Conditions: Ovarian Cancer
Keywords: DNA damage repair replication stress
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 172
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of prexasertib in women with platinum-resistant or refractory recurrent ovarian cancer.

Detailed description:

Arms:
arm 1: Participants received 105 milligram per square meter (mg/m²) prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. Participants were with platinum-resistant disease, breast cancer susceptibility gene (BRCA) negative and have received ≥3 lines of prior therapy. arm 2: Participants received 105 mg/m² prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. Participants were with platinum-resistant disease, BRCA negative and have received \<3 lines of prior therapy. arm 3: Participants received 105 mg/m² prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. Participants were with platinum-resistant disease, BRCA positive and received a prior poly ADP ribose polymerase (PARP) inhibitor. arm 4: Participants received 105 mg/m² prexasertib as an approximately 60 (+10) minute IV infusion on Day 1 and 15 of a 28-day cycle. Participants were with platinum refractory disease, BRCA positive or negative, no restriction on number of lines of prior therapy.

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

Protocol document:
Prot_000.pdf: 
Protocol: I4D-MC-JTJN(b)
A Phase 2 Study of Prexasertib in Platinum-Resistant or Refractory Recurrent 
Ovarian Cancer
NCT03414047   
Approval Date: 17-Sep-2018


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Protocol I4D-MC-JTJN(b)
A Phase 2 Study of Prexasertib in Platinum-Resistant or
Refractory Recurrent Ovarian 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 prexasertib (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.
Prexasertib (LY2606368)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 20 November 2017
Amendment (a) Electronically Signed and Approved by Lilly:  28 June 2018
Amendment (b) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 17-Sep-2018 GMT


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Table of Contents
Section
Page
Protocol I4D-MC-JTJN(a) A Phase 2 Study of Prexasertib in Platinum-
Resistant or RefractoryRecurrent Ovarian Cancer ...............................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Study Activities .............................................................................................10
3.
Introduction ......................................................................................................................17
3.1.
Study Rationale............................................................................................................17
3.2.
Background..................................................................................................................18
3.2.1.
Description of CHK1 and Prexasertib...................................................................18
3.2.2.
Rationale for Prexasertib in Ovarian Cancer.........................................................18
3.2.2.1.
Role in DNA-Damage Repair and Replication Stress......................................18
3.2.2.2.
Nonclinical Data.............................................................................................19
3.2.2.3.
Clinical Data in Patients with High-Grade Serous 
Ovarian Cancer...............................................................................................19
3.2.2.4.
Rationale for JTJN Cohorts.............................................................................21
3.3.
Benefit/Risk Assessment..............................................................................................22
4.
Objectives and Endpoints..................................................................................................23
5.
Study Design.....................................................................................................................24
5.1.
Overall Design .............................................................................................................24
5.2.
Number of Patients.......................................................................................................24
5.3.
End of Study Definition ...............................................................................................24
5.4.
Scientific Rationale for Study Design...........................................................................24
5.5.
Justification for Dose ...................................................................................................24
6.
Study Population...............................................................................................................26
6.1.
Inclusion Criteria..........................................................................................................26
6.2.
Exclusion Criteria ........................................................................................................28
6.3.
Lifestyle Restrictions....................................................................................................30
6.4.
Screen Failures.............................................................................................................30
7.
Treatments........................................................................................................................31
7.1.
Treatments Administered .............................................................................................31
7.1.1.
Packaging and Labelling ......................................................................................31
7.2.
Method of Treatment Assignment ................................................................................31
7.2.1.
Selection and Timing of Doses.............................................................................31
7.3.
Blinding .......................................................................................................................31


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7.4.
Dose Modification........................................................................................................32
7.5.
Preparation/Handling/Storage/Accountability...............................................................34
7.6.
Treatment Compliance .................................................................................................34
7.7.
Concomitant Therapy...................................................................................................34
7.8.
Treatment after the End of the Study............................................................................35
8.
Discontinuation Criteria ....................................................................................................37
8.1.
Discontinuation from Study Treatment.........................................................................37
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................37
8.2.
Discontinuation from the Study....................................................................................37
8.3.
Lost to Follow-Up........................................................................................................38
9.
Study Assessments and Procedures ...................................................................................39
9.1.
Efficacy Assessments...................................................................................................39
9.1.1.
Appropriateness of Assessments ..........................................................................39
9.2.
Adverse Events ............................................................................................................39
9.2.1.
Serious Adverse Events........................................................................................40
9.2.2.
Suspected Unexpected Serious Adverse Reactions ...............................................41
9.2.3.
Complaint Handling.............................................................................................42
9.3.
Treatment of Overdose.................................................................................................42
9.4.
Safety...........................................................................................................................42
9.4.1.
Safety Measures and Monitoring..........................................................................42
9.4.1.1.
Special Hepatic Safety Data Collection and Monitoring 
Criteria ...........................................................................................................42
9.5.
Pharmacokinetics .........................................................................................................43
9.6.
Pharmacodynamics ......................................................................................................43
9.7.
Pharmacogenomics ......................................................................................................43
9.8.
Biomarkers...................................................................................................................44
9.8.1.
Tissue Samples for Biomarker Research...............................................................44
9.8.2.
Other Samples for Biomarker Research................................................................46
9.9.
Health Economics ........................................................................................................46
9.10. Health Outcome Measures............................................................................................46
10.
Statistical Considerations ..................................................................................................48
10.1. Sample Size Determination ..........................................................................................48
10.2. Populations for Analyses..............................................................................................49
10.3. Statistical Analyses ......................................................................................................49
10.3.1.
Efficacy Analyses ................................................................................................50
10.3.2.
Safety Analyses....................................................................................................50
10.3.3.
Other Analyses.....................................................................................................51
10.3.3.1.
Patient Disposition..........................................................................................51


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10.3.3.2.
Patient Characteristics ....................................................................................51
10.3.3.3.
Treatment Compliance....................................................................................51
10.3.3.4.
Extent of Exposure .........................................................................................51
10.3.3.5.
Concomitant Therapy .....................................................................................51
10.3.3.6.
Post-Study-Treatment Therapy.......................................................................51
10.3.3.7.
Pharmacokinetic/Biomarker Analyses.............................................................52
10.3.3.8.
Biomarker Analyses .......................................................................................52
10.3.3.9.
Health Outcome/Patient-Reported Outcomes..................................................52
10.3.3.10. Healthcare Resource Utilization......................................................................53
10.3.4.
Interim Analyses..................................................................................................53
11.
References ........................................................................................................................55


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List of Tables
Table
Page
Table JTJN.1.
Schedule of Inclusion and Baseline Assessments....................................11
Table JTJN.2.
On-Study Treatment Schedule of Activities............................................13
Table JTJN.3.
Post-Study-Treatment Follow-Up Schedule of Activities........................15
Table JTJN.4.
Continued Access Schedule of Activities................................................16
Table JTJN.5.
Objectives and Endpoints .......................................................................23
Table JTJN.6.
Hematologic Parameters Required Prior to Each Dose............................32
Table JTJN.7.
Dose Adjustments and Delays ................................................................33
Table JTJN.8.
Prexasertib Dose Reductions ..................................................................34
Table JTJN.9.
Instruments Used to Assess Patient-Reported Outcomes.........................47
Table JTJN.10.
Observed ORR and 60% Credible Interval..............................................49


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List of Figures
Figure
Page
Figure JTJN.3.1
Best response for target lesions, among patients with platinum-
sensitive, -resistant, or -refractory disease treated with prexasertib..........21
Figure JTJN.7.1.
Continued access diagram.......................................................................36


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................60
Appendix 2.
Clinical Laboratory Tests........................................................................64
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................65
Appendix 4.
Sampling Schedule for Pharmacokinetics ...............................................68
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............69
Appendix 6.
Creatinine Clearance Formula.................................................................70
Appendix 7.
Protocol Amendment I4D-MC-JTJN(a) Summary
A Phase 2 Study of Prexasertib in Platinum-Resistant or Refractory
Recurrent Ovarian Cancer .......................................................................71


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1.
Synopsis
Protocol Title:
A Phase 2 Study of Prexasertib in Platinum-Resistant or Refractory Recurrent Ovarian Cancer
Rationale:
Effective treatment options for patients with platinum-resistant or platinum-refractory high-grade 
serous ovarian (HGSOC), primary peritoneal, or fallopian tube cancer who have failed standard 
of care are limited.  Over 75% of HGSOCs are associated with alterations in DNA damage 
response (DDR) pathways or increased replication stress.  These alterations are predicted to 
increase sensitivity to a CHK1 inhibitor such as prexasertib. Study I4D-MC-JTJN (Study JTJN) 
will evaluate the efficacy of prexasertib in both platinum-resistant and platinum-refractory 
patients with HGSOC, primary peritoneal, or fallopian tube cancer.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To estimate the overall response rate 
(ORR) for each cohort

ORR: proportion of all enrolled patients who achieve a best overall
response of PR+CR as determined per RECIST version 1.1.
Secondary
To characterize the safety and
toxicity profile of prexasertib

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 
prexasertib

Prexasertib concentrations in plasma
To estimate secondary efficacy
measures including DCR, DoR, 
CA-125 response, PFS, OS

DCR:
proportion of patients who achieve a best overall response of
CR, PR and SD (for at least 4 months) as determined per RECIST
version 1.1.

DoR:
time from the date measurement criteria for CR or PR 
(whichever is first recorded) are first met until the first date of
documented PD, per RECIST 1.1, or the date of death from any
cause in the absence of documented PD.

CA-125 response: at least a 50% reduction in CA-125 levels from a
pretreatment sample that is at least twice the upper limit of the reference 
range and obtained within 2 weeks before starting the treatment, with 
confirmation after 4 weeks according to GCIG criteria.

PFS: time from enrollment until the first radiographic
documentation (as assessed by the investigator) of progression
or death from any cause in the absence of documented PD

OS:
time from enrollment until death from any cause
Abbreviations:  AEs = adverse events; CR = complete response; DCR = disease control rate; DoR = duration of
response; ECG = electrocardiogram; GCIG = Gynecologic Cancer Intergroup; 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 version 1.1 (Eisenhauer et al. 
2009); SAEs = serious adverse events; SD = stable disease.


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Overall Design:
Study JTJN is a multicenter, nonrandomized, parallel cohort, Phase 2 study in patients with
high-grade serous ovarian, primary peritoneal, or fallopian tube cancer.
Patients will be assigned to the following cohorts:

Cohort 1: Platinum-resistant, BRCA negative, and received ≥3 lines of prior therapy

Cohort 2: Platinum-resistant, BRCA negative, and received <3 lines of prior therapy

Cohort 3: Platinum-resistant, BRCA positive, there is no restriction on number of lines of 
prior therapy, but patients must have received prior poly (ADP-ribose) polymerase 
(PARP) inhibitor

Cohort 4:  Platinum-refractory, BRCA positive or negative, no restriction on number of 
lines of prior therapy
Patients with BRCA test results positive for deleterious or suspected deleterious mutations are 
referred to as BRCA positive, and patients with BRCA test results negative for deleterious or 
suspected deleterious BRCA mutations are referred to as BRCA negative.  Patients with variants 
of unknown significance should be considered BRCA negative.
Number of Patients:
The total sample size is estimated to be approximately up to 180 patients.
Treatment Arms and Duration:
Patients in all cohorts will receive 105 mg/m2 prexasertib as an approximately 60 (+10) minute 
intravenous (IV) infusion on Day 1 and 15 of a 28-day cycle.  Patients will be treated until 
radiographically documented disease progression, unacceptable toxicity, or another permitted 
reason for study discontinuation.


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2.
Schedule of Study Activities


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Table JTJN.1.
Schedule of Inclusion and Baseline Assessments
Study Period
Baseline
Cycle
Baseline (Screening)
Visit
0
Duration
Up to 42 days
Relative Day C1D1
≤42
≤28
≤14
Procedure 
Category
Procedure
Comments
Study Entry/
Enrollment
Informed Consent 
Form signed
X
Prior to conducting any protocol specific tests/procedures.
Cohorts 1-3: 
Confirm availability
of local BRCA result
X
Data from a blood or tissue based test are acceptable (i.e., either germline 
or somatic tests are acceptable). The test may have occurred prior to 
consent. If both somatic and germline status are known, the somatic 
status should be used for cohort assignment. Patients in Cohort 4 do not 
need to have local BRCA results.
Inclusion/Exclusion 
evaluation
X
All criteria except the confirmation of availability of local BRCA test
results must be assessed within 28 days from first dose.
Medical History
Initial history/
preexisting 
conditions
X
Including significant historical illnesses that resolved.
Habits 
X
Only smoking history.
Physical 
Examination
Physical 
examination
X
Includes height and weight.
ECOG performance 
status
X
Vital signs
X
Temperature, blood pressure, pulse rate.
Tumor 
Assessment
Radiologic imaging 
according to 
RECIST version 1.1
and tumor 
measurement 
(palpable or visible)
X
Baseline radiological tumor assessment per RECIST version 1.1. 
Radiologic assessments obtained previously as part of routine clinical 
care may be used as baseline assessment provided they were done no 
more than 28 days before the first dose of study drug.
Adverse Events Collection/ CTCAE 
Grading
X
CTCAE version 4.0.
Concomitant Medication Notation
X
Includes information on over-the-counter and prescription analgesics 
Laboratory/
Diagnostic Tests
Hematology
X
See Appendix 2
Chemistry
X
See Appendix 2
Urinalysis
X
See Appendix 2
CA-125
X
Centrally assessed.
Pregnancy test
X
Women of childbearing potential must have negative pregnancy test prior 
to biopsy (to confirm eligibility) and a negative pregnancy test within 24 
hours prior to drug exposure.  Either a urine or serum test is acceptable.
ECG
X
Single local ECG.
Pretreatment biopsy 
X
May be performed at any time, but sample should be taken only after 
study eligibility is confirmed.


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Schedule of Inclusion and Baseline Assessments
Study Period
Baseline
Cycle
Baseline (Screening)
Visit
0
Duration
Up to 42 days
Relative Day C1D1
≤42
≤28
≤14
Procedure Category
Procedure
Comments
Health Outcome 
Assessments
Worst Pain NRS
X
One question assessing worst pain will be 
administered by site personnel and 
completed by the patient prior to extensive 
interaction with site staff.
NFOSI-18
X
NFOSI-18 will be administered by site 
personnel and completed by the patient prior 
to extensive interaction with site staff.
Abbreviations:  C1D1 = Cycle 1 Day 1; CTCAE = Common Terminology Criteria for Adverse Events; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; 
IV = intravenous; NRS = numeric rating scale; NFOSI-18 = National Comprehensive Cancer Network –
Functional Assessment of Cancer Therapy – Ovarian Symptom Index-18; RECIST = Response Evaluation 
Criteria in Solid Tumors version 1.1 (Eisenhauer et al. 2009).


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Table JTJN.2.
On-Study Treatment Schedule of Activities
Study Period
Cycle
Cycle/Visit
1
2-n
Duration
28 days
28 days
Relative Day within Dosing Cycle
1
15
1
15
Procedure 
Category
Procedure
Notes
Physical
Examination
Physical examination
X
X
Includes weight and calculated BSA.  May be completed up to 7 days prior to treatment 
infusion.
Vital signs
X
X
X
X
Includes blood pressure, pulse, and temperature.  Complete before each treatment 
infusion.
ECOG performance status
X
X
Complete before treatment infusion on Day 1.
Laboratory/ 
Diagnostic 
Tests
Hematology
X
X
X
X
May be drawn up to 3 days before the day of dosing. Additional assessments may be 
obtained at the discretion of the investigator. 
Chemistry
X
X
May be drawn up to 3 days before the day of dosing. Additional assessments may be 
obtained at the discretion of the investigator. 
Pregnancy test
X
X
Applies only to women of childbearing potential.  Where required by local law/ regulation 
or institutional guidelines, perform once every 28 days (±7 days). Either a urine or serum 
test is acceptable.
CA-125
X
X
May be drawn up to 3 days before the day of dosing
PK sampling
X
X
Sparse PK sampling will be conducted over multiple cycles of therapy (see Appendix 4
for additional details).
Stored blood sample for 
pharmacogenetics
X
Collect once.  Sample can be collected at any time if not collected on Day 1 of Cycle 1.
Plasma biomarker sample 
X
X
Collect only in Cycles 1 and 4.  May be drawn up to 3 days before the day of dosing.
ECG
X
X
X
X
Single local ECG collected at each time point only. Cycle 1 Day 1 and Cycle 2 Day 1:  
predose, within 15 min after EOI.  Cycle 1 Day 15, Cycle 2 Day 15, and Cycle 3-n: Day 1 
and 15 prior to each dose. Additional ECGs may be obtained at the discretion of the 
investigator.  When ECGs and PK are required at the same time point, the ECG should be 
obtained prior to the PK draw.
Optional tumor biopsy
X
Can occur at any time during patient's treatment. Patients should have adequate 
neutrophils and platelets prior to biopsy. See Section 9.8.1.


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On-Study-Treatment Schedule of Activities
Study Period
Cycle
Cycle/Visit
1
2-n
Duration
28 days
28 days
Relative Day within Dosing Cycle
1
15
1
15
Procedure 
Category
Procedure
Notes
Tumor 
Assessment
Radiologic imaging according to 
RECIST version 1.1 and 
tumor measurement 
(palpable or visible)
X
Perform approximately every 8 weeks (±1 week) up to 1 year, thereafter every 12 weeks 
(±1 week). The first scan should be approximately 8 weeks (±1 week) from Cycle 1
Day 1. The 8-week/12-week scanning interval should be maintained even if cycles are 
delayed.  As a result, 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.  Scans to confirm responses may be 
performed sooner than 8 weeks, but should be at least 4 weeks following the initial 
observation of an objective response.  The next scan should be 8 weeks (±1 week) 
following the confirmatory scan.
Adverse Events Collection/ CTCAE Grading
X
Collect throughout the study, CTCAE version 4.0; includes hospitalizations, emergency 
department visits, and/or occurrence of SBO.
Concomitant Medication Notation
X
Collect throughout the study; includes transfusions (platelets and RBC) and information 
on over-the-counter and prescription analgesics use.
Health 
Outcome 
Assessments
Worst Pain NRS
X
The patient will complete the single item worst pain NRS, at home immediately prior to 
bedtime every day.  Collection of the Worst Pain NRS will be discontinued during study 
treatment at progression or Day 28 of Cycle 6, whichever comes first.
NFOSI-18
X
The NFOSI-18 will be administered by site personnel prior to extensive interaction with 
site staff as well as administration of study drug on Day 1 of every cycle, beginning with 
Cycle 2.
Study 
Treatment
Prexasertib
X
X
X
X
Administer on Days 1 and 15 of every 28-day cycle, IV over approximately 60 (+10) 
minutes.
Note:  Baseline/screening labs drawn within the indicated window of C1D1 may be used for both screening/baseline and C1D1 labs.  Note that eligibility
(including baseline/screening labs) must be confirmed prior to obtaining the biopsy and patient should fully recover from the acute effects of the biopsy prior 
to starting treatment.
Abbreviations:  BSA = body surface area; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI =  end of infusion; IV = intravenous; NRS = numeric rating scale; 
NFOSI-18 = National Comprehensive Cancer Network – Functional Assessment of Cancer Therapy – Ovarian Symptom Index-18, PK = pharmacokinetics; 
QTcF = corrected QT interval using Fridericia’s formula; RBC = red blood cell; RECIST = Response Evaluation Criteria in Solid Tumors version 1.1 
(Eisenhauer et al. 2009); SBO = small bowel obstruction.


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Table JTJN.3.
Post-Study-Treatment Follow-Up Schedule of Activities
Study Period
Post-Discontinuation Follow-Up
Short-Term Follow-Upa
Long-Term Follow-Upb
Duration
30 ± 5 days
60 ± 14 days
Visit
801
802-X
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 version 1.1
X
X
Perform approximately every 8 weeks (±1 week) up to 1 year, 
thereafter every 12 weeks (±1 week) by the same method used at 
baseline and throughout the study, until the patient has documented 
disease progression, starts another therapy, or study completion. 
The same method of imaging used at baseline should be used for 
each subsequent assessment.  Scans should also be obtained as 
clinically indicated.
Tumor measurement (palpable or visible)
X
Adverse Events Collection/ CTCAE Grading
X
X
CTCAE version 4.0; for visit 801: includes hospitalizations, 
emergency department visits, and/or occurrence of SBO. After Visit 
801, only study treatment-related serious events are to be reported.
Concomitant Medication Notation
X
Includes transfusions (platelets and RBCs) and information on over-
the-counter and prescription analgesics use.
Laboratory/
Diagnostic Tests
Hematology
X
See Appendix 2.
Chemistry
X
See Appendix 2.
CA-125
X
X
Collect approximately every 8 weeks (±1 week) up to 1 year, 
thereafter every 12 weeks (±1 week) at same time as radiologic 
imaging (+/- 3 days), until the patient has documented disease 
progression, starts another therapy, or study completion.
ECG
X
Plasma biomarker sample
X
Optional post-treatment biopsy
X
Can be obtained any time prior to the start of next therapy


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Post-Study-Treatment Follow-Up Schedule of Activities
Study Period
Post-Discontinuation Follow-Up
Short-Term Follow-Upa
Long-Term Follow-Upb
Duration
30 ± 5 days
60 ± 14 days
Visit
801
802-X
Procedure 
Category
Procedure
Comments
Health Outcome 
Assessments
Worst Pain NRS, NFOSI-18 
X
PRO instrumentation will be administered during the short term 
follow-up visit prior to extensive interaction with site staff.
Follow-Up
Survival assessment
X
Approximately every 90 (±14) days (telephone assessment is 
acceptable)
Abbreviations:  CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; NRS = numeric rating scale; NFOSI-18 = National Comprehensive Cancer Network – Functional Assessment of Cancer Therapy – Ovarian Symptom Index-18; NRS = 
numeric rating scale; PRO = patient-reported outcome; RECIST = Response Evaluation Criteria in Solid Tumors version 1.1 (Eisenhauer et al. 2009); SBO =small bowel 
obstruction.
a
Period begins the day after the decision that the patient will discontinue study treatment is made and lasts approximately 30 days.
b
For patients who have discontinued without progression, follow-up should occur every 60 days.  For patients with progression, the follow-up interval is 90 
days for survival assessments.  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.
Table JTJN.4.
Continued Access Schedule of Activities
Study Treatment
Follow-Upa
Visit
501-5XX
901
Comments
Procedureb
Adverse event collection
X
X
Administer prexasertib
X
IV over approximately 60 (+10) minutes once every 14 days.
Abbreviations:  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
Ovarian cancer is the fifth leading cause of cancer deaths for women in the United States (Siegel 
et al. 2017).  Approximately 80-85% of all carcinomas are serous tumors, the vast majority being 
high-grade serous ovarian cancer (HGSOC) (Soslow 2008). High-grade serous adenocarcinomas 
from the fallopian tube or peritoneal cavity are extrauterine adenocarcinomas of Müllerian
epithelial origin and are staged and treated like HGSOC.  As a result, they are commonly 
included in ovarian cancer clinical trials (Dubeau and Drapkin 2013).  Frontline chemotherapy 
consists of a platinum and taxane doublet with or without bevacizumab (Ozols et al. 2003; Vasey 
et al. 2004; Katsumata et al. 2009; Burger et al. 2011; Perren et al. 2011).  Although HGSOCs
are initially chemo-sensitive, up to 80% of patients relapse leading to a disappointing 46.2% 
overall survivorship at 5 years from ovarian cancer diagnosis (Ozols et al. 2003; Rustin et al. 
2010; SEER [WWW]).  Therapy at the time of recurrence is determined largely by the time 
elapsed since completing initial platinum-based chemotherapy; patients with 
“platinum-sensitive” and “platinum-resistant” relapse have disease progressing >6 months or 
<6 months from the previous platinum-based treatment, respectively (Gore et al. 1990; Hoskins 
et al. 1991; Davis et al. 2014). Patients with platinum-refractory disease progress during or 
within 4 weeks of the last dose of the initial line of platinum-based chemotherapy for ovarian 
cancer. The standard of care for a woman with a platinum-sensitive recurrence is retreatment 
with a platinum doublet (Parmar et al. 2003).
Unlike platinum-sensitive disease, there is not a clear standard of care for platinum-resistant or 
platinum-refractory disease, and the agents used vary by center and geography.  A variety of 
single-agent chemotherapies are used for platinum-resistant disease, including PEGylated
liposomal doxorubicin (PLD), gemcitabine, paclitaxel, topotecan, docetaxel, and etoposide 
(National Comprehensive Cancer Network [NCCN] [WWW]). However, patients will ultimately 
relapse and new agents are needed for platinum-resistant patients who have failed or exhausted
standard treatment options.
Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib and rucaparib have been 
approved as monotherapy for patients with recurrent ovarian cancer, especially for patients with
germline BRCA1 or BRCA2 mutations (Alsop et al. 2012; Pennington et al. 2014; NCCN 
[WWW]). Notably, a pooled subgroup analysis of the rucaparib studies ARIEL2 and Study 10 
showed that in HGSOC patients who had received ≥2 prior therapies, rucaparib monotherapy had 
a higher overall response rate (95% confidence interval [CI]) in platinum-sensitive patients 
(65.8% [54.3-76.1]) compared with platinum-resistant (25.0% [8.7-49.1]) or platinum-
refractory patients (0% [0.0-41.0]) (Oza et al. 2017).


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3.2.
Background
3.2.1. Description of CHK1 and Prexasertib
Checkpoint kinase 1 (CHK1) is a multifunctional protein kinase and regulator of the DNA 
damage response (Dai and Grant 2010). In response to exogenous DNA damage, CHK1
mediates cell-cycle arrest to allow time for DNA repair or if the damage is extensive, to trigger
apoptosis.
CHK1 is essential for homologous recombination repair (HRR) of double-strand
DNA 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).  Thus, the inhibition of CHK1
disrupts DNA replication, induces DNA damage, and subsequently prevents repair, leading 
eventually to death by replication or mitotic catastrophe due to the presence of unresolved DNA
breaks (King et al. 2015).  CHK1 inhibition also enhances the activity of DNA-damaging
cytotoxic chemotherapeutics by interfering with cell-cycle control and DNA repair (McNeely et
al. 2014). Tumors that have high levels of replication stress and/or defects in DNA damage
repair pathways such as HGSOC are hypothesized to be susceptible to the effects of a CHK1 
inhibitor (Lin et al. 2017; Murai 2017).
Prexasertib is an inhibitor of CHK1 which has been evaluated as a treatment for patients with 
advanced cancers and may have utility both as monotherapy and in combination with other 
DNA-damaging agents, targeted agents, or radiation (Zeng et al. 2017).
3.2.2. Rationale for Prexasertib in Ovarian Cancer
3.2.2.1.
Role in DNA-Damage Repair and Replication Stress
Preclinical data suggest that tumors with high endogenous levels of replication stress are more
sensitive to single-agent CHK1 inhibitors (Cole et al. 2011; Brooks et al. 2013; Lecona and
Fernández-Capetillo 2014). CCNE1 (cyclin E1) is amplified in 15-20% of HGSOCs
(Etemadmoghadam et al. 2013; Konstantinopoulos et al. 2015), and overexpression of cyclin E
induces replication stress and DNA damage that activates HRR (Jones et al. 2013).
CHK1
inhibition by prexasertib in CCNE1-amplified ovarian cancers may diminish the ability of cells
to tolerate high levels of replication stress induced by cyclin E overexpression by inhibiting
CHK1-mediated replication fork stabilization and repair of collapsed forks through HRR as well
as exacerbating replication stress by promoting late replication origin firing.
Defective DNA repair also results in increased sensitivity to single-agent CHK1 inhibitors
(Rundle et al. 2017).  Approximately half of HGSOCs harbor mutations in genes that modulate
HRR (Konstantinopoulos et al. 2015; Lord and Ashworth 2016).
Germline BRCA1 and BRCA2
mutations are present in about 15% of epithelial ovarian cancers and as many as 22.6% of
HGSOCs, and somatic BRCA1 and BRCA2 mutations have been identified in about 7% of 
high-grade serous epithelial ovarian cancers (Konstantinopoulos et al. 2015).  Furthermore,
epigenetic silencing of BRCA1 and RAD51C has been observed in 10-20% and 3% of 
HGSOCs, respectively (Konstantinopoulos et al. 2015; Lord and Ashworth 2016).
HRR 
deficiency through inactivation of RAD51 confers hypersensitivity to CHK1 inhibition 


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(Krajewska et al. 2015); therefore, defects in HRR may confer an increased sensitivity to 
double-strand DNA breaks induced by prexasertib. Alterations in other DNA damage response 
and repair pathways may similarly contribute to CHK1 inhibitor sensitivity in ovarian cancer 
(Murai 2017) and include mutations in ATM or ATR observed in 2% of HGSOCs and mutations 
in genes of the Fanconi anemia DNA repair pathway observed in 5% of HGSOCs (Lord and 
Ashworth 2016).
The potential for synthetic lethality between HRR deficiencies or other DNA repair defects and
prexasertib as well as the role of CCNE1 in increasing replication stress make CHK1 an
attractive target in this disease.
3.2.2.2.
Nonclinical Data
Broad antiproliferative effects of prexasertib monotherapy were demonstrated in various tissue 
culture studies using growth inhibition or clonogenic survival in soft agar as a phenotypic 
endpoint.  A panel of 621 genomically characterized tumor cell lines derived from multiple 
cancer types and various histologies were tested.  Prexasertib showed widespread 
antiproliferative effects; growth of 66% of these lines was inhibited at half-maximal inhibitory 
concentration (IC50) concentrations of ≤50 nM .  Further, the antiproliferative activity of 
prexasertib in the subset of 23 cell lines derived from human ovarian cancers showed IC50 values 
that ranged between 2 and 320 nM; 70% (16 of 23) of these lines had IC50 values ≤50 nM.
Studies in xenograft tumors also demonstrated prexasertib to be a potent inhibitor of tumor cell 
growth.  Studies in the orthotopically implanted intraperitoneal SKOV-3 model using a 3-days-
on/4-days-off schedule showed prexasertib monotherapy resulted in a dose-dependent inhibition 
of tumor growth.  At the end of the dosing period (Day 31), inhibition was 52.7% and 70.7% for 
groups treated with 4 and 12 mg/kg of prexasertib, respectively, compared with vehicle.  
Necropsy showed dose-dependent reductions in ascites fluid volume and number of tumor 
colonies (localized metastases) in the peritoneal cavity.  These results are concordant with 
studies of subcutaneous-implanted xenograft such as the A-2780 model, in which tumor growth 
inhibition at the end of the active dosing period was 60.3%, 63.1%, and 93% after monotherapy 
with 1, 4, and 12 mg/kg of prexasertib, respectively (McNeely et al. 2011).
3.2.2.3.
Clinical Data in Patients with High-Grade Serous Ovarian Cancer
The safety profile of prexasertib is consistent with toxicities commonly observed with standard 
of care cytotoxic agents used to treat cancer.  Hematologic toxicity is the most frequent and 
severe toxicity after treatment with 105 mg/m2 prexasertib every 14 days.  Nonhematologic 
toxicity occurs at a lower frequency than hematologic toxicity and has been predominantly 
Grade 1 or 2 in severity.  Complications from hematologic toxicities such as febrile neutropenia, 
infections, and clinically significant bleeding events have also been observed, but can be 
mitigated by supportive care approaches such as granulocyte colony stimulating factor (G-CSF)
and transfusions. Events with a fatal outcome have occurred following sepsis/infection and 
clinically significant bleeding.  Patients should be closely monitored for signs of infections, 
sepsis, and bleeding complications.  Clinical data from completed and ongoing studies across the 


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clinical program are summarized in the Investigator’s Brochure (IB).  Interim data available from 
1 study in patients with ovarian cancer are summarized below.
The National Cancer Institute (NCI; principal investigator, Jung-min Lee, MD) is sponsoring a 
Phase 2 pilot study with a primary objective of determining the overall response rate (ORR) of 
prexasertib monotherapy in patients with breast cancer, ovarian cancer, or prostate cancer 
(NCT02203513, I4D-MC-E001[E001]).  Patients receive prexasertib on Days 1 and 15 of a 
28-day cycle at the recommended Phase 2 dose (RP2D) of 105 mg/m2 (NCI 2017b).  Preliminary 
results from 32 heavily pretreated female patients with HGSOC were presented at the meeting of 
the European Society for Medical Oncology (ESMO) in October 2016 (Lee et al. 2016).  Interim 
data included 7 patients in Group 1 (with documented deleterious germline BRCA1/BRCA2
mutation [gBRCA1/2m]) and 25 patients in Group 2 (with negative family history of hereditary
breast ovarian cancer syndrome or negative gBRCA1/2m test) (Lee et al. 2016).
Grade 4 neutropenia was observed in 69% of patients and 75% of the Grade 3 and 4 neutropenia 
events resolved to Grade ≤2 within 8 days after onset; 2 patients (6%) had febrile neutropenia
and 56% received G-CSF.  Other toxicities included decreased white blood cell (WBC) count
(78%), anemia (66%), and decreased platelet count (34%).  Nonhematologic adverse events 
(AEs) included fatigue, nausea, vomiting, and diarrhea (9% each); all were generally mild (Lee 
et al. 2016).  One patient had Grade 3 diarrhea and vomiting during infusion.  Only 1 patient 
(3%) required a dose reduction (80 mg/m2) (Lee et al. 2016).
Figure JTJN.3.1 presents a plot of best responses for target lesions by patient among patients 
treated with prexasertib.  Of the 25 patients treated in Group 2, 20 were evaluable for tumor 
response.  Seven (35%) evaluable patients achieved partial response (PR) (including 2 whose 
disease was platinum-sensitive and 5 whose disease was platinum-resistant or -refractory).  The 
median duration of response was 6 months (range:  2-13 months), and 5 (25%) patients achieved 
stable disease (SD) lasting ≥4 months, for a DCR of 60%.  Patients were heavily pretreated.  
Platinum-resistant patients had a median of 4 prior lines of therapy (range: 1-13).  Of the 7 
patients treated in Group 1, 6 were evaluated for tumor response.  None of the evaluable patients 
in Group 1 achieved CR or PR, but 4 (67%) achieved SD lasting ≥4 months, for a DCR of 67%.  
As with Cohort 2, patients had received numerous prior treatments (median:  7, range: 3-12).  
These preliminary results suggest that prexasertib could be a novel approach to improve the
outcomes of patients with HGSOC (Lee et al. 2016). 


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Abbreviations:  gBRCAm = germline BRCA mutated; HGSOC = high-grade serous 
ovarian cancer. White bar = platinum-sensitive disease; black bar = platinum-resistant 
or –refractory disease.
Figure JTJN.3.1
Best response for target lesions, among patients with platinum-
sensitive, -resistant, or -refractory disease treated with prexasertib.
3.2.2.4.
Rationale for JTJN Cohorts
Patients enrolled in Study JTJN will be assigned to one of 4 cohorts:

Cohort 1: Platinum-resistant, BRCA negative, and received ≥3 lines of prior therapy

Cohort 2: Platinum-resistant, BRCA negative, and received <3 lines of prior therapy

Cohort 3: Platinum-resistant, BRCA positive, there is no restrictions on number of lines 
of prior therapy, but patients must have received prior PARP inhibitor

Cohort 4: Platinum-refractory, BRCA positive or negative, no restrictions on number of 
lines of prior therapy.
Patients with BRCA test results positive for deleterious or suspected deleterious mutations are 
referred to as BRCA positive, and patients with BRCA test results negative for deleterious or 
suspected deleterious BRCA mutations are referred to as BRCA negative.  Patients with variants 
of unknown significance should be considered BRCA negative.
As described in Section 3.2.2.3, preliminary data from Study E001 suggest clinical benefit of 
prexasertib in heavily pretreated patients (Lee et al. 2016).  To test this hypothesis, Cohort 1 and 
2 will segregate patients based on the number of prior lines of therapy.  Similarly, Study E001 
suggests potential differences in activity in patients with and without BRCA mutation.  Although 
data are limited, the cohort of patients without BRCA mutation had a higher response rate than 
those with BRCA mutation. The reason for this difference is not clear. Alternations in the HRR
pathway, such as BRCA mutations, are reported to be mutually exclusive with CCNE1
amplification (Kroeger and Drapkin 2017).  As described in Section 3.2.2.1, CCNE1
amplification may increase replication stress and result in sensitivity to a CHK1 inhibitor such as 
prexasertib.  Notably, in Study E001 all patients with BRCA mutation had been treated with a 
PARP inhibitor (Lee et al. 2016). Mechanisms of PARP inhibitor resistance that restore HRR 
may lead to diminished sensitivity to prexasertib; prior treatment with PARP inhibitors could
-80
-60
-40
-20
0
20
40
60
80
100
120
Change from baseline 
in sum of longest diameters (%)
HGSOC
gBRCAm


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confound results in BRCA mutant patients who are subsequently treated with prexasertib, as
tumors in these patients may be proficient for HRR. Note that mechanisms of resistance to 
PARP inhibitors that do not involve restoration of HRR also have been characterized (Lord and 
Ashworth 2013; Rondinelli et al. 2017), some of which would not be implicated in cross-
resistance to prexasertib.  Cohort 3 of Study JTJN was designed to better characterize effects of 
prexasertib in patients with a BRCA mutation who had a prior PARP inhibitor. Study E001 
enrolled a cohort of 7 patients with the germline BRCA mutation, of which 6 patients had 
platinum-resistant or –refractory disease (Lee et al. 2016).  Cohort 4 in Study JTJN will include 
platinum-refractory patients to determine any prexasertib benefit in these high-unmet medical 
need patients.
As described in Section 3.1, gemcitabine, paclitaxel, and PLD are common standard of care 
agents for HGSOC recurrent disease. The present study, JTJN, could prompt the initiation of a 
randomized controlled trial that may include investigator's choice of these chemotherapy options 
as the control arm. Excluding patients (Cohorts 1-3) that have received more than two of these 
agents for platinum resistant disease is consistent with the entry criteria that are likely to be
applied in future studies.
3.3.
Benefit/Risk Assessment
Given the high unmet need for additional therapies to treat platinum-resistant or –refractory 
HGSOC, the mechanistic rationale supporting a role for CHK1 inhibition to improve outcomes 
for patients with HGSOC, nonclinical model data (including HGSOC) on prexasertib 
monotherapy, prexasertib clinical safety profile, and preliminary efficacy observed in patients 
with HGSOC, the risk/benefit assessment supports evaluation of prexasertib monotherapy in the 
proposed patient population.  More information on known and expected benefits, risks, serious 
adverse events (SAEs), and reasonably anticipated AEs of prexasertib are described in the IB.


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4.
Objectives and Endpoints
Table JTJN.5 shows the objectives and endpoints of the study.
Table JTJN.5.
Objectives and Endpoints
Objectives
Endpoints
Primary
To estimate the ORR for each cohort

ORR: proportion of all enrolled patients who achieve a best overall
response of PR+CR as determined per RECIST version 1.1.
Secondary
To characterize the safety and toxicity
profile of prexasertib

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 prexasertib

Prexasertib concentrations in plasma
To estimate secondary efficacy
measures including DCR, DoR, 
CA-125 response, PFS, OS

DCR:
proportion of patients who achieve a best overall 
response of CR, PR and SD (for at least 4 months) as
determined per RECIST version 1.1.

DoR:
time from the date measurement criteria for CR or PR 
(whichever is first recorded) are first met until the first date of
documented PD, per RECIST 1.1 criteria, or the date of death
from any cause in the absence of documented PD.

CA-125 response: at least a 50% reduction in CA-125 levels from a
pretreatment sample that is at least twice the upper limit of the 
reference range and obtained within 2 weeks before starting the 
treatment, with confirmation after 4 weeks according to GCIG 
criteria.

PFS:
time from enrollment until the first radiographic
documentation (as assessed by the investigator) of
progression or death from any cause in the absence of
documented PD

OS:
time from enrollment until death from any cause
Tertiary/Exploratory
To assess the relationship between 
biomarkers, prexasertib exposure 
(PK), and clinical outcomes 

Biomarker research assessed from blood or tissue samples, unless
precluded by local regulations

Plasma concentration of prexasertib

Clinical outcomes data
To evaluate patient-reported outcomes 
using NCCN-FACT-FOSI 18 and 
Worst Pain NRS 

Change from baseline

Time to progression

Association between time to pain progression and analgesic 
consumption

Association between time to progression and select efficacy 
outcomes
Abbreviations:  AEs = adverse events; CR = complete response; DCR = disease control rate; DoR = duration of
response; ECG = electrocardiogram; GCIG =Gynecologic Cancer Intergroup; NFOSI-18 = National Comprehensive 
Cancer Network – Functional Assessment of Cancer Therapy – Ovarian Symptom Index-18; NRS = numeric 
rating 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 version 1.1 (Eisenhauer et al. 2009); SAEs = serious adverse events; SD = stable disease.


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5.
Study Design
5.1.
Overall Design
Study I4D-MC-JTJN is a multicenter, nonrandomized, parallel cohort, Phase 2 study in
approximately up to 180 patients with high-grade serous ovarian, primary peritoneal, or fallopian
tube cancer.  Patients will be assigned to the following cohorts:

Cohort 1: Platinum-resistant, BRCA negative, and received ≥3 lines of prior therapy

Cohort 2: Platinum-resistant, BRCA negative, and received <3 lines of prior therapy

Cohort 3: Platinum-resistant, BRCA positive, there is no restriction on number of lines of 
prior therapy, but must have received prior PARP inhibitor

Cohort 4: Platinum-refractory, BRCA positive or negative, no restrictions on number of 
lines of prior therapy
Interim analyses will occur at specified intervals. Based on protocol-defined rules, enrollment to
a cohort can stop due to lack of efficacy or continue at each interim analysis until the total
sample size is reached. See Section 10.3.4 for further details regarding interim analyses.
5.2.
Number of Patients
The maximum total sample size of this study is estimated to be approximately 180 patients. For 
each of the 4 cohorts, the minimum sample size is approximately 20 patients.  The sample size 
for each cohort will be dependent on the outcomes of the interim analyses. As cohorts are 
halted, new eligible patients will be allocated to the enrolling cohorts. As a result, the maximum 
sample size of a single cohort is approximately 120 patients (e.g., if enrollment to all but one of 
the cohorts is stopped after the first interim analysis).
5.3.
End of Study Definition
Study completion occurs after the clinical trial database is locked and final analysis of primary 
and secondary endpoints have been performed. End of the trial is the date of the last visit or last 
scheduled procedure shown in the Schedule of Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
An open-label, parallel cohort, nonrandomized Phase 2 study without concurrent controls is 
appropriate for patients with high-grade serous ovarian, primary peritoneal, or fallopian tube 
cancer. There is not a clear world-wide standard of care for HGSOC patients with 
platinum-resistant or platinum-refractory disease.  Given the high unmet medical need, this 
nonrandomized design will enable all participants to receive study drug. The details of the study 
design are described in Section 5, and details of the sample size determination are provided in 
Section 10.1.
5.5.
Justification for Dose
Based on the nonclinical prexasertib pharmacokinetic (PK)/pharmacodynamic model (inhibition 
of phosphorylated CHK1 and tumor growth response in Calu-6 xenografts) used to predict the 


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human efficacious exposure range, the population based PK analysis from the first-in-human 
dosing (FHD) study JTJA demonstrating that a body surface area (BSA)-based dose regimen is 
justified for prexasertib administration, the similar systemic exposure and similar safety profile 
between schedules of administration, as well as the increased patient convenience, 105 mg/m2 of 
prexasertib on Day 1 of a 14-day schedule was selected as the RP2D.
The population PK predicted (from 1000 simulated individual PK profiles) median AUC(0-72)
(2034 ng•hr/ml) following administration of 105 mg/m2 every 14 days is greater than the median 
AUC(0-72) (1896 ng•hr/mL) predicted from a Calu-6 xenograft model before clinical 
investigation to achieve the maximal tumor response with prexasertib monotherapy. In addition, 
the average prexasertib plasma concentrations over the first 72 hours (Cav,72) predicted from the 
population PK model from Study JTJA after 105 g/m2 (approximately 28 ng/mL) is greater than 
the IC50 (14.1 ng/mL) determined from the single-agent nonclinical Calu-6 xenograft 
PK/pharmacodynamic model, also demonstrating that the prexasertib systemic exposure at the 
R2PD is in a potentially efficacious range.  Additional details are described in Sections 5.2.3 and
6 of the IB.


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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]
Women who have histologically or cytologically verified high-grade serous ovarian,
primary peritoneal or fallopian tube cancer.
[2]
Cohorts 1 to 3:  Have platinum-resistant disease, which is defined as disease
progression within 6 months of last dose of platinum-based chemotherapy.  
Progression due to rising CA125 only is not considered as platinum-resistant disease.
Cohort 4: Have primary platinum-refractory disease defined as disease progression
during or within 4 weeks after the last dose of initial line of platinum-based
chemotherapy.
Note:  disease progression may be either radiographic progression or documented 
clinical progression.  Residual disease is not considered progression.
[3]
Cohort 1:  Are BRCA negative and have received 3 or more prior lines of therapy for 
high-grade serous ovarian, primary peritoneal, or fallopian tube cancer (including 
immunotherapy, targeted therapies, or chemotherapy (systemic or intraperitoneal).
Cohort 2:  Are BRCA negative and have received less than 3 prior lines of therapy for 
high-grade serous ovarian, primary peritoneal, or fallopian tube cancer (including 
immunotherapy, targeted therapies, or chemotherapy (systemic or intraperitoneal).
Note for Cohorts 1 and 2:  Each line of therapy is preceded by evidence of clinical or 
radiographic disease progression (initial therapy is considered the first line).  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.  Hormonal therapy is not considered a 
line of therapy.  All adjuvant therapy should be considered as a line of therapy. 
Cohort 3:  Are BRCA positive and have previously received a PARP inhibitor at any 
time following diagnosis. Note: there is no restriction on number of lines of prior 
therapy.
Cohort 4: Are BRCA positive or negative; no restriction on number of lines of prior
therapy. 
[4]
Have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) scale (Oken et al. 1982).
[5]
Have discontinued all previous treatments for cancer and recovered from acute 
effects of therapy.  Patients must be discontinued from previous treatments, as per
below:


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Previous Treatment
Length of Time Prior to First Dose of
Prexasertib
Cytotoxic therapies or targeted agents that are 
small molecule inhibitors
21 days or 5 half-lives, whichever is shorter
Biologic agents that are large molecules including
immunotherapy
28 days
Investigational agents
28 days.  If the agent has a long half-life (e.g. 
>2 weeks), then 3 months or 5 half-lives 
(whichever is longer) should have passed
Radiotherapy
Limited-field radiotherapywith palliative intent
14 days
Other radiotherapy
28 days
Major surgery, excluding biopsy
28 days
[6]
Have at least 1 measurable lesion using standard techniques by Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer et al. 2009).
[7]
Have given written informed consent prior to any study-specific procedures and agree 
and are able to follow the requirements of the protocol.
[8]
Are of an acceptable age to provide informed consent according to the local
regulations and are at least 18 years of age.
[9]
Have adequate organ function, as defined below.  These values must be met during 
the baseline visit (prior to biopsy) as well as predose Cycle 1 Day 1:
System
Laboratory Value
Hematologic
ANC
1.5×109/L
Platelets
100×109/L
Hemoglobin
9 g/dL
Note:  transfusions to increase a patient’s hemoglobin level or initiation of erythropoietin or G-CSF 
therapy to meet enrollment criteria are not allowed in the 14 days preceding the first dose of study drug.
If a patient receives transfusions, erythropoietin, or G-CSF therapy ≥14 days prior to the first dose, the 
hematologic criteria listed above must be met following the 14 day window and prior to the first dose 
of study therapy.
Hepatic
Direct bilirubin
1.5×ULN
ALT and AST
3×ULN OR
5×ULN if the liver has tumor involvement
Renal
Serum creatinine OR
Measured creatinine clearance OR
Calculated creatinine clearance
<1.5×ULN OR
40 mL/min/1.73 m2
Albumin
Albumin
>30 g/L OR
25-30 g/L and the value does not decrease across 
2 readings separated by ≥14 days (without an 
intravenous albumin infusion)


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Abbreviations:
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate
aminotransferase; G-CSF = granulocyte colony stimulating factor; ULN = upper limit of normal.
[10] Women of child-bearing potential participating must agree to use one highly effective 
(less than 1% failure rate) method of contraception or use a combination of two 
effective methods of contraception during treatment with study drug and for at least
12 weeks following the last dose of study drug.
Note:  Unless not allowed by local regulations, women of child-bearing potential who 
are abstinent (if this is complete abstinence, as their preferred and usual lifestyle) or 
in a same sex relationship (as part of their preferred and usual lifestyle) must agree to 
either remain abstinent or stay in a same sex relationship without sexual relationships 
with males. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence just for the duration of a trial, and 
withdrawal are not acceptable methods of contraception.
[11] Women of child-bearing potential participating must test negative for pregnancy prior 
to initiation of treatment as indicated by a negative pregnancy test at the screening 
visit (prior to biopsy) and within 24 hours prior of drug exposure.
[12] Cohorts 1-3:  Have documented test results assessing alterations in the BRCA1 and
BRCA2 genes by a local laboratory prior to receiving study treatment. Results from 
either a blood or tissue based test are acceptable.
[13] Must be able and willing to undergo mandatory tumor biopsy which will be collected
following determination of eligibility and before treatment (≤28 days before C1D1).  
Note that the biopsy may be collected prior to the predose Cycle 1 Day 1 pregnancy 
test and labs. Tumor tissue obtained from a prior biopsy may be permitted for the
pretreatment sample after discussion and agreement between Lilly clinical research 
physician (CRP) / clinical research scientist (CRS) and investigator if a patient has
not received any therapies for the disease between the time biopsy was obtained to 
start of prexasertib treatment.  The decision to use a tumor tissue sample from a prior 
biopsy will be documented in writing.
6.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[14] Cohorts 1-3: Have previously received all of the following agents at any time in the 
platinum-resistant setting: gemcitabine, PEGylated liposomal doxorubicin, and 
paclitaxel.  It is acceptable to have received 1 or 2 of these agents for platinum-
resistant disease.
[15] Have non-epithelial or mixed epithelial/non-epithelial tumors (including malignant 
mixed Müllerian tumors), ovarian tumors with low malignant potential (borderline 
tumors), endometrioid, clear cell, mucinous or low-grade serous carcinomas or not 
otherwise specified (NOS) ovarian tumors.


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[16] Have known central nervous system (CNS) malignancy or metastasis.  Patients with 
treated brain metastases that have been CNS recurrence-free for 1 year prior to study 
treatment may be considered if approved by the Lilly CRP/CRS.
[17] Have prior malignancies unless approved by the Lilly CRP/CRS.  For instance, 
patients with carcinoma in situ of any origin and patients with prior malignancies 
who are in remission and whose likelihood of recurrence is very low, as judged by the 
Lilly CRP/CRS, may be eligible for this study.
[18] Are currently enrolled in a clinical study involving an investigational product or any 
other type of medical research judged not to be scientifically or medically compatible 
with this study.
[19] Have previously completed or withdrawn from this study or any other study 
investigating prexasertib or a CHK1 inhibitor or have shown hypersensitivity to the 
study drug or excipients.
[20] Have a known serious medical condition (e.g., active infection, increased risk of 
bleeding events) that, in the opinion of the investigator, would compromise the 
patient’s ability to adhere to the protocol or tolerate the study treatment.
[21] Have at least one of the following:

history of abdominal fistula or gastrointestinal (GI) perforation

intra-abdominal abscess within last 3 months prior to the first dose of study drug

a radiographically confirmed bowel obstruction (including sub-occlusive disease)
within 3 months prior to the first dose of study drug.
[22] Have a symptomatic human immunodeficiency virus (HIV) infection or symptomatic 
activated/reactivated hepatitis A, B, or C (screening is not required).
[23] Have a serious cardiac condition, such as:

symptomatic congestive heart failure or any uncontrolled cardiac disease

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

have a QT interval using Fridericia’s correction (QTcF) of >480 msec on more 
than one electrocardiogram (ECG) obtained during the baseline (screening) period

family history of long-QT syndrome.
[24] Have a history of prior radiotherapy to the whole pelvis.
[25] Have chronic daily treatment with corticosteroids (dose >10 mg/day methyl-
prednisolone equivalent), excluding inhaled and topical steroids.
[26] Have known factors that may increase the risk of infection while on study drug 
treatment.  These may include, but are not limited to, an indwelling peritoneal 
catheter or open wounds.  Catheters for vascular access are permitted.


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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 
rescreened.  Individuals may be rescreened a maximum of 2 times.  The interval between 
rescreenings should be ≥2 weeks.  Each time rescreening 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 screening period or repeating screening tests to comply with the 
protocol-designated screening period does not constitute rescreening.


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7.
Treatments
7.1.
Treatments Administered
Patients in all cohorts will receive 105 mg/m2 prexasertib as an approximately 60 (+10) minute 
intravenous (IV) infusion on Day 1 and 15 of a 28-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 prexasertib 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, prexasertib (LY2606368) for injection, is supplied for clinical trial use as a 
lyophilized, yellow to white powder, in glass vials and is composed of prexasertib lactate 
monohydrate and the inactive ingredients trehalose, polysorbate 80 and mannitol.  Clinical trial 
materials will be labeled according to the country’s regulatory requirements.
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 a cohort based on BRCA status, 
platinum resistant vs refractory, and/or lines of prior therapy.  The IWRS will be used to 
dispense study drug to and/or track the allocation of each patient.
7.2.1. Selection and Timing of Doses
A cycle is defined as an interval of 28 days.
The actual doses of study treatment to be administered will be determined by calculating the 
patient’s BSA at the beginning of each cycle.  Although it is acceptable to recalculate more 
frequently, if the patient’s weight does not fluctuate by more than 10% from the weight used to 
calculate the prior cycle or from baseline, 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 study treatment until she meets 1 or more of the specified 
reasons for discontinuation.
7.3.
Blinding
This is an open-label study.


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7.4.
Dose Modification
The following rules should guide dosing:

Before each dose:

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, pain, alopecia, fatigue, nausea, vomiting, or diarrhea)

Neutropenia and anemia must resolve to Grade ≤2, and thrombocytopenia to Grade ≤1, as 
shown in Table JTJN.6.
Table JTJN.6.
Hematologic Parameters Required Prior to Each Dose
Dose
Neutrophils
≥1000/mm3
Platelets
≥75/mm3
Hemoglobin
≥8 g/dL

A delay of a dose 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.

Initiation of a dose may be delayed for a maximum of 14 days (28 days from prior dose) 
to allow a patient sufficient time for recovery from study treatment related toxicity (for 
example, a delay of 14 days from the planned Day 1 of the cycle).  Note that if the 
Day 15 dose cannot be administered within 7 days of the planned Day 15 (e.g. 21 days 
from the prior dose (by Day 22), it should be omitted and the next dose administered 
28 days of the prior dose as the start of a new cycle. In addition, if there is a persistent 
downward trend in the predose neutrophil/platelet counts a treatment delay may be 
considered.

In exceptional circumstances, a longer delay is permitted upon agreement between the 
investigator and the Lilly CRP/CRS. Dosing delay of study drugs due to non-study drug 
related AEs may be permissible if deemed clinically necessary by the investigator and 
following discussion between the investigator and the CRP/CRS.  The interval between 
prexasertib doses must not be less than 14 days.  If a dose is delayed (for toxicity or other 
circumstances), the next dose should be adjusted so that there is a ≥14-day interval.
If needed, the cycle length should be extended to accommodate the delay. 

Dose adjustments and delays on either Day 1 or 15 will be made based on the clinical 
assessment of hematologic and nonhematologic AEs as shown in Table JTJN.7.  In addition, 
the dose can also be delayed or adjusted at the investigator’s discretion as clinically 
indicated. 


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Table JTJN.7.
Dose Adjustments and Delays
Toxicity
CTCAE
Grade
Action
Dose Adjustments and 
Considerations
Neutropenia 
Grade 3 or 
Grade 4
Delay treatment until ≤Grade 2 (≥1000/mm3)
Recommend prophylactic 
G-CSFa
Thrombocytopenia
Grades 2, 
3 or Grade 
4 
Delay treatment until ≤Grade 1 (≥75/mm3)
Investigator discretion
Anemia
Grade 3 or 
Grade 4 
Consider RBC transfusion or EPO (if consistent 
with institutional guidelines).  Delay treatment 
until ≤Grade 2 (≥8 g/dL)
Investigator discretion
Febrile neutropenia
(without 
prophylactic 
G-CSF)
Any 
Grade
Delay treatment until afebrile and neutrophils
≤Grade 2 (≥1000/mm3)
Investigator discretion  
Recommend prophylactic
G-CSFa
Febrile neutropenia
(with 
prophylactic 
G-CSF)
Any 
Grade
Delay treatment until afebrile and neutrophils
≤Grade 2 (≥1000/mm3)
Reduce to next lower dose 
level unless there is 
documented agreement 
between investigator and 
CRP/CRS.
Allergic/
hypersensitivity 
reactionb
Grade 1 or 
Grade 2 
Administer treatment per institutional guidelines
for allergic/hypersensitivity reactions. Monitor 
closely for any worsening symptoms.  A reduced 
infusion rate can be used for subsequent 
infusions.
Investigator discretion
≥Grade 3
Stop infusion immediately and disconnect infusion tubing from the patient.  
Administer treatment per institutional guidelines.  Patient must not receive any 
further treatment with prexasertib.
Other 
nonhematologic 
toxicityc
Grade 2 
Delay treatment until ≤Grade 1 or baselined
Investigator discretion
Grade 3 or 
Grade 4
Delay treatment until ≤Grade 1 or baseline
Reduce to next lower dose 
level
Abbreviations:  CRP = clinical research physician; CRS = clinical research scientist; CTCAE = Common 
Terminology Criteria for Adverse Events version 4.0; G-CSF = granulocyte colony stimulating factor; 
RBC = red blood cells
a
Refer to Section 7.7.
b
Please refer to the IB for the most recent guidance on allergic/hypersensitivity reactions
c
Except alopecia, fatigue, or toxicities that can be controlled with adequate treatment such as nausea, vomiting, 
diarrhea, or asymptomatic electrolyte disturbances.
d
Baseline is considered prior to dosing on Cycle 1 Day 1.
If a patient requires a dose reduction, prexasertib should be reduced as shown in Table JTJN.8. 
After a dose reduction, re-escalation is acceptable.


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Table JTJN.8.
Prexasertib Dose Reductions
Reduction
Dose
1st prexasertib dose reduction
80 mg/m2
2nd prexasertib dose reduction
60 mg/m2
3rd prexasertib dose reduction
Discontinue from prexasertib
7.5.
Preparation/Handling/Storage/Accountability
All prexasertib should be refrigerated.
Prexasertib will be administered as an IV infusion using a central or peripheral IV line and will 
be filtered through an in-line filter. Prexasertib should be handled according to standard 
procedures and precautions consistent with a cytotoxic anticancer drug.
The dosage strength of 67-mg prexasertib lactate monohydrate drug product will be used in 
Study JTJN.  The vial will contain a slight excess to facilitate the withdrawal of the labeled
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 
3.3 mg/mL of prexasertib.
For the most current detailed formulation information and preparation instructions, refer to the 
IB and Pharmacy Binder.
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
Except as noted, no other chemotherapy, immunotherapy, cancer-related hormone therapy, 
herbal drugs, or experimental drugs will be permitted while the patients are on study treatment.  
Patients on stable doses of bisphosphonates or RANK-L targeted agents (for example, 
denosumab) are allowed to continue. These agents should not be initiated within the 2 weeks 
prior to study enrollment or at any point while on the study. Replacement hormonal therapy or 
tamoxifen or aromatase inhibitors initiated before study entry will be allowed.
Radiotherapy (including palliative radiotherapy) will only be permitted if it is agreed upon by 
both the investigator and the Lilly CRP/CRS.  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 prexasertib may be required if radiotherapy is administered.
In addition, any disease progression requiring other forms of specific antitumor therapy will 
necessitate discontinuation from study treatment.
Patients should receive full supportive care during the trial.  Guidelines from ASCO (Smith et al. 
2015) should be followed for patients requiring support with G-CSF.  Primary or secondary 


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prophylactic G-CSF support is permitted at the discretion of the investigator.  Primary 
prophylaxis with G-CSF starting in the first cycle and continuing through subsequent cycles of 
chemotherapy is recommended in patients who have an approximately 20% or higher risk for 
febrile neutropenia on the basis of patient-, disease-, and treatment-related factors.  As outlined 
in the ASCO guidelines, the following factors may be relevant to the JTJN patient population 
and should be considered when estimating the patient’s overall risk of febrile neutropenia:  Age 
≥65, advanced disease, previous chemotherapy or radiation therapy, poor nutritional status, 
cardiovascular disease, or multiple comorbid conditions.  It is recommended that prophylactic 
short-acting G-CSF be initiated within 24-72 hours of study drug administration and continued 
through post-nadir recovery (Crawford et al. 2010).  It is recommended that long-acting G-CSFs, 
such as pegfilgrastim, be administered the day after treatment (Crawford et al. 2017).  Per NCCN 
guidelines, Phase 2 data support the use of pegfilgrastim in regimens with a 2-week cycle, with
uniform consensus that this is appropriate (Category 2A) (Crawford et al. 2017).  .
Prophylactic antibiotics may be considered for use in patients who 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).
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. Patients who are stable on 
erythropoietin for >1 month before study entry may continue their treatment.
On days when prexasertib is administered, patients should avoid taking multiple (>1) 
concomitant medications that are known or suspected to cause prolonged QTc or Torsades de 
Pointes and, if possible, alternative agents should be considered. In addition, at the start of the 
study and on days when prexasertib is administered, care should be taken to ensure that serum 
electrolyte levels are within the normal range.
Strong P-gp and BRCP inhibitors (e.g., amiodarone, carvedilol, clarithromycin, dronedarone, 
itraconazole, propafenone, quinidine, ranolazine, verapamil, cyclosporine A, or eltrombopag)
should be used with caution, as prexasertib is a substrate of both P-gp and BCRP. 
7.8.
Treatment after the End of the Study
Patients who are still on prexasertib at the time of study completion may continue to receive 
prexasertib if they are experiencing clinical benefit and no undue risks.  The continued access 
period will apply to this study only if ≥1 patient is still on prexasertib when study completion 
occurs.  Lilly will notify investigators when the continued access period begins.  Lilly may allow 
patients to enroll in a “rollover” protocol to provide long-term continued access for patients 
enrolled in this study.
The continued access period will begin after study completion and ends at End of Trial 
(Figure JTJN.7.1). The patient’s continued access to prexasertib 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 prexasertib and lasts approximately 30 (±7) 


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days.  Follow-up procedures will be performed as shown in the Continued Access Schedule of 
Activities Table JTJN.3.
Figure JTJN.7.1.
Continued access diagram.
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 following circumstances:

the patient is enrolled in any other clinical study involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study

the patient becomes pregnant during the study

the patient is significantly noncompliant with study procedures and/or treatment

disease progression

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 prexasertib will occur prior to introduction of the new agent

the investigator decides that the patient should be discontinued from prexasertib

the patient requests to be discontinued from prexasertib

the patient’s designee (legal representative) requests that the patient be 
discontinued from prexasertib.
Patients who are discontinued from prexasertib 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/CRS 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/CRS to allow 
the inadvertently enrolled patient to continue in the study. Patients who are discontinued from 
prexasertib will have follow-up procedures performed as shown in the Schedule of Activities 
(Section 2).
8.2.
Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:

the investigator or Lilly, for any reason, but considering the rights, safety and well-being 
of the patient(s) and in accordance with International Council for Harmonization
(ICH)/Good Clinical Practice (GCP) Guidelines and local regulations, stops the study or 
stops the patient’s participation in the study.

the patient becomes pregnant during the study.  See Section 9.2.1 regarding 
regulatory reporting requirements on fetal outcome.


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
the investigator decides that the patient should be discontinued from the study:

the patient requests to be discontinued from the study:

the patient’s designee (legal representative) requests that the patient be 
discontinued from the study. 
The study will be discontinued if Lilly judges it is necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.  Prior to discontinuation, 
the Ethical Review Board (ERB) (which approved the trial) will be notified according to local 
regulation.
Patients who are discontinued from the study will have follow-up 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.
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, including enrolled patients who do not receive
prexasertib, 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 2 provides a list of the laboratory tests that will be performed for this study.
Appendix 4 provides the schedule for collection of PK 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, including tumor markers, 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 site can document that the CT is of identical diagnostic quality to a 
diagnostic CT (with intravenous and oral contrast). A PET scan alone or as part of a PET-CT 
may be performed for additional analyses but cannot be used to assess response according to 
RECIST 1.1 (Eisenhauer et al. 2009).
The method of tumor assessment used at baseline must be used consistently throughout the 
study.  Radiologic scan of the thorax, abdomen, and pelvis is required. As an independent review 
of all or a subset of radiographic imaging scans may be conducted, copies of scans will be 
collected throughout the study and stored by a coordinating vendor designated by Lilly.
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 is consistent with those used in 
most conventional oncology studies.
9.2.
Adverse Events
The investigator should provide adverse event (AE) verbatim terms and then the terms will be 
mapped by Lilly or its designee to corresponding terminology within the Medical Dictionary for 
Regulatory Activities (MedDRA) Lower Level term (LLT) dictionary. The investigator will use 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 to assign AE 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 prexasertib 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 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 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 study treatment via CRF/electronic data entry.
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.
Adverse event grading of toxicities related to estimated glomerular filtration rate (GFR) should 
be evaluated based on the Cockcroft-Gault method or measured GFR (Appendix 6).
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, 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

important medical events that may not be immediately life-threatening or result in 
death or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above.
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to Lilly begins after the patient has signed the ICF and has received prexasertib.  
However, if an SAE occurs after signing the ICF, but prior to receiving prexasertib, it needs to be 
reported ONLY if it is considered reasonably possibly related to study procedures.
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 exposure to prexasertib) 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 SAEs.
Serious adverse events, including death, caused by disease progression should not be reported 
unless the investigator deems them to be possibly related to prexasertib.
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 Regulation (EU) No 536/2014 and the associated detailed 
guidances or national regulatory requirements in participating countries require the reporting of 
SUSARs.  Lilly has procedures that will be followed for the recording and expedited reporting of 
SUSARs that are consistent with global 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, to monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Refer to the IB for current guidance on overdose.
9.4.
Safety
9.4.1. Safety Measures and Monitoring
For each patient, ECGs, vital signs, laboratory tests, and other tests should be collected as shown 
in the Schedule of Activities (Section 2).
Results from any clinical laboratory test analyzed by a central laboratory (refer to Appendix 2)
will be provided to investigative sites by Lilly or its designee.
Refer to Section 9.2 for details on the recording of AEs.
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.1.1.
Special Hepatic Safety Data Collection and Monitoring Criteria
Hepatic data should be collected on the appropriate CRF forms in the event that ≥1 of the 
following condition(s) are met for the patient during the course of the study:

elevation of serum alanine aminotransferase (ALT) ≥10×upper limit of normal (ULN)

without liver tumors or metastasis: ALT ≥5×ULN and total bilirubin ≥2×ULN

with liver tumors or metastasis: ALT ≥8×ULN and total bilirubin ≥2×ULN

discontinuation from study treatment due to hepatic event or liver test abnormality

occurrence of a hepatic event considered to be an SAE.
Close hepatic monitoring as outlined below should be initiated if the following conditions are
met by a patient: 

elevated ALT 5×ULN and elevated total bilirubin 2×ULN or ALT 8×ULN 

for patients entering the study with ALT >3×ULN, monitoring should be triggered at 
ALT >2×baseline and elevated total bilirubin 2×ULN.
Liver tests (Appendix 5), including ALT, aspartate aminotransferase (AST), total bilirubin, direct 
bilirubin, gamma-glutamyl transferase (GGT), and creatine phosphokinase (CPK), should be 
repeated within 3 to 5 days to confirm the abnormality and to determine if it is increasing or 
decreasing.  If the abnormality persists or worsens, clinical and laboratory monitoring should be 
initiated by the investigator, based on the hepatic monitoring tests (Appendix 5) and in 


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consultation with the Lilly CRS/CRP.  Monitoring of ALT, AST, and total bilirubin should 
continue until levels normalize or return to approximate baseline levels.
9.5.
Pharmacokinetics
The PK samples will be collected as specified in the PK Sampling Schedule (Appendix 4). 
Sparse PK samples for prexasertib will be collected over multiple cycles of therapy to determine 
the plasma concentrations of prexasertib.  The data from this study will be pooled with other PK 
data in a planned population based PK meta-analysis.
At the visits and times specified in the Study Schedule, venous blood samples will be collected 
to determine the plasma concentrations of prexasertib. 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 prexasertib 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
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 may be used to investigate variable response to prexasertib and to 
investigate genetic variants thought to play a role in high-grade serous ovarian, primary 
peritoneal, or fallopian tube cancer.  Assessment of variable response may include evaluation of 
AEs or differences in efficacy.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the study site personnel.  Samples will be retained at a 
facility selected by Lilly for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ERBs/IRBs impose shorter time limits.  This 
retention period enables use of new technologies, response to questions from regulatory 
agencies, and investigation of variable response that may not be observed until later in the 
development of prexasertib or after prexasertib 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 


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sequencing, genome-wide association studies, multiplex assays, and candidate gene studies.  
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 deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), proteins, lipids, and other cellular elements.  This study may analyze 
biomarkers relevant to prexasertib, the mechanism of action of prexasertib, the variable response 
to study drugs, immune function, tumor microenvironment, replication stress, angiogenesis, and 
pathways associated with high-grade serous ovarian, primary peritoneal, or fallopian tube cancer.  
These samples may also be used to develop related research methods or to validate diagnostic 
tools or assays.
The collection of a pretreatment tumor biopsy is required in Study JTJN for exploratory 
correlative biomarker research because archival tumor tissue obtained from biopsies collected 
years earlier might not accurately reflect the molecular alterations that may have occurred during 
the evolution of the disease (Olson et al. 2011). Both archived tissue and a pretreatment biopsy 
are collected in Study JTJN so that changes in potential markers that may be related to sensitivity 
to prexasertib can be assessed.
Testing to assess BRCA status will be completed at the Study JTJN central laboratory on newly 
obtained pretreatment biopsies or archival tissues accepted in place of newly obtained 
pretreatment biopsies (See Section 9.8.1).  This testing is in addition to the local laboratory 
BRCA testing used to meet eligibility and for cohort assignment.
It is possible that biomarker data for patients in the study have already been generated from 
samples that were collected and analyzed prior to enrolling in this study.  This may include data 
generated from genetic analyses.  If available, these data may be requested from medical records
for use in the research described in Sections 9.7, 9.8.1, and 9.8.2.  The report containing the 
BRCA results from the local laboratory will be sent to the Study JTJN central laboratory.
9.8.1. Tissue Samples for Biomarker Research
Tissue samples for biomarker research will be collected for the purposes described in 
Section 9.8.  The following samples for biomarker research will be collected according to the 
sampling schedule in Section 2, where local regulations allow.
Collection of the following tumor tissue samples is required for all patients to participate in 
this study:

a newly obtained biopsy specimen collected following determination of eligibility and 
before treatment (≤28 days before C1D1) (see Section 6.1, Inclusion Criterion [13]).


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Note: a tumor tissue sample obtained from a prior biopsy may be permitted for the 
pretreatment sample after discussion and agreement between Lilly CRP / CRS and 
investigator if a patient has not received any therapies for the disease between the time 
biopsy was obtained to start of prexasertib treatment.  This will be permitted only if a 
formalin-fixed paraffin-embedded (FFPE) tissue block is available (slides are not 
acceptable).

an archived tumor sample collected at any time prior to discontinuation of last therapy for 
the disease, if available and not restricted by local regulations.  Archived samples should 
be sent within 2 weeks of C1D1.  It will not be considered a protocol deviation if this 
timeframe is not met, unless there are multiple occurrences at a single site.
Collection of the following tumor tissue sample(s) is optional for all patients participating in this 
study:

additional optional biopsy samples may be requested at additional study time points, if 
warranted and agreed upon by the investigator and Lilly.  If these additional samples are 
requested, they will be used to further investigate biomarkers that may help further 
characterize treatment response and resistance mechanisms, particularly in patients that 
have experienced clinical benefit from prexasertib.
The sponsor has a right to retain a portion of the submitted tissue, and archival blocks will be 
returned to the study site.  Slides and tissue samples collected on study will not be returned.
Tumor tissue samples should be obtained using an excisional or core needle (minimum 
18 gauge) biopsy.  Cytological samples and fine-needle aspiration specimens are not acceptable.
Archival FFPE 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.  The pathology report
accompanying tissue may also be requested. The pathology report must be coded with the 
patient number. Personal identifiers, including the patient’s name and initials, must be removed
from the institutional pathology report prior to submission.
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last patient visit of the study, or for a shorter period if local regulations and/or 
ERBs/IRBs impose shorter time limits.  This retention period enables the use of new
technologies, response to questions from regulatory agencies, and investigation of variable 
response that may not be observed until later in the development of prexasertib or after 
prexasertib becomes commercially available.
Technologies are expected to improve during the 15-year storage period and, therefore, cannot 
be specifically named.  Existing approaches, including mutation profiling, copy number 
variability analysis, gene expression assays, multiplex assays, and/or immunohistochemistry may 
be performed on these tissue samples to assess potential associations between these biomarkers 
and clinical outcomes.


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9.8.2. Other Samples for Biomarker Research
The following samples for biomarker research will be collected according to the sampling 
schedule in Section 2, where local regulations allow:

whole blood 

plasma.
A maximum of 5 samples may be collected at additional study time points, if warranted and 
agreed upon by the investigator and Lilly.  All samples will be coded with the patient number.  
These samples and any data generated can be linked back to the patient only by the study site 
personnel.  Samples will be retained at a facility selected by Lilly or its designee for a maximum 
of 15 years after the last patient visit for the study, or for a shorter period if local regulations 
and/or ERBs/IRBs impose shorter time limits.  This retention period enables use of new 
technologies, response to questions from regulatory agencies, and investigation of variable 
response that may not be observed until later in the development of prexasertib or after
prexasertib becomes commercially available.  Technologies are expected to improve during the 
15-year storage period and, therefore, cannot be specifically named.  Existing approaches, 
including mutation profiling, copy number variability analysis, gene expression assays, and/or 
multiplex assays may be performed on these tissue samples to assess potential associations 
between these biomarkers and clinical outcomes.
9.9.
Health Economics
Health care resource use information related to the frequency of hospitalizations, emergency 
department (ED) visits, and small bowel obstruction (SBO) will be collected to support the 
safety assessment of prexasertib.  Similarly, information on the following concomitant 
medications will also be collected:  granulocyte or macrophage colony stimulating factor 
(G[M]-CSF), erythropoiesis stimulating agents (ESAs), transfusions (platelets and RBCs), 
antibiotics, antifungals, and analgesics (over-the-counter [OTC] and prescription).
9.10. Health Outcome Measures
Palliation and symptom control are central to the treatment of most patients with advanced 
ovarian cancer, given the limited opportunity for cure.  The patient-reported outcome (PRO) 
assessments in this study will focus on two fundamental concepts: ovarian cancer-related 
symptoms and worst pain.  These 2 focused dimensions are among the highest priority to 
advanced ovarian cancer patients, based on direct input from patients as well as gynecologic 
oncology specialists (Jensen et al. 2011 and Cella et al. 2003).
The impact of prexasertib on ovarian-cancer related symptoms will be measured via the National 
Comprehensive Cancer Network – Functional Assessment of Cancer Therapy – Ovarian 
Symptom Index-18 (NFOSI-18) (Table JTJN.9). This instrument consists of 18 questions that 
comprise 3 domains: disease-related symptoms, treatment-related side effects, and functional 
well-being. It is a 5-level, Likert scale with the following response options: “not at all,” “a little 
bit,” “somewhat,” “quite a bit,” or “very much.” The recall period is 7 days. It was developed 


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based on input from patients with advanced ovarian cancer and gynecologic oncology experts in 
an effort to prioritize the most relevant symptoms experienced by patients (Jensen et al. 2011).
The impact of prexasertib on worst pain will be evaluated via the Worst Pain Numeric Rating 
Scale (NRS) (Table JTJN.9). The Worst Pain NRS was developed after similar principles seen 
within Effect of Cancer on Quality of Life (Cleeland 1991).  The Worst Pain NRS is a single-
item, subject-administered, 11-point horizontal scale anchored at 0 and 10, with 0 representing 
“no pain” and 10 representing “pain as bad as you can imagine.” 
Table JTJN.9.
Instruments Used to Assess Patient-Reported Outcomes
Concept(s) of Interest
Instrument
Number of questions
Ovarian cancer-related symptoms
NCCN-FACT-FOSI-18
18
Worst pain
Worst Pain NRS
1
Abbreviations: NRS = numeric rating scale; NFOSI-18 = National Comprehensive Cancer Network–Functional 
Assessment of Cancer Therapy-Ovarian Symptom Index-18.
Both instruments will be administered electronically via a handheld device. Only patients fluent 
in an available translation will complete the questionnaires. If a translation is not available, the 
patient is still permitted to enter the study; however, this scenario must first be communicated to 
the study team.  
Data on OTC and prescription analgesic medications including dose, unit, frequency, and route 
of administration will be collected by site personnel at baseline and at every infusion day; it will 
be analyzed in conjunction with patient-reported data from the Worst Pain NRS.  Any changes 
compared to the prior infusion will be recorded.  Pain medication will be classified into 
medication categories, using the analgesic quantification algorithm (Chung et al. 2014). 


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10. Statistical Considerations
10.1. Sample Size Determination
The study employs a Bayesian adaptive design that may close enrollment in specific cohorts 
early based on the interim analysis results during the course of the trial. The study will initially 
enroll approximately 20 patients to each cohort and then a Bayesian model will be used to 
evaluate the posterior probability of activity for each cohort. A cohort will be closed if the 
posterior probability of activity is <20%. Subsequent interim analyses will be done to further 
evaluate the posterior probability of activity after additional patients are enrolled to each cohort. 
The study will enroll up to approximately 180 patients in total. The sample size for each cohort 
will be dependent on the outcomes of the interim analyses.  As cohorts are halted, new eligible 
patients will be allocated to the enrolling cohorts. As a result, the maximum sample size of a 
single cohort is approximately 120 patients (e.g., if enrollment to all but one of the cohorts is 
stopped after the first interim analysis).  The posterior credible intervals of ORR when the 
observed ORR is in the range of 0-35% are summarized in Table JTJN.10. For illustrative 
purpose, the study drug will be considered active if ORR>25% and the uniform prior beta (1,1) is 
assumed in the Bayesian model.  With the minimum sample size of N=20, the posterior 
probability of ORR exceeding 25% is <20% if the upper bound of 60% credible interval is 
<25%. With the maximum sample size of N=120, the posterior probability of ORR exceeding
25% is >80% if the lower bound of 60% credible interval is >25%.
The study efficacy may be monitored on an ongoing basis. The decision to close a cohort early 
may be made if results suggest the posterior probability of ORR exceeding the prespecified 
threshold of activity is well below 20%. For example, if the true response rate is 25%, the 
probability of observing 0 responses out of 6 patients is 17.8%. Under the uniform prior beta 
(1,1), the posterior probability that ORR is greater than 25% is only 13.3%. If the true response 
rate is 15%, the probability of observing 0 responses out of 10 patients is 19.7%. Under the 
same prior, the posterior probability that ORR is greater than 15% is only 16.7%.
Patients who have been assigned to a cohort but not treated may be replaced to ensure that a 
sufficient number of patients can be treated for each interim analysis.


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Table JTJN.10.
Observed ORR and 60% Credible Interval
N=20
N=120
Number of 
Responders
Observed 
ORR
60% 
Credible Interval
Number of 
Responders
Observed 
ORR
60% 
Credible Interval
0
0%
1.1%-7.4%
0
0%
0.2%-1.3%
1
5%
3.9%-13.6%
6
5%
3.9%-7.4%
2
10%
7.4%-19.3%
12
10%
8.3%-12.9%
3
15%
11.1%-24.7%
18
15%
12.8%-18.3%
4
20%
15.1%-29.9%
24
20%
17.4%-23.5%
5
25%
19.1%-35.0%
30
25%
22.1-28.7%
6
30%
23.3%-40.0%
36
30%
26.8%-33.8%
7
35%
27.6%-44.9%
42
35%
31.6%-38.9%
Abbreviations: ORR=overall response rate.
10.2. Populations for Analyses
The following analysis sets will be defined for this study:
Intent-to-Treat (ITT) population: will include all enrolled patients (i.e., patients have been 
assigned to a cohort). The ITT population will be used for all baseline, efficacy and PRO
analyses.
Per-Protocol population: will include all treated patients who do not have any major protocol
violations that could potentially affect the efficacy conclusions of the study. This population will 
be used for efficacy and PRO sensitivity analyses.
Safety population:  will include all enrolled patients who have received ≥1 dose of prexasertib, 
regardless of their eligibility for the study. The safety population will be used for all 
dosing/exposure, and safety analyses.
Pharmacokinetic population: will include all enrolled patients who have received ≥1 full dose 
of prexasertib and have baseline and ≥1 postbaseline evaluable PK sample.
Biomarker population: will include all enrolled patients 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.
The primary analysis will be conducted approximately 6 months after the last responder’s first 
response date or approximately 1 year after the last patient has been enrolled, whichever occurs 
first. Additional updated analyses of efficacy and safety may be conducted at later times 
(approximately 6-12 months after the primary analysis) if deemed appropriate by the sponsor.
All CIs will be given at a 2-sided 95% level, unless otherwise stated.
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other change to the data analysis 


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methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) and the clinical study report.  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 complete response (CR) or partial response (PR) divided by the total number of 
enrolled patients per cohort.  The ORR, with corresponding 95% exact CI, will be summarized
for each cohort. The posterior estimates of ORR and posterior probability of ORR that is greater 
than the cutoff value will also be derived via a Bayesian model. See details in Section 10.3.4.
Disease control rate (DCR) is defined as the number of patients who achieve a best overall 
response of CR, PR or stable disease for ≥4 months divided by the total number of enrolled
patients per cohort.  The DCR, with corresponding 95% exact CI, will be summarized for each 
cohort.
CA-125 response is defined as ≥50% reduction in CA-125 levels from a pretreatment sample. 
The response must be confirmed and maintained for ≥28 days according to GCIG criteria. 
Patients must have a pretreatment sample that is ≥2 times the upper limit of the reference range 
and obtained within 2 weeks before starting the treatment. The response rate based on CA-125 
will be summarized for each cohort.
Progression-free survival (PFS) is defined as the time from the first dose until the first
occurrence of documented disease progression per RECIST 1.1, or death from any cause in the 
absence of progressive disease. Patients known to be alive and without disease progression will 
be censored at the time of the last adequate tumor assessment (a detailed PFS event/censoring 
scheme is provided in SAP).
Duration of response (DoR) is defined as the time from the date measurement criteria for CR or 
PR (whichever is first recorded) are first met until the first date that disease is recurrent or 
objective progression is observed, per RECIST 1.1, or the date of death from any cause in the 
absence of objectively determined disease progression or recurrence.  The DoR will be censored 
according to the same rules as PFS.
Overall survival (OS) is defined as the time from the first dose until death from any cause.  If 
the patient is alive, lost to follow-up or withdrawn from study at the time of data analysis, OS 
data will be censored on the last date the patient is known to be alive.  
For time-to-event variables, such as PFS, DoR and OS, the Kaplan-Meier method (Kaplan and 
Meier 1958) will be used to estimate the curves, median time and 95% CI for each cohort.
10.3.2. Safety Analyses
All patients who receive ≥1 dose of prexasertib will be evaluated for safety and toxicity.
The Medical Dictionary for Regulatory Activities (MedDRA®) Version 20.0 (or higher) will be 
used when reporting AEs by MedDRA terms.  The MedDRA LLT will be used in the treatment-


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emergent computation.  Adverse events will be summarized by System Organ Class (SOC) and 
by decreasing frequency of Preferred Term (PT) within SOC. CTCAE version 4.0 will be used 
to report AE severity grades.
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, enrolled in the study, and treated, as 
well as number and percentage of patients completing the study (patients who receive ≥1 dose of 
study drug and have ≥1 post-baseline tumor assessment), 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.
A summary of baseline patient and disease characteristics, historical diagnoses, preexisting 
conditions, and prior therapies will be reported by cohort using descriptive statistics. Other 
patient baseline characteristics will be summarized by cohort as deemed appropriate.
10.3.3.3. Treatment Compliance
Study treatment will be administered at the investigator site; therefore, treatment compliance is 
assured.
10.3.3.4. Extent of Exposure
The number of cycles received, cumulative dose, duration of therapy, dose omissions, dose 
reductions, dose delays, and dose intensity will be summarized for all treated patients by cohort.
10.3.3.5. Concomitant Therapy
A summary of prior and concomitant medications by cohort will be reported.
10.3.3.6. Post-Study-Treatment Therapy
The numbers and percentages of patients receiving post-study-treatment 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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10.3.3.7. Pharmacokinetic/Biomarker Analyses
A descriptive summary (for example, end of infusion, minimum plasma concentration [Cmin], 
and accumulation ratio) of the prexasertib PK data collected from all patients who receive ≥1 
dose of prexasertib and have samples collected for analysis of prexasertib plasma concentration 
data will be provided across multiple cycles of treatment.  The observed PK data will also be 
compared with the current prexasertib human population PK model (from Study JTJA) and 
included with the descriptive summary in the final clinical study report.
Mean population PK parameters for prexasertib in plasma (clearance, volume of distribution, and 
half-life) and inter-individual PK variability will also be computed for this study using nonlinear 
mixed-effect modelling implemented in NONMEM in order to describe the dose-concentration 
relationship in the target population.  Covariate effects (such as age, BSA, prior therapies, 
hepatic/renal function, etc.) on the PK parameters of prexasertib will also be investigated.
Additional exploratory population based PK/pharmacodynamic analyses using nonlinear mixed 
effect modeling implemented in NONMEM may be performed (if the data warrant) that include 
the re-estimation of prexasertib PK parameters at the patient level to:

evaluate the potential relationship between PK and biomarkers

evaluate the relationship between exposure and response in terms of safety and 
efficacy (e.g., neutropenia, CA-125, change in tumor size, PFS, OS, etc.).
The population based PK and PK/ pharmacodynamic analyses will be reported in separate 
standalone reports for this study.  The version of any software used for the analyses will be 
documented, and the program will meet the Lilly requirements of software validation.  It is 
possible that other validated equivalent PK software programs may be used if appropriate, 
warranted, and approved by Global Pharmacokinetic Management.
10.3.3.8. Biomarker Analyses
Summary statistics for biomarkers (e.g., BRCA status based on the central lab) will be reported.  
The association between biomarkers and clinical outcomes will be explored. Further exploratory 
analysis of biomarkers may be conducted if deemed necessary and a sufficient number of 
patients who express the biomarker(s) are available.
10.3.3.9. Health Outcome/Patient-Reported Outcomes
For each questionnaire, 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 will be calculated for each questionnaire. Reasons for noncompliance
will be collected only for assessments administered via the site-based device.
Home device: 
For the worst pain NRS, missed assessments will not be considered a protocol deviation 
provided that in a given cycle all of the following criteria are met:

≥50% of the assessments are completed

4/7 assessments are completed in the 7 days preceding the first dose of each cycle,
starting prior to cycle 2.


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Collection of the Worst Pain NRS will be discontinued at progression, or after Day 28 of 
Cycle 6, whichever comes first.  
Site-based device:
The target compliance threshold/completion rate for the NFOSI-18 and worst pain NRS is 100%;
every missed assessment will be considered a protocol deviation.
Change from baseline for pre-specified concepts of interest (worst pain and ovarian cancer 
related symptoms) will be descriptively analyzed. Time to progression will be summarized for 
the pre-specified concepts of interest descriptively using the KM method. Data for cohorts that 
have stopped early may not be analyzed. Exploratory analyses may be conducted on other 
domains as well as individual items of the NFOSI-18. Data on analgesic consumption will be
analyzed in conjunction with PRO data from the worst pain NRS. The association between PRO
measures and efficacy outcomes will be evaluated. Further details will be defined in the SAP.
10.3.3.10.
Healthcare Resource Utilization
Hospitalizations, transfusions, ED visits, SBO, and concomitant medications during study 
treatment will be summarized by cohort.
10.3.4. Interim Analyses
Interim analyses will be conducted regularly to evaluate closing enrollment early due to futility. 
For each cohort, the first futility interim analysis will be conducted after approximately 
20 patients have been treated and completed ≥2 cycles or have discontinued before the first post-
baseline tumor assessment. Although confirmation of response is not required to complete the 
interim analysis, the interim analysis may be potentially delayed to obtain confirmation of 
response. The futility rule is based on the posterior probability of activity via a Bayesian model. 
A cohort will be closed if the posterior probability is less than the prespecified futility threshold 
(e.g., 20% probability that ORR exceeds the prespecified threshold of activity). Borrowing of 
information across cohorts may be allowed, and the strength of borrowing may depend on the 
similarity among the cohorts. The prior distribution of response rate used in the model may be
derived from the ongoing NCI-sponsored Phase 2 Study E001 (NCT02203513).  The futility 
rules for each cohort are described as follows (ORR of 25% and 15% are considered the 
threshold of activity for Cohorts 1 – 3 and 4, respectively):

Cohorts 1 to 3 (platinum-resistant): Pr (ORR>25%) <20%

Cohort 4 (platinum-refractory): Pr (ORR>15%) <20%.
It is planned that enrollment can continue while interim analyses are conducted, but the sponsor 
may decide to pause the enrollment, if necessary.  For the cohorts that can continue after the 
evaluation of the approximately first 20 patients, subsequent interim analyses will occur after 
approximately every 20 additional patients.  The interval between interim analyses may be 
adjusted if deemed appropriate based on enrollment rates and available data. At each subsequent 
interim for each cohort, the posterior probability of response rate will be updated based on the 
available data and a higher futility threshold for the posterior probability may be adopted if 
deemed appropriate by the sponsor.


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At each interim analysis, although the decision of whether to continue a cohort will be made 
primarily based on the futility rules, the totality of data (including safety, efficacy, PK, and 
biomarker data, if available) will also be reviewed and considered in the final decision made by 
the sponsor. The decision will be communicated to sites in writing if the sponsor determines a 
cohort is to be closed. The evaluation of efficacy may be based on all treated patients with 
centrally confirmed BRCA mutation status if available.  Other interim analyses may be conducted 
if deemed appropriate by the sponsor.  The interim analyses may be combined if they are 
expected to occur within a similar timeframe; interim analyses may also be combined with any 
prespecified safety review or annual reporting (such as an update to the IB or Development 
Safety Update Review, etc.).


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Krajewska M, Fehrmann RS, Schoonen PM, Labib S, de Vries EG, Franke L, van Vugt MA. 
ATR inhibition preferentially targets homologous recombination-deficient tumor cells. 
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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
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
BRCA negative
refers to patients with BRCA test results negative for deleterious or suspected 
deleterious BRCA mutations.
BRCA positive
refers to patients with BRCA test results positive for deleterious or suspected 
deleterious BRCA mutations
BUN
blood urea nitrogen
BSA
body surface area
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmin
minimum plasma concentration
CNS
central nervous system
collection database
a computer database where clinical study data are entered and validated
CPK
creatine phosphokinase
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.
CRS
clinical research scientist
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events


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Term
Definition
DCR
disease control rate
DDR
DNA-damage response
DoR
duration of response
ECG
electrocardiogram
ED
emergency department
ECOG
Eastern Cooperative Oncology Group
Effective method of 
contraception
examples of effective methods of contraception include male or female condoms with 
spermicide, diaphragms with spermicide
end of study
date of the last visit or last scheduled procedure shown in the Schedule of Activities 
for the last patient
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ePRO
electronic patient-reported-outcome
ERB
ethical review board
EU
European Union
FFPE
formalin-fixed paraffin-embedded
FHD
first-in-human dosing
GCP
good clinical practice
G[M}-CSF
Granulocyte or macrophage colony stimulating factor
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GI
gastrointestinal
Highly effective method 
of contraception
Contraception methods that have <1% failure rate.  Examples include oral 
contraceptives implanted contraceptives or intrauterine devices
HGSOC
high-grade serous ovarian cancer
HIV
human immunodeficiency virus
HRR
homologous recombination repair
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration
ICF
informed consent form


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Term
Definition
ICH
International Council for Harmonization (formerly the International Conference on 
Harmonization)
interim analysis
an analysis of clinical study 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 study, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IRB
institutional review board
ITT
intent-to-treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to 
the planned course of treatment.
IWRS
interactive Web response system
LC-MS/MS
liquid chromatography–mass spectrometry/mass spectrometry
LLT
MedDRA Lower Level Term
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NFOSI-18
National Comprehensive Cancer Network–Functional Assessment of Cancer Therapy-
Ovarian Symptom Index-18
NRS
numeric rating scale
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PARP
Poly (ADP-ribose) polymerase
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PLD
PEGylated liposomal doxorubicin
PR
partial response


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Term
Definition
PS
performance status
PT
MedDRA Preferred Term
QTc
corrected QT interval
QTcF
QT interval using Fridericia’s correction
randomize
the process of assigning patients to an experimental group on a random basis
RBC
red blood cell
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.
rescreen
to screen a patient who was previously declared a screen failure for the same study
SAE
serious adverse event
SAP
statistical analysis plan
SBO
small bowel obstruction
SD
stable disease
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 study
SOC
MedDRA System Organ Class
study completion
Study completion occurs after the clinical trial database is locked and the final analysis 
of the primary and secondary endpoints have been performed., as determined by Lilly.
SUSARs
suspected unexpected serious adverse reactions
ULN
upper limit of normal
WBC
white blood cell


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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya,c
Clinical Chemistrya,b
Leukocytes (WBC)
Serum Concentrations of:
Neutrophilsc
Alanine aminotransferase (ALT)
Lymphocytes
Albumin
Monocytes
Alkaline phosphatase
Eosinophils
Aspartate aminotransferase (AST)
Basophils
Bilirubin, direct
Erythrocytes (RBC)
Bilirubin, total
Hemoglobin (HGB)
Blood urea nitrogen (BUN) or blood urea
Hematocrit (HCT)
Calcium
Platelets (PLT)
Creatinine
Glucose (random)
Urinalysisc
Potassium
Blood
Protein
Glucose
Sodium
CA-125
Ketones
pH
Pregnancy Testc,d
Protein
Urine pregnancy test
Specific gravity
Serum pregnancy test
Urine leukocyte esterasee
Abbreviations:  CRF = case report form; RBC = red blood cells; WBC = white blood cells.
a
Treatment and enrollment decisions will be based on local laboratory results.
Note:  Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. When a manual differential is needed to report the neutrophils, the segmented and band forms should be 
added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands.
b
Central laboratory.  In addition, local labs may be collected at investigator’s discretion.
c
Local or investigator-designated laboratory.
d
For female patients of childbearing potential.
e
Urine microscopy may be used in place of the urine leukocyte esterase assessment to test for the presence of 
WBC


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Appendix 3.
Study Governance, Regulatory, and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the nature of the study, the potential risks 
and benefits of participating in the study, and that the patient’s participation is 
voluntary

ensuring that informed consent is given by each patient.  This includes obtaining 
the appropriate signatures and dates on the informed consent form (ICF) prior to 
the performance of any study procedures and prior to the administration of 
prexasertib

providing a copy of the signed ICF(s) to the patient and retaining a copy of the 
signed ICF in the site file

answering any questions the patient may have throughout the study and sharing in 
a timely manner any new information that may be relevant to the patient’s 
willingness to continue the patient’s participation in the study.
Ethical Review
Documentation of ERBs/IRBs 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 good clinical practice (GCP).
The study site’s ERBs/IRBs should be provided with the following:

protocol, protocol amendments, and relevant protocol addenda, and the current IB
and updates during the course of the study

ICFs

other relevant documents (for example, curricula vitae advertisements).
Regulatory Considerations
This study will be conducted in accordance with the protocol and with:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines 

applicable ICH GCP Guidelines

applicable laws and regulations.
Some obligations of Lilly may be assigned to a third-party organization.


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Investigator Information
Physicians with a specialty in oncology will participate as investigators in this clinical trial.
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 investigators and study coordinators.  This session 
will give instruction on the protocol, completion of case report forms (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/evaluate CRF data using 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 Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide Lilly, 
applicable regulatory agencies, and applicable ERBs/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 Lilly-provided electronic data capture system.
Electronic patient-reported outcome (ePRO) measures (for example, a rating scale) or other data 
reported directly by the patient (for example, daily dosing schedule, event diary) are entered into 
an ePRO instrument 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.
If ePRO records are stored at a third-party site, 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, 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.  Paper 
documentation provided by the patient may include, for example, a daily dosing schedule, or an 
event diary.
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 4.
Sampling Schedule for Pharmacokinetics
Pharmacokinetic samples will be collected for prexasertib in this study.  It is essential that the 
exact infusion start and stop times are recorded using actual clock readings.  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 (that is, prior to infusion of prexasertib) sample should be taken as close as possible to 
the start of the infusion (<2 hours and ideally <10 minutes prior to start), 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 +15 minutes), and exact clock 
reading should be recorded. Although every effort to should be made to obtain the samples in 
the timeframes described above and noted below in the table, PK samples taken outside the 
specified windows will not be considered a protocol deviation. Similarly, a missed PK sample
(i.e., not collected at all or collected improperly) will not be considered a protocol deviation.
Prexasertib Pharmacokinetic Sampling Schedule
Sample Series
Cycle
Day
Prexasertib PK Sampling Timesa
1
1
1
End of prexasertib infusion (+15 min)b
2
1
1
1-2 hours following end of prexasertib infusionb
3
2
1
Prior to start of prexasertib infusion 
4
2
1
End of prexasertib infusion (+15 min)b
5
2
1
1-2 hours following end of prexasertib infusionb
6
4
1
End of prexasertib infusion (+15 min)b
7
4
1
1-2 hours following end of prexasertib infusionb
8
6
1
End of prexasertib infusion (+15 min)b
9
6
1
1-2 hours following end of prexasertib infusionb
Abbreviations: min = minute; PK = pharmacokinetic.
a
The sampling schedule is relative to the prexasertib 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 PK data become available.  
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 (record in CRF if the case).


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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 Serologya
Aspartate aminotransferase (AST)
Anti-nuclear antibody
Gamma-glutamyl transferase (GGT)
Anti-smooth muscle antibody
Creatine phosphokinase (CPK) 
Anti-actin antibody
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
Note:  This formula is to be used for calculating creatinine clearance (CrCl) from 
local laboratory results only.
Cockcroft-Gault prediction of creatinine clearance from serum creatinine (1976)
For serum creatinine concentration in mg/dL:
CrCl =
(mL/min)
(140 – agea) (wt) 0.85 (if female), or 1.0 (if male)
72 serum creatinine (mg/dL)
For serum creatinine concentration in µmol/L:
CrCl =
(mL/min)
(140 – agea) (wt) 0.85 (if female), or 1.0 (if male)
0.81 serum creatinine (mol/L)
a
Age in years, weight (wt) in kilograms.
Source:  Cockcroft and Gault 1976.


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Appendix 7.
Protocol Amendment I4D-MC-JTJN(b) 
Summary
A Phase 2 Study of Prexasertib in Platinum-Resistant or
Refractory Recurrent Ovarian Cancer
Overview
Protocol I4D-MC-JTJN (A Phase 2 Study of Prexasertib in Platinum-Resistant or Refractory
Recurrent Ovarian Cancer) has been amended.  The new protocol is indicated by amendment (b) 
and will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Section 2 Table JTJN.1. Schedule of Inclusion and Baseline Assessments: clarified that 
Cohort 4 does not need local BRCA results

Section 2 Post-Study Treatment Follow-Up Schedule of Activities: differentiated follow-
up intervals for patients who have discontinued without progression versus with 
progression

Section 6.1 Inclusion Criteria: inclusion [3] clarifies what is considered as a line of 
therapy

Section 7.4 Table JTJN.7: included Grade 2 for consideration in thrombocytopenia; 
specified when treatment should be delayed for anemia

Section 10.2: included definition for per-protocol population

Section 10.3: modified when to conduct primary analysis and additional updated analyses 
of efficacy and safety, based on a recommendation from the FDA

Section 10.3.3.4 Extent of Exposure: clarified definition with additional criteria

Section 10.3.4 Interim Analyses: defined threshold of activity for each cohort


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
The numbering system used for inclusion and exclusion criteria provides a unique number for 
each criterion and allows for efficiency in data collection.
In case an amendment to the protocol adds a criterion, that criterion will receive the next 
available number, regardless of whether it is an inclusion or exclusion criterion.


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Table JTJN.11.
Schedule of Inclusion and Baseline Assessments
Procedure 
Category
Procedure
Comments
Study Entry/ 
Enrollment
…
Cohorts 1-3: 
Confirm availability 
of local BRCA result
X
Data from a blood or tissue based test are acceptable (i.e., either germline 
or somatic tests are acceptable).  The test may have occurred prior to 
consent. If both somatic and germline status are known, the somatic 
status should be used for cohort assignment. Patients in Cohort 4 do not 
need to have local BRCA results.
Post-Study-Treatment Follow-Up Schedule of Activities
…
a
Period begins the day after the decision that the patient will discontinue study treatment is made and lasts 
approximately 30 days.
b
For patients who have discontinued without progression, follow-up should occur every 60 days.  For patients 
with progression, the follow-up interval is 90 days for survival assessments.  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. 
6.1  Inclusion Criteria
[3] 
…
Note for Cohorts 1 and 2:  Each line of therapy is preceded by evidence of clinical 
or radiographic disease progression (initial therapy is considered the first line).  
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.  Neither 
adjuvant therapy nor hormonal therapy are considered lines of therapy. Hormonal 
therapy is not considered a line of therapy.  All adjuvant therapy should be 
considered as a line of therapy. 


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Table JTJN.12.
Dose Adjustments and Delays
Toxicity
CTCAE
Grade
Action
Dose Adjustments and 
Considerations
…
Thrombocytopenia
Grades 2,
3 or Grade 
4 
Delay treatment until ≤Grade 1 (≥75/mm3)
Investigator discretion
Anemia
Grade 3 or 
Grade 4 
Consider RBC transfusion or EPO (if consistent 
with institutional guidelines).  Treatment may 
proceed or be delayed at the discretion of the 
investigator. Delay treatment until ≤Grade 2 (≥8 
g/dL)
Investigator discretion
…
10.2. Populations for Analyses
The following analysis sets will be defined for this study:
…
Per-Protocol population: will include all treated patients who do not have any major protocol
violations that could potentially affect the efficacy conclusions of the study.  This population will 
be used for efficacy and PRO sensitivity analyses.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee.
The primary analysis of the primary endpoint of ORR will be performed when all enrolled 
patients have completed ≥2 months of follow-up and/or investigator-assessed best response 
assessments have been completed for all patients.  All secondary endpoints will be evaluated at 
this time. will be conducted approximately 6 months after the last responder’s first response date 
or approximately 1 year after the last patient has been enrolled, whichever occurs first.
Additional updated analyses of efficacy and safety may be conducted at later times 
(approximately 10-18 6-12 months after last patient is enrolled the primary analysis) if deemed 
appropriate by the sponsor.
10.3.3.4 Extent of Exposure
The number of cycles received, cumulative dose, duration of therapy, dose omissions, dose 
reductions, dose delays, and dose intensity will be summarized for all treated patients by cohort.


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10.3.4 Interim Analyses
Interim analyses will be conducted regularly to evaluate closing enrollment early due to futility.  
For each cohort, the first futility interim analysis will be conducted after approximately 
20 patients have been treated and completed ≥2 cycles or have discontinued before the first post-
baseline tumor assessment.  Although confirmation of response is not required to complete the 
interim analysis, the interim analysis may be potentially delayed to obtain confirmation of 
response. The futility rule is based on the posterior probability of activity via a Bayesian model.  
A cohort will be closed if the posterior probability is less than the prespecified futility threshold 
(e.g., 20% probability that ORR exceeds the prespecified threshold of activity).  Borrowing of 
information across cohorts may be allowed, and the strength of borrowing may depend on the 
similarity among the cohorts.  The prior distribution of response rate used in the model will be
may be derived from the ongoing NCI-sponsored Phase 2 Study E001 (NCT02203513).  The 
futility rules for each cohort are described as follows (ORR of 25% and 15% are considered the 
threshold of activity for Cohorts 1 – 3 and 4, respectively):

Cohorts 1 to 3 (platinum-resistant):  Pr (ORR>25%) <20%

Cohort 4 (platinum-refractory):  Pr (ORR>15%) <20%.
It is planned that enrollment can continue while interim analyses are conducted, but the sponsor 
may decide to pause the enrollment, if necessary.  For the cohorts that can continue after the 
evaluation of the approximately first 20 patients, subsequent interim analyses will occur after 
approximately every 20 additional patients.  The interval between interim analyses may be 
adjusted if deemed appropriate based on enrollment rates and available data.  At each subsequent 
interim for each cohort, the posterior probability of response rate will be updated based on the 
available data and a higher futility threshold for the posterior probability may be adopted if 
deemed appropriate by the sponsor(e.g., 40% probability ORR exceeds the prespecified 
threshold of activity).


Leo Document ID = dff0e9fc-5663-410a-a5b6-e796458f5426
Approver:
Approval Date & Time: 17-Sep-2018 14:05:08 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
Statistical Analysis Plan: I4D-MC-JTJN (V1)
A Phase 2 Study of Prexasertib in Platinum-Resistant or Refractory Recurrent 
Ovarian Cancer
NCT03414047   
Approval Date: 02-Apr-2018


I4D-MC-JTJN Statistical Analysis Plan Version 1
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1.
Statistical Analysis Plan:  
I4D-MC-JTJN:  A Phase 2 Study of Prexasertib in
Platinum-Resistant or Refractory Recurrent Ovarian
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.
Prexasertib (LY2606368) Ovarian Cancer
This study is a multicenter, nonrandomized, parallel cohort, Phase 2 study in patients with 
high-grade serous ovarian, primary peritoneal, or fallopian tube cancer.  Patients will be 
assigned to cohorts based on their BRCA status and response to the platinum-based 
chemotherapy.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I4D-MC-JTJN
Phase 2
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly on date 
provided below.
Approval Date: 02-Apr-2018 GMT


I4D-MC-JTJN Statistical Analysis Plan Version 1
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I4D-MC-JTJN:  A Phase 2 Study of
Prexasertib in Platinum-Resistant or RefractoryRecurrent Ovarian
Cancer.................................................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Study Objectives.................................................................................................................6
4.
Study Design.......................................................................................................................7
4.1.
Summary of Study Design..............................................................................................7
4.2.
Determination of Sample Size ........................................................................................7
5.
A Priori Statistical Methods ................................................................................................9
5.1.
General Considerations ..................................................................................................9
5.2.
Populations ....................................................................................................................9
5.3.
Handling of Dropouts or Missing Data.........................................................................10
5.4.
Patient Disposition .......................................................................................................10
5.5.
Patient Characteristics ..................................................................................................10
5.6.
Treatment Compliance .................................................................................................10
5.7.
Concomitant Therapy...................................................................................................10
5.8.
Post-Study-Treatment Therapy.....................................................................................11
5.9.
Efficacy Analyses ........................................................................................................11
5.9.1.
Primary Efficacy Analyses...................................................................................11
5.9.2.
Sensitivity Analyses.............................................................................................12
5.10. Health Outcomes/Quality-of-Life Analyses..................................................................13
5.11. Pharmacokinetic/Pharmacodynamic Analyses..............................................................14
5.12. Biomarker Analyses.....................................................................................................14
5.13. Safety Analyses............................................................................................................14
5.13.1.
Extent of Exposure...............................................................................................14
5.13.2.
Adverse Events ....................................................................................................15
5.13.3.
Deaths, Serious Adverse Events, Other significant Adverse 
Events..................................................................................................................15
5.13.4.
Clinical Laboratory Evaluation.............................................................................15
5.13.5.
Vital Signs and Other Physical Findings...............................................................15
5.13.6.
Electrocardiograms ..............................................................................................15
5.13.7.
Healthcare Resource Utilization ...........................................................................16
5.14. Protocol Violations.......................................................................................................16
5.15. Interim Analyses ..........................................................................................................16
5.16. Annual Report Analyses...............................................................................................17


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5.17. Clinical Trial Registry Analyses...................................................................................17
6.
References ........................................................................................................................19


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Table of Contents
Table
Page
Table JTJN.4.1.
Objectives and Endpoints............................................................................6
Table JTJN.5.1.
Observed ORR and 60% Credible Interval..................................................8
Table JTJN.6.1.
PFS events/Censoring Scheme..................................................................12


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Revision History
SAP Version 1 was approved prior to the first patient visit.  


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3.
Study Objectives
Table JTJN.4.1 shows the objectives and endpoints of the study.
Table JTJN.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To estimate the ORR for each cohort

ORR: proportion of all enrolled patients who achieve a best overall
response of PR+CR as determined per RECIST version 1.1.
Secondary
To characterize the safety and toxicity
profile of prexasertib

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 prexasertib

Prexasertib concentrations in plasma
To estimate secondary efficacy
measures including DCR, DoR, 
CA-125 response, PFS, OS

DCR:  proportion of patients who achieve a best overall 
response of CR, PR and SD (for at least 4 months) as
determined per RECIST version 1.1.

DoR:  time from the date measurement criteria for CR or PR 
(whichever is first recorded) are first met until the first date of
documented PD, per RECIST 1.1 criteria, or the date of death
from any cause in the absence of documented PD.

CA-125 response: at least a 50% reduction in CA-125 levels from a
pretreatment sample that is at least twice the upper limit of the 
reference range and obtained within 2 weeks before starting the 
treatment, with confirmation after 4 weeks according to GCIG 
criteria.

PFS:  time from enrollment until the first radiographic
documentation (as assessed by the investigator) of
progression or death from any cause in the absence of
documented PD

OS:  time from enrollment until death from any cause
Tertiary/Exploratory
To assess the relationship between 
biomarkers, prexasertib exposure 
(PK), and clinical outcomes 

Biomarker research assessed from blood or tissue samples, unless
precluded by local regulations

Plasma concentration of prexasertib

Clinical outcomes data
To evaluate the patient-reported 
outcomes using NCCN-FACT-FOSI 
18 and Worst Pain NRS 

Change from baseline

Time to progression

Association between time to pain progression and analgesic 
consumption

Association between time to progression and select efficacy 
outcomes
Abbreviations:  AEs = adverse events; CR = complete response; DCR = disease control rate; DoR = duration of
response; ECG = electrocardiogram; GCIG =Gynecologic Cancer InterGroup; NFOSI-18 = National Comprehensive 
Cancer Network – Functional Assessment of Cancer Therapy – Ovarian Symptom Index-18; NRS = numeric 
rating 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 version 1.1 (Eisenhauer et al. 2009); SAEs = serious adverse events; SD = stable disease.


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4.
Study Design
4.1.
Summary of Study Design
Study I4D-MC-JTJN is a multicenter, nonrandomized, parallel cohort, Phase 2 study in
approximately up to 180 patients with high-grade serous ovarian, primary peritoneal, or fallopian
tube cancer.  Patients will be assigned to the following cohorts:

Cohort 1:  Platinum-resistant, BRCA negative, and received ≥3 lines of prior therapy

Cohort 2:  Platinum-resistant, BRCA negative, and received <3 lines of prior therapy

Cohort 3:  Platinum-resistant, BRCA positive, there is no restriction on number of lines of 
prior therapy, but must have received prior PARP inhibitor

Cohort 4:  Platinum-refractory, BRCA positive or negative, no restrictions on number of 
lines of prior therapy
The study employs a Bayesian adaptive design that may close enrollment in specific cohorts 
early based on the interim analysis results during the course of the trial.  The study will initially 
enroll approximately 20 patients to each cohort and then a Bayesian model will be used to 
evaluate the posterior probability of activity for each cohort.  A cohort will be closed if the 
posterior probability of activity is <20%.  Subsequent interim analyses will be done to further 
evaluate the posterior probability of activity after additional patients are enrolled to each cohort. 
4.2.
Determination of Sample Size
The maximum total sample size of this study is estimated to be approximately 180 patients.  For 
each of the 4 cohorts, the minimum sample size is approximately 20 patients.  The sample size 
for each cohort will be dependent on the outcomes of the interim analyses.  As cohorts are 
halted, new eligible patients will be allocated to the enrolling cohorts.  As a result, the maximum 
sample size of a single cohort is approximately 120 patients (e.g., if enrollment to all but one of 
the cohorts is stopped after the first interim analysis).  The posterior credible intervals of ORR 
when the observed ORR is in the range of 0-35% are summarized in Table JTJN.5.1.  For 
illustrative purpose, the study drug will be considered active if ORR>25% and the uniform prior 
beta (1,1) is assumed in the Bayesian model.  With the minimum sample size of N=20, the 
posterior probability of ORR exceeding 25% is <20% if the upper bound of 60% credible 
interval is <25%.  With the maximum sample size of N=120, the posterior probability of ORR 
exceeding 25% is >80% if the lower bound of 60% credible interval is >25%.
The study efficacy may be monitored on an ongoing basis.  The decision to close a cohort earlier
may be made if results suggest the posterior probability of ORR exceeding the prespecified 
threshold of activity is well below 20%.  The evaluation of the posterior probability of activity 
may occur before 20 patients are enrolled.  For example, if the target response rate is 25%, under 
the uniform prior beta (1,1), the posterior probability that ORR is greater than 25% is only 13.3%
if 0 response is observed out of 6 patients.  If the target response rate is 15%, under the same 
prior, the posterior probability that ORR is greater than 15% is only 16.7% if 0 response is 
observed out of 10 patients.


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.
Table JTJN.5.1.
Observed ORR and 60% Credible Interval
N=20
N=120
Number of 
Responders
Observed 
ORR
60% 
Credible Interval
Number of 
Responders
Observed 
ORR
60% 
Credible Interval
0
0%
1.1%-7.4%
0
0%
0.2%-1.3%
1
5%
3.9%-13.6%
6
5%
3.9%-7.4%
2
10%
7.4%-19.3%
12
10%
8.3%-12.9%
3
15%
11.1%-24.7%
18
15%
12.8%-18.3%
4
20%
15.1%-29.9%
24
20%
17.4%-23.5%
5
25%
19.1%-35.0%
30
25%
22.1-28.7%
6
30%
23.3%-40.0%
36
30%
26.8%-33.8%
7
35%
27.6%-44.9%
42
35%
31.6%-38.9%
Abbreviations:  ORR = overall response rate.


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5.
A Priori Statistical Methods
5.1.
General Considerations
Statistical analysis of this study will be the responsibility of Lilly.  The interpretation of study 
results will be the responsibility of the Lilly clinical research physician (CRP) / clinical research 
scientist (CRS) and the statistician.  The Lilly CRP/CRS and the statistician will also be 
responsible for the appropriate conduct of an internal review process for both the final study 
report and any study-related material to be authorized for publication.
The primary analysis of the primary endpoint of overall response rate (ORR) will be performed 
when all enrolled patients have completed ≥2 months of follow-up and/or investigator-assessed 
best response assessments have been completed for all patients.  All secondary endpoints will be 
evaluated at this time.  Additional updated analyses of efficacy (including but not limited to 
time-to-event variables) and safety (including but not limited to adverse events) may be 
conducted at later times (approximately 10-18 months after last patient is enrolled) if deemed 
appropriate by the sponsor.
All confidence intervals (CIs) will be given at a 2-sided 95%, unless otherwise stated. 
Unless otherwise specified, baseline for the time-to-event endpoints will be the date of 
enrollment (the date of assigning patients to a cohort) and baseline for the safety analysis will be 
the last assessable baseline prior to the dose administration.
Any change to the data analysis methods described in the protocol/SAP will require an 
amendment ONLY if it changes a principal feature of the protocol/SAP.  Any other change to the 
data analysis methods described in the protocol/SAP, and the justification for making the change, 
will be described in the clinical study report.  Additional exploratory analyses will be conducted 
as deemed appropriate. 
5.2.
Populations
The following analysis sets will be defined for this study:
Intent-to-Treat (ITT) population:  will include all enrolled patients (i.e., patients have been 
assigned to a cohort). The ITT population will be used for all baseline, efficacy and PRO
analyses.
Per-Protocol population:  will include all treated patients who do not have any major protocol 
violations that could potentially affect the efficacy conclusions.  This population will be used for 
efficacy and PRO sensitivity analyses.
Safety population:  will include all enrolled patients who have received ≥1 dose of prexasertib, 
regardless of their eligibility for the study.  This population will be used for all dosing/exposure, 
and safety analyses.
Pharmacokinetic population:  will include all enrolled patients who have received ≥1 full dose 
of prexasertib and have baseline and ≥1 postbaseline evaluable PK sample.


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Biomarker population:  will include all enrolled patients from whom a valid assay result has 
been obtained. 
5.3.
Handling of Dropouts or Missing Data
Missing data, except dates, will not be imputed.  Historical data such as historical diagnosis, 
historical illness, pre-existing conditions and prior therapies should be collected in a sufficiently
informative way.  For example, in order to be considered as historical illness, events occurring in
the same year as study entry should have at least a known month and year for the end date, while
events occurring in previous years should have at least a known year for the end date.  When
dates need to be imputed, missing days will be replaced with 15th of the month and missing 
day/month with 01 JULY.
5.4.
Patient Disposition
Patient disposition will be summarized by cohort and overall.  It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated, as 
well as number and percentage of patients completing the study (patients who receive ≥1 dose of 
study drug and have ≥1 post-baseline tumor assessment), or discontinuing (overall and by reason 
for discontinuation).  Reason for discontinuation from both the study treatment and the study will 
be summarized by pre-determined categories.  
5.5.
Patient Characteristics
Patient demographics including age, race, ethnicity, country, screening height, weight and body 
surface area (BSA) will be reported using descriptive statistics.
Patient baseline disease characteristics including pathological diagnosis, disease stage, and 
Eastern Cooperative Oncology Group (ECOG) performance status will be summarized.
Patient preexisting condition, historical illness, prior anti-cancer therapies and other baseline 
characteristics such as smoking status will be summarized.
Patient characteristics will be summarized by cohort and overall.
5.6.
Treatment Compliance
Treatment with prexasertib will be administered at the investigator site, therefore treatment 
compliance is assured.
5.7.
Concomitant Therapy
All medications will be coded to the generic preferred name according to the current World 
Health Organization (WHO) drug dictionary.  All concomitant medications will be summarized 
for the safety population using the preferred name by cohort and overall.  
The use of analgesic medications will be summarized and listed, including dose, unit, frequency, 
and route of administration.  Each analgesic may be analyzed according to the WHO pain ladder 
(WHO cancer pain relief, 1986) and/or the Analgesic Quantification Algorithm (AQA) (Chung 
et al. 2014).  Additional exploratory analysis about the analgesic use may be conducted if 
deemed appropriate.


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5.8.
Post-Study-Treatment Therapy
The numbers and percentages of patients receiving post-study-treatment 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.  The therapies will be summarized by cohort and 
overall for the safety population.
5.9.
Efficacy Analyses
Efficacy analyses will be conducted on the ITT population and summarized by cohort.  Efficacy 
analyses for interim analyses may be based on the safety population.
5.9.1. Primary Efficacy Analyses
Overall response rate (ORR) is defined as the number of patients who achieve a best overall 
response of complete response (CR) or partial response (PR) divided by the total number of 
enrolled patients per cohort.  The ORR, with corresponding 95% exact CI, will be summarized
for each cohort.  The posterior estimates of ORR and posterior probability of ORR that is greater 
than the cutoff value will also be derived via a Bayesian model. 

Cohort 1, 2 and 3:  posterior Pr (ORR>25%)

Cohort 4:  posterior Pr (ORR>15%)
Disease control rate (DCR) is defined as the number of patients who achieve a best overall 
response of CR, PR or stable disease for ≥4 months divided by the total number of enrolled 
patients per cohort.  The DCR, with corresponding 95% exact CI, will be summarized for each 
cohort.
CA-125 response is defined as ≥50% reduction in CA-125 levels from a pretreatment sample. 
The response must be confirmed and maintained for ≥28 days according to GCIG criteria. 
Patients must have a pretreatment sample that is ≥2 times the upper limit of the reference range 
and obtained within 2 weeks before starting the treatment.  The response rate based on CA-125,
with corresponding 95% exact CI, will be summarized for each cohort.
Progression-free survival (PFS) is defined as the time from the date of enrollment until the first
occurrence of documented disease progression per RECIST 1.1, or death from any cause in the 
absence of progressive disease (PD). Progression-free survival curves, median PFS, and PFS 
rates at 3 months intervals up to 12 months with 95% CI for each cohort will be estimated using 
the Kaplan-Meier (KM) method (Kaplan and Meier 1958). 
If a patient is not known to have progressed or died at the time of analysis, PFS time will be 
censored at the last known progression-free assessment.  The detailed censoring rules are 
described in Table JTJN.6.1.


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Table JTJN.6.1.
PFS events/Censoring Scheme
Situation
a
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 randomization (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 missing 2 scan intervals 
following randomization
b,c
Censored
Date of enrollment
Tumor progression or death documented
immediately after missing 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
New anticancer therapy started before 
tumor progression or death
Censored
Date of last adequate radiological assessment
prior to the start of new anticancer therapy 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
2 scan intervals = 4 months.  
Duration of response (DoR) is defined as the time from the date measurement criteria for CR or 
PR (whichever is first recorded) are first met until the first radiographic documentation of 
progression or death from any cause in the absence of PD.  The analysis is for confirmed 
responders only.  Median duration of response will be estimated using the KM method.  The 
DoR will be censored according to the same rules as PFS.
Overall survival (OS) is defined as the time from the date of enrollment until death from any 
cause.  If the patient is alive, lost to follow-up or withdrawn from study at the time of data 
analysis, OS data will be censored on the last date the patient is known to be alive.  Overall 
survival curves, median overall survival, and survival rates at 6 months intervals up to 24 months
with 95% CI for each cohort will be estimated using the KM method. 
5.9.2. Sensitivity Analyses
Patients are assigned to cohorts based on the local BRCA results.  Sensitivity analyses of the 
efficacy endpoints may be done based on the centrally confirmed BRCA results.  Other 
sensitivity analyses may be conducted if deemed appropriate.


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5.10. Health Outcomes/Quality-of-Life Analyses
Patient reported outcomes data is being collected via a site and home-based device.  The 
schedules of the health outcome assessments are summarized below.  Daily collection of the 
Worst Pain NRS via the home device will be discontinued at progression or after Day 28 of 
Cycle 6, whichever comes first. 
For each questionnaire, the compliance rate will be calculated as the number of completed 
assessments divided by the number of expected assessments.  The compliance rate for the Worst 
Pain-NRS will be calculated at baseline, per week and per cycle, with reasons for non-
compliance to be collected and reported for the baseline and short-term follow-up visit only.  
Additionally, the proportion of patients who have completed ≥50% of daily Worst Pain NRS 
assessments in the 7-day period prior to the first dose of each cycle and during each consecutive 
7 day period post-baseline will be computed at each cycle.  Patients will be considered compliant 
if they have completed ≥50% of the daily assessments during each period (e.g., week, cycle).  
The number of expected assessments for each period is the number of patients who have 
received last scheduled study drug before the scheduled assessment days (e.g., patients who have 
received Day 1 drug should be expected to complete all daily assessments before they receive 
Day 15 drug).  For the NFOSI-18, the compliance rate will be calculated at baseline, each post-
baseline visit (starting with cycle 2), with reasons for noncompliance to be collected and reported 
for all visits.  The number of expected assessments at each post-baseline visit (starting with cycle 
2) is the number of patients who have received study drug in a previous cycle.
For the Worst Pain NRS, a 7-day average of scores prior to the first dose of each cycle and a 
rolling 7-day average of scores regardless of dosing will be computed if ≥50% assessments are 
completed during each period.  A 7-day average of scores based on any available data may be 
computed for sensitivity analysis even if compliance is less than 50%.  For the NFOSI-18, the 
total score will be computed at baseline, each cycle (starting with cycle 2), and short term 
follow-up along with scores for the Disease Related Symptoms-Physical subscale, the Disease 
Related Symptoms-Emotional subscale, the Treatment Side Effects subscale, and the 
Function/Well-Being subscale. 
Change from baseline for pre-specified concepts of interest (worst pain and NFOSI Total Score 
and Subscales) will be descriptively analyzed.  For the Worst Pain NRS, change from baseline 
will be assessed in the 7-day average prior to the first dose of each cycle. 
Questionnaires
administered in 
clinic
Baseline 
visit
Administered on day 1 of each cycle, 
beginning with cycle 2
Short term follow-up
Worst Pain NRS
x
x
NFOSI-18
x
X
x


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Time to deterioration in the total score as well as specific subscales and items in the NFOSI-18 is 
defined from the time of the patient’s baseline visit to the time of the first increase in the 
respective score with confirmation at the next consecutive cycle or death from any cause, 
whichever comes first (a threshold characterizing meaningful worsening will be determined 
based on forthcoming psychometric analyses).  Time to pain progression based on Worst Pain 
NRS and the weekly average of the worst pain scores will also be assessed.  Median time to pain 
progression/deterioration with 95% CI for each cohort will be estimated using the KM method. 
Data for cohorts that have stopped early may not be analyzed.  Correlation analysis between 
NFOSI pain item and the worst pain NRS will be conducted to account for lack of NRS data 
after cycle 6.
Data on analgesic consumption will be analyzed independently as well as in conjunction with 
PRO data from the worst pain NRS.  For example, patients with pain progression based on worst 
pain NRS and their analgesic consumption will be summarized.
The association between PRO measures and efficacy outcomes may also be explored if deemed 
appropriate. 
5.11. Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic (PK) and pharmacodynamic analyses will be performed according to a separate 
PK analysis plan.
5.12. Biomarker Analyses
The biomarkers of interest (e.g., BRCA status based on the local or central lab) will be 
summarized.  The association between biomarkers and clinical outcomes will be explored.  
Further exploratory analysis of biomarkers may be conducted if deemed necessary and a
sufficient number of patients who express the biomarker(s) are available.
5.13. Safety Analyses
Safety analyses will be based on the safety population.  Safety analyses will be summarized by 
cohort and overall.
5.13.1. Extent of Exposure
Study drug exposure information will be summarized by cohort and overall, including cycles 
received per subject, duration on therapy, cumulative dose (mg/m^2), dose intensity and relative 
dose intensity.
Prexasertib will be administered as an intravenous infusion on Day 1 and 15 of a 28-day cycle.  
Duration on therapy is calculated as the last dosing date+14-first dosing date.  Dose intensity of 
prexasertib (mg/m^2/week) is calculated as cumulative dose/ duration on therapy in weeks.  
Relative dose intensity of prexasertib is calculated as actual dose intensity per week/planned 
dose intensity per week ×100, where planned dose intensity per week=(105/2) mg/m^2/week. 
Dose adjustments, delays and omissions, along with the reasons, will be summarized and listed.


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5.13.2. Adverse Events
Adverse event (AE) verbatim terms will be provided by the investigators and then will be 
mapped by Lilly or its designee to corresponding terminology within the Medical Dictionary for 
Regulatory Activities (MedDRA) Lower Level term (LLT) dictionary.  The investigator will use 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (NCI 2009) to assign 
AE severity grades.
Pre-existing conditions are defined as AEs that begin but do not resolve prior to the first dose of 
study drug in each study period.  Pre-existing conditions will be presented by patient and can be 
combined with the listing of AE, so that the history of the pre-existing conditions/AEs can be 
traced.
A treatment emergent adverse event (TEAE) is defined as any AE that begins on or after the day 
of first dose in the reporting study period or any pre-existing condition that increases in CTCAE 
grade on or after the day of first dose in the reporting study period.  The MedDRA LLT will be 
used in the treatment-emergent computation.  
The number of patients who experienced a TEAE, or TEAE possibly related to study drug, will 
be summarized.  Treatment-emergent adverse events will be summarized by SOC, by Preferred 
Term (PT) of decreasing frequency within SOC, and by maximum CTCAE grade and grade 
categories (any, Grade 3 or higher).  
5.13.3. Deaths, Serious Adverse Events, Other significant Adverse 
Events
All deaths that occur during the study, within 30 days of the study treatment discontinuation, as 
well as the cause of death, will be summarized and listed.
Serious adverse events (SAEs) are those events that result in death, are life-threatening, require 
or prolong hospitalization, result in persistent or significant disability/incapacity, or cause 
congenital anomaly/birth defect.  Serious adverse events will be tabulated by SOC, PT terms, 
and relationship to study drug.
5.13.4. Clinical Laboratory Evaluation
All relevant hematology and chemistry laboratory values will be graded according to CTCAE 
Version 4.  Shift tables showing the change from baseline to the worst grade on study will be 
presented. 
5.13.5. Vital Signs and Other Physical Findings
Temperature, blood pressure, pulse rate, weight and ECOG performance score will be 
summarized by cohort and overall.
5.13.6. Electrocardiograms
Local electrocardiograms (ECGs) will be summarized by cycle and overall.  The summary by 
cycle will classify patients as having normal or abnormal.  Additionally, QT, RR, and QRS 


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intervals will also be collected and QTcF will be calculated based on these parameters.  Adverse 
events that could be associated with abnormal ECGs will be presented, if appropriate.  
5.13.7. Healthcare Resource Utilization
The frequency and percentage of patients with hospitalizations, transfusions, ED visits 
experienced during the study treatment period or 30-day post discontinuation follow-up period 
will be summarized.
5.14. Protocol Violations
Significant protocol violations that potentially compromise the data integrity and patients’ safety 
will be summarized by cohort and overall.  These violations will include deviations which can be 
identified programmatically and those which can only be identified by the clinical research 
associate (CRA) during monitoring.  Significant protocol deviations are described in another 
document within the study Trial Master File.
5.15. Interim Analyses 
Interim analyses will be conducted regularly to evaluate closing enrollment early due to futility.  
For each cohort, the first futility interim analysis will be conducted after approximately 
20 patients have been treated and completed ≥2 cycles or have discontinued before the first post-
baseline tumor assessment.  The interim analysis may be potentially delayed if the confirmation 
of response is required.  The futility rule is based on the posterior probability of activity via a 
Bayesian model.  A cohort will be closed if the posterior probability is less than the prespecified 
futility threshold (e.g., 20% probability ORR exceeds the prespecified threshold of activity).  
Borrowing of information across cohorts may be allowed, and the strength of borrowing may 
depend on the similarity between the cohorts.  The prior distribution of response rate used in the
model will be derived from the ongoing NCI-sponsored Phase 2 Study E001 (NCT02203513).  
The futility rules for each cohort are described as follows:

Cohorts 1 to 3 (platinum-resistant):  Pr (ORR>25%) <20%

Cohort 4 (platinum-refractory):  Pr (ORR>15%) <20%.
It is planned that enrollment can continue while interim analyses are conducted, but the sponsor 
may decide to pause the enrollment, if necessary.  For the cohorts that can continue after the 
evaluation of the first 20 patients, subsequent interim analyses will occur after approximately 
every 20 additional patients.  The interval between interim analyses may be adjusted if deemed 
appropriate based on enrollment rates and available data.  At each subsequent interim for each 
cohort, the posterior probability of response rate will be updated based on the available data and 
a higher futility threshold for the posterior probability may be adopted if deemed appropriate by 
the sponsor (e.g., 40% probability ORR exceeds the prespecified threshold of activity).
At each interim analysis, although the decision of whether to continue a cohort will be made 
primarily based on the futility rules, the totality of data (including safety, efficacy, PK, and 
biomarker data, if available) will also be reviewed and considered in the final decision made by 
the sponsor.  The decision will be communicated to sites in writing if the sponsor determines a 


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cohort is to be closed.  The evaluation of efficacy may be based on all treated patients with 
centrally confirmed BRCA mutation status if available.  Other interim analyses may be conducted 
if deemed appropriate by the sponsor.  The interim analyses may be combined if they are 
expected to occur within a similar timeframe; interim analyses may also be combined with any 
prespecified safety review or annual reporting (such as an update to the IB or Development 
Safety Update Review, etc.).
5.16. Annual Report Analyses
The following reports are needed as requested for annual reporting purposes.
Development Safety Update Report:

Cumulative Subject Exposure by Age Group and Sex

Cumulative Subject Exposure by Racial Group

Estimated Cumulative Subject Exposure

Exposure Information

Listing of Discontinuations Due to AE During the Reporting Period

Listing of Subjects Who Died During the Reporting Period
Clinical Investigator’s Brochure (IB):

Listing and Summary of SAE

Listing and Summary of Death

Listing and Summary of TEAE (and by maximum CTCAE grade)

Listing and Summary of Patient Disposition

Listing and Summary of Study Drug Adjustment
Other reports may be requested if deemed appropriate for the IB.
5.17. 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:

Summary of AEs, provided as a dataset which will be converted to an XML file.  
Both SAEs and ‘Other’ AEs will be summarized by:  MedDRA PT within treatment 
group.

An AE is considered ‘Serious’ whether or not it is a TEAE.


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
An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  
For each SAE 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).

Adverse event reporting is consistent with other document disclosures for example, 
the clinical study report (CSR), manuscripts, and so forth. 
In addition, a participant flow will be created that will describe how many enrolled patients 
completed the study, and for those who did not, the frequency of each reason for not completing.  
This analysis will be based on study discontinuation, not treatment discontinuation.  A patient 
will be identified as having completed the study if the patient has received ≥1 dose of study drug 
and have ≥1 post-baseline tumor assessment at the time of the final analysis.


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6.
References
Chung KC, Barley A, Braun AH, Qian Y, Zagari M. Assessing analgesic use in patients with 
advanced cancer: development of a new scale – the analgesic quantification algorithm. Pain 
Med. 2014;15(2):225-232.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc.
1958;53:457-481.
World Health Organization. Cancer pain relief. Geneva: World Health Organization, 1986.


Leo Document ID = e72aeac3-8686-4ac4-b3b8-31fa9dd9b338
Approver:
Approval Date & Time: 02-Apr-2018 17:13:05 GMT
Signature meaning: Approved
PPD