receive an archival copy at the end of 
the study for retention.
Any data for which the ePRO instrument record will serve to collect source data will be 
identified and documented by each site in that site’s study file.
Case report form data collected via InForm, the clinical trial database, will be encoded by a 
third-party organization and stored electronically in the third-party organization’s database 
system. Data managed by a central vendor, such as laboratory test data or ECG data, will be 
stored electronically in the central vendor’s database system. Validated data will be transferred
from these systems to the Lilly data warehouse, using standard Lilly file transfer processes.  Any 
data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Study and Site Closure
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, or other reasons 
consistent with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 3.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology - local or investigator-designated laboratorya
Leukocytes (WBC)
Erythrocytes (RBC)
Neutrophilsb
Hemoglobin (HGB)
Lymphocytes
Hematocrit (HCT)
Monocytes
Eosinophils
Basophils
Platelets (PLT)
Coagulation- local or investigator-designated laboratory
Activated partial thromboplastin time (aPTT)
International normalized ratio (INR) or Prothrombin time (PT)
Clinical Chemistry - central laboratory.  In addition, local labs may be collected at investigator discretion.
Serum Concentrations of:
Alanine aminotransferase (ALT)
Creatinine
Albumin
Glucose random
Alkaline phosphatase
Potassium
Aspartate aminotransferase (AST)
Sodium
Bilirubin, direct
Uric acid
Bilirubin, total
Total protein
Blood urea nitrogen (BUN) or blood urea
Lactate dehydrogenase
Calcium
Clinical Laboratory Tests
Urinalysis - local or investigator-designated laboratory
Blood
Protein
Glucose
Specific gravity
Ketones
Urine leukocyte esterase
pH
Pregnancy Test (for female patients of childbearing potential) – local or investigator-designated laboratory
Serum pregnancy test or
Urine pregnancy test
Abbreviations:  CRF = case report form; RBC = red blood cells; WBC = white blood cells.
a
Treatment decisions 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.


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Appendix 4.
Sampling Schedule for Pharmacokinetics
Pharmacokinetic samples will be collected for LY2606368 in Cohorts 1 and 2 of this study.  It is 
essential that the exact infusion start and stop times are recorded using actual clock readings, as 
well as infusion parameters (such as, total dose infused and if intended dose was administered).  
The exact time of collection of each venous blood sample will be based on the clock used to 
record infusion times.  The PK blood samples should not be withdrawn from the same IV site as 
the drug infusion.
Predose samples should be taken as close as possible to the start of first infusion (<10 minutes), 
and the exact clock reading should be recorded.  Postdose (that is, end of infusion) PK samples 
should be drawn immediately after end of infusion (range = after end of infusion +10 minutes), 
and exact clock reading should be recorded.
PK Sampling Schedule – Cohorts 1 and 2
Sample Series
Cycle
Day
LY2606368 PK Sampling Timesa
1
1
1
Prior to start of LY2606368 infusion (<10 min)
2
1
1
End of LY2606368 infusion (+10 min)b
3
1
8
Anytimeb
4
2
1
Prior to start of LY2606368 infusion (<10 min)
5
3
1
Prior to start of LY2606368 infusion (<10 min)
6
3
1
End of LY2606368 infusion (+10 min)b
7
3
8
Anytimeb
8
4
1
Prior to start of LY2606368 infusion (<10 min)
9
5
1
Prior to start of LY2606368 infusion (<10 min)
10
5
1
End of LY2606368 infusion (+10 min)b
11
5
8
Anytimeb
12
6
1
Prior to start of LY2606368 infusion (<10 min)
13
7
1
Prior to start of LY2606368 infusion (<10 min)
14
7
1
End of LY2606368 infusion (+10 min)b
Abbreviations: min = minute; PK = pharmacokinetic.
a
The sampling schedule is relative to the LY2606368 infusion times as noted in the table.  The actual timing of 
the samples may be adjusted at the discretion of Lilly and the investigators as pharmacokinetic data become
available.  The total number or volume of samples will either remain the same or be reduced.
b
PK samples that are collected after the start of the infusion will need to be drawn from a clean site, unless an 
adequately flushed vascular access catheter is the only option.


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Appendix 5.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly 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:  CRF = case report form; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated laboratory.
b
Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. Whenever a manual differential is needed to report the neutrophils, the segmented and band forms should 
be added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands.
c
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 6.
Creatinine Clearance Formula
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation 
(2009)
The CKD-EPI creatinine equation is based on the same 4 variables as the Modification of Diet in 
Renal Disease (MDRD) Study equation, but uses a 2-slope spline to model the relationship 
between estimated glomerular filtration rate (GFR) and serum creatinine, and a different 
relationship for age, sex, and race. The equation was reported to perform better and with less 
bias than the MDRD Study equation, especially in patients with higher GFR. This results in 
reduced misclassification of CKD. As of November 2009, very few clinical laboratories report 
the estimated GFR using the CKD-EPI creatinine equation. In the future, other GFR-estimating 
equations may outperform CKD-EPI.
The CKD-EPI creatinine equation is:
Source:  Levey et al. 2009.


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Appendix 7.
Protocol Amendment I4D-MC-JTJH(a)
Summary 
A Phase 2 Study of LY2606368 in Patients with Extensive 
Stage Disease Small Cell Lung Cancer
Overview
Protocol I4D-MC-JTJH, A Phase 2 Study of LY2606368 in Patients with Extensive Stage 
Disease Small Cell Lung Cancer, 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.
This amendment was developed to address requests resulting from member states participating in 
the Voluntary Harmonisation Procedure during the assessment of the initial clinical trial 
application for Study JTJH in the European Union.  The request resulted in the following 
changes:  

Inclusion criterion #8 was updated to include a definition for fertile men.

Inclusion criterion #9 was updated to include a definition of women of childbearing 
potential and postmenopausal women.

Exclusion criterion #14 was updated to include known hypersensitivity to LY2606368.

Exclusion criterion #16 was updated to clarify how patients with HIV or symptomatic 
activated or reactivated hepatitis A, B, or C would be excluded.

Text was added to Section 9.4.1 to establish additional actions to be taken in case of 
prolongation of the QTcF interval >480 msec.  Text was also added to provide guidance
on patient management if a patient experiences a QTcF interval of >500 sec.
In addition, several other changes were made to the protocol as follows:

Minor wording changes and clarifications were made to the Schedule of Activities in
Section 2.

A clarification to time to progression was made in Section 3.1.

Adverse events were corrected for a literature reference in the rationale section.

The wording for exclusion criterion#11 was clarified.

A table was added to clarify the parameters required to start each cycle.

Section 7.5.2 was modified to remove the stability information in the lactate monohydrate 
formulation.

Section 7.8.1 was modified to remove the provision that patients must sign new ICFs to 
enter the continued access period.

A clarification to the radiologic scans required was made in Section 9.1.

A clarification to the PK analysis was made in Section 9.5


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
A clarification to the biomarker collection was made in Section 9.8.

Section 10.3.4 was modified to remove the final analysis from the stopping rules.

Minor editing and formatting changes were made.
Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.


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Table JTJH.2.1.
Schedule of Screening Activities
Study Period
Baseline
Cycle
BL
Visit
0
Duration
Up to 28 days
Relative Day 
≤28
≤14
≤7
Procedure 
Category
Procedure
Comments
Study
Entry/Enrollment
Informed Consent Form signed 
(prior to conducting any protocol specific 
tests/procedures)
X
Inclusion/Exclusion evaluation
X
Medical History
Initial history/preexisting conditions
X
Historical illness
X
Habits assessment
X
Includes smoking history
Physical 
Examination
Physical examination
X
Includes height and weight
ECOG performance status
X
Vital signs
X
Tumor 
Assessment
Radiologic imaging according to 
RECIST 1.1
X
Baseline radiological tumor assessment per RECIST 
version 1.1 should be done (see Section 9.1).  during 
screening.  Radiologic assessments obtained previously 
as part of routine clinical care may be used as the 
baseline assessment provided that they were done no 
more than 28 days before the first dose of study drug.
Tumor measurement (palpable or visible)
X
Performed at the same time as radiologic imaging
Adverse Events Collection/CTCAE Grading
X
Concomitant Medication Notation
X
Laboratory/
Diagnostic Tests
Hematology
X
Chemistry
X
Urinalysis
X
Coagulation
X
Serum or urine pPregnancy test
X
X
Women of childbearing potential must have negative 
serum pregnancy tests at their baseline visits and have 
negative urine pregnancy tests within 7 days before 
their first doses of  LY2606368 (see Section 6.1).  As 
required by local regulations
ECG
X
Single local ECG
Confirm availability of pretreatment 
tumor tissue
X
If archived tissue is not available, a fresh tumor biopsy 
should be obtained after all other study entry criteria 
have been confirmed, unless the sponsor and 
investigator document that the patient may be enrolled 
without pre-treatment tissue.
Exploratory blood sample for biomarkers
X
Optional pretreatment biopsy
X
Optional and may be performed at any time before 
starting treatment with LY2606368.  See Section 9.8.2.
Health Outcome 
Measure
Lung Cancer Symptom Scale
X
The LCSS should be administered prior to extensive 
interaction with site personnel.


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Table JTJH.2.2.
On-Study-Treatment Schedule of Activities
Study Period
Study Treatment Period
Cycle/Visit
1
2
3-na
Duration
14 days
14 days
14 days
Relative Day within Dosing Cycle
1
8
1
8
1
8
Procedure 
Category
Procedure
Comments
Physical 
Examination
Physical Exam
X
X
X
Includes weight and calculated BSA.  May be completed up to 7 days prior to treatment 
infusion.  In Cycle 4 and beyond may be completed every other cycle (for example, 
Cycle 4, 6, 8, etc.).
Vital signs
X
X
X
Includes blood pressure, pulse, and temperature.  Complete before treatment infusion.
ECOG performance status
X
X
X
Complete before treatment infusion
Laboratory/ 
Diagnostic Tests
Hematology
X
X
X
X
X
X
May be drawn up to 3 days before the planned assessment.  In Cycles 4-n, the Day-8 
sample may be collected at the discretion of the investigator.  
Chemistry
X
X
X
May be drawn up to 3 days before the planned assessment
Urinalysis
X
May be collected up to 3 days before the planned assessment
Urine pregnancy test
X
Day 1 of every other cycle.  Only to be performed on women of childbearing potential
PK sampling
X
X
X
X
X
See PK Schedule for collection information.
Stored sample for pharmacogenetics
X
Collect once.  Sample can be collected at any time if not collected on Day 1 of Cycle 1.
Exploratory blood sample for biomarkers
X
Only to be collected on the same day when the CT scan is obtained (every 3 cycles 
starting with Cycle 3).
Plasma biomarker sample 
X
X
Collect prior to dosing on Day 1 of Cycles 1 and 3 only
ECG
X
X
X
Single local ECG collected at each time point.  Day 1:  predose, 10 min after EOI (±5 
min), 30 min after EOI (±10 min), and >1 hour after EOI.
Cycle 2-X:  predose.  However, if QTcF >480 msec is observed on Day 1, then 10 min 
after EOI (±5 min), 30 min after EOI (±10 min), and >1 hour after EOI should also be 
collected in subsequent cycles.
Optional Tumor Biopsy
X
Can occur at any time during patient's treatment.


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Study Period
Study Treatment Period
Cycle/Visit
1
2
3-na
Duration
14 days
14 days
14 days
Relative Day within Dosing Cycle
1
8
1
8
1
8
Tumor 
Assessment
Radiologic imaging according to 
RECIST 1.1
X
For the first 52 weeks following enrollment, perform approximately every 6 weeks (that 
is, every 3 cycles) starting at the end of Cycle 3 (eg, Days 8-14).  Thereafter, perform 
approximately every 12 weeks.  The scanning interval (6 or 12 weeks [±1 week]) should 
be maintained even if cycles are delayed.  As a result, after Cycle 3, the scans may not 
always occur at the end of a cycle.  The same method of imaging used at baseline should 
be used for each subsequent assessment.  Scans should also be obtained as clinically 
indicated.
Tumor 
Assessment
Tumor measurement (palpable or visible)
X
Perform at least every 6 weeks (that is, every 3 cycles) starting in Cycle 3 on the same day 
as the radiologic imaging.
Adverse Events Collection/ CTCAE Grading
X
X
X
Concomitant Medication Notation
X
X
X
Lung Cancer Symptom Scale
X
X
X
The LCSS is to be administered prior to extensive interaction with site personnel and prior 
to administration of study drug.
Study 
Treatment
LY2606368
X
X
X
IV over approximately 60 (+10) min


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Table JTJH.2.3.
Post-Treatment Follow-Up Schedule of Activities
Study Period
Post-discontinuation Follow-Up
Short-term Follow-Up
Long-term Follow-Up
Duration
30 ± 5 days
60 ± 14 days
Visit
801
802-X
Relative day within a cycle
Period begins the day 
after stopping of study 
treatment and lasts 
approximately 30 days
Period begins 1 day after 
short-term follow-up period is 
completed and continues until 
death, study withdrawal, or the 
patient is lost to follow-up
Procedure 
Category
Procedure
Comments
Physical 
Examination
Physical examination (including  weight)
X
Vital signs
X
Includes blood pressure, pulse, and temperature
ECOG performance status
X
Tumor 
Assessment
Radiologic imaging according to RECIST 1.1
X
The same method of imaging (CT scan, spiral CT, etc.) used at 
baseline should be used for each subsequent assessment.  Not 
required if progressive disease is documented while on treatment or 
if there are clear signs of clinical progression.
Tumor measurement (palpable or visible)
X
Performed at the same time as radiologic imaging
Adverse Events Collection/CTCAE Grading
X
X
After Visit 801, only study treatment-related serious events are 
reported.
Concomitant Medication Notation
X
Lab/Diagnostic 
Tests
Hematology
X
Chemistry
X
ECG
X
Exploratory blood sample for biomarkers
X
Plasma biomarker sample
X
Optional posttreatment biopsy
X
The optional post-treatment biopsy must be taken prior to the 
patient starting a new treatment for their cancer.See Section 9.8.2
Health Outcome 
Measure
Lung Cancer Symptom Scale
X
The LCSS will need to be administered prior to extensive 
interaction with site personnel.
Follow-Up
Survival Assessment
X
Approximately every 60 (±14) days (telephone assessment is 
acceptable)


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Section 3.1 Study Rationale
…
SCLC is highly sensitive to chemotherapy, with combination chemotherapy remaining the focus 
of treatment for patients with ED-SCLC.  About 60% to 80% of patients with extensive stage 
disease respond to combination chemotherapy (Hann and Rudin 2008).  Cisplatin or carboplatin 
in combination with etoposide are commonly used regimens in the first-line treatment of SCLC.  
After an initial response, however, nearly all patients with extensive disease will relapse and the 
majority of patients will eventually die from their disease (Sundstrom et al. 2002).  
Platinum-refractory disease shows progression during therapy or within ≤<90 days of the last 
dose of platinum.  Platinum-sensitive disease shows progression >≥90 days after the last dose of 
platinum.  Patients with platinum-sensitive disease have a higher likelihood of response to 
second-line treatment. Their response rate is approximately 20% to 25% (Fruh et al. 2013; 
Kalemkerian et al. 2013).  In contrast, patients with platinum-refractory disease have a ≤10% 
chance of response to a second-line treatment (Kalemkerian et al. 2013).  If left untreated, a 
relapsed patient will typically live 2 months to 4 months (Wakuda et al. 2015).
Several other agents have been shown to have activity in SCLC, and many studies have 
compared 3-drug regimens to the standard 2-drug regimens with no improvement in efficacy.  
Topotecan is approved for patients that have ED-SCLC that have failed or relapsed after first line 
chemotherapy (Demedts et al. 2010). Patients receiving topotecan (1.5 mg/m2 daily for 5 days 
every 21 days) had an overall response rate of 24.3% (von Pawel et al. 1999).  The median time 
to progression was 13.3 weeks and median survival was 25.0 weeks (von Pawel et al. 1999).  
Grade 4 neutropenia occurred in 37.8% of patients, while Grade 4 thrombocytopenia occurred in 
9.8% of patients Adverse events (AEs) associated with this treatment included Grade 4 
neutropenia (70.2%), Grade 3/4 anaemia (42.3%), Grade 4 thrombocytopenia (28.8%), and
documented infection within 2 days of Grade 4 neutropenia (28%) (von Pawel et al. 1999).  
Other agents, including paclitaxel, irinotecan, vinorelbine, and gemcitabine, have been tested in 
the second-line setting in an effort to improve on the efficacy and tolerability of topotecan.  
Despite the modest benefit of topotecan, they have not increased efficacy over topotecan (Chan 
and Coward 2013), demonstrating the clear need for new agents to improve outcomes for 
patients with ED-SCLC.
…
3.4.
Rationale for JTJH Amendment (a)
Amendment (a) was developed to address requests resulting from member states participating in 
the Voluntary Harmonisation Procedure during the assessment of the initial clinical trial 
application for Study JTJH in the European Union.  At the member states’ request, the protocol 
was modified to incorporate those states’ recommendations in the inclusion and exclusion 
criteria and to establish the actions to be taken in case of prolongation of the QT/QTc interval 
>480 msec.  Because a protocol amendment was required, the opportunity was taken to also 
include several other minor protocol improvements and clarifications.


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6.1
Inclusion Criteria
…
[8]
men must be sterile or agree to use an effective method of contraception or a highly 
effective method of contraception during the study and for at least 12 weeks following the last 
dose of LY2606368
Refer to Appendix 1 for definitions of fertile men, effective method of contraception,
and highly effective method of contraception.
[9]
women of childbearing potential must:
a.
have a negative serum pregnancy test at the baseline visit
b. have a negative urine pregnancy test within 7 days prior to the first dose of  LY2606368 
c.
agree to use a highly effective method of contraception (Appendix 1) during the study 
and for 12 weeks following the last dose of LY2606368
d. not be breast-feeding
Refer to Appendix 1 for definitions of women of childbearing potential and 
postmenopausal women.
6.2
Exclusion Criteria
…
[11] have symptomatic central nervous system (CNS) malignancy or metastasis.  
Asymptomatic Ppatients with treated CNS metastases are eligible for this study if 
they are not currently receiving corticosteroids to treat CNS metastases. and/or 
anticonvulsants.  CNS metastases should be stable for at least 14 days by clinical 
assessment, and patients should not have received corticosteroids to treat CNS 
metastases within 14 days of the first dose of study drug.
…
[14] have previously completed or withdrawn from this study or any other study 
investigating LY2606368 or a CHK1 inhibitor or have shown hypersensitivity to 
any of the components of the LY2606368 formulation
…
[16] have a symptomatic human immunodeficiency virus (HIV) infection or 
symptomatic activated/reactivated hepatitis A, B, or C (screening is not required).  
If the medical history, symptoms, and/or laboratory values suggest that the patient 
may have HIV or hepatitis A, B, or C, appropriate assessment should be conducted 
to determine whether the patient should be excluded.


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7.4 
Dosage Modification
Before the start of each cycle:

Nonhematologic toxicities must resolve to Grade 0 or 1 or baseline, except AEs with no 
immediate medical consequence or those that can be controlled with adequate treatment 
(for example, alopecia, fatigue, nausea, vomiting, diarrhea, or asymptomatic changes in 
electrolytes).

Neutropenia, thrombocytopenia, and anemia must resolve to Grade 0, 1, or 2, as shown in 
Table JTJH.7.2.
Table JTJH.7.2.
Hematologic Parameters Required for the Start of Each Cycle
Dose
Neutrophils
≥1000/mm3
Platelets
≥75/mm3
Hemoglobin
≥8 g/dL
Treatment may be delayed for a maximum of 14 days to allow a patient sufficient time for 
recovery from LY2606368-related toxicity.  If a patient does not recover from the toxicity within 
28 days from the time of last treatment, the patient should be discontinued from LY2606368.  In 
exceptional circumstances, a longer delay is permitted upon agreement between the investigator 
and the Lilly clinical research physician (CRP).
If a patient, in the investigator’s opinion, experiences a toxicity warranting a dose reduction, 
LY2606368 should be reduced as shown in Table JTJH.7.3.2.
Table JTJH.7.2.3.
LY2606368 Dose Reductions
Reduction
Dose
1st LY2606368 dose reduction
80 mg/m2
2nd LY2606368 dose reduction
60 mg/m2
3rd LY2606368 dose reduction
Discontinue from LY2606368
7.5.2. LY2606368 Lactate Monohydrate
A 67-mg strength of LY2606368 lactate monohydrate drug product is in development and may 
be used in Study JTJH.  The vial will contain a slight excess to facilitate the withdrawal of the 
label amount 67 mg/vial for use with an appropriate device, such as an infusion set.  The drug 
product is stable when stored at room temperature.  Reconstituting the vial contents with water 
for injection yields a clear yellow solution with a concentration of 3.35 mg/mL of LY2606368.  
For the most current detailed information on this strength refer to the IB and Pharmacy Binder.


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7.8.1
Continued Access
Patients who are still on LY2606368 at the time of study completion may continue to receive 
LY2606368 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 LY2606368 when study 
completion occurs.  Lilly will notify investigators when the continued access period begins.  
Lilly may allow patients to enroll in a LY2606368 “rollover” protocol to provide long-term 
continued access for patients enrolled in this study.  Patients must sign a new ICF before 
continued access is provided.  The continued access period is shown in Figure JTJH.7.1.
9.1
Efficacy Assessments
Tumor assessments will be performed for each patient at the times shown in the Schedule of 
Activities (Section 2).
Computed tomography (CT) scans, including spiral CT, are the preferred methods of 
measurement (CT scan thickness recommended to be 5 mm); however, magnetic resonance 
imaging (MRI) is also acceptable in certain situations, such as when body scans are indicated or 
if there is a concern about radiation exposure associated with CT.  Intravenous and oral contrast 
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 CT is of identical diagnostic quality to a diagnostic CT (with IV and 
oral contrast).  A PET scan alone or as part of a PET-CT may be performed for additional 
analyses but cannot be used to assess response according to RECIST v.1.1 (Eisenhauer et al. 
2009).
Radiologic scans of the thorax and abdomen are required.  A baseline intracranial evaluation 
with CT or MRI should be conducted.  Scans of the pelvis or bone scans should be performed if 
clinically indicated.  Copies of the scans may be requested by the sponsor for central review.
See Section 10.3.1 for definitions of the efficacy endpoints.
9.4.1
Other Safety Measures
For each patient, safety assessments, including ECGs, vital signs, and laboratory tests, should be 
collected as shown in the Schedule of Activities (Section 2).  ECGs should be recorded 
according to the study-specific recommendations that will be provided separately.
As of 27 August 2015, no patients treated with LY2606368 monotherapy have had an average 
QTcF interval >480 msec at any time point.  However, if a patient experiences a QTcF interval 
>480 msec, the patient should be monitored for signs of life-threatening arrhythmias such as 
torsades de pointes.  It should be confirmed that the measurement is correct by repeating the 
ECG and ruling out other causes such as atrial fibrillation or the presence of a pacemaker.  If the 
result is confirmed, institutional guidelines or standard of care measures for management of 
QTcF interval >480 msec and/or associated arrhythmias should be initiated.  These actions may 
include the administration of IV magnesium sulfate and the assessment of clinical chemistry.  If 
electrolytes are abnormal, they should be repeated as indicated.  The QTcF value should be 


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monitored until the interval has returned to <480 msec or at least to predose levels.  It is 
recommended that the patient be assessed by a cardiologist before leaving the treating facility.  
For all subsequent doses, an ECG must be obtained at 10 minutes after the end of infusion (EOI) 
(±5 minutes), 30 minutes after EOI (±10 minutes), and >1 hour after EOI.
If a patient experiences a QTcF interval >500 msec and has an associated life-threatening 
arrhythmia, he/she should be discontinued from study treatment.  If a patient experiences a QTcF 
interval >500 msec without an associated life-threatening arrhythmia and if the investigator 
deems it in the best interest of the patient, the patient may continue treatment with LY2606368.  
If a patient has a second occurrence of QTcF interval >500 msec, he/she should be discontinued 
from study treatment.  
Any clinically significant findings that result in a diagnosis and that occur after the patient 
receives the first dose of LY2606368 should be reported to Lilly or its designee as an AE via 
CRF/electronic data entry/designated data transmission methods.
9.5
Pharmacokinetics
…
These samples will be analyzed at a laboratory designated by the sponsor by using a validated 
liquid chromatography–mass spectrometry/mass spectrometry (LC-MS/MS) method.
…
9.8
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, mechanism of action, variability of patient response (including safety), and clinical 
outcome.  Sample collection is incorporated into clinical studies to enable examination of these 
questions through measurement of biomolecules including DNA, RNA, proteins, lipids, and 
other cellular elements.
As part of Lilly’s ongoing efforts to understand the relationship between cancer, genetics, and 
response to therapy, this study will analyze biomarkers relevant to the mechanism of action of 
CHK1, DNA damage response pathways or downstream effects, cell cycle markers, immune 
function, and cancer pathobiology and/or for related research methods or validation of 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 have already been 
generated from samples that were collected and analyzed before the patients’ enrollment in this 
trial.  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 9.8.1 and 9.8.2.  
Samples for biomarker research will be collected as specified Section 2, where local regulations 
allow.


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10.3.4. Interim Analyses
For each cohort, one interim analysis of futility will be conducted after the 29th patient in the 
cohort has completed Cycle 3, and, if required, the response is confirmed.  The interim analysis 
will be conducted to assess whether the respective cohort is unlikely to achieve statistical 
significance on its primary endpoint and may also include PK data in order to confirm that 
patients are in the expected exposure range.
The stopping rule for interim analysis and final analysis is defined as follows:
…
Appendix 1
Abbreviations and Definitions
fertile men
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy.
women of 
childbearing 
potential 
A woman is considered of childbearing potential (ie, fertile), after menarche and until 
becoming postmenopausal unless permanently sterile.  Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  A high follicle-stimulating hormone level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy; however, in the absence of 12 months of amenorrhea, a single follicle-
stimulating hormone measurement is insufficient.

SAP_001.pdf: 
Protocol 14D-MC-JTJH A Phase 2 Study of LY2606368 in Patients with Extensive Stage Disease Small Cell 
Lung Cancer 
 
NCT# NCT02735980 
 
Approval Date: 16-May-2016 


I4D-MC-JTJH Statistical Analysis Plan Version 1
Page 1
LY2606368
1.
Statistical Analysis Plan:  
I4D-MC-JTJH: A Phase 2 Study of LY2606368 in Patients 
with Extensive Stage Disease Small Cell Lung Cancer
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities: this document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY2606368
This is a multicenter, nonrandomized, parallel-cohort Phase 2 study of LY2606368 in 
patients with extensive-stage disease small cell lung cancer (ED-SCLC) who have either 
platinum-sensitive or platinum-resistant/refractory disease.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I4D-MC-JTJH
Phase 2
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 16-May-2016 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I4D-MC-JTJH:  A Phase 2 Study of 
LY2606368 in Patients with Extensive Stage Disease Small Cell 
Lung Cancer .......................................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................5
4.
Study Objectives.................................................................................................................6
4.1.
Primary Objective ..........................................................................................................6
4.2.
Secondary Objectives.....................................................................................................6
4.3.
Exploratory Objectives...................................................................................................6
5.
A Priori Statistical Methods ................................................................................................7
5.1.
General Considerations ..................................................................................................7
5.2.
Adjustments for Covariates ............................................................................................9
5.3.
Handling of Dropouts or Missing Data...........................................................................9
5.4.
Multicenter Studies ......................................................................................................10
5.5.
Multiple Comparisons/Multiplicity...............................................................................10
5.6.
Patient Disposition .......................................................................................................10
5.7.
Patient Characteristics ..................................................................................................10
5.8.
Treatment Compliance .................................................................................................10
5.9.
Concomitant Therapy...................................................................................................10
5.10. Efficacy Analyses ........................................................................................................11
5.10.1.
Primary Outcome and Methodology.....................................................................11
5.10.2.
Secondary Efficacy Analyses ...............................................................................11
5.11. Health Outcomes/Quality-of-Life Analyses..................................................................12
5.12. Pharmacokinetic/Pharmacodynamic Analyses..............................................................13
5.13. Safety Analyses............................................................................................................13
5.13.1.
Extent of Exposure...............................................................................................13
5.13.2.
Adverse Events ....................................................................................................13
5.13.3.
Deaths..................................................................................................................14
5.13.4.
Clinical Laboratory Evaluation.............................................................................14
5.13.5.
Vital Signs and Other Physical Findings...............................................................14
5.13.6.
Electrocardiograms ..............................................................................................14
5.14. Subgroup Analyses.......................................................................................................14
5.15. Important Protocol Deviations......................................................................................15
5.16. Interim Analyses and Data Monitoring.........................................................................15
5.17. Planned Exploratory Analyses......................................................................................15


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5.17.1.
Biomarker Analyses.............................................................................................15
5.17.2.
Correlation between Change in Tumor Size and Efficacy 
Measures..............................................................................................................16
5.18. Clinical Trial Registry Analyses...................................................................................16
6.
References ........................................................................................................................18


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Table of Contents
Table
Page
Table JTJH.5.1.
Data Handling Conventions ........................................................................9
Table JTJH.5.2.
PFS Event/Censoring Scheme...................................................................12


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


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4.
Study Objectives
4.1.
Primary Objective

Cohort 1:  To estimate the overall response rate (ORR) when a dose of 105 mg/m2
LY2606368 every 14 days is administered to patients with ED-SCLC that have platinum-
sensitive disease

Cohort 2: To estimate the ORR when a dose of 105 mg/m2 LY2606368 every 14 days is 
administered to patients with ED-SCLC that have platinum resistant/refractory disease
4.2.
Secondary Objectives

To characterize the safety and toxicity profile of LY2606368

To characterize the pharmacokinetics (PK) of LY2606368

To estimate secondary efficacy measures including disease control rate (DCR), duration 
of response (DoR), progression-free survival (PFS), and overall survival (OS)

To evaluate the association between best tumor response and change from baseline in 
lung cancer specific-symptoms, symptomatic distress, activity status, overall quality of 
life, total Lung Cancer Symptom Scale (LCSS) score, and Average Symptom Burden 
Index (ASBI) for patients who have platinum-sensitive or platinum resistant/refractory 
SCLC
4.3.
Exploratory Objectives

To explore biomarkers associated with the efficacy and safety of LY2606368, the 
exposure (PK) of LY2606368, the mechanism of action of CHK1, DNA damage response 
pathways or downstream effects, cell cycle markers,  immune function, or cancer 
pathobiology

To explore whether ongoing measurement of tumor shrinkage (such as changes in tumor 
size) correlate with efficacy measures


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5.
A Priori Statistical Methods
5.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company.  The 
interpretation of the study results will be the responsibility of the Lilly Clinical Research 
Physician/Clinical Research Scientist (CRP/CRS) and statistician.  The CRP/CRS and statistician 
will also be responsible for the appropriate conduct of internal reviews for both the final study 
report and any study-related material to be authorized by Lilly for publication.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol and the justification for making the change will be described 
in the clinical study report.
The study will enroll approximately 116 patients (58 platinum-sensitive patients, 58 platinum-
refractory/resistant patients).
For the platinum-sensitive cohort, it is assumed that a true ORR of less than 20% indicates 
inadequate antitumor activity.  Given that a futility interim analysis will be conducted on the first 
29 patients’ response data, then with a one-sided significance level of 0.1, a sample size of 58 
patients will provide approximately 90% power to detect a true ORR of at least 35%. 
For the platinum-refractory/resistant cohort, it is assumed that a true ORR of less than 5% 
indicates inadequate anti-tumor activity.  Given that a futility interim analysis will be conducted 
on the first 29 patients’ response data, then with a one-sided significance level of 0.1, a sample 
size of 58 patients will provide approximately 90% power to detect a true ORR of at least 15%.
The stopping rule for interim analysis and decision rule for final analysis are defined as follows:

Platinum-sensitive cohort:
o
If 4 or fewer overall responses of confirmed CR or PR are observed in the first 
29 patients, then the cohort will be terminated for futility; otherwise, the cohort will
continue
o
If 16 or more overall responses of confirmed CR or PR are observed in all 
58 patients, then the ORR is statistically significantly greater than 20%

Platinum-refractory/resistant cohort:
o
If no overall response of confirmed CR or PR is observed in the first 29 patients, then 
the cohort will be terminated; otherwise, the cohort will continue
o
If 6 or more overall responses of confirmed CR or PR are observed in all 58 patients, 
then the ORR is statistically significantly greater than 5%
For each cohort, the overall type II error rate, i.e. the probability of terminating an effective 
cohort, will be controlled using a Lan-DeMets spending function (Lan and DeMets 1983), which 
generates boundaries that are very similar, though not identical, to the classical stopping 


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boundaries of O’Brien and Fleming (1979).  The type II error rate spent at interim analysis after 
the first 29 patients for each cohort is approximately 2%; the cumulative type II error rates spent 
at final analysis for platinum-sensitive cohort and platinum-refractory/resistant cohort are 9.9% 
and 9.4%, respectively.
The following patient populations will be analyzed in this study:

Full analysis set: will include all enrolled patients.  This population will be used for all 
baseline, efficacy, health economics, dosing/exposure, and safety analyses

Per-protocol population: will include all enrolled patients who do not have any major 
protocol violations that could potentially affect the efficacy conclusions of the study.  
This population will be determined after study team review of the list of important 
protocol deviations at end of the study, following the guideline below: 
o
Patients who either have a post-baseline tumor assessment (radiological imaging 
and/or tumor measurement [palpable or visible]) of any level of response
(excluding “not evaluable”), or discontinue from study treatment prior to tumor 
assessment due to an AE
o
The absence of the violation of inclusion/exclusion criteria, significant deviations 
in efficacy assessments, and instances of suspected misconduct

Pharmacokinetic population:  will include all enrolled patients who received at least 1 
full infusion (dose) of LY2606368 and have evaluable PK samples collected

Biomarker population:  will include the subset of patients from the full analysis set 
from whom a valid assay result has been obtained
Unless otherwise stated, all confidence intervals (CIs) will be given at a 2-sided 95% level.
Summary statistics for continuous variables will include number of patients (N), mean, median, 
standard deviation (SD), minimum, and maximum.  Summary statistics for categorical endpoints 
will include N, frequency, percentages, and associated SE and 95% CI.  Exploratory analyses 
will be conducted as deemed appropriate.  Time-to-event variables will be summarized using the 
Kaplan-Meier (KM) method. Kaplan-Meier estimates of median and quartiles will be reported 
along with 95% CIs.
Analyses will be implemented using Statistical Analysis System (SAS®, SAS Institute) version 
9.1 or higher; any exceptions will be documented in the outputs. 
The following data handling conventions will be used in the analysis (see Table JTJH.5.1).


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Table JTJH.5.1.
Data Handling Conventions
Term
Definition or Rule
Relative Study Day
If assessment is on or after date of first dose then
(date of assessment) – (date of first study treatment dose) +1
If assessment precedes first dose of drug then
(date of assessment) – (date of first study treatment dose)
There is no Study Day 0.  Study Day 1 is the date of first dose and study day -1 is the 
day before the first dose.
Baseline
For change from baseline analyses, baseline value is defined as the last reported 
measure on or before the first dose date (prior to the dose administration), unless 
otherwise specified.
For change from baseline within a cycle, baseline value is defined as the measure prior 
to the first dose of that cycle, unless otherwise specified.
Entered
Patients who have signed the informed consent form directly or through their legally 
acceptable representatives.
Enrolled
Patients who have been assigned to study treatment and have received at least one dose 
of study treatment.
Screen Failures
Patients who have signed informed consent, do not meet eligibility criteria and are not 
enrolled.
5.2.
Adjustments for Covariates
Please refer to Sections 5.11 and 5.17.1 for analyses with adjustments for covariates. 
5.3.
Handling of Dropouts or Missing Data
The full analysis set, which includes all enrolled patients, will be used for all baseline, efficacy, 
health outcomes, dosing/exposure, and safety analyses.  
Baseline will refer to the last non-missing observation prior to first administration of any 
treatment unless stated otherwise.  Missing data, except for dates, will not be imputed.  When 
dates are used in calculations, missing days will be replaced with 15th of the month and missing 
day/month with 01 JULY.  Where windows are allowed for data collection and there is more 
than one reading in any window, appropriate consideration will be given as to whether only one 
value from the window should be used, and if so how it should be chosen.  This could either be 
the mean (geometric mean) or the value closest to the mid-point of the window or the value 
closest to the data collection time of another variable if the analysis involves time-matched 
analyses.
If a patient discontinues from study treatment for any reason other than becoming lost to follow-
up or death, regular follow-up visits will be conducted to collect information on subsequent non-
protocol defined therapy, first disease recurrence, and death.  Therefore, it is possible to obtain 
information for time-to-event endpoints for these patients.
In the primary efficacy analysis, a patient with a tumor response of “not evaluable” will be 
included in the denominator for the purpose of calculating ORR. 


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In the health outcomes/quality-of-life analyses, if any of the 6 symptom-specific questions have 
not been completed, the ASBI will not be calculated.  Similarly, if any of the 9 LCSS questions 
have not been completed, the total LCSS score will not be calculated.
5.4.
Multicenter Studies
This is a multicenter study. Enrollment by center will be summarized. Due to limited sample 
size, analyses will not be conducted by center.  
5.5.
Multiple Comparisons/Multiplicity
The error spending for interim analysis is described in Section 5.16.  No other multiple 
comparison/multiplicity adjustments will be made. 
5.6.
Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, reasons for 
discontinuation from study treatment, and reasons for discontinuation from the study.  Reason 
for discontinuation from both study treatment and the study will be listed by the pre-determined 
categories.  If the reason for discontinuation is adverse event (AE) or death, the associated AE or 
cause of death will be reported.  All patients entered in the study will be included in the 
summary.
5.7.
Patient Characteristics
Patient characteristics will be listed for all patients on therapy by cohort, including:

Patient demographics (including age, sex, race, screening height and weight, and 
screening derived body surface area)

Baseline disease characteristics (including basis for initial diagnosis, initial pathological 
diagnosis, stage at initial diagnosis, baseline Eastern Cooperative Oncology Group
performance status)
5.8.
Treatment Compliance
The study treatment will be administered only at the investigational sites by the authorized study 
site personnel.  As a result, treatment compliance is ensured.  Patients should attend scheduled 
clinic visits and must comply with study criteria under their control.  Deviations from the 
prescribed dosage regimen should be recorded on the case report form and listed.
5.9.
Concomitant Therapy
All medications will be coded to the generic preferred name according to the current World 
Health Organization drug dictionary.  All concomitant medications will be listed and 
summarized using the preferred name for all patients on therapy by cohort.  If concomitant 
medication use is due to an AE, the associated National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (CTCAE) v4.0 (NCI 2009) term will be listed.


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5.10. Efficacy Analyses
5.10.1. Primary Outcome and Methodology
Best overall response (BOR) is defined as the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for confirmation, and 
will be derived based on investigator assessment of response and Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) (Eisenhauer et al. 2009).  
Overall response rate is defined as the number of patients who achieve a BOR of CR or PR, 
divided by the total number of patients enrolled to the corresponding cohort (full analysis set).  
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point (greater than 4 weeks).  The ORR, with exact 95% and 80% CIs, will be 
summarized for each cohort using the Clopper-Pearson method.
5.10.2. Secondary Efficacy Analyses
Secondary efficacy variables are defined as follows: 
Disease control rate is defined as the number of patients who achieve a BOR of CR, PR, or 
stable disease (SD) divided by the total number of patients enrolled to the corresponding cohort
(full analysis set).  The confirmation of CR and PR is required.  The BOR for patients with an 
unconfirmed PR or CR observation will be classified as SD, as long as they otherwise meet those 
requirements (see following sentence).  In the case of SD, measurements must have met the SD 
criteria at least once after study entry at a minimum interval (not less than 5 weeks).  The DCR,
with exact 95% CI, will be summarized for each cohort using the Clopper-Pearson method.
Duration of response is defined as the time from the date measurement criteria for CR or PR 
(whichever is first recorded) are first met until the first date that disease is recurrent or objective 
progression is observed, per RECIST 1.1 criteria, or the date of death from any cause in the 
absence of objectively determined disease progression or recurrence.
Overall survival is defined as the time from enrollment until death from any cause.  If the 
patient is alive or lost to follow-up at the time of data analysis, OS data will be censored on the 
last date the patient is known to be alive.  Overall survival curves, median OS, and OS rates at 
various time points with 95% CI, for each cohort will be estimated using the Kaplan-Meier 
method (Kaplan and Meier 1958).
Progression-free survival is defined as the time from enrollment until the first radiographic 
documentation of progression or death from any cause in the absence of PD. Patients known to 
be alive and without disease progression will be censored at the time of the last adequate tumor 
assessment prior to study completion (a detailed PFS event/censoring scheme is provided in
Table JTJH.5.2).  Progression-free survival curves, median PFS, and PFS rates at various time 
points with 95% CI for each cohort will be estimated using the Kaplan-Meier method (Kaplan 
and Meier 1958).


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Table JTJH.5.2.
PFS Event/Censoring Scheme
Situationa
Event/Censor
Date of Event or Censor
Tumor progression or death
Event
Earliest date of PD or death
No tumor progression and no death
Censored
Date of last adequate radiological assessment 
or date of enrollment (whichever is later)b
Unless
No baseline radiological tumor assessment 
available
Censored
Date of enrollment
No adequate postbaseline radiological 
tumor assessment available and death 
reported after 2 scan intervals following 
enrollmentb,c
Censored
Date of enrollment
Tumor progression or death documented
immediately after 2 or more scan intervals 
following last adequate radiological tumor 
assessment or enrollment (whichever is 
later)b,c
Censored
Date of last adequate radiological assessment 
or date of enrollment (whichever is later)b
Abbreviations:  CR = complete response; PD = progressive disease; PFS = progression-free survival; PR = partial 
response; SD = stable disease.
a
Symptomatic deterioration (that is, symptomatic progression that is not radiologically confirmed) will not be 
considered as tumor progression.
b
Adequate radiological tumor assessment refers to an assessment with one of the following responses: CR, PR, 
SD, or PD.
c
For the first 52 weeks following enrollment, radiologic imaging for tumor assessment will be performed 
approximately every 6 weeks (that is, every 3 cycles) starting at the end of Cycle 3.  Thereafter, it will be
performed approximately every 12 weeks.  The same method of imaging used at baseline should be used for each 
subsequent assessment.  Scans should also be obtained as clinically indicated.
5.11. Health Outcomes/Quality-of-Life Analyses
For the LCSS, the compliance rate by cohort will be calculated as the number of completed 
assessments divided by the number of expected assessments (that is, patients still on study).  
Compliance rates, reasons for noncompliance, and data collected will be summarized for all 
patients (cohort 1 and 2) and by cohort. 
The ASBI will be calculated as the mean of 6 symptom-specific questions; the total LCSS score 
will be calculated as the mean of 9 questions from the LCSS. For a given assessment, if any of 
the 6 symptom-specific questions have not been completed, the ASBI will not be calculated.  
Similarly, if any of the 9 LCSS questions have not been completed, the total LCSS score will not 
be calculated.
Change in tumor size (defined as the percent change in tumor size from the baseline evaluation 
to the evaluation at the time point where BOR is observed. The correlation between CTS and 
LCSS score and ASBI will be tested using the Spearman’s correlation coefficient. 
Descriptive statistics for each of the domain scores/items of interest by category of BOR (that is, 
CR, PR, SD, PD) will be summarized and a linear model will be fitted for each cohort in order to 
evaluate the association between BOR and change from baseline/the maximum improvement 


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from baseline in lung cancer-specific symptoms, symptomatic distress, activity status, overall 
quality of life, total LCSS score, and ASBI for patients who have platinum-sensitive or platinum-
resistant/refractory SCLC.  The model will include change from baseline/maximum change from 
baseline as the response variable and category of best overall response as an independent 
variable.  
5.12. Pharmacokinetic/Pharmacodynamic Analyses
Planned pharmacokinetic and PK/pharmacodynamic (PD) analyses are specified in a separate 
standalone population based PK/PD analysis plan.  
5.13. Safety Analyses
All patients who receive at least one dose of study treatment will be evaluated for safety and 
toxicity.  Adverse event terms and severity grades will be assigned by the investigator using 
CTCAE, version 4.0.
5.13.1. Extent of Exposure
A summary of drug exposure for study treatment will be presented.  
A summary of the dose administration, detailing the number of doses given as planned, reduced, 
omitted, and delayed will be presented for study treatment.  Reasons for dose adjustments will 
also be summarized.
Dose intensity and relative dose intensity will be summarized for study treatment.  Dose intensity 
is defined as actual cumulative amount of drug taken (mg/m2)/ duration of treatment (week).
5.13.2. Adverse Events
All patients who receive at least one dose of study treatment will be evaluated for safety and 
toxicity.  Adverse event terms and severity grades will be assigned by the investigator using 
CTCAE v4.0X.  In addition, AE verbatim text will also be mapped by the sponsor or designee to 
corresponding terminology within the Medical Dictionary for Regulatory Activities (MedDRA).  
Adverse events will be reported using a unified CTCAE/MedDRA reporting process:

The CTCAE v4.0 term reported by the investigator will be mapped to the MedDRA 
preferred term (PT) and system organ class (SOC) of the corresponding MedDRA lowest 
level term (LLT), unless the reported CTCAE term is ‘Other – specify’

If the reported CTCAE term is ‘Other – specify’ the MedDRA LLT, PT and SOC 
mapped from the verbatim AE term will be used

All listings and summaries will use the MedDRA LLT and the MedDRA PT resulting 
from this process.
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened in CTCAE grade after the first dose of study treatment. The MedDRA LLT will be 
used in the treatment-emergent computation.


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All observed AEs will be graded using CTCAE version 4.0.  Adverse events, deaths and serious 
adverse events (SAEs) will be listed and summarized.  Summaries for patients on therapy will 
include:

Summary of all pre-existing conditions and AEs

Summary of all TEAEs

Summary of TEAEs possibly related to study treatment

Summary of all TEAEs by maximum CTCAE grade

Summary of TEAEs possibly related to study treatment by maximum CTCAE grade

Summary of deaths on treatment or post-study treatment deaths possibly related to study 
treatment.
5.13.3. Deaths
All deaths recorded in this study will be included as part of the complete AE listing, where 
appropriate, and listed separately.  A summary of deaths may be presented for all patients on 
therapy if there are a sufficient number of events for this to be deemed useful.
5.13.4. Clinical Laboratory Evaluation
Laboratory data (hematology, chemistry) will be listed for all patients on therapy.  Abnormal 
results will be listed separately for all patients on therapy.
In addition to the investigator-reported AEs, all relevant hematology and chemistry laboratory 
values will be graded according to CTCAE version 4.0.  These derived values will be included 
on the listings of laboratory data and summary tables will be produced in a similar manner to 
those created for the investigator reported AEs.
5.13.5. Vital Signs and Other Physical Findings
All vital signs including blood pressure, pulse, and temperature will be listed for all patients on 
therapy.
5.13.6. Electrocardiograms
For each patient, single local electrocardiogram (ECG) will be collected according to the study 
schedule.  The ECG data will be summarized and listed.  
5.14. Subgroup Analyses
The selected primary and secondary endpoints may be analyzed in the following subgroups: 

Performance status (0 vs. 1)

Number of prior treatments (2 vs. 3)

Nature of prior treatments (e.g. cisplatin vs. carboplatin, etoposide/no etoposide,  
adjuvant radiation/no radiation)  


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
CNS metastasis (present/absent)

Geographic region (North America, Europe, Asia)
5.15. Important Protocol Deviations
Important protocol deviations that potentially compromise the data integrity and patients’ safety 
will be listed.  These deviations will include those defined by:

Informed consent

Inclusion/Exclusion Criteria

Investigational Product

Study Procedures

Administrative/Oversight

Safety

Other
Based on the discussion with study team, the detailed description of each deviation within the 
above category and the method to identify each deviation will be documented.   
5.16. Interim Analyses and Data Monitoring
For each cohort, one interim analysis of futility will be conducted after the 29th patient in the 
cohort has completed Cycle 3, and, if required, the response is confirmed.  The interim analysis 
will be conducted to assess whether the respective cohort is unlikely to achieve statistical 
significance on its primary endpoint and may also include PK data in order to confirm that 
patients are in the expected systemic exposure range.
5.17. Planned Exploratory Analyses
5.17.1. Biomarker Analyses
Descriptive summaries and statistical analyses results will be provided to support the biomarker 
research objectives outlined in the protocol.
For biomarkers obtained from whole-blood samples, descriptive statistics will be reported at pre-
treatment (baseline), post-treatment and post-regression time points. Each biomarker will be 
described using summary statistics at the study, cohort, and at the level of other patient 
subgrouping of interest. Any correlations or associations between the biomarkers measured on 
the same patient will also be looked at.
For biomarkers obtained from biopsies done on lesions, descriptive statistics will be reported at 
pre-treatment (baseline), post-treatment and post-regression time points as described in the 
paragraph above. In addition, descriptive statistics on lesions that regressed after treatment will 
be provided. Provided a sufficient number of patients with such biopsies are available, additional 


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analyses may be undertaken to investigate the correlation between the change in the status/level 
of the biomarker and the change in the size of the lesion.
All biomarkers deemed relevant may be specifically investigated with the aim of understanding 
the biomarker profile of patients who receive the greatest clinical benefit from LY2606368.  
These investigations will look at the correlation/association between the baseline (archival or 
pre-treatment) status/level of the biomarker(s) and measures of clinical benefit such as objective 
clinical response status (CR/PR or no-CR/PR) or disease control status (CR/PR/SD or no-
CR/PR/SD).  Where a change in the status/level of a biomarker over time can be ascertained, 
additional exploratory analyses may be undertaken to assess the effect of the change or its 
magnitude on the same clinical efficacy endpoints.  For secondary efficacy measures of PFS and 
OS, parametric and semi-parametric survival analysis will be undertaken to quantify the 
association between the biomarker status and the time-to-event efficacy measure.
For serially measured plasma-based biomarkers, change from baseline to subsequent time points 
may be associated with clinical response outcomes. In addition, the time-course relationship of
these biomarkers with safety and/or PK parameters (systemic exposure) may also be 
investigated.
Biomarker results may also be analyzed to elucidate the associations between the baseline 
status/level, or change in status/level and including, but not limited to, the mechanism of action 
of LY2606368, sensitivity to CHK1 inhibition, and sensitivity or resistance to platinum-based 
therapies.
5.17.2. Correlation between Change in Tumor Size and Efficacy 
Measures
Change in tumor size (CTS) will be assessed in each patient using radiographic imaging. This 
endpoint will be based on tumor measurements collected by the centers according to RECIST 
1.1. Tumor size is the sum of the tumor measurements for target lesions at each tumor 
evaluation. Change in tumor size is defined as the percent change in tumor size from the 
baseline evaluation to the evaluation at the end of Cycle 3. 
CTS = (tumor size at Cycle 3 – tumor size at baseline)/(tumor size at baseline)
The correlation between CTS and PFS will be tested using the Spearman’s correlation 
coefficient. 
Additional exploratory analyses of the data will be conducted as deemed appropriate.
5.18. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:


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Summary of adverse events, provided as a dataset which will be converted to an XML file.   
Both Serious Adverse Events and ‘Other’ Adverse Events are summarized: by treatment 
group, by MedDRA preferred term.

An adverse event is considered ‘Serious’ whether or not it is a TEAE.

An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment group, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth.


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6.
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O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics.
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