Clinical trial NCT01663857
Conditions: Epithelial Ovarian Cancer Fallopian Tube Cancer Primary Peritoneal Cancer
Sponsor: Eli Lilly and Company
Start date: 2012-07-01; Completion date: 2018-05-11
Enrollment: 118 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study for women with ovarian cancer that has returned at least 6 months after platinum-based chemotherapy.

Detailed description:
Phase 1b is unblinded and will have a small number of participants that will take LY2228820 plus gemcitabine and carboplatin to test the safety of the combination and determine a recommended dose for the Phase 2 portion.

Phase 2 will be blinded and all study participants will receive carboplatin and gemcitabine. Participants of one group will receive LY2228820, and the other group will receive placebo.

If the participant achieves at least stable disease, there is a maintenance phase following the first 6 cycles. The participant will take either LY2228820 or placebo. The participant will continue therapy until disease progression or other discontinuation criteria are fulfilled.

Arms: arm 1: Cohort 1: Cycles 1-6 (21 day cycles)- LY2228820 200 mg administered orally every 12 hours on days 1-10. Gemcitabine 1000 milligrams per square meter (mg/m\^2) administered intravenously (IV) over 30 minutes on days 3 and 10. Carboplatin dose Area Under Curve (AUC) 4 (maximum dose 600 mg) administered IV over 30 minutes on day 3..

Cohort 1: Cycles 7+ (28 day cycles)- LY2228820 300 mg administered orally every 12 hours on days 1-14. arm 2: Cohort 2: Cycles 1-6 (21 day cycles)- LY2228820 300 mg administered orally every 12 hours on days 1-10. Gemcitabine 1000 mg/m\^2 administered IV over 30 minutes on days 3 and 10. Carboplatin dose Area Under Curve (AUC) 4 (maximum dose 600 mg) administered IV over 30 minutes on day 3.

Cohort 2: Cycles 7+ (28 day cycles)- LY2228820 300 mg administered orally every 12 hours on days 1-14. arm 3: Arm A: Cycles 1-6 (21 day cycles)- LY2228820 200 mg administered orally every 12 hours on days 1-10. Gemcitabine 1000 mg/m\^2 administered IV over 30 minutes on days 3 and 10. Carboplatin dose Area Under Curve (AUC) 4 (maximum dose 600 mg) administered IV over 30 minutes on day 3.

Arm A: Cycles 7+ (28 day cycles)- LY2228820 300 mg administered orally every 12 hours on days 1-14. arm 4: Arm B: Cycles 1-6 (21 day cycles)- Placebo administered orally every 12 hours on days 1-10. Gemcitabine 1000 mg/m\^2 administered IV over 30 minutes on days 3 and 10. Carboplatin dose Area Under Curve (AUC) 4 (maximum dose 600 mg) administered IV over 30 minutes on day 3.

Arm B: Cycle 7+ (28 day cycles)- Placebo administered orally on days 1-14 to maintain blind.
Interventions: intervention 1: LY2228820 intervention 2: Carboplatin intervention 3: Placebo intervention 4: Gemcitabine
Intervention descriptions: intervention 1: Administered Orally intervention 2: Administered IV intervention 3: Administered Orally intervention 4: Administered IV

Protocol documents:
Prot_000.pdf: 
Protocol I1D-MC-JIAE(c) 
 
A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Study of LY2228820, a p38 MAPK Inhibitor, plus 
Gemcitabine and Carboplatin versus Gemcitabine and Carboplatin for Women with Platinum-Sensitive Ovarian 
Cancer 
 
 
NCT01663857 
 
Approval date: 16-Mar-2017 


I1D-MC-JIAE(c) Clinical Protocol
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LY2228820
1. Protocol I1D-MC-JIAE(c)
A Randomized, Double-Blind, Placebo-Controlled Phase1b/2
Study of LY2228820, a p38 MAPK Inhibitor, plus Gemcitabine 
and Carboplatin versus Gemcitabine and Carboplatin for 
Women with Platinum-Sensitive 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 
LY2228820, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.  This document and its associated attachments are 
subject to United States Freedom of Information Act Exemption 4.
p38 Mitogen-Activated Protein Kinase (MAPK)Inhibitor (LY2228820)
This trial is a Phase Ib dose escalation study followed by a randomized, double-blind, 
placebo-controlled Phase2studyof a p38 MAPK inhibitor administered in combination with 
gemcitabineand carboplatin to patients with platinum-sensitive ovariancancer.
Approval Date: 16-Mar-2015 GMT
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 11 January 2012
Amendment (a) Electronically Signed and Approved by Lillyon 06 April 2012
Amendment (b) Electronically Signed and Approved by Lilly 08 January 2014
Amendment (c) Electronically Signed and Approved by Lilly on date provided below.


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LY2228820
2.
Synopsis
Study Rationale
p38 mitogen-activated protein kinase (MAPK) is a signaling protein activated by cancer cells to 
enable survival after exposure to either radiation or chemotherapy.  p38 MAPK phosphorylates a 
number of substrates, including MAPK-activated protein kinase 2 (MAPKAP-K2), and also 
regulates the tumor microenvironment’s production of such key cytokines as tumor necrosis 
factor-α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8).  These 
cytokines are upregulated in many human malignancies, including ovarian cancer.  In addition to 
promoting survival, these cytokines also enhance growth, invasion, angiogenesis, and metastasis.  
Thus, pharmacologic inhibition of p38 MAPK in both the cancer cell and its supportive 
microenvironment represents a novel therapeutic strategy for improving outcomes for patients 
with ovarian cancer.
Study I1D-MC-JIAE will evaluate efficacy of the p38 MAPK inhibitor, LY2228820, in 
combination with gemcitabine and carboplatin for patients with platinum-sensitive ovarian 
cancer.


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Clinical Protocol Synopsis:  Study I1D-MC-JIAE(c)
Name of Investigational Product:  LY2228820
Title of Study:  A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Study of LY2228820, a p38 MAPK 
Inhibitor, plus Gemcitabine and Carboplatin versus Gemcitabine and Carboplatin for Women with Platinum-
Sensitive Ovarian Cancer
Number of Planned Patients:
   Entered: ~130
   Enrolled/Randomized: ~120/110
   Completed: ~110
Phase of Development:  1b/2
Length of Study:  40 months
Planned first patient visit: April 2012
Planned last patient visit: August 2015
Planned interim analyses: 
1.
All patients in Phase 1b have received at least 1 cycle: safety and pharmacokinetics (PK) 
2.
Approximately 30 patients in Phase 2 have received at least 1 cycle: safety and PK
3.
Approximately 60 patients in Phase 2 have received at least 2 cycles: safety, and PK
For the purposes of database lock and completion of the study report, this study will be considered complete 
following the analysis of PFS (primary Phase 2 objective).  After the study is considered complete, patients and 
investigators will remain blinded and survival data will continue to be collected. The analysis of overall survival 
(OS) will be performed after all patients in the Phase 2 portion of the study have been followed for at least 2 years.
Objectives:  
The primary objective of the Phase 1b portion of this study is to determine the recommended Phase 2 dose of 
LY2228820 that can be safely administered in combination with gemcitabine and carboplatin.
The primary objective of the Phase 2 portion of this study is to compare progression-free survival in patients 
treated with LY2228820 plus gemcitabine and carboplatin versus placebo plus gemcitabine and carboplatin.
The secondary objectives of the study are to evaluate:

Change in tumor size, CA125 (serum biomarker for ovarian cancer), overall response rate, and overall 
survival

Safety and tolerability of the combination: LY2228820 plus gemcitabine and carboplatin

Pharmacokinetics (PK) of LY2228820 and evaluation for effect of LY2228820 on the PK of gemcitabine, 
its metabolite (dFdU), and carboplatin

Biomarkers related to p38 MAPK pathway activity and the pathogenesis of ovarian cancer

Patient-reported outcomes for patients enrolled in the Phase 2 portion of the study
Study Design:  
This trial is a Phase 1b dose escalation followed by a randomized, double-blind, placebo-controlled Phase 2 study 
of LY2228820 plus gemcitabine and carboplatin versus gemcitabine and carboplatin for women with platinum-
sensitive ovarian cancer. 
In the Phase 1b portion of the trial, approximately 2 cohorts will be needed to determine the maximum tolerated 
dose of LY2228820 in combination with gemcitabine and carboplatin.
Once the maximum tolerated dose for LY2228820 in combination with gemcitabine and carboplatin is defined, 
approximately 110 patients will be randomized 1:1 to the LY2228820 or placebo arm.  All patients will receive 
gemcitabine and carboplatin. After completion of 6 cycles of combination therapy, patients with stable disease or
evidence of biomarker and/or tumor response will receive maintenance therapy with LY2228820 or placebo until 
disease progression.  Maintenance therapy will be administered based on original 1:1 randomization.


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Diagnosis and Main Criteria for Inclusion and Exclusions:
Main inclusion criteria for study entry are: 

Women at least 18 years of age at the time of randomization who have cytologically or histologically
proven epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with evidence of 
recurrence or progression, which is advanced and not amenable to curative surgery or radiotherapy

Have recurrence of cancer at least 6 months after completion of first-line platinum-based therapy

For Phase 1b, have either measurable or non-measurable disease; for Phase 2, must have at least 
1 measurable lesion assessable using standard techniques according to the Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) guidelines (Eisenhauer et al. 2009)

Have a performance status of 2 on the Eastern Cooperative Oncology Group (ECOG) scale

Have adequate hematologic, hepatic, and renal function
Main exclusion criteria for study entry are: 

Are currently enrolled in, or discontinued <14 days from, a clinical trial involving an investigational drug 
or device 

Have previously completed or withdrawn from this study or any other study investigating LY2228820

Have previously been treated with gemcitabine for epithelial ovarian cancer, fallopian tube cancer, or 
primary peritoneal cancer

Receiving concomitant cytotoxic or other antineoplastic treatment

Have had, in the judgment of the investigator, a major bowel resection that would alter oral drug 
absorption

Are receiving, in the judgment of the investigator, concurrent administration of immunosuppressive 
therapy

Have, in the judgment of the investigator, serious concomitant systemic disorders (e.g., acute myocardial 
infarction within 6 months of study entry, uncontrolled hypertension) incompatible with the study

Have received more than 1 previous chemotherapy regimen for ovarian cancer, fallopian tube cancer or 
primary peritoneal cancer
Test Product, Dose, and Mode of Administration:  
Study drugs are administered on a 21-day cycle during induction therapy (Cycles 1 through 6) and on a 28-day 
cycle during maintenance therapy (Cycle 7 and beyond).  LY2228820 is administered orally every 12 hours on 
Days 1 through 10 of a 21-day cycle during induction therapy and on Days 1 through 14 of a 28-day cycle during 
maintenance therapy.  Gemcitabine (1000 mg/m2) is administered intravenously (IV) over 30 minutes (+15 min)
on Days 3 and 10 of induction therapy only. Carboplatin (area under the plasma concentration–time curve [AUC]
4 with maximum dose of 600 mg) is administered IV over 30 minutes (+15 min) on Day 3 of induction therapy 
only.
Planned Duration of Treatment:  
Induction therapy (Cycles 1 through 6):  six 21-day cycles or until discontinuation criteria are fulfilled
Maintenance therapy (Cycle 7 and beyond):  until discontinuation criteria are fulfilled
Short-term post-discontinuation period:  approximately 30 days
Long-term post-discontinuation period:  until death or lost to follow-up (for a maximum of 2 years after enrollment 
in study)


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Reference Therapy, Dose, and Mode of Administration:  
Study drugs are administered on a 21-day cycle during induction therapy (Cycles 1-6) and on a 28-day cycle 
during maintenance therapy (Cycle 7 and beyond).  Placebo is administered orally every 12 hours on Days 1 
through 10 of a 21-day cycle during induction therapy and on Days 1 through 14 of a 28-day cycle during 
maintenance therapy.  Gemcitabine (1000 mg/m2) is administered IV over 30 (+15) minutes on Days 3 and 10 of 
induction therapy only.  Carboplatin (AUC4 with maximum dose of 600 mg) is administered IV over 30 (+15) 
minutes on Day 3 of induction therapy only.
Criteria for Evaluation:  
Efficacy:  Progression-free survival, change in tumor size, CA-125, overall response rate, and overall survival 
Safety:  Adverse events, safety laboratories, and electrocardiograms
Health outcomes:  FACT-Ovarian (FACT-O) instrument
Pharmacokinetic:  PK parameters, such as Cmax , tmax, AUC, Vd/F, CL/F, and t½, and other relevant parameters 
for LY2228820, gemcitabine and its metabolite (dFdU), and carboplatin; population PK parameters for 
LY2228820  
Statistical Methods:  
Efficacy:  Although an efficacy analysis is not appropriate for the Phase Ib portion of this trial, any tumor 
response data will be tabulated.  In the Phase 2 portion of the study, PFS is the primary endpoint; the hazard ratio
will be estimated from survival data on all randomized patients using a Cox proportional hazard model with 
appropriate covariates.  The Kaplan-Meier method (Kaplan and Meier 1958) will be used to estimate the survival 
curve as well as survival rates at various time points for each treatment group. The following secondary 
endpoints will be summarized for each treatment group:

Change in tumor size

CA-125

Overall response rate

Overall survival
Safety:  During the study, interim analyses will be performed to evaluate safety, PK, futility, and efficacy. 
Interim analyses for the Phase 2 portion of the study will be performed under the guidance of an internal 
assessment committee.
Health outcomes: Patient-reported outcomes will be evaluated only during the Phase 2 portion of the study.  
Time to worsening of symptoms and changes in symptoms from baseline will be measured using the FACT-O 
instrument.
Pharmacokinetic:  For all patients in Phase 1b and a subset of patients (10 patients/arm) in Phase 2, the 90% 
confidence interval for the difference of means will be used to estimate potential for drug interactions among 
patients who are treated with LY2228820 plus gemcitabine and carboplatin compared with those treated with 
placebo plus gemcitabine and carboplatin. Log-transformed PK parameters will be used to assess such 
interactions with back transformation to the original scale.


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3.
Table of Contents
A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2
Study of LY2228820, a p38 MAPK Inhibitor, plus Gemcitabine 
and Carboplatin versus Gemcitabine and Carboplatin for 
Women with Platinum-Sensitive Ovarian Cancer
Section
Page
1.
Protocol I1D-MC-JIAE(c) A Randomized, Double-Blind, Placebo-
Controlled Phase 1b/2 Study of LY2228820, a p38 MAPK Inhibitor, 
plus Gemcitabine and Carboplatin versus Gemcitabine and 
Carboplatin for Women with Platinum-Sensitive Ovarian Cancer .......................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................6
4.
Abbreviations and Definitions...........................................................................................13
5.
Introduction ......................................................................................................................18
5.1.
Rationale and Justification for the Study ......................................................................18
5.2.
Ovarian Cancer ............................................................................................................18
5.3.
General Introduction to LY2228820.............................................................................18
5.4.
Mechanism of Action and In Vitro/In Vivo Activity.....................................................19
5.5.
Biomarkers...................................................................................................................19
5.6.
Nonclinical Pharmacokinetics ......................................................................................19
5.7.
Nonclinical Toxicology................................................................................................20
5.8.
Interaction with Cytochrome P450 (CYP) Enzymes and Enzymes 
Responsible for the Metabolism of LY2228820............................................................21
5.9.
Rationale for Selection of Dose Range .........................................................................22
5.10. Rationale for Amendment (a).......................................................................................22
5.11. Rationale for Amendment (b).......................................................................................23
5.12. Rationale for Amendment (c).......................................................................................24
6.
Objectives.........................................................................................................................25
6.1.
Primary Objective ........................................................................................................25
6.2.
Secondary Objectives...................................................................................................25
7.
Study Population...............................................................................................................26
7.1.
Inclusion Criteria..........................................................................................................26
7.2.
Exclusion Criteria ........................................................................................................27
7.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................28


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7.3.
Discontinuations ..........................................................................................................28
7.3.1.
Discontinuation of Patients...................................................................................28
7.3.2.
Discontinuation of Study Sites .............................................................................29
7.3.3.
Discontinuation of the Study................................................................................29
8.
Investigational Plan...........................................................................................................30
8.1.
Summary of Study Design............................................................................................30
8.1.1.
Phase 1b...............................................................................................................30
8.1.2.
Phase 2.................................................................................................................31
8.1.3.
Maintenance Therapy...........................................................................................31
8.1.4.
Interim Analyses..................................................................................................32
8.1.5.
Study Period Definitions ......................................................................................32
8.1.6.
Baseline and Study Treatment Period Assessments ..............................................33
8.1.7.
Post-discontinuation Follow-Up Period Assessments ...........................................33
8.1.8.
Study Extension ...................................................................................................33
8.2.
Discussion of Design and Control ................................................................................34
9.
Treatment..........................................................................................................................35
9.1.
Treatments Administered .............................................................................................35
9.1.1.
Carboplatin Dosing ..............................................................................................37
9.1.1.1.
Calculated Creatinine Clearance .....................................................................38
9.2.
Materials and Supplies .................................................................................................38
9.2.1.
LY2228820..........................................................................................................38
9.2.2.
Gemcitabine.........................................................................................................38
9.2.3.
Carboplatin ..........................................................................................................38
9.2.4.
Placebo ................................................................................................................39
9.3.
Method of Assignment to Treatment ............................................................................39
9.4.
Selection and Timing of Doses.....................................................................................39
9.4.1.
Phase 1b...............................................................................................................40
9.4.1.1.
Induction Therapy ..........................................................................................40
9.4.1.2.
Maintenance Therapy .....................................................................................40
9.4.2.
Phase 2.................................................................................................................40
9.4.2.1.
Induction Therapy ..........................................................................................40
9.4.2.2.
Maintenance Therapy .....................................................................................41
9.4.3.
Dose Adjustments ................................................................................................41
9.4.3.1.
Treatment Delays between Cycles ..................................................................41
9.4.3.1.1.
LY2228820 Dose Adjustments .................................................................41
9.4.3.1.2.
Gemcitabine Dose Adjustments ................................................................42
9.4.3.1.3.
Carboplatin Dose Adjustments..................................................................43
9.4.3.1.4.
Clinically Significant Effusions ................................................................43


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9.5.
Dose Escalation (Phase Ib)...........................................................................................43
9.5.1.
Dose-Limiting Toxicity Determination and Maximum 
Tolerated Dose Definition....................................................................................44
9.6.
Continued Access to Study Drug..................................................................................44
9.7.
Blinding .......................................................................................................................45
9.8.
Concomitant Therapy...................................................................................................45
9.8.1.
Supportive Care ...................................................................................................46
9.8.2.
Carboplatin Infusion Reactions ............................................................................46
9.8.3.
Colony-Stimulating Factors..................................................................................46
9.9.
Treatment Compliance .................................................................................................47
10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements...................................................................................................................48
10.1. Efficacy Measures........................................................................................................48
10.1.1.
Efficacy Assessments at Baseline and during Study .............................................48
10.1.2.
Efficacy Assessments during the Post-discontinuation Period...............................48
10.1.3.
Primary Efficacy Measure....................................................................................48
10.1.4.
Secondary Efficacy Measures...............................................................................49
10.1.4.1.
Overall Response Rate....................................................................................49
10.1.4.2.
Change in Tumor Size ....................................................................................49
10.1.4.3.
Overall Survival .............................................................................................49
10.2. Health Outcome/Quality of Life Measures ...................................................................49
10.2.1.
Patient-Reported Outcomes..................................................................................49
10.2.2.
Resource Utilization.............................................................................................51
10.3. Safety Evaluations........................................................................................................51
10.3.1.
Adverse Events ....................................................................................................51
10.3.1.1.
Serious Adverse Events ..................................................................................53
10.3.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................54
10.3.2.
Other Safety Measures .........................................................................................54
10.3.2.1.
Collection of Electrocardiograms....................................................................54
10.3.3.
Safety Monitoring ................................................................................................54
10.3.4.
Complaint Handling.............................................................................................55
10.4. Sample Collection and Testing.....................................................................................55
10.4.1.
Samples for Standard Efficacy, Safety Laboratory Testing ...................................56
10.4.2.
Archival Tumor Tissue Sample ............................................................................56
10.4.3.
Pharmacogenetic Samples....................................................................................57
10.4.4.
Samples for Drug Concentration Measurements 
Pharmacokinetics/Pharmacodynamics..................................................................57
10.5. Appropriateness of Measurements................................................................................58


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11.
Data Quality Assurance.....................................................................................................59
11.1. Data Capture System....................................................................................................59
12.
Sample Size and Statistical Methods .................................................................................60
12.1. Determination of Sample Size ......................................................................................60
12.2. Statistical and Analytical Plans.....................................................................................60
12.2.1.
Patient Disposition...............................................................................................61
12.2.2.
Patient Characteristics..........................................................................................61
12.2.3.
Concomitant Therapy...........................................................................................61
12.2.4.
Treatment Compliance .........................................................................................61
12.2.5.
Primary Outcome and Methodology.....................................................................61
12.2.6.
Efficacy Analyses ................................................................................................62
12.2.7.
Pharmacokinetic/Pharmacodynamic Analyses......................................................63
12.2.7.1.
Pharmacokinetic Analyses..............................................................................63
12.2.7.2.
Pharmacodynamic Analysis............................................................................64
12.2.8.
Health Outcome/Quality of Life Analyses:  FACT-O...........................................64
12.2.9.
Safety Analyses....................................................................................................65
12.2.10. Subgroup Analyses ..............................................................................................65
12.2.11. Interim Analyses..................................................................................................65
12.2.11.1. Interim Analysis for Phase 1b.........................................................................66
12.2.11.2. Interim Analyses for Phase 2 ..........................................................................67
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................68
13.1. Informed Consent.........................................................................................................68
13.2. Ethical Review.............................................................................................................68
13.3. Regulatory Considerations ...........................................................................................68
13.3.1.
Investigator Information.......................................................................................69
13.3.2.
Protocol Signatures ..............................................................................................69
13.3.3.
Final Report Signature .........................................................................................69
14.
References ........................................................................................................................70


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List of Tables
Table
Page
Table JIAE.9.1. Treatment Regimens/Dosing Schedule...........................................................36
Table JIAE.9.2. Intercycle Dose Adjustments for LY2228820 or Placebo...............................41
Table JIAE.9.3. Dosage Reduction Guidelines for Gemcitabine for Myelosuppression 
on Day of Treatment......................................................................................42
Table JIAE.9.4. Gemcitabine Dose Modification for Myelosuppression in Previous 
Cycle.............................................................................................................43
Table JIAE.10.1. Adverse Event and Serious Adverse Reporting Guidelines for Study 
JIAE ..............................................................................................................51


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List of Figures
Figure
Page
Figure JIAE.1.
Study design for Protocol 1ID-MC-JIAE. ......................................................30


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List of Attachments
Attachment
Page
Attachment 1.
Protocol JIAE Study Schedule .......................................................................73
Attachment 2.
Protocol JIAE Clinical Laboratory Tests........................................................80
Attachment 3.
PK and PD Sampling Schedule......................................................................81
Attachment 4.
International Federation of Gynecology and Obstetrics (FIGO) Staging.........90
Attachment 5.
ECOG Performance Status.............................................................................91
Attachment 6.
Formula for Calculating Creatinine Clearance................................................92
Attachment 7.
Formula for Calculating Carboplatin Dose.....................................................93
Attachment 8.
RECIST Criteria 1.1 ......................................................................................94
Attachment 9.
Protocol JIAE Sampling Summary ..............................................................101
Attachment 10.
FACT-Ovarian (FACT-O) Instrument .........................................................102
Attachment 11.
Protocol JIAE Amendment (c) Summary.....................................................106


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4.
Abbreviations and Definitions
Term
Definition
AC
assessment committee
adverse event (AE)
any untoward medical occurrence in a patient or clinical investigation subject 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
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
assent
agreement from a child or other individual who is not legally capable of providing consent, 
but who can understand the circumstances and risks involved in participating in a study 
(required by some institutional review boards [IRBs]) 
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
audit
a systematic and independent examination of the trial-related activities and documents to 
determine whether the evaluated trial-related activities were conducted, and the data were 
recorded, analyzed, and accurately reported according to the protocol, applicable standard 
operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory 
requirement(s)
blinding/masking
a procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s); unless otherwise specified, blinding will remain in effect until final database 
lock; a single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the patient are not; a double-blind study is one in 
which neither the patient nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the patients are aware of the treatment received
BMI
body mass index
case report form 
(CRF) and 
electronic case 
report form (eCRF)
sometimes referred to as clinical report form;  printed or electronic form for recording 
study participants’ data during a clinical study, as required by the protocol
clinical research 
physician (CRP)
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
CI
confidence interval


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CNS
central nervous system
complaint
any written, electronic, or oral communication that alleges deficiencies related to the 
identity, quality, purity, durability, reliability, safety or effectiveness, or performance of a 
drug or drug delivery system
compliance
adherence to all the trial-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements
CR
complete response
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Change in tumor 
size (CTS)
a measure of tumor dynamics from which tumor response is derived; tumor size is the sum 
of tumor measurements across all target tumors at a given evaluation (RECIST criteria
version 1.1)
DLT
dose-limiting toxicity
DMC
data monitoring committee
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
end of study (trial)
the date of the last visit or last scheduled procedure shown in the Study Schedule for the 
last active patient in the study  
enroll/randomize
the act of assigning a patient to a treatment; patients who are enrolled in the trial are those 
who have been assigned to a treatment
enter/consent
the act of obtaining informed consent for participation in a clinical trial from patients 
deemed eligible or potentially eligible to participate in the clinical trial; patients entered 
into a trial are those who sign the informed consent form directly or through their legally 
acceptable representatives
ePRO/PRO
(electronic) patient-reported outcome
ESAs
erythropoiesis-stimulating agents
evaluable patient
(for Phase 1b)
any patient who experiences a DLT or receives at least 75% of planned doses of 
LY2228820 in Cycle 1
evaluable patient 
(for Phase 2)
any randomized patient 
FSH
follicle-stimulating hormone
GCP
good clinical practice
GFR
glomerular filtration rate


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LY2228820
GnRH
gonadotropin-releasing hormone
H0
null hypothesis
Ha
alternative hypothesis
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMS
Isotope Dilution Mass Spectrometry
IND
Investigational New Drug application
institutional review 
board/ethical 
review board 
(IRB/ERB)
a board or committee (institutional, regional, or national) composed of medical and 
nonmedical members whose responsibility is to verify that the safety, welfare, and human 
rights of the patients participating in a clinical trial are protected
intention-to-treat 
(ITT)
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
interim analysis
an analysis of clinical trial data, separated into treatment groups, that is conducted before 
the final reporting database is created/locked
investigator
a person responsible for the conduct of the clinical trial at a trial site; if a trial is conducted 
by a team of individuals at a trial site, the investigator is the responsible leader of the team 
and may be called the principal investigator
IV
intravenous
IVRS
interactive voice-response system
legal 
representative
an individual, judicial, or other body authorized under applicable law to consent on behalf 
of a prospective patient to the patient’s participation in the clinical study
LLT
Lower Level Term
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose


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LY2228820
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
ORR
overall response rate
OS
overall survival
OUS
outside the United States
patient
a study participant who has the disease or condition for which the investigational product is 
targeted
PD
pharmacodynamic
PDA
personal data assistant
per protocol set 
(PPS)
the set of data generated by the subset of patients who sufficiently complied with the 
protocol to ensure that these data would be likely to exhibit the effects of treatment, 
according to the underlying scientific model
PET
positron emission tomography
PFS
progression-free survival
PO
oral
PK
Pharmacokinetic
PR
partial response
PS
performance status
PT
Preferred Term
QTc 
corrected QT interval
Q12H
every 12 hours
RECIST Version 1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1
RP2D
Recommended Phase 2 dose (in combination with gemcitabine and carboplatin)
SAE
serious adverse event
Screen
The act of determining if an individual meets minimum requirements for participation in a 
clinical study.  
SD
stable disease
SOC
System Organ Class
suspected 
unexpected 
serious adverse 
serious events that are not listed in the Investigator’s Brochure (IB) and that the 
investigator identifies as related to investigational product or procedure


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LY2228820
reactions
TPO
third-party organization
treatment-
emergent adverse 
event (TEAE)
any untoward medical occurrence that either occurs or worsens at any time after treatment 
baseline and that does not necessarily have to have a causal relationship with this treatment
TTTF
time to treatment failure
UGT
UDP-glucuronosyltransferase
US
United States


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LY2228820
A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2
Study of LY2228820, a p38 MAPK Inhibitor, plus Gemcitabine 
and Carboplatin versus Gemcitabine and Carboplatin for 
Women with Platinum-Sensitive Ovarian Cancer
5.
Introduction
5.1.
Rationale and Justification for the Study 
p38 mitogen-activated protein kinase (MAPK) is a signaling protein activated by cancer cells to 
enable survival after exposure to either radiation or chemotherapy.  p38 MAPK phosphorylates a 
number of substrates, including MAPK-activated protein kinase 2 (MAPKAP-K2), and also 
regulates the tumor microenvironment’s production of such key cytokines as tumor necrosis 
factor-α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8).  These 
cytokines are upregulated in many human malignancies, including ovarian cancer.  In addition to 
promoting survival, these cytokines also enhance growth, invasion, angiogenesis, and metastasis 
(Balkwill and Mantovani 2001; Lewis et al. 2006).  Thus, pharmacologic inhibition of p38 
MAPK in both the cancer cell and its supportive microenvironment represents a novel 
therapeutic strategy for improving outcomes for patients with ovarian cancer.  
Study I1D-MC-JIAE will evaluate efficacy of the p38 MAPK inhibitor, LY2228820, in 
combination with gemcitabine and carboplatin for patients with platinum-sensitive ovarian 
cancer.
5.2.
Ovarian Cancer
Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies.  It is the 
fifth most frequent cause of cancer death in women after cancers of the lung, breast, 
colon/rectum, and pancreas (Howlader 2011).  Seventy percent of patients present with advanced 
disease (Fleming et al, 2009).  In 2010, an estimated 21,900 new cases were diagnosed, and an 
estimated 13,900 deaths were due to this cancer in the United States alone (Jemal 2010).  The 5-
year survival rate of women with diagnosed ovarian cancer is approximately 40% (Jemal 2009).  
However, for women with platinum-sensitive recurrent ovarian cancer, the median progression-
free survival (PFS) is only 8.6 months (Pfisterer et al. 2006), indicating the importance of 
improving therapeutic outcomes for these women.
5.3.
General Introduction to LY2228820 
LY2228820 dimesylate (hereafter referred to as LY2228820) is a potent and selective inhibitor 
of p38 MAPK that binds competitively to the ATP binding site of the kinase to impair 
phosphorylation of its substrates.  In multiple ovarian cancer xenograft studies, LY2228820 has 
demonstrated in vivo antineoplastic activity.  LY2228820 has been evaluated previously for 
safety and tolerability in a Phase 1 study (I1D-MC-JIAD, hereafter referred to as Study JIAD)


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LY2228820
for patients with advanced cancer.  Detailed information about LY2228820 is provided in the 
Investigator’s Brochure (IB).
5.4.
Mechanism of Action and In Vitro/In Vivo Activity 
LY2228820 inhibits phosphorylation of p38 MAPK substrates and abrogates signaling events 
critical not only to cancer cell survival but also to production of key cytokines by the tumor 
microenvironment.  LY2228820 exhibits inhibitory activity against p38 MAPK with more than 
1000-fold selectivity towards the alpha isoform of p38 MAPK (IC50 = 5.3 nM) compared with a 
panel of 179 representative kinases.  Furthermore, LY2228820 strongly inhibits the p38 MAPK 
pathway as indicated by reduction in phosphorylation of MAPKAP-K2 and TNFα production.  
Specifically, LY2228820 inhibits anisomycin-induced MAPKAP-K2 phosphorylation in mouse 
RAW264.7 cells (IC50 = 35.3 nM) and lipopolysaccharide (LPS)-induced TNFα secretion by 
mouse macrophages (IC50 = 6.3 nM). Finally, a single 10-mg/kg oral dose of LY2228820
achieves more than 40% inhibition of phosphorylated MAPKAP-K2 in murine B16-F10 
melanoma xenografts for approximately 4 to 8 hours after the dose.  Most importantly,
LY2228820 demonstrates in vivo antineoplastic activity in xenograft models of human 
glioblastoma, multiple myeloma, lung cancer, and ovarian cancer.  
5.5.
Biomarkers
In this study, a number of biomarkers related to p38 MAPK pathway activity and the 
pathogenesis of ovarian cancer will be assayed in either blood or archived tumor samples for 
correlation with safety and efficacy outcomes associated with LY2228820 therapy.  These 
evaluations will help to determine the potential usefulness of the selected biomarkers for patient 
tailoring in future clinical studies.
Circulating plasma proteins regulated by p38 MAPK (such as TNF, IL-1, IL-6, and IL-8) will 
be measured.  The tumor suppressor p53 will be evaluated for gene expression and mutation as 
well as for protein expression in archived tumors.  The tumor suppressor PTEN will be evaluated 
for gene mutation and protein expression in archived tumors.  For p53 and PTEN, a whole blood 
sample will also be obtained for the isolation and mutational analysis of germline 
deoxyribonucleic acid (DNA) from peripheral blood mononuclear cells (PBMCs).  Additional 
biomarkers related to the pathogenesis of ovarian cancer and to the p38 MAPK pathway (such as 
p-MAPKAP-K2) may be assessed in either blood or archived samples.
5.6.
Nonclinical Pharmacokinetics
Plasma pharmacokinetics of [14C] LY2228820 were evaluated after a single dose in male Fischer 
344 rats and cynomolgus monkeys.  Based on AUC, LY2228820 accounted for 56% and 3% of 
the plasma radioactivity in rats and monkeys, respectively.  The half-life of LY2228820 was 
similar in both species (approximately 10 hours), whereas the half-life of radioactivity was 
longer (104 hours in monkeys and 32 hours in rats), indicating that some metabolite(s) are 
cleared more slowly than parent.
In multiple-dose pharmacokinetic studies in Fischer 344 rats for 7 cycles (14 consecutive dosing 
days followed by 14 days of a washout period between each cycle), exposure to LY2228820, as 


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LY2228820
determined by AUC and Cmax, increased over the dose range from 25 mg/kg to 150 mg/kg, but 
the increase was not consistently dose proportional.  The exposures were slightly higher in 
females than in males, but the differences in general were not over 2-fold.  No accumulation of 
LY2228820 was observed in rat plasma after multiple dosing.  In similar studies in monkeys, 
systemic exposure to LY2228820, although highly variable, increased with increasing dose from 
15 mg/kg to 60 mg/kg. Exposures generally appeared to be lower after multiple dosing when 
compared to a single dose and the toxicokinetics of LY2228820 were similar in both male and 
female monkeys.
The nonclinical tumor growth delay models from 2 studies in mice indicated efficacy in the 10-
mg/kg groups corresponding to an AUC(0-24hr) of 13.4 g*hr/mL. The preclinical 
pharmacokinetic/pharmacodynamic (PK/PD) model in mouse was developed to characterize the 
relationship between drug concentrations and phosphorylated MAPKAP-K2 levels.  This PK/PD 
model integrated the time course of the pharmacokinetics of the compound and the inhibition of 
phosphorylated MAPKAP-K2 in PBMCs.  Allometric scaling was performed using data from 4 
preclinical species:  mouse, rat, dog, and monkey.  The initial (pre-FHD) human PK predictions 
assumed linear pharmacokinetics at therapeutic doses and employed a 2-compartment PK model.  
The human PK/PD simulations (based on allometric prediction of PK and the murine xenograft 
model) predicted that a range of 40 to 120 mg administered orally every 12 hours would achieve 
the required 80% maximal inhibition of phosphorylated MAPKAP-K2 associated with tumor 
growth delay in preclinical efficacy studies. However, interim human PK data from the first 7 
cohorts in Study JIAD indicated that the predicted efficacious dose range required to achieve this 
threshold may be higher than the initial preclinical PK/PD model predictions.  
5.7.
Nonclinical Toxicology
The toxicity of LY2228820 has been characterized in a broad range of nonclinical safety studies.  
In monkeys, repeat-dose studies of 1 month’s duration with daily dosing, and of 3 and 6 months’
duration using an intermittent dosing schedule of 2 weeks on treatment and 2 weeks off 
treatment have been conducted.  In rats, repeat-dose studies of 1 month’s duration (daily dosing) 
and 6 months’ duration (intermittent dosing schedule) have been conducted. Other nonclinical 
studies include a single-dose study in rat; a battery of safety pharmacology studies (assessing the 
central nervous, cardiovascular, respiratory and gastrointestinal systems), a battery of genetic 
toxicity studies, an embryo-fetal development study in rats, and a phototoxicity assessment. 
Collectively, these studies have adequately characterized the toxicology profile to support 
clinical testing with LY2228820.
Gastrointestinal tract, liver and skin have been identified as the primary target organs toxicity in
nonclinical species. In addition, hypercellular bone marrow and peripheral leukocytosis have 
been observed in both rat and monkey.  Intermittent dosing generally ameliorated the toxicities 
observed with daily dosing, or resulted in similar toxicity despite longer durations of dosing 
(three to six months).  With daily dosing for 1 month in monkeys, the no observed adverse effect 
level (NOAEL) was not identified (<3 mg/kg), and the maximum tolerated dose (MTD) was 15 
mg/kg; however, in a 6-month intermittent dosing study, the NOAEL was 15 mg/kg and the 
MTD was 30 mg/kg.  In rats, a NOAEL for daily dosing for 1 month was not identified (<25 


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LY2228820
mg/kg), and the MTD was 150 mg/kg.  When the duration was extended to 6 months with 
intermittent dosing, the NOAEL and the MTD were 25 mg/kg due to a small number of deaths at 
75 mg/kg; however, most rats tolerated 75 mg/kg, and most male rats tolerated 150 mg/kg for the 
duration of the study. Decreased fetal weight, increased skeletal developmental variations, 
increased postimplantation loss, malformed fetuses, and decreased numbers of viable fetuses 
were observed in pregnant rats treated with LY22288200 during the period of organogenesis.  In 
safety pharmacology studies, monitorable and manageable increases in blood pressure, decreases 
in tidal volume, and central nervous system effects were observed.
5.8.
Interaction with Cytochrome P450 (CYP) Enzymes and Enzymes 
Responsible for the Metabolism of LY2228820
The effect of LY2228820 on drug-metabolizing enzymes has been studied in vitro using human 
liver microsomes.  LY2228820 was found to competitively inhibit the biotransformation of 
midazolam to 1′-hydroxy-midazolam with an estimated Ki of 1.2 µM (0.5 µg/mL).  LY2228820 
was also shown to inhibit CYP3A in a time-dependent manner with a kinact of 0.069 min-1 and 
KI of 9.5 µM (3.99 µg/mL).  These data suggested the possibility that LY2228820 might
modulate clearance of drugs that are metabolized by CYP3A in vivo.
The ability of LY2228820 to induce catalytic activities associated with CYP1A2, CYP2B6, and 
CYP3A was examined in primary cultures of fresh human hepatocytes.  LY2228820 was found 
unlikely to cause in vivo induction of the above CYP isoforms within the concentration range 
examined (0.01 to 10 µM).
The effect of LY2228820 on the activity of CYP3A in vivo has been evaluated in the dose 
confirmation phase of Study JIAD (Part B) in which patients were administered a 2-mg oral dose 
of midazolam in the absence or presence of 420 mg LY2228820 administered every 12 hours 
(after fourteen doses).  Results showed that mean PK parameters (Cmax and AUC) of midazolam 
administered with LY2228820 were no higher than those of midazolam administered alone,
indicating that LY2228820 may not inhibit the CYP3A activity up to the dose level investigated 
(18 patients at 420 mg given every 12 hours).
In vitro studies using human liver microsomes indicated that the metabolic clearance of 
LY2228820 is primarily mediated by the UDP-glucuronosyltransferase (UGT) pathway (87%), 
with CYP-mediated pathway contributing to only 13%.  Further CYP phenotyping studies using 
recombinant human CYPs indicated that CYP3A contributed to 72% of the CYP-mediated 
metabolic clearance of LY2228820.  Taken together, the contribution of CYP3A to the total 
metabolic clearance of LY2228820 is estimated to be less than 10%.  The regulatory guidance 
suggests that any enzyme contributing <25% to the systemic clearance of the drug is not 
clinically significant (FDA 2012).
Collectively, the above in vitro and in vivo data suggest that clinical interactions are unlikely 
when LY2228820 is coadministered with substrates, inhibitors and or inducers of CYP3A.  
When coadministered, inhibitors of UGT may increase the plasma concentrations of LY2228820 
and inducers of UGT may decrease the plasma concentrations of LY2228820.


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LY2228820
Refer to Section 9.8, Concomitant Therapy, for more information regarding inhibitors and
inducers of UGT.
5.9.
Rationale for Selection of Dose Range
The dose range of LY2228820 for the Phase 1b component of this study consists of doses 
previously explored in the first-in-human Phase 1 Study JIAD, wherein the single-agent MTD 
was identified at a dose level of 420 mg administered every 12 hours on Days 1 through 14 of a 
28-day cycle.  However, a relatively high frequency of Grade 1/Grade 2 dizziness and tremor
and Grade 3 rash were observed in a subsequent dose-confirmation cohort, and led to a decision 
to further explore the 300-mg every 12 hours (Q12H) dose.  Of the 11 patients in Study JIAD
who received LY2228820 at 300 mg Q12H, 2 patients (18%) experienced a possibly related 
Grade 3 rash dose-limiting toxicity (DLT)-equivalent event and only 1 patient (9.1%) each 
experienced a possibly related Grade 1 dizziness event and possibly related Grade 1 tremor 
event.  Therefore, the 300-mg Q12H dose was recommended as the Phase 2 dose for 
monotherapy, and will be the maximum dose of LY2228820 administered for this Phase 1b/2 
study (JIAE).  
The Phase 1b portion of JIAE will include 2 cohorts at LY2228820 doses of 200 mg and 300 mg 
every 12 hours and the Phase 2 portion of JIAE will be conducted at a single recommended 
LY2228820 dose not exceeding 300 mg every 12 hours.  In JIAE, LY2228820 (or placebo) is 
administered on a 21-day cycle (every 12 hours on Days 1 through 10) in combination with 
gemcitabine (Days 3 and 10) and carboplatin (Day 3) during induction therapy (Cycles 1 through 
6) and on a 28-day cycle (every 12 hours on Days 1 through 14) as a single agent during 
maintenance therapy (Cycle 7 and beyond).
The dose of LY2228820 for the Phase 2 component of this study will be a single-dose level 
identified during the Phase 1b portion of the study as the MTD when LY2228820 is administered 
in combination with gemcitabine and carboplatin.  
Throughout induction therapy (Cycles 1 through 6), the dose for gemcitabine will start at 1000
mg/m2 on Days 3 and 10 and the dose for carboplatin will start at AUC 4 (with a maximum dose 
of 600 mg) on Day 3 of a 21-day cycle.
5.10. Rationale for Amendment (a)
In April 2012, Study JIAE was amended to address a number of protocol issues noted since the 
start of enrollment. The most significant changes included the following:  revisions to allow
measurement of serum creatinine by the Isotope Dilution Mass Spectrometry (IDMS) method; 
changes to a secondary objective to clarify rationale for measuring plasma concentrations of 
gemcitabine, its metabolite (dFdU), and carboplatin; inclusion of a 600-mg maximum dose for 
carboplatin; decrease in the fasting period around the LY2228820 dose; and addition of a Day 10 
electrocardiogram (ECG) during Cycles 1 and 2.


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LY2228820
5.11. Rationale for Amendment (b)
After 2 reported DLTs of Grade 4 thrombocytopenia occurred in patients enrolled in the 
Phase 1b portion of Study JIAE, the Phase 2 portion of the study was opened on 21 May 2013, 
utilizing a dose of 200 mg of LY2228820 in combination with gemcitabine and carboplatin as 
the recommended Phase 2 dose for induction therapy.
Lilly then conducted a thorough review of the Phase 1b data and blinded adverse event data from 
patients enrolling concurrently in the Phase 2 portion, noting the following:
1. Thirty-three percent of Phase 1b patients (2/6) experienced Grade 4 transient 
thrombocytopenia (lasting 1 and 4 days or less).  The expected incidence of Grade 3/4 
thrombocytopenia for the gemcitabine/carboplatin combination is approximately 35% 
(Pfisterer et al. 2006).  Lilly, in collaboration with study investigators, concluded that the 
protocol hematologic DLT criteria did not take into account the known toxicities of the 
gemcitabine/carboplatin combination, and thus limited the use of those criteria (alone) for 
the identification of maximum tolerated dose of LY2228820 to be administered with the 
standard-of-care combination.
2. Drug-related adverse events that characterized the DLTs of LY2228820 administered as a 
single agent (Study JIAD), such as ataxia, dizziness, and rash, were infrequent and low 
grade in Study JIAE to that point (no dermatological toxicities were reported; 2 of 6 
patients experienced Grade 3 syncope judged by the investigators to be unrelated to study 
therapy).  
3. PK analyses from Studies JIAD and JIAE and preclinical modeling studies suggest that a 
300-mg dose of LY2228820 administered every 12 hours provides a greater chance to 
achieve potentially efficacious exposures.
4. Blinded adverse event data from 9 patients in the Phase 2 portion of Study JIAE (200-mg 
dose LY2228820) showed a relatively low rate of DLT-level toxicity.  Neurological and 
dermatological toxicities included Grade 1 dizziness, Grade 1 rash, Grade 2 rash, and 
Grade 3 rash (1 patient each).  Hematological toxicities reported were Grade 2 
neutropenia (2 patients) and Grade 3 neutropenia (2 patients), with no Grade 3/4 
thrombocytopenia reported. These findings supported further exploration of the 300-mg 
dose of LY2228820.
Therefore, as of 25 September 2013, enrollment in the Phase 2 portion of Study JIAE was 
temporarily halted.  The protocol is amended here to reflect revised DLT criteria to better 
account for expected toxicities from the gemcitabine/carboplatin combination and to resume the 
Phase 1b investigation of the 300-mg LY2228820 dose in combination with gemcitabine and 
carboplatin in an additional cohort of 3 patients.


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LY2228820
5.12. Rationale for Amendment (c)
Metabolic clearance analysis has recently been completed which revealed that CYP3A mediated 
metabolism is not the primary clearance pathway of LY2228820. This allows for the restriction 
of the CYP3A inhibitors, inducers, or substrates to be removed and for the use of dexamethasone 
and other anti-emetics during treatment with LY2228820. 
Based on the available preclinical data, there is a possible risk of clinical drug–drug interaction 
when LY2228820 is administered with inhibitors or inducers of UGT enzymes.  In the absence 
of clinical data to refine the risk of interaction, caution is warranted in the concomitant use of 
UGT enzyme inhibitors such as valproic acid and probenecid and inducers such as 
carbamazepine, phenytoin and rifampin.  When, in the clinical investigator's opinion, 
concomitant use of valproic acid or probenecid is indicated, LY2228820-related DLTs of ataxia, 
dizziness and rash should be carefully monitored.
The ovarian cancer landscape has changed during the course of this study.  Maintenance therapy 
as a part of or after a first line platinum regimen has become more prevalent. Several studies are 
examining the effect of maintenance after patients achieve a CR with the first line platinum 
regimen. In order to balance these patients between the placebo and LY2228820 arms, prior
maintenance therapy has been added as a randomization factor. 
The original sample size calculation for the Phase 2 portion of the study included a censoring 
rate assumption of 6% with 103 PFS events needed from 110 patients.  Upon reflection, Lilly 
considers that this assumed censoring rate is too low.  If just 8 or more patients are lost to follow 
up, the actual censoring rate would be higher.  With this protocol amendment, the censoring rate 
estimate has been increased to 28% resulting in a reduction in the number of PFS events needed 
to 79.  The hazard ratio of 0.7 has been maintained but the power has been reduced to 77% from 
83%.  These assumptions are consistent with enrollment and censoring experience in this phase 
of development. 
In addition, the interim analyses for the study have been updated as follows:

The third interim analysis will be performed when approximately 60 patients in the 
Phase 2 portion of the study have completed 2 cycles of treatment, and will examine 
safety and PK only.  Futility has been eliminated as Lilly does not expect that enough 
PFS events will have been observed to allow a futility analysis to occur at that time. 

The fourth interim analysis has been removed as all patients will have been enrolled and 
the PFS data will be immature.  This interim would not be informative for futility or 
efficacy.  Trial level safety will continue to be monitored throughout the study. 


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LY2228820
6.
Objectives
6.1.
Primary Objective
The primary objective of the Phase 1b portion of this study is to determine the recommended 
Phase 2 dose of LY2228820 that can be safely administered in combination with gemcitabine 
and carboplatin.
The primary objective of the Phase 2 portion of this study is to compare the progression-free 
survival in patients treated with LY2228820 plus gemcitabine and carboplatin versus placebo 
plus gemcitabine and carboplatin.
6.2.
Secondary Objectives
The secondary objectives of the study are to evaluate:

Change in tumor size, CA125 (serum biomarker for ovarian cancer), overall response 
rate, and overall survival (OS)

Safety and tolerability of the combination:  LY2228820 plus gemcitabine and carboplatin

Pharmacokinetics (PK) of LY2228820 and evaluation for effect of LY2228820 on the PK 
of gemcitabine, its metabolite (dFdU), and carboplatin

Biomarkers related to p38 MAPK pathway activity and the pathogenesis of ovarian 
cancer

Patient-reported outcomes for patients enrolled in the Phase 2 portion of the study


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LY2228820
7.
Study Population
7.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
Women ≥18 years of age who have a cytologically or histologically proven 
epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer 
with evidence of recurrence or progression, which is advanced and not 
amenable to curative surgery or radiotherapy. See Attachment 4
(International Federation of Gynecology and Obstetrics [FIGO] Staging) 
(Odicino et al. 2008).
[2]
Have recurrence of cancer at least 6 months after completion of first-line 
platinum-based therapy.  
[3]
For Phase 1b, have either measurable or non-measurable disease.  For Phase 
2, must have at least 1 measurable lesion assessable using standard techniques 
according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
guidelines (Eisenhauer et al. 2009).
[4]
Have a performance status of 2 on the Eastern Cooperative Oncology Group 
(ECOG) scale.  See Attachment 5.
[5]
Have discontinued all previous therapies for cancer (including chemotherapy, 
investigational therapy) for at least 14 days prior to study enrollment and 
recovered from the acute effects of therapy.  Previous radiotherapy must be 
terminated at least 21 days before study drug administration.
[6]
Have adequate organ function, including:

Hematologic:  absolute neutrophil count  1.5 × 109/L, platelets 100 ×
109/L, and hemoglobin 8 g/dL. Patients may receive erythrocyte 
transfusions to achieve this hemoglobin level at the discretion of the 
investigator.  Initial treatment must not begin until 1 day after the 
erythrocyte transfusion.

Hepatic:  bilirubin 1.5 times upper limits of normal and alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5 times 
upper limits of normal.

Renal:  creatinine clearance ≥50 ml/min calculated using the Cockcroft 
and Gault formula (Attachment 6).
[7]
For women of child-bearing potential, must have a negative serum pregnancy 
test within 7 days prior to the first dose of LY2228820 and agree to use a 
reliable method of birth control during the study and for 3 months following 
the last dose of LY2228820.  All women are deemed to be of child-bearing 
potential unless they fulfill one or both of the following criteria:  1) 50 years 
of age with no menstrual period for at least 24 months or 2) prior surgical 
castration.


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LY2228820
[8]
Have given written informed consent/assent prior to any study-specific 
procedures.
[9]
Are able to swallow tablets. 
7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[10] Are currently enrolled in, or discontinued 14 days from, a clinical trial 
involving an investigational drug or device.
[11] Have previously completed or withdrawn from this study or any other study 
investigating LY2228820.
[12] Have previously been treated with gemcitabine for epithelial ovarian cancer, 
fallopian tube cancer, or primary peritoneal cancer.
[13] Receiving concomitant cytotoxic or other antineoplastic treatment. Hormone 
replacement therapy is allowed.
[14] Have had, in the judgment of the investigator, a major bowel resection that 
would alter oral drug absorption.
[15] Have a diagnosis of inflammatory bowel disease (Crohn’s disease or 
ulcerative colitis).
[16] Exclusion criterion [16] has been deleted
[17] Require concurrent administration of immunosuppressive therapy such as 
corticosteroids (prednisone >10 mg/day, or equivalent). Intermittent 
corticosteroids used as part of an antiemetic regimen are permitted. 
[18] Have known central nervous system malignancy or metastasis.
[19] Have a concurrent or previous malignancy (other than epithelial ovarian 
cancer, fallopian tube cancer, or primary peritoneal cancer), unless that prior 
malignancy was treated with definitive therapy at least 5 years previously with 
no evidence of recurrence.  However, cervical carcinoma (in situ) or localized 
non-melanoma skin cancer treated with definitive therapy with no evidence of 
recurrence are not subject to this 5-year requirement.
[20] Have serious concomitant systemic disorders (e.g., acute myocardial 
infarction within 6 months of study entry, uncontrolled hypertension) 
incompatible with the study.
[21] Have received more than 1 previous chemotherapy regimen for ovarian
cancer.
[22] Have any diagnosis of ovarian borderline tumor.
[23] Exclusion Criterion [23] has been deleted.
[24] Are pregnant or lactating women.


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7.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion Criterion [10] eliminates drugs that cannot be mapped to a standard drug dictionary, or 
for which little data are known to analyze the potential relationship of adverse events (AEs) or 
drug interactions.  Exclusion Criteria [11], [12], [13], [17], [20], [21], [23], and [24] exclude 
patients with confounding therapy, conditions, or circumstances.  Exclusion Criteria [14], [15], 
and [16] exclude patients receiving medications that may alter absorption or metabolism of 
LY2228820.  Exclusion Criteria [18], [19], and [22] exclude patients with conditions that have a 
distinct prognosis.
7.3.
Discontinuations
7.3.1. Discontinuation of Patients
The criteria for enrollment must be followed explicitly.  If a patient who does not meet 
enrollment criteria is inadvertently enrolled, Lilly or its designee must be contacted.  In these 
cases, the investigator must obtain documented approval from Lilly to allow the patient to 
continue to receive study drug.
In addition, patients will be discontinued from the study treatment and/or study in the following 
circumstances.

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Investigator/physician decision
o
The investigator/physician decides that the patient should be withdrawn from the 
study treatment and/or study.  If this decision is made because of toxicity, a 
serious AE, or a clinically significant laboratory value, the study drug(s) should
be discontinued and appropriate measures taken.
o
If 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 the study treatment occurs prior to introduction of the new 
agent.

Patient decision 
o
The patient, or the patient’s designated representative, requests that the patient be 
withdrawn from the study treatment and/or study.

Sponsor decision
o
The investigator or Lilly stops the study or stops the patient’s participation in the 
study for medical, safety, regulatory, or other reasons consistent with applicable 
laws, regulations, and good clinical practice.

The patient is noncompliant with study treatment and/or procedures.

Evidence of progressive disease as defined by RECIST 1.1.

Unacceptable toxicity.

It is necessary to delay a patient’s treatment more than 21 days due to toxicity.


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
A patient’s calculated creatinine clearance has not returned to 50 mL/min at the 
beginning of an induction cycle (see Section 9.1.1.1).

The patient becomes pregnant or fails to use adequate birth control (for those patients 
who are able to conceive).
Exceptions may be granted in rare circumstances in which the patient has a serious or life-
threatening condition for which there is no effective alternative therapy and, in the judgment of 
the investigator, is receiving benefit from study treatment.  In these rare cases, the investigator 
must obtain documented approval from Lilly to allow the patient to continue to receive study 
treatment.
The reason and date for discontinuation will be collected for all patients.  All patients who
discontinue but receive at least one dose of study treatment will have procedures performed as 
shown in the Study Schedule (Attachment 1).
For Phase 1b, any patient who experiences a dose-limiting toxicity or receives at least 75% of 
planned doses of LY2228820 in Cycle 1 will be deemed evaluable for safety assessment at that
dose level.  Non-evaluable patients may be replaced to ensure at least 3 evaluable patients at 
each dose level, unless accrual to that cohort has stopped because 2 or more patients at that dose 
level have experienced a DLT.  In no case should patients be replaced if they were discontinued 
from the study due to toxicity.  Patients who are evaluable for safety assessment at a dose level
but have insufficient PK sampling may be replaced upon consultation with the investigator(s) 
and the Lilly Clinical Research Physician (CRP) to ensure adequate PK data, unless accrual to 
that cohort has stopped because 2 or more patients at that dose level have experienced a DLT.
7.3.2. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges it necessary for medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP).
7.3.3. Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, ethical, 
or other reasons consistent with applicable laws, regulations, and GCP.


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8.
Investigational Plan
8.1.
Summary of Study Design
Study JIAE consists of Phase 1b dose escalation followed by a  Phase 2 randomized, double-
blind, placebo-controlled trial in women with advanced epithelial ovarian cancer, fallopian tube 
cancer, or primary peritoneal cancer who have relapsed at least 6 months after first-line 
platinum-based therapy (refer to Figure JIAE.1).
Platinum-Sensitive
Ovary Cancer
(relapse 6 months)
R
LY + GC
(6 cycles)
Placebo + GC
(6 cycles)
LY
(until progression)
Placebo
(until progression)
GC  =  gemcitabine + carboplatin
LY = LY2228820
Maintenance
1:1 randomization
Interim analyses
More involved PK
for Phase 1b and
for a subset of pts in Phase 2
Phase 2
LY + GC
(6 cycles) 
followed by
LY maintenance
Phase 1b
Figure JIAE.1.
Study design for Protocol 1ID-MC-JIAE.
Throughout the study, LY2228820 (or placebo) will be administered orally on an intermittent 
schedule (every 12 hours on Days 1 through 10 of a 21-day cycle during induction therapy and 
every 12 hours on Days 1 through 14 of a 28-day cycle during maintenance therapy).
During induction therapy, gemcitabine will be administered IV over approximately 30 (+15)
minutes on Days 3 and 10 of the 21-day cycle and carboplatin will be administered IV 30 
minutes after gemcitabine over approximately 30 (+15) minutes on Day 3 of the 21-day cycle.
8.1.1. Phase 1b
An unblinded, Phase 1b dose escalation of LY2228820 in combination with standard doses of 
gemcitabine and carboplatin will be completed prior to opening the randomized, double-blind, 
placebo-controlled Phase 2 portion of this study.  Using a “3+3” dose escalation method, cohorts 
of 3 patients will be treated with induction therapy at escalating doses of LY2228820, orally 


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administered every 12 hours on Days 1 through 10 of a 21-day cycle, in combination with 
gemcitabine (1000 mg/m2 on Days 3 and 10) and carboplatin (AUC 4 on Day 3).  Patients will 
receive 6 cycles of induction therapy unless the discontinuation criteria are fulfilled.  All patients 
in the Phase 1b portion of the study that achieve stable disease or better will also receive 
maintenance therapy consisting of LY2228820 as a single agent at a dose of 300 mg every 
12 hours on Days 1 through 14 of a 28-day cycle.  Patients will continue maintenance therapy 
until the discontinuation criteria are fulfilled.
8.1.2. Phase 2
After the optimal dose of LY2228820 in combination with gemcitabine and carboplatin has been 
determined from the Phase 1b portion and discussed with study investigators, the Phase 2 portion 
of the study will open to enrollment.  The recommended Phase 2 dose of LY2228820 in 
combination with gemcitabine and carboplatin will not exceed the single-agent LY2228820 dose 
of 300 mg every 12 hours.  In the Phase 2 portion, approximately 110 patients will be 
randomized 1:1 to receive either LY2228820 plus gemcitabine and carboplatin (Arm A) or 
placebo plus gemcitabine and carboplatin (Arm B).  Patients will receive 6 cycles of induction 
therapy unless the discontinuation criteria are fulfilled.  All patients in the Phase 2 portion of the 
study that achieve stable disease or better will also receive maintenance therapy consisting of 
LY2228820 as a single agent at a dose of 300 mg every 12 hours on Days 1 through 14 of a 
28-day cycle.  Patients will continue maintenance therapy until the discontinuation criteria are 
fulfilled.
Approximately 110 patients will be randomized 1:1 to provide 83% power for identifying a 
hazard ratio of 0.7 (LY2228820 arm to placebo arm) with a false-positive rate of 0.2 (one-sided) 
(refer to Section 12 for additional details regarding the sample size description). Patients will be 
randomized with a minimization method (Pocock and Simon 1975) using the following factors: 
time from completion of first line platinum-based therapy to relapse (6 to 12 months versus over 
12 months) and ECOG performance status (0 and 1 versus 2).
Starting from protocol (c), randomization scheme is updated by adding another randomization 
factor. Patients who consent to protocol (c) will be randomized using following factors: time 
from completion of first line platinum-based therapy to relapse (6 to 12 months versus over 12 
months), ECOG performance status (0 and 1 versus 2) and maintenance therapy as a part of or 
after a first line platinum regimen (yes versus no).
8.1.3. Maintenance Therapy
After completion of 6 cycles of combination therapy, patients with stable disease or better will 
receive maintenance therapy with either LY2228820 or placebo according to the original 
randomization until the discontinuation criteria are fulfilled (refer to Section 7.3.1).  After 
discontinuation from study treatment, patients will have a short-term follow-up period of 
approximately 30 days with a long-term follow-up period until death or until the patient is lost to 
follow-up.  Patients who benefit may continue to receive study treatment for long-term durations 
even after the study has met its primary objective.


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This study will be considered complete following the analysis of PFS. The database will be 
locked, and the Clinical Study Report will be completed after at least 103 PFS events have been 
observed.  After the study is considered complete, patients and investigators will remain blinded 
and survival data will continue to be collected.  The analysis of OS will be performed after all 
patients in the Phase 2 portion of the study have been followed for at least 2 years.  After the 
analysis of OS, both patients and investigators will be unblinded; patients receiving maintenance 
therapy with placebo will discontinue study treatment, whereas patients receiving maintenance 
therapy with LY2228820 may continue study treatment on the extension phase of the study until 
the discontinuation criteria are fulfilled.
8.1.4. Interim Analyses
The first interim analysis will be conducted to assess safety and PK; it will be performed when 
all evaluable patients in the Phase 1b portion of the study have received at least 1 cycle of study 
treatment.
The second interim analysis will be conducted to assess safety and PK; it will be performed
when approximately 30 patients in the Phase 2 portion of the study have received at least 1 cycle 
of study treatment.
The third interim analysis will be conducted to assess safety, and PK; it will be performed when 
approximately 60 patients in the Phase 2 portion of the study have received at least 2 cycles of 
study treatment.
Interim analyses for the Phase 2 portion of the study will be performed under the guidance of an 
internal assessment committee. See Section 12.2.11 for further details regarding interim 
analyses.
8.1.5. Study Period Definitions
Terms used to describe the study periods are defined below:

Baseline:  from the time of screening to first study treatment (or discontinuation, if no 
treatment is given)

Study Treatment Period:  time from treatment start to discontinuation from study 
treatment

Post-discontinuation Follow-Up:  begins the day after the patient discontinues study 
treatment. 
o
The short-term follow-up period begins 1 day after the patient discontinues study 
treatment and lasts approximately 30 days.
o
The long-term follow-up period begins 1 day after the short-term follow-up 
period is completed and continues until death or until the patient is lost to follow-
up. During the long-term follow-up period, patients should be assessed for 
survival every 84 ±14 days.
Patients will receive study treatment until the discontinuation criteria are fulfilled (refer to 
Section 7.3.1).


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All patients in the Phase Ib portion of the study will have intensive PK sampling.  Approximately 
20 patients (10 patients/arm) in the Phase 2 portion of the study will also have intensive PK 
sampling; all other patients in the Phase 2 portion will have standard PK sampling at regularly 
scheduled clinic visits as outlined in the study schedule.
8.1.6. Baseline and Study Treatment Period Assessments
The Study Schedule (Attachment 1) describes the timing of baseline and study treatment period 
assessments for both phases.  All patients who receive at least one dose of study treatment will 
have procedures performed as shown in the Study Schedule (Attachment 1).
Written informed consent must be obtained prior to any study-specific pretreatment evaluations.  
At baseline and/or during the study treatment period, the following assessments will be 
completed:  medical history, physical examination, tumor assessment, radiologic imaging, 
clinical laboratory tests, ECG, stored sample for pharmacogenomics (where local regulations 
allow), samples for PK, circulating plasma proteins, Functional Assessment of Cancer Therapy-
Ovarian Cancer (FACT-O) instrument, and archived tumor sample.
Tumor measurements will be performed by radiologic imaging every 2 cycles according to the
study schedule until evidence of progressive disease as defined by RECIST 1.1 is observed (refer 
to Section 10.1).  Tumor responses will be confirmed. Imaging methods used at baseline must 
be consistently used during study.  For patients continuing on study treatment after the analysis 
of PFS and secondary objective are complete (see Section 8.1.3), efficacy assessments will be 
done at the investigator’s discretion based on the standard of care.
All enrolled patients will be assessed for toxicity using Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0.  Adverse event reporting will be done as specified in
Table JIAE.10.1 (Section 10.3).
8.1.7. Post-discontinuation Follow-Up Period Assessments
All patients should be followed and AEs reported for a minimum of 30 days after the patient 
discontinues study treatment.  Other follow-up assessments will be conducted according to the 
Study Schedule (Attachment 1).
8.1.8. Study Extension
The analysis of OS will be performed after all patients in the Phase 2 portion of the study have 
been followed for at least 2 years.  After the final analysis of OS, both patients and investigators 
will be unblinded; patients receiving maintenance therapy with placebo will discontinue study 
treatment, whereas patients receiving maintenance therapy with LY2228820 may continue study 
treatment on the extension phase of the study until the discontinuation criteria are fulfilled.
Serious AEs will be collected and reported to Lilly Global Patient Safety (see Section 10.3.1).  In 
the event that an SAE occurs, additional information (such as local laboratory results, 
concomitant medications, and hospitalizations) may be requested by Lilly in order to evaluate the 
reported SAE.


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Adverse events leading to discontinuation and dose reduction of treatment will also be collected. 
Investigators may perform other standard procedures and tests needed to treat and evaluate 
patients; however, the results of all these assessments may not be routinely collected by the 
sponsor.
The patient’s participation in the study extension will be completed after discontinuation of study 
treatment.  There will be no post-discontinuation follow-up period in the extension phase of the 
study.
8.2.
Discussion of Design and Control
The Phase 1b portion of this study utilizes a standard 3+3 design involving 2 sequential cohorts 
of at least 3 patients treated during induction therapy with gemcitabine and carboplatin plus 
escalating LY2228820 doses (200 mg and 300 mg every 12 hours on Days 1 through 10 of a 21-
day cycle, respectively).
The Phase 2 portion of this study utilizes a randomized, controlled design.  Randomization 
minimizes systematic bias in the selection and assignment of patients to study treatment and 
provides justification for inferential statistical methods applied to data from this study.  Using an 
appropriate concurrent control arm enables direct statistical estimation of benefits and harms due 
to study treatment and minimizes bias in the assessment and interpretation of observed treatment 
effects.
Investigational treatment administration in this study is double-blind.  Patients, study personnel 
at investigational sites, and study personnel at the sponsor do not have immediate access to 
treatment assignments for any patients.  This design feature minimizes potential bias due to 
knowledge of treatment assignments during the study.


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9.
Treatment
9.1.
Treatments Administered
Study treatments will be administered as summarized in Table JIAE.9.1.


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Table JIAE.9.1.
Treatment Regimens/Dosing Schedule
Treatment
Cycle Duration
Regimen
Phase 1b (Cohort 1)
21 days (Cycles 1-6)
(Induction)
28 days (Cycles 7+)    
(Maintenance)
LY2228820 200 mg PO Q12H on Days 1-10
Gemcitabine 1000 mg/m2 IV over 30 minutes on 
Days 3 and 10a
Carboplatin AUC 4 [max dose 600 mg] IV over 30 
minutes on Day 3a, b
LY 2228820 300 mg PO Q12H on Days 1-14
Phase 1b (Cohort 2)
21 days (Cycles 1-6)
(Induction)
28 days (Cycles 7+)    
(Maintenance)
LY2228820 300 mg PO Q12H on Days 1-10
Gemcitabine 1000 mg/m2 IV over 30 minutes on 
Days 3 and 10a
Carboplatin AUC 4 [max dose 600 mg] IV over 30 
minutes on Day 3a, b
LY2228820 300 mg PO Q12H on Days 1-14
Phase 2 (Arm A)
21 days (Cycles 1-6)
(Induction)
28 days (Cycles 7+)
(Maintenance)
LY2228820 RP2D PO Q12H on Days 1-10c
Gemcitabine 1000 mg/m2 IV over 30 minutes (+15
minutes) on Days 3 and 10a
Carboplatin AUC 4 [max dose 600 mg] IV over 30 
minutes (+15 minutes) on Day 3a, b
LY2228820 300 mg PO Q12H on Days 1-14
Phase 2 (Arm B)
21 days (Cycles 1-6)
(Induction)
28 days (Cycles 7+)
(Maintenance)
Placebo RP2D PO Q12H on Days 1-10c
Gemcitabine 1000 mg/m2 IV over 30 minutes (+15
minutes) on Days 3 and 10a
Carboplatin AUC 4 [max dose 600 mg] IV over 30 
minutes (+15 minutes) on Day 3a, b
Placebo 300 mg PO Q12H on Days 1-14
Abbreviations:  PO = oral; IV = intravenous; Q12H = every 12 hours; max = maximum; RP2D = recommended 
phase 2 dose (in combination with gemcitabine and carboplatin).
a
An extension of the gemcitabine and/or carboplatin infusion times to 45 minutes is permissible; however, every 
effort should be made to adhere to a 30-minute infusion time. The total infusion time should be recorded in the 
case report form.
b
The carboplatin dosage will be calculated as follows: Dose (mg)= target (AUC)[4] x (GFR +25).  For a target 
AUC=4, the maximum dose is 600 mg.
c
Therecommended Phase 2 dose will be communicated to investigative sites by a formal study communication.


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Any measurements used to determine dose should be taken at each cycle, and dose should be re-
calculated for each cycle.  Patients must meet the criteria to receive all 3 drugs on Day 1 in order 
to start the next cycle.
The investigator or his/her designee is responsible for the following:

Explaining the correct use of the drug(s) and planned duration of each individual’s 
treatment to the patient and site personnel

Verifying that instructions are followed properly 

Maintaining accurate records of study drug dispensing and collection 

Returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose clinical trial materials.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug(s) so that the situation can be assessed.
9.1.1. Carboplatin Dosing
Carboplatin dosing, using the Calvert formula, is often based upon a calculated creatinine 
clearance using serum creatinine as a surrogate for renal function.  Several assays are available to 
measure serum creatinine.  In the United States and many parts of the world, most laboratories 
use methods that are standardized against reference material in which the creatinine value has 
been assigned by IDMS.  After 31 December 2010, all clinical laboratories in the United States, 
and some laboratories in countries outside the US (OUS), will use creatinine methods 
standardized relative to the IDMS reference material.
The recalibration of serum creatinine measurements against the IDMS reference material may 
result in slight differences in reported serum creatinine levels in the low range of normal.  
Consequently, measurement of serum creatinine relative to the IDMS standard could result in an 
overestimation of glomerular filtration rate (GFR) in some patients with normal renal function.  
If the total carboplatin dose is calculated based on an estimated GFR using an IDMS-
standardized serum creatinine and the Calvert formula, carboplatin dosing could be higher than if 
the GFR had been directly measured, and could result in increased toxicity.
At sites where creatinine is determined by a method standardized to the IDMS reference 
material, the estimated GFR used in the Calvert formula to calculate AUC-based dosing should 
not exceed 125 mL/min for patients who have not begun therapy.  After 31 December 2010, all 
US sites and any other OUS site where the IDMS method is available should calculate 
carboplatin doses based upon serum creatinine values that were measured by the IDMS method.  
At sites where the IDMS method is not available, for the estimated GFR used to calculate the 
Calvert formula, all sites will follow the dosing guidelines outlined below and cap the GFR at 
125 mL/min.


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The site is responsible to consult the local lab to determine what method of serum creatinine 
measurement is used by that laboratory.
For this study, the carboplatin dose must be calculated using the Calvert formula (Attachment 7).
9.1.1.1.
Calculated Creatinine Clearance
Creatinine clearance will be calculated using the Cockcroft and Gault formula (Attachment 6).  
This formula should be used to calculate a patient’s creatinine clearance at baseline and for all 
subsequent cycles of induction therapy.  If a patient’s calculated creatinine clearance has not 
returned to 50 mL/min at the beginning of a cycle during induction therapy, the patient must 
not receive further carboplatin unless approved by the Lilly CRP. Alternative formulas, such as 
Modification of Diet in Renal Disease (MDRD) Study Group formula, may not be used to 
calculate the creatinine clearance.
9.2.
Materials and Supplies
LY2228820 will be provided by Lilly.  Gemcitabine, carboplatin, and other standard of care 
drugs will be provided according to local requirements. Clinical trial materials will be labeled 
according to the country’s regulatory requirements.  All study drugs should be stored within the 
temperature range stated on the label.
9.2.1. LY2228820
LY2228820 will be supplied as tablets for oral administration.  LY2228820 tablets should be 
stored within the temperature range stated on the label.  Investigators should instruct patients to 
store the tablets at home in the original package and to keep out of the reach of children.  Tablets 
should not be split, crushed, or dissolved.
9.2.2. Gemcitabine
Gemcitabine is supplied as a lyophilized powder in sterile vials containing either 200 mg or 1 g 
of gemcitabine as the hydrochloride salt with mannitol and sodium acetate. The lyophilized 
product should be stored at room temperature. Drug will be reconstituted with normal saline 
added to the vial to make a solution ideally containing 10 mg/mL (not to exceed 40 mg/mL).  
Once the drug has been reconstituted it should be stored at room temperature and used within 
24 hours. Any unused portion of a vial must not be stored for future use and must be discarded.
9.2.3. Carboplatin
Carboplatin is supplied as a sterile, pyrogen-free solution available in 10 mg/mL multiple-dose 
vials containing 50 mg, 150 mg, 450 mg, or 600 mg of carboplatin for administration by 
intravenous infusion.
Note: Aluminum reacts with carboplatin, causing precipitate formation and loss of potency;
therefore, needles or IV sets containing aluminum parts that may come in contact with the drug 
must not be used for the preparation or administration of carboplatin.


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9.2.4. Placebo
Placebo will be supplied as tablets (consisting of inactive ingredients) for oral administration.
9.3.
Method of Assignment to Treatment
In the Phase 1b portion of the study, patients will be assigned to a specific dose level in cohorts 
of 3 patients as described in Section 9.5.
In the Phase 2 portion of the study, approximately 110 patients will be randomized 1:1 in a 
double-blind manner by an interactive voice-response system (IVRS) to either Arm A 
(LY2228820 plus gemcitabine and carboplatin) or Arm B (placebo plus gemcitabine and 
carboplatin). Randomization will minimize imbalance between treatment arms according to the 
following factors:  time from completion of first line platinum-based therapy to relapse (6 to 12 
months versus over 12 months) and ECOG performance status (0 and 1 versus 2). 
Starting from protocol (c), the randomization scheme is updated by adding another 
randomization factor.  Patients who consent to protocol (c) will be randomized using following 
the factors: time from completion of first line platinum-based therapy to relapse (6 to 12 months 
versus over 12 months), ECOG performance status (0 and 1 versus 2) and maintenance therapy 
as a part of or after a first line platinum regimen (yes versus no).
This procedure is based on a well-defined algorithm (Pocock and Simon 1975).  The 
randomization probability factor will be set at 0.75.
The IVRS will be used to assign blisterpacks containing double-blind study drug to each patient.  
Site personnel will confirm that they have located the correct blisterpacks by entering a 
confirmation number found on the blisterpacks into the IVRS.
9.4.
Selection and Timing of Doses
As described in Table JIAE.9.1, Phase 1b is the dose escalation phase of the study and Phase 2 is 
the randomized phase of the study.
Patients will receive LY2228820 (or placebo) in combination with gemcitabine and carboplatin 
for 6 cycles as induction therapy. LY2228820 (or placebo) will be administered every 12 hours 
on Days 1 to 10 of a 21-day cycle.  Gemcitabine 1000 mg will be administered on Days 3 and 10 
and carboplatin AUC 4 will be administered on Day 3. After the completion of induction 
therapy, LY2228820 (or placebo) will be taken on Days 1 to 14 of a 28-day cycle for 
maintenance therapy.  .
LY2228820 is administered prior to chemotherapy to allow LY2228820 to reach steady state and
achieve maximal p38 MAPK inhibition, blocking a potential survival mechanism by which
tumor cells evade gemcitabine- and carboplatin-induced DNA damage. The study drug 
administration schedule is intended to mimic the 50% on/off schedule of single-agent usage of 
LY2228820 within the 21-day schedule required for the gemcitabine /carboplatin combination.


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9.4.1. Phase 1b
9.4.1.1.
Induction Therapy
LY2228820 will be administered orally every 12 hours (±3 hours) on Days 1 through 10 of a 21-
day cycle.  Patients should not consume food beginning 1 hour before and ending 1 hour after 
taking the study drug.  LY2228820 should be taken at the same time of the day (for example, 
0800 hours and 2000 hours) with a full glass of water.   If a patient misses or vomits a dose, that 
dose should be omitted.  Patients must record the time and amount of each dose taken (or 
alternatively, the time and amount of the dose missed or vomited) in a daily diary.
Gemcitabine, 1000 mg/m2, will be administered IV over approximately 30 (+15) minutes on 
Days 3 and 10 of a 21-day cycle.  The gemcitabine infusion will be started following the 
morning dose of LY2228820.
Carboplatin, AUC 4 (maximum dose, 600 mg), will be administered IV over approximately 
30 (+15) minutes on Day 3 of a 21-day cycle.  The carboplatin infusion will follow the 
gemcitabine infusion.  Antiemetics should be administered according to institutional standard 
procedures.
9.4.1.2.
Maintenance Therapy
After completion of 6 cycles of induction therapy, patients with stable disease or better will 
receive maintenance therapy with LY2228820 until the discontinuation criteria are fulfilled 
(refer to Section 7.3.1).  After discontinuation from study treatment, patients will have a short-
term follow-up period of approximately 30 days with a long-term follow-up period until death or 
until the patient is lost to follow-up.  Patients who benefit may continue to receive study 
treatment even after the study has met its primary and secondary objectives.
9.4.2. Phase 2
9.4.2.1.
Induction Therapy
LY2228820 or placebo will be administered orally every 12 hours (±3 hours) on Days 1 through 
10 of a 21-day cycle.  Patients should not consume food beginning 1 hour before and ending 
1 hour after taking the study drug.  LY2228820 or placebo should be taken at the same time of 
the day (for example, 0800 hours and 2000 hours) with a full glass of water.  If a patient misses 
or vomits a dose, that dose should be omitted.  Patients must record the time and amount of each 
dose taken (or alternatively, the time and amount of the dose missed or vomited) in a daily diary.
Gemcitabine, 1000 mg/m2, will be administered IV over approximately 30 (+15) minutes on 
Days 3 and 10 of a 21-day cycle.  The gemcitabine infusion will be started following the 
morning dose of LY2228820.
Carboplatin, AUC 4 (maximum dose, 600 mg), will be administered IV over approximately 30 
(+15) minutes on Day 3 of a 21-day cycle.  The carboplatin infusion will follow the gemcitabine 
infusion.  


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9.4.2.2.
Maintenance Therapy
After completion of 6 cycles of induction therapy, patients with stable disease or better will 
receive maintenance therapy with LY2228820 or placebo according to their original treatment 
assignment until the discontinuation criteria are fulfilled (refer to Section 7.3.1).  After 
discontinuation from study treatment, patients will have a short-term follow-up period of 
approximately 30 days followed by a long-term follow-up period until death or until the patient 
is lost to follow-up.  Patients who benefit may continue to receive study treatment even after the 
study has met its primary objective.
9.4.3. Dose Adjustments
9.4.3.1.
Treatment Delays between Cycles
A cycle may be delayed to allow a patient sufficient time for recovery from toxicity related to 
study treatment.  Before the start of each cycle, hematologic toxicities must resolve according to 
the guidelines in Table JIAE.9.3.  Nonhematologic toxicities must resolve to the patient’s 
baseline CTCAE grade or lower.  If a delay in the start of treatment is necessary, all 3 study 
drugs (LY2228828 or placebo, gemcitabine, and carboplatin) should be held. A cycle may be 
delayed by 7 days to accommodate a patient’s schedule or for other unforeseen circumstances.  
Treatment delays between cycles that fulfill these criteria do not constitute a protocol violation.  
Patients who require a delay in treatment of more than 21 days for toxicity will be required to 
discontinue study treatment and enter the Post-Discontinuation Follow-up Period (Attachment 
1).
9.4.3.1.1. LY2228820 Dose Adjustments
Dose adjustments for LY2228820/placebo should be managed according to Table JIAE.2.
Please note these toxicities apply to those attributed to LY2228820/placebo and not necessarily 
those expected from gemcitabine and carboplatin.
Table JIAE.9.2.
Intercycle Dose Adjustments for LY2228820 or Placebo
If
Then
Patient experiences a Grade 3 
or Grade 4 toxicity related to 
LY2228820/placebo…
During induction 
therapy
Decrease dose (between cycles) by a 100 mg decrement
(required).
Continue gemcitabine and carboplatin according to the 
Study Schedule (Attachment 1).
During maintenance 
therapy
Decrease dose (between cycles) by a 100 mg decrement
(required).
Patient experiences a Grade 1 
or Grade 2 toxicity related to 
LY2228820/placebo…
During induction 
therapy
Dose may be decreased (between cycles) by a 100 mg
decrement at the discretion of the investigator.
Continue gemcitabine and carboplatin according to the 
Study Schedule (Attachment 1).
During maintenance 
therapy
Dose may be decreased (between cycles) by a 100 mg
decrement at the discretion of the investigator.


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Any patient who requires a dose reduction in LY2228820/placebo will continue to receive the 
reduced dose for the remainder of the study.  
Any patient who experiences a Grade 3 or Grade 4 toxicity related to LY2228820/placebo at a 
dose of 100 mg every 12 hours (during either induction or maintenance therapy) must be 
discontinued from LY2228820/placebo; however, gemcitabine and carboplatin should be 
continued during induction therapy according to the Study Schedule (Attachment 1). If 
LY2228820/placebo was discontinued during induction therapy due to a Grade 3 or 4 toxicity 
related to LY2228820/placebo, it may not be re-started in maintenance therapy. 
9.4.3.1.2. Gemcitabine Dose Adjustments
Gemcitabine dosage adjustment for hematologic toxicity within a cycle of treatment or between 
cycles of treatment is based on the absolute neutrophil count ANC and platelet count. These 
dose modifications are based on hematologic labs obtained on Day 1 and Day 10 of a cycle.  If 
marrow suppression is detected, gemcitabine dosage should be modified according to guidelines 
in Table JIAE.9.3.
Table JIAE.9.3.
Dosage Reduction Guidelines for Gemcitabine for 
Myelosuppression on Day of Treatment
Treatment Day
Absolute 
Neutrophil 
Count
Platelets
% of Full Dose
Day 1
(for gemcitabine 
dosing on Day 3)
≥1500/mm3
and
≥100,000/mm3
100
≤1500/mm3
or
≤100,000/mm3
Delay treatment cycle
Day 10
≥1500/mm3
and
≥100,000/mm3
100
1000–1499/mm3
or
75,000–99,999/mm3
50
≤1000/mm3
or
<75,000/mm3
Hold gemcitabine
Dose adjustments for gemcitabine in combination with carboplatin for subsequent cycles are
based upon observed toxicity and should be managed according to the guidelines in Table 
JIAE.9.4.


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Table JIAE.9.4.
Gemcitabine Dose Modification for Myelosuppression in Previous 
Cycle
Occurrence
Myelosuppression During Previous Treatment 
Cycle
Dose Modification
Initial Occurrence
Absolute granulocyte count less than 500 x 106/L 
for more than 5 days
Absolute granulocyte count less than 100 x 106/L 
for more than 3 days
Febrile neutropenia
Platelets less than 25,000 x106/L
Cycle delay of more than one week due to toxicity
Permanently reduce gemcitabine to 
800 mg/m2 on Days 3 and 10.
Subsequent Occurrence
If any of the above toxicities occur after the initial 
dose reduction
Permanently reduce gemcitabine to 
800 mg/m2 and administer on Day 
3 only (Day 10 dose omitted).
Withhold gemcitabine or reduce dose by 50% for other severe (Grade 3 or 4) nonhematologic 
toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or 
vomiting.
Gemcitabine therapy should be permanently discontinued for any of the following:

Unexplained dyspnea deemed related to study drug, or other evidence of 
severe pulmonary toxicity

Severe hepatic toxicity

Hemolytic Uremic Syndrome

Capillary Leak Syndrome
9.4.3.1.3. Carboplatin Dose Adjustments
There will be no dose adjustment for carboplatin in this study.  For patients with a calculated 
creatinine clearance <50 mL/min, refer to Section 9.1.1.1 for additional guidance.
9.4.3.1.4. Clinically Significant Effusions
For patients who have a clinically significant pleural or peritoneal effusion (on the basis of 
symptoms or clinical examination), consideration should be given to draining the effusion prior 
to study treatment.
9.5.
Dose Escalation (Phase Ib)
The dose will be escalated following assessment of toxicity using the standard scoring system, 
Common Terminology Criteria for Adverse Events (CTCAE Version 4.0), established by the 
National Cancer Institute (NCI). 
During Phase 1b, dose escalation of LY2228820 will occur in cohorts of 3 patients treated at the 
dose levels outlined in Table JIAE.9.1. The LY2228820 starting dose of 200 mg every 12 hours
in Study JIAE has been explored previously in Study JIAD and is 1 dose level lower than the 


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single-agent recommended Phase 2 dose of 300 mg every 12 hours.  All patients in Study JIAE
will receive gemcitabine and carboplatin during induction therapy, as outlined in Section 9.4.
Dose escalation will proceed cohort by cohort until 1 patient at a given dose level experiences a 
DLT, as defined in Section 9.5.1. In the event a DLT occurs in 1 of 3 patients at a given dose 
level, the cohort will be expanded up to a total of 6 patients.  If no further DLTs are observed at 
that dose level, the dose escalation can resume.  If a DLT occurs in 2 or more of 6 patients or 
33.3% of patients at a given dose level, then the combination MTD has been identified or 
exceeded and dose escalation will cease. However, following discussions between the 
investigators and the sponsor, additional patients may be treated at intermediate doses to define 
the combination MTD more precisely.  During Phase 1b, intrapatient dose escalation is not 
permitted, and dose escalation to the next cohort cannot occur without prior discussion and 
agreement between the investigator and the responsible Lilly CRP.
9.5.1. Dose-Limiting Toxicity Determination and Maximum Tolerated 
Dose Definition
A DLT is defined as an AE likely related to LY2228820 that occurs during Cycle 1 in Phase 1b
and fulfills any one of the following criteria:

Grade 3 or 4 nonhematologic toxicity except for nausea/vomiting, diarrhea, or electrolyte 
disturbances

Grade 3 or 4 nausea/vomiting or diarrhea that persists 2 days despite the use of adequate 
or maximal medical intervention

Grade 3 or 4 electrolyte disturbances that persist 5 days despite maximal supportive 
treatment

Grade 4 hematologic toxicity that persists more than 5 days

Grade 3 or 4 thrombocytopenia with bleeding

Febrile neutropenia
All toxicities should be graded according to CTCAE Version 4.0.
Investigators, in consultation with the Lilly CRP, can declare a DLT if a patient has increasing 
toxicity and therapy cannot be continued without exposing the patient to excessive risk.
The MTD is defined as the highest dose level at which no more than 33% of patients experience 
a DLT during Cycle 1 that does not exceed the single-agent MTD for LY2228820 (300 mg 
Q12H).
9.6.
Continued Access to Study Drug
Study drug may be made available after conclusion of the study to patients who are still 
receiving and benefitting from study treatment in countries where the drug cannot be lawfully 
prescribed. 


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9.7.
Blinding
The Phase 1b portion of this study is open-label whereas the Phase 2 portion of this study is 
double-blind.
To preserve blinding of the study, a minimum number of sponsor personnel will see the 
randomization table and treatment assignments before PFS and OS analyses are completed.
Emergency unblinding for AEs may be performed through an IVRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used only if the patient’s well-being requires knowledge of the patient’s treatment
assignment.  All calls resulting in an unblinding event are recorded and reported by the IVRS.
The investigator should make every effort to contact the Lilly CRP prior to unblinding a patient’s 
treatment assignment.  If a patient’s treatment assignment is unblinded, Lilly must be notified 
immediately by telephone.
Every effort will be made to blind both the patient and the investigator to the treatment
assignment, but the inadvertent unblinding of a patient may occur.  A double-blind study design 
is known to be imperfect because the potential for individual unblinding exists due to treatment-
related signs and symptoms.  If a patient or investigator is unblinded, the unblinding will not 
alone be sufficient cause for that patient to be discontinued from study treatment or excluded 
from any safety or efficacy analyses.
Additionally, there may be ethical reasons to have the patient remain on study treatment.  For 
patients to continue on study treatment in the event of unblinding, the investigator must obtain 
specific approval from a Lilly CRP for the patient to continue in the study.  
Patients and investigators will remain blinded to study treatment with no sharing of efficacy 
information among sites until both PFS and OS analyses are completed.  Treatment assignment 
will be blinded in the reporting database except for a minimum number of sponsor personnel 
required to perform the interim and final analyses.  This will ensure unblinded aggregate efficacy 
results are not available outside of the Assessment Committee until the time of final data 
analysis.   Patients and investigators may be unblinded after both PFS and OS analyses are 
completed.
For this study, there are 4 planned interim analyses (1 for Phase 1b and 3 for Phase 2).  During 
Phase 2, blinding of the study requires that interim analyses be conducted under the guidance of 
an Assessment Committee. See Section 12.2.11 for further details.
9.8.
Concomitant Therapy
With the exceptions listed in the following sections, no other chemotherapy, experimental 
medications, other anticancer therapy, immunotherapy, hormonal cancer therapy, radiation, 
surgery for cancer, or experimental medications will be permitted while patients are on study 
treatment.  The need for any form of radiotherapy (including palliative) will be cause for early 
discontinuation from study treatment.  In addition any disease progression requiring other forms 
of specific antitumor therapy will also necessitate early discontinuation from study treatment.  


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Appropriate documentation of all forms of premedication’s, supportive care, and concomitant 
medications must be captured at each visit in the case report form (CRF).  Concomitant 
medications and supportive care therapies must be documented at the time of discontinuation and 
also at the 30-day follow-up visit.
Based on the available preclinical data, there is a possible risk of clinical drug–drug interaction 
when LY2228820 is administered with inhibitors or inducers of UGT enzymes. In the absence 
of clinical data to refine the risk of interaction, caution is warranted in the concomitant use of 
UGT enzyme inhibitors such as valproic acid and probenecid and inducers such as 
carbamazepine, phenytoin and rifampin.  When, in the clinical investigator's opinion, 
concomitant use of valproic acid or probenecid is indicated, LY2228820-related DLTs of ataxia, 
dizziness and rash should be carefully monitored.
It is recommended that patients minimize alcohol use during the study and, if clinically feasible, 
avoid medications acting as depressants of the central nervous system.
9.8.1. Supportive Care
Patients should receive full supportive care if necessary.  Supportive care is defined as a 
treatment that lacks antineoplastic activity and is given specifically with the intent to maximize 
quality of life.  Those therapies considered acceptable include, but are not limited to, transfusions 
of red blood cells and platelets as well as medications that are not excluded as “concomitant 
therapy.”  Patients will receive supportive care as judged by their treating physician.  If it is 
unclear whether a therapy should be regarded as supportive care, the investigator should consult
the Lilly CRP.  Use of any supportive care therapy should be reported on the case report forms.
9.8.2. Carboplatin Infusion Reactions
Patients who experience a hypersensitivity reaction to carboplatin should receive epinephrine, 
corticosteroid, and antihistamine therapy according to institutional standards.  If the institutional 
standards differ from this regimen, the Lilly CRP should be consulted.
9.8.3. Colony-Stimulating Factors
The protocol permits the routine use of granulocyte colony-stimulating factors and 
erythropoiesis-stimulating agents (ESAs) as supportive care agents according to ASCO 
guidelines (Rizzo et al. 2010).  Granulocyte colony-stimulating factors should not be used 
prophylactically unless previously discussed with the Lilly CRP. The protocol does not allow 
the use of products that stimulate thrombopoiesis.
Erythropoietic therapy may be considered for treatment of chemotherapy-induced anemia for 
patients with hemoglobin 10 g/dL after the patients has been counseled about the risks and 
benefits of ESA use (Rizzo et al. 2008; Smith et al. 2006).  Because recommendations on the use 
of ESAs are rapidly evolving, investigators should refer to the National Comprehensive Cancer 
Network (NCCN), American Society of Clinical Oncology (ASCO), and/or Centers for Medicare 
and Medicaid Services web sites for the latest guidelines.


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9.9.
Treatment Compliance
Patient compliance with LY2228820 will be assessed at each visit.  Compliance will be assessed 
by patient diary entries, direct questioning, and counting returned tablets.  Patients must take 
75% of the scheduled doses of LY2228820 in a cycle to be judged compliant with oral study 
drug administration.  Similarly, a patient will be considered significantly noncompliant if judged 
by the investigator to have intentionally or repeatedly taken ≥125% of the scheduled doses of 
LY2228820.  Any missed doses will be omitted and not replaced during the treatment period.  In 
the event of a missed dose, patients should resume and continue the dosing schedule beginning 
with the next scheduled dose.
Discontinuation of a patient due to oral study drug noncompliance will be discussed between the 
investigator and the Lilly CRP before making the final determination for discontinuation.  If a 
patient is discontinued due to noncompliance, the patient may be replaced.
Gemcitabine and carboplatin will be administered only at the investigational sites by the 
authorized study personnel.  As a result, treatment compliance is ensured.


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10. Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements
Study procedures and their timing are described in the sections below and shown in the Study 
Schedule (Attachment 1).
10.1. Efficacy Measures
Each patient will be assessed by one or more of the following radiologic tests for tumor 
measurement at the time specified in the Study Schedule:

Computerized tomography (CT) scan

Magnetic resonance imaging (MRI)
Each patient’s extent of disease will also be assessed with the following procedures:

Tumor measurement of palpable or visible lesions (refer to Modified Response 
Evaluation Criteria in Solid Tumors [RECIST] Guidelines Version 1.1, Attachment 8)

CA125

Evaluation of performance status (refer to the ECOG Scale, Attachment 5)
10.1.1. Efficacy Assessments at Baseline and during Study
Within 28 days before the first dose of study drug, baseline tumor measurement(s) will be 
performed on each patient.  Computed tomography, including spiral CT scans, and MRI are the 
preferred methods of measurement.
The method of assessment used at baseline must be used consistently for tumor assessment and 
will be repeated every other cycle.
10.1.2. Efficacy Assessments during the Post-discontinuation Period
For those patients who discontinue study treatment without progressive disease, the investigative 
sites will continue to monitor patients and periodically evaluate tumor response according to the 
institutional standard of care frequency by the same method used at baseline and throughout the 
study until the discontinuation criteria are fulfilled.  After the patient has confirmed progressive 
disease, radiologic tests are no longer required and the patient will be followed every 84 days 
(14 days) until death or until the patient is lost to follow up.
After patients have discontinued study treatment, they may receive additional anticancer therapy 
at the discretion of the investigator.  The additional treatments should be documented on the 
CRF.
10.1.3. Primary Efficacy Measure
In the Phase 2 portion of the study, the primary efficacy measure is PFS.  This measure is 
calculated from the date of randomization to the date of objective progression or death due to any 
cause, whichever occurs first.  Section 12.1 describes the method used for censoring PFS.


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10.1.4. Secondary Efficacy Measures
The following secondary efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1).
10.1.4.1. Overall Response Rate
Overall response rate is the percentage of patients who achieved a best response of either 
complete response (CR) or partial response (PR), as determined by RECIST 1.1.
Best response is determined from a sequence of responses assessed. For CR or PR, best
response must be confirmed with a second assessment that is performed ≥28 days after the first 
evidence of response.  Two objective status determinations of CR before progression are 
required for a best response of CR. Two determinations of PR or better before progression, but 
not qualifying for a CR, are required for a best response of PR.  Best response of stable disease 
(SD) is defined as disease that does not meet the criteria for CR, PR, or progressive disease and 
has been evaluated at least 1 time, at least 6 weeks after the start of study treatment. All lesions 
must be assessed by the same method as at baseline to qualify for response confirmation. The 
date of first documented objective disease progression will be recorded on the CRF.
10.1.4.2. Change in Tumor Size
Change in tumor size will be assessed in each patient using radiographic imaging.  This endpoint 
will be based on tumor measurements collected by the centers according to RECIST 
(version 1.1).  Tumor size is the sum of the tumor measurements for target tumors at each tumor 
evaluation.  Change in tumor size is defined as the ratio of tumor size from the evaluation at the 
end of Cycle 2 to the baseline evaluation.
10.1.4.3. Overall Survival
Overall survival is defined as the time from date of randomization to the date of death due to any 
cause.  For patients who are not known to have died as of the data inclusion cut-off date, OS will 
be censored at the date that the patient was last known to be alive.
10.2. Health Outcome/Quality of Life Measures
The multiple burdens of cancer and the effects of anticancer treatment can have a profound 
impact on patients’ health-related quality of life (HRQoL).  A diminished HRQoL can have 
detrimental effects on the efficacy of cancer treatment and may affect treatment outcomes.  The 
FACT-O will be used in this study to assess and compare changes in HRQoL between the 
2 treatment arms.  Health outcome measures will only be collected during the Phase 2 part of this 
study.
10.2.1. Patient-Reported Outcomes
The FACT-O instrument (refer to Attachment 10) is a reliable and valid instrument to measure 
HRQoL in patients with ovarian cancer (Basen-Engquist 2001).  The instrument consists of 
38 items with 5-point rating scales in which 0 equals “not at all” and 4 equals “very much.”  The 
questionnaire is organized into 5 sections with physical, social/family, emotional, functional
well-being and ovarian subscales.


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The validated FACT-O instrument will be used in the Phase 2 portion of the study to help better 
understand the properties of the instrument in this specific patient population and to generate 
hypotheses for subsequent studies. Patient-reported outcome data will be analyzed for 
statistically significant, clinically important, and favorable differences in assessments associated 
with abdominal pain and gastrointestinal symptoms as measured by the FACT-O items O3 
(cramps in stomach), GP2 (nausea), O2 (vomiting), and C6 (good appetite), as well as by 
assessments associated with treatment-related AEs/intolerance as measured by the FACT item 
GP5 (bothered by side effects of treatment).  The FACT-O scores will be calculated using
scoring criteria proposed by the developer (Cella 2004).  Results of the FACT-O can be reported 
as the scores for 5 individual subscales, a FACT-General total score (sum of physical, 
social/family, emotional, and functional well-being subscales), a Trial Outcome Index (TOI) 
(sum of physical well-being, functional well-being, and ovarian subscale), and a FACT-O total 
score (sum of the FACT-General total score and the ovarian subscale).  For all reports, a higher 
score represents a better quality of life.
Both, time to worsening (TTW) and changes from baseline in dimensions of HRQoL using 
FACT-O will be compared between treatment arms.  Minimally important difference (MID) for 
change in scores will be used to determine meaningful differences in patients’ FACT-O scores 
(Yost and Eton 2005).
The TOI is considered to be a valuable summary measure of physical well-being, functional 
well-being, and disease-specific symptoms (Yost and Eton 2005).  In patients with ovarian 
cancer, the patients’ well-being (including functional/physical abilities and disease-specific 
symptoms) will generally continue to worsen as disease progresses.  The TTW is defined as a 
decrease in the TOI score that is considered at least a MID, as compared with the patient’s 
baseline score.  The upper range of MID points (Yost and Eton 2005) will be used as a guide to 
determine the meaningful decrease for individual patient’s score.  The TTW is measured from 
the date of randomization to the first date of a worsening in the TOI (as defined by a decrease 
from baseline in TOI that is at least the MID) or of death from any cause.  For patients who 
receive any subsequent systemic anticancer therapy prior to an observation of worsening, TTW 
will be censored at the date of the last worsening-free assessment prior to the subsequent 
systemic anticancer therapy.  For patients not known to have died or with an observation of 
worsening as of the data cut-off date, TTW will be censored at the date of the last worsening-free 
assessment.  Time to worsening in other dimensions of FACT-O will be measured in a similar 
fashion. The looser range of MID (Yost and Eton 2005) will be used for interpreting the group 
mean change, and the upper limit will be used for interpreting the change in an individual 
patient’s score.
The FACT-O is to be completed at baseline, on Day 3 of Cycles 1 through 6 (induction therapy), 
and at the 30-day post-study follow-up visit as shown in the Study Schedule (Attachment 1).
The FACT-O should be completed at the beginning of office visits, before extensive contact and 
consultation with the clinician/study investigator.  Consultation with the clinician may bias 
perceptions about HRQoL and symptoms and thus affect assessments.  Patients will complete the 
questionnaire prior to administration of subsequent cycles of study drug.


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The FACT-O will be completed by the patient.  Only patients with adequate literacy and for 
whom there is a validated translation in the language in which the patient is fluent will be asked 
to complete any self-administered questionnaires.
10.2.2. Resource Utilization
Investigators will be asked to document the use of best supportive care measures, concomitant 
medications, transfusions, and treatment-related hospitalization days.  Such assessments are to be 
taken throughout the study through the 30-day post-discontinuation visit and will largely be 
derived from clinical data routinely collected through the CRFs.  Medical resource utilization 
data will be analyzed for exploratory purposes.
10.3. Safety Evaluations
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or that caused the patient to discontinue before completing the study.  The 
patient should be followed until the event is resolved or explained.  Frequency of follow-up 
evaluation is left to the discretion of the investigator.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  
Table JIAE.10.1 describes AE and SAE collection with regard to the type of events to be 
collected in each study period.
Table JIAE.10.1.
Adverse Event and Serious Adverse Reporting Guidelines for 
Study JIAE
Treatment Period
Types of AEs/SAEs Collected/Reported
Baseline (pretreatment)
Pre-existing conditions
Procedure-related AEs/SAEs
Study treatment period (on therapy)
All AEs/SAEs 
30-day post-discontinuation follow-
up visit after the last dose 
All AEs/SAEs 
Subsequent post-discontinuation 
follow-up visits, if necessary 
SAEs are required to be reported only if the investigator feels the 
events were related to either study drug or a protocol procedure
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
10.3.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical event 
associated with the use of a drug or drug delivery system in humans, whether or not it is 
considered related to that drug or drug delivery system.


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Lack of drug effect is not an AE in clinical trials, because the purpose of the clinical trial is to 
establish drug effect.
Any clinically significant findings from ECGs, laboratory assessments, vital sign measurements, 
other procedures, and so on that result in a diagnosis should be reported to Lilly or its designee.
Cases of pregnancy that occur during maternal exposures to study drug or drug delivery system 
should be reported.  Data on fetal outcome and breast-feeding are collected for regulatory 
reporting and drug safety evaluation.
Study site personnel will record the occurrence and nature of each patient’s pre-existing 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the informed consent form (ICF) is signed, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs.  All AEs related to protocol procedures 
are reported to Lilly or designee.
In addition, all AEs occurring after the patient receives the first dose of study drug must be 
reported to Lilly or its designee via CRF/electronic data entry.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, study drug, and/or drug delivery system via 
CRF/electronic data entry.
The investigator will decide whether he or she interprets the observed AEs as related to disease, 
to the study medication, study procedure, or other concomitant treatment or pathologies.  To 
assess the relationship of the AE to the study drug or procedure, the following terminologies are 
defined:

Probably related:  a direct cause and effect relationship between the study treatment and 
the AE is likely

Possibly related:  a cause-and-effect relationship between the study treatment and the 
AE has not been demonstrated at this time and is not probable, but is also not impossible

Does not know:  the investigator cannot determine

Not related:  without question, the AE is definitely not associated with the study 
treatment
The investigator should classify all “probably related,” “possibly related,” or “does not know” 
AEs and SAEs as related to study drug/study procedure.
Patients will be evaluated for AEs at each visit and will be instructed to call their physician to 
report any AEs between visits.
The National Cancer Institute (NCI)-CTCAE version 4.0 will serve as the reference document 
for choosing appropriate terminology for, and grading the severity of, all AEs and other 
symptoms.  For AEs without matching terminology within the NCI-CTCAE version 4.0 criteria, 
the investigator will be responsible for selecting the appropriate system organ class and assessing 


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severity grade based on the intensity of the event.  Note that both CTCAE term (actual or coded) 
and severity grade must be selected by study site personnel and collected on the CRF.  This 
collection is in addition to verbatim text used to describe the AE.
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by the sponsor or designee to corresponding terminology 
within the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via CRF/electronic data entry the 
circumstances and data leading to any such dosage reduction or discontinuation of treatment.
10.3.1.1. Serious Adverse Events
Serious adverse event collection begins after the patient has signed informed consent and has 
received study drug.  If a patient experiences an SAE after signing informed consent but prior to 
receiving study drug, the event will not be collected unless the investigator feels the event may 
have been caused by a protocol procedure.
Study site personnel must alert Lilly or its designee of any serious adverse event (SAE) within 
24 hours of investigator awareness of the event via a sponsor-approved method.  Alerts issued 
via telephone 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.  An SAE is any adverse event from this study that results in one of 
the following outcomes:

death

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

initial or prolonged inpatient hospitalization

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Previously planned (prior to signing the ICF) surgeries should not be reported as SAEs unless the 
underlying medical condition has worsened during the course of the study.
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to study drug.
Serious adverse events occurring after a patient has taken the last dose of study drug will be 
collected in the pharmacovigilance system and clinical data collection database for 30 days after 
discontinuation from study treatment, regardless of the investigator’s opinion of causation.  


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Thereafter, SAEs are not required to be reported unless the investigator feels the events were 
related to either study drug, drug delivery system, or a protocol procedure.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.  Adverse events reasonably anticipated in the ovarian cancer population include
fatigue, anorexia, constipation, anemia, venous thrombosis/embolism, pain, confusion, liver 
dysfunction, hypercalcemia, hyperuricemia, major cardiovascular events (such as myocardial 
infarction and stroke), and infections.
10.3.1.2. Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions are serious events that are not listed in the 
Development Core Safety Information (DCSI) in the IB and that the investigator identifies as 
related to the study drug or procedure.  Lilly has procedures that will be followed for the 
recording and expedited reporting of suspected unexpected serious adverse reactions that are 
consistent with global regulations and associated detailed guidances.
10.3.2. Other Safety Measures
10.3.2.1. Collection of Electrocardiograms
For each subject, 12-lead ECGs will be collected according to the Study Schedule 
(Attachment 1) as a single ECG.  Patients must be supine for approximately 5 to 10 minutes 
before ECG collection and remain supine but awake during ECG collection.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed to 
ensure high-quality records.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria and for immediate 
subject management, should any clinically relevant findings be identified.
After enrollment, if a clinically significant increase in the QT/corrected QT (QTc) interval from 
baseline, or other clinically significant quantitative or qualitative change from baseline, is 
present, the investigator will assess the subject for symptoms (for example, palpitations, near 
syncope, syncope) and to determine if the subject can continue in the study.  The investigator or 
qualified designee is responsible for determining if any change in patient management is needed 
and must document his/her review of the ECG printed at the time of evaluation.
The investigator (or qualified designee) must document his/her review of the ECG printed at the 
time of evaluation.
10.3.3. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.


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Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CRP
will, as appropriate, consult with the functionally independent Global Patient Safety therapeutic 
area physician or clinical scientist, and review:

trends in safety data

laboratory analytes 

AEs
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the data monitoring board (an advisory group for this study 
formed to protect the integrity of data; refer to the Interim Analysis Section that follows) can 
conduct additional analyses of the safety data.
For the purpose of this study, in which survival is a primary endpoint, all deaths and SAE reports 
will be reviewed in a blinded manner by Lilly during the clinical trial.  These reports will be 
reviewed to ensure completeness and accuracy but will not be unblinded to Lilly during the 
clinical trial.  If a death or clinical AE is deemed serious, unexpected, and possibly related to 
study drug, only Lilly Global Patient Safety will be unblinded for regulatory reporting and safety 
monitoring purposes.  These measures will preserve the integrity of the data collected during this 
trial and minimize any potential for bias while providing for appropriate safety monitoring.
10.3.4. Complaint Handling
Lilly collects product complaints on study drugs and drug delivery systems used in clinical trials 
in order to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements.
Complaints related to unblinded comparator drugs or concomitant drugs are reported directly to 
the manufacturers of those drugs/devices in accordance with the package insert.
For blinded studies, all product complaints associated with material packaged, labeled, and 
released by Lilly or delegate will be reported.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.4. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study.


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Attachment 9 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.  Although fewer invasive samples may actually occur, this will 
not require a protocol amendment.
10.4.1. Samples for Standard Efficacy, Safety Laboratory Testing
Blood samples will be collected at the times specified in the Study Schedule (Attachment 1).  
Standard laboratory tests, including chemistry and hematology panels will be performed.  A 
pregnancy test will be performed (if applicable).  Other clinical laboratory tests will be analyzed 
by a central and/or local laboratory.  Attachment 2 lists the specific tests that will be performed 
for this study.
Enrollment and treatment decisions may be based upon results of tests performed locally.  If 
local lab tests are used for this purpose, then a duplicate specimen must be sent to the central 
laboratory for use in the safety analysis.  Discrepancies between local and central laboratory 
results that may have an impact on eligibility or treatment decisions will not be considered 
protocol violations.  When both a local and a central laboratory result are obtained and there is a 
discrepancy in the laboratory values, the local laboratory values will be used for determining 
patient eligibility and this data will be recorded in the study case report forms.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant; however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.4.2. Archival Tumor Tissue Sample
A small amount of preserved tissue previously taken to diagnose the patient’s disease will be 
obtained for biomarker research related to the p38 MAPK pathway in ovary cancer. The tumor 
suppressor p53 will be evaluated for gene expression, mutation, and protein expression in 
archived tumors.  Additionally, the tumor suppressor PTEN will be evaluated for mutation and 
protein expression in archived tumors.
Pretreatment formalin-fixed, paraffin-embedded tumor tissue obtained at the time of original 
diagnosis should be in a whole block, partial block, or unstained slides.  Stored samples will 
retain the patient identifier and therefore, will not be stored indefinitely.  Any blocks or slides 
submitted will either be returned to the site or discarded within 15 years after last patient visit for 
the trial. If archival tissue is not available for a specific patient, it will not constitute a protocol 
violation.
For p53 and PTEN mutation analyses comparing tumor to germline DNA, a single whole-blood 
sample will be collected one time to isolate DNA from PBMCs.  Samples will be identified by 
the patient number (coded) and stored for up to 15 years after the last patient visit for the study at 


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a facility selected by the sponsor.  The sample and any data generated from it can only be linked 
back to the patient by investigator site personnel.
Supplies required for the collection and shipment of the patients stored samples will be supplied 
by the sponsor.  Sample handling and shipment to the central laboratory will occur according to 
instructions given to the study sites.
10.4.3. Pharmacogenetic Samples
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, excretion, the mechanism of action of the drug, the disease etiology 
and/or the molecular subtype of the disease being treated.  Therefore, where local regulations 
allow, a blood sample will be collected for pharmacogenetic analysis.  It is a one-time collection, 
as noted in the Study Schedule (Attachment 1).
Samples will be stored, and analysis may be performed on genetic variants thought to play a role 
in metabolism of LY2228820 and gemcitabine and carboplatin, including but not limited to 
CYP3A, correlations among genotype, and pharmacokinetics to evaluate their association with 
observed clinical outcomes to LY2228820.
In the event of an unexpected AE or the observation of unusual response, the samples may be 
genotyped and analysis may be performed to evaluate a genetic association with response to 
LY2228820.  These investigations may be limited to a focused candidate gene study or, if 
appropriate, genome wide association studies may be performed to identify regions of the 
genome associated with the variability observed in drug response.  Samples will only be used for 
investigations related to disease and drug or class of drugs under study in the context of this 
clinical program.  They will not be used for broad exploratory unspecified disease or population 
genetic analysis.
Samples will be identified by the patient number (coded) and stored for up to 15 years after the 
last patient visit for the study at a facility selected by the sponsor.  The sample and any data 
generated from it can only be linked back to the patient by investigator site personnel.
10.4.4. Samples for Drug Concentration Measurements 
Pharmacokinetics/Pharmacodynamics
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel.
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 2 years following the last patient visit for the study.
Pharmacokinetic (PK) sampling in Phase 1b will be intensive, with samples collected to measure 
LY2228820 at the times and visits indicated in the Pharmacokinetic Sampling Schedule 
(Attachment 1 and Attachment 3). Another intensive PK sampling schedule will also be used for 
approximately 20 patients (10 patients/arm) in the Phase 2 portion of the study.  The remainder 
of the patients in the Phase 2 portion of the study will have PK samples drawn during regularly 


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scheduled clinic visits.  On these days, the dose of LY (or placebo) should be held until after the 
pre-dose PK sample has been taken.  The actual date/time of dosing on the day of sampling and 
the actual date/time of collection for each of the samples must be recorded. In the Phase 2 
portion of the study, dose information (date, time, and dosing amount for LY2228820/placebo, 
gemcitabine, and carboplatin) must be collected for the last and next-to-last dose taken prior to 
the sampling.
At the visits and times specified in the Study Schedule (Attachment 1) and PK/PD Sampling 
Schedule (Attachment 3), venous blood samples will be collected.  Blood samples will be used to 
determine the plasma concentrations of LY2228820, gemcitabine and its metabolite (dFdU), and 
carboplatin.  For carboplatin, both total and free platinum drug concentrations will be measured.  
The actual date and time (24-hour clock time) of each sampling will be recorded.
For measurement of LY2228820 and carboplatin, approximately 4 mL of whole blood will be 
collected in a sodium heparin tubes.  For measurement of gemcitabine and its deaminated 
metabolite deoxydifluorouridine (dFdU), approximately 4 mL of whole blood will be collected 
in a sodium heparin tube containing tetrahydrouridine (THU).  Sites will be supplied by the 
central laboratory with THU and instructions for the addition of THU to collection tubes.
A maximum of 5 samples may be drawn at additional time points during the study if warranted 
and agreed upon between both the investigator and sponsor.  Instructions for the collection and 
handling of blood samples will be provided by the sponsor.
Pharmacodynamic samples will be collected as specified in the PK and PD Sampling Schedule 
(Attachment 3).  Circulating plasma proteins regulated by p38 MAPK (such as such as TNF, 
IL-1, IL-6, and IL-8) will be measured.  Supplies required for the collection and shipment of the 
patients stored samples will be supplied by the sponsor.  Sample handling and shipment to the 
central laboratory will occur per instructions given to the study sites.  Pharmacodynamic samples 
collected to measure circulating plasma proteins will be retained for a maximum of 15 years after 
the last patient visit for the study.
10.5. Appropriateness of Measurements
Progression-free survival, change in tumor size, overall response rate, OS, and patient-reported 
outcomes are acceptable endpoints that are clinically relevant for patients with platinum-
sensitive ovarian cancer.  The FACT-O is a reliable and valid instrument used to assess quality 
of life in patients with cancer (Basen-Engquist 2001).


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11. 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 a start-up training session to instruct the investigators and study coordinators;  
this session will give instruction on the protocol, the completion of the CRFs, and study 
procedures

Make periodic visits to the study site

Be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

Review and evaluate CRF data and use standard computer edits to detect errors in data 
collection

Conduct a quality review of the database.
In addition, Lilly or its representatives may 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.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable ERBs with 
direct access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this trial.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data collected by the third-party organization (TPO) will be encoded and stored 
electronically in the TPO’s database system.  Validated data will subsequently be transferred to 
the sponsor’s data warehouse, using standard Lilly file transfer processes.
Data managed by a central vendor, such as laboratory test data or ECG data, will be stored 
electronically in the central vendor’s database system.  Data will subsequently be transferred 
from the central vendor according to the contract.
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 paper diary to collect patient-
reported outcome measures (for example, a rating scale), 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.


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12. Sample Size and Statistical Methods
12.1. Determination of Sample Size
The primary objective of the Phase 1b portion of this study is to determine the recommended 
Phase 2 dose of LY2228820 that can be safely administered in combination with gemcitabine 
and carboplatin.  The sample size for this part of the study is customary and not subject to 
statistical calculations.
The primary objective of the Phase 2 portion of this study is to compare the progression-free 
survival in patients treated with LY2228820 plus gemcitabine and carboplatin versus placebo 
plus gemcitabine and carboplatin.  A group sequential design will be used to control type 1 error 
across the interim analyses and the final PFS analysis in Phase 2 (see Section 12.2.11 for details).  
The primary analysis will be performed after 79 PFS events have occurred.  Assuming a hazard 
ratio (HR) of 0.7, this sample size yield at least 77% power with a false-positive rate of 0.2 
(1-sided) using a log-rank test.  This assumes exponentially distributed PFS times, median PFS 
of 8.6 months for the control arm, enrollment duration of 12 months, and follow-up time of 18 
months after the last patient is enrolled.  Assuming 28% censoring rate of the PFS, a total of 
110 patients will be randomized (55 patients in each arm) to achieve 79 PFS events at the 
primary analysis.
12.2. Statistical and Analytical Plans
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designated TPO.
No formal statistical analysis will be performed on the Phase 1b portion of the study in which the
primary objective is to assess safety and tolerability of LY2228820 plus gemcitabine and 
carboplatin.  Efficacy analyses for the Phase 2 portion of the study will be conducted on the full 
analysis set.  This set includes all data from all patients receiving at least 1 dose of 
LY2228820/placebo.  All patients who receive at least 1 dose of the LY2228820/placebo will be 
subject to safety evaluation.
All tests of treatment effects will be conducted at a 1-sided alpha level of 0.2 unless otherwise 
stated.  All CIs will be given at a 2-sided 90% level unless otherwise stated.
Starting from protocol (c), an additional factor is included during patient enrollment as 
randomization factor (see Section 8.1.2).  For patients who randomized to phase 2 before the 
approval of protocol (c), the value of maintenance therapy as a part of or after a first line 
platinum regimen for these patients will be imputed as “not collected”.
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.
Before unblinding of the aggregate database, minor modifications or clarifications to the data 
analysis methods may be described and justified in the statistical analysis plan.  Any other 


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change to the data analysis methods described in the protocol, and the justification for making 
the change, will be described in the clinical study report.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
This study will be considered complete following final validation and authorization to “lock” the 
database after the protocol-specified primary objective has been met.  The Lilly CRP will notify 
investigators in the event of study closure.
12.2.1. Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients completing the study, or discontinuing (overall and by 
reason for discontinuation).  A summary of all important protocol violations will be provided.
12.2.2. Patient Characteristics
Patient demographics including age, gender, screening height and weight will be summarized 
using descriptive statistics.  Other baseline disease characteristics that need to be summarized 
include:

Time from completion of first-line platinum-based therapy to relapse

Pathologic diagnosis

Disease stage at the time of initial diagnosis

Pre-existing conditions

Prior cancer therapies

Concomitant drugs

ECOG performance status
12.2.3. Concomitant Therapy
Concomitant medications will be listed and summarized for the safety population. 
12.2.4. Treatment Compliance
The number of dose omissions, reductions, delays, cycles received, and dose intensity will be 
summarized for all treated patients by treatment arm.
12.2.5. Primary Outcome and Methodology
The primary objective of the Phase 1b portion of this study is to determine the recommended 
Phase 2 dose of LY2228820 that can be safely administered in combination with gemcitabine 
and carboplatin.
The primary objective of the Phase 2 portion of this study is to compare the progression-free 
survival in patients treated with LY2228820 plus gemcitabine and carboplatin versus placebo 
plus gemcitabine and carboplatin.


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The PFS time is measured from the date of randomization to the date of objective progression or 
the date of death due to any cause, whichever is earlier.  The censoring is taken in the following 
order:

If a patient does not have a complete baseline disease assessment, then the PFS time will 
be censored at the enrollment date, regardless of whether or not objectively determined 
disease progression or death has been observed for the patient; otherwise,

If a patient is not known to have died or have objective progression as of the data 
inclusion cutoff date for the analysis, the PFS time will be censored at the last complete 
objective progression-free disease assessment date
For the primary endpoint of PFS, the HR will be estimated from survival data on all randomized 
patients using a Cox proportional hazards model with assigned study treatment arm as fixed 
effect along with cofactors for time from completion of first line platinum-based therapy to 
relapse (6 to 12 months versus over 12 months), ECOG performance status (0 and 1 versus 2)
and maintenance therapy as a part of or after a first line platinum regimen (yes versus no versus 
not collected). 
The Kaplan-Meier method (Kaplan and Meier 1958) will be used to estimate the survival curve 
as well as survival rates at various time points for each treatment group.  The log-rank test will 
be used to compare PFS distributions between treatment groups in phase 2.
12.2.6. Efficacy Analyses
The primary objective of the Phase 1b portion of this study is to determine the recommended 
Phase 2 dose of LY2228820 that can be safely administered in combination with gemcitabine 
and carboplatin.  Thus, no formal efficacy analysis is planned for this part of the trial.  Any 
antitumor activity observed will be reported.
The primary objective of the Phase 2 portion of this study is to compare the progression-free 
survival in patients treated with LY2228820 plus gemcitabine and carboplatin versus placebo 
plus gemcitabine and carboplatin.  To support the primary efficacy analysis, additional efficacy 
analysis will be performed on change in tumor size, CA125 (serum biomarker for ovarian 
cancer), overall response rate, and OS.
CA125 data will be log-transformed first and analyzed using a mixed-effect model repeated 
measures analysis with treatment, time, and treatment by time interaction as fixed effect, along 
with cofactors for time from completion of first line platinum-based therapy to relapse (6 to 
12 months versus over 12 months), ECOG performance status (0 and 1 versus 2) and 
maintenance therapy as a part of or after a first line platinum regimen (yes versus no versus not 
collected).
The log ratio of tumor size at the end of Cycle 2 to tumor size at baseline will be calculated for 
each patient.  This measure follows a normal distribution and will be compared between 
treatment groups using a t-test. Analysis of variance will be used to assess the effect of baseline 
factors on the change in tumor size.


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The overall response rate is estimated as the total number of CRs and PRs, based on RECIST 
version 1.1, divided by the total number of randomized patients.  The efficacy endpoint of 
overall response rate and its exact 90% confidence interval will be estimated for each treatment 
arm.  The proportion in each treatment arm will be compared using the Chi-square test.
The efficacy analysis on OS will be conducted after all the patients have been followed for at 
least 2 years.  The HR will be estimated from survival data on all randomized patients using a 
Cox proportional hazards model using assigned study treatment arm as fixed effect with time 
from completion of first line platinum-based therapy to relapse (6 to 12 months versus over 
12 months), ECOG performance status (0 and 1 versus 2) and maintenance therapy as a part of or 
after a first line platinum regimen (yes versus no versus not collected).
Additional exploratory analyses may be performed as deemed appropriate.
12.2.7. Pharmacokinetic/Pharmacodynamic Analyses
12.2.7.1. Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on data from patients who have received at least 
1 dose of the study drug and have had sufficient post-dose samples collected to allow estimation 
of the PK parameters.
The PK parameters for LY2228820 will be computed by standard noncompartmental methods.  
The Cmax, AUC, half-life, apparent volume of distribution (Vd/F), apparent clearance (CL/F), 
and other relevant parameters (such as intercycle accumulation) that can be calculated from the 
data will be reported.  Parameters will be calculated following administration on Day 1 and on 
Day 10 of Cycle 1 as well as on Day 10 of Cycle 2 for the Phase 1b portion; on Day 3 and on 
Day 10 of Cycle 1 for the induction part of the Phase 2 portion, and on Day 3 of Cycle 7 for the 
maintenance part of the Phase 2 portion.
The version of any software used for the analysis will be documented and the program will meet 
the Lilly requirements of software validation.  It is possible that other validated equivalent PK 
software programs may be used if appropriate, warranted, and approved by Global 
Pharmacokinetic management.
Providing that data allow in the Phase 1b portion, the pharmacokinetic parameter estimates 
(Cmax and AUC) for LY2228820 will be evaluated statistically to delineate the effects of dose 
proportionality using the methods described previously (Smith et al. 2000).  Least-square 
estimates of geometric means and their corresponding 90% confidence intervals will be provided 
by dose and with the dose-normalized ratio of geometric means and confidence interval.
The primary PK parameters for gemcitabine, its metabolite (dFdU), and carboplatin that will be 
used to detect potential drug–drug interaction are the maximum plasma concentration (Cmax), 
area under the plasma concentration-time curve from zero to the last measurable time [AUC(0-
tlast)], area under the plasma concentration-time curve from 0 to 24 hours [AUC(0-24hr)], and area 
under the plasma concentration-time curve from time 0 to infinity [AUC(0-)].  The AUC 
values will be calculated by the linear/log trapezoidal method, in which the linear trapezoidal 


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method will be employed up to the tmax, and the log trapezoidal rule will be used for 
concentrations beyond tmax.  Descriptive statistics will be reported for other secondary PK
parameters (for example, tmax, CL/F, Vd/F, and terminal elimination half-life).
The 90% confidence interval for the AUC and Cmax ratios will be computed to assess the 
potential effect of LY2228820 on gemcitabine and carboplatin.  The ratios will be calculated for 
the Phase 2 portion for gemcitabine, its metabolite (dFdU), and carboplatin on Day 3 of Cycle 1 
in the LY2228820 arm versus the placebo arms.
The 90% confidence interval for the AUC and Cmax ratios will be computed to assess the 
potential effect of gemcitabine and carboplatin on LY2228820. The ratios will be calculated for 
the Phase 2 portion for LY2228820 on Day 3 of Cycle 1 versus Day 3 of Cycle 7.
In addition to a standard noncompartmental assessment, the plasma LY2228820 data will also be 
analyzed using nonlinear mixed effect modeling (as implemented in NONMEM).
All available plasma data from all patients may be analyzed to determine the compartmental 
pharmacokinetics parameters and between and within patient variability.  The drug–drug
interaction may also be assessed using this approach using the typical covariates approach.
12.2.7.2. Pharmacodynamic Analysis
Pharmacodynamic data from all patients undergoing PD assessments will be analyzed.  
Pharmacodynamic data will be documented in the study report by dose.  Absolute and
percentage change from baseline for PD markers may be summarized by providing the mean, 
standard deviation, median, minimum, and maximum for each cohort.  Data may be log-
transformed prior to summarizing if necessary.  The interpatient variability in human PD 
response may also be assessed where appropriate.
12.2.8. Health Outcome/Quality of Life Analyses:  FACT-O
Findings of the FACT-O and compliance with completing the questionnaire will be summarized 
for all treated patients for the given time points: baseline, each treatment cycle, and 
discontinuation visit.  Frequency distributions, including measures of central tendency and 
variability, will be calculated for individual items and for the total scale. The time-to-worsening 
variables, including TTW in TOI, will be analyzed using the same methods utilized for other 
time-to-event variables.  All randomized patients with a baseline assessment will be included in 
the TTW analysis.  Clinically important difference thresholds will be used to define the 
proportion of patients that improve, remain stable, or worsen.  The FACT-O scores will be 
summed at baseline and for each visit in order to calculate changes from baseline mean scores.  
These data will be compared between the 2 treatment arms.  The scores will include the FACT-O 
total and subscale scores and TOI-O. All randomized patients with baseline and at least 1 post-
baseline measure will be included in the change from baseline analysis.  Other exploratory 
analyses may be performed, including longitudinal modeling (for example, repeated measures 
models and the impact of covariates) and subgroup analysis (for example, age ≤70 versus >70
years, and subgroups based on ECOG performance status, tumor response status, PFS, and OS).  
Individual responses, using an a priori responder definition (that is, the individual patient PRO 


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score change over a predetermined time period that should be interpreted as a treatment benefit) 
will be displayed using the cumulative distribution function of responses between treatment 
groups.
Exploratory analysis may be performed to assess potential relationships between patient reported 
symptoms and endpoints of interest such as OS and PFS.  Compliance with completing the 
FACT-O will be summarized.
12.2.9. Safety Analyses
Overall exposure to study drug, the numbers of patients completing each cycle, and the dose 
intensity will be summarized using descriptive statistics.  The number of patients with any dose 
adjustment will be presented for entire treatment period as well as for each cycle.  The number of 
patients with dose reductions, dose delays, or dose omissions will also be summarized, as will 
the reasons for dose adjustments.
An overall summary of AEs will be provided for AEs deemed by the investigator to be possibly 
related to study medication, and repeated for events regardless of study drug causality.  Incidence 
rates of these events will be compared between treatment arms using Fisher’s exact test.
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened in severity after baseline.
The number of patients who experienced a TEAE, SAE, or AE related to study drug, as well as 
those who died or discontinued from the study due to an AE will be summarized by treatment.
Common Terminology Criteria for Adverse Events version 4.0 will be used to report AEs by 
CTCAE terms.
Laboratory and nonlaboratory CTCAEs will be summarized by CTCAE term and maximum 
CTCAE grade, including the total for maximum Grade 3 and 4.  These summaries will be 
provided for events regardless of study drug causality, and repeated for events deemed by the 
investigator to be possibly related to study medication.
Reasons for death will be summarized separately for on-therapy and within 30 days of last dose 
of study drug/last visit.  All SAEs will be summarized by preferred term.
Hospitalizations and transfusions during the study treatment period or during the 30-day post-
discontinuation follow-up period will be summarized by treatment group.
12.2.10.
Subgroup Analyses
There are no planned subgroup analyses.  However, exploratory analyses may be performed to 
generate hypotheses about the efficacy of study therapy in certain subgroups for evaluation in 
future clinical studies.
12.2.11.
Interim Analyses
All interim analyses will be conducted under the guidance of an internal assessment committee
(AC).


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12.2.11.1.
Interim Analysis for Phase 1b
Safety data for all patients will be reviewed continuously throughout this component of the 
study.  One interim analysis is planned for the Phase 1b portion of the study and will be 
conducted for safety and pharmacokinetics after all patients in Phase 1b have completed at least 
1 cycle of study treatment.  If the combination MTD has been identified prior to completion of 
the interim analysis and patients are available for Phase 2, with investigator and Lilly CRP 
approval, those patients will be randomized into the Phase 2 component of the study without 
delay.


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12.2.11.2.
Interim Analyses for Phase 2
Two interim analyses are planned for the Phase 2 portion of the study. The first analysis will be 
conducted for safety and pharmacokinetics when approximately 30 patients in Phase 2 have 
completed at least 1 cycle of study treatment.  The second interim analysis will be conducted for 
safety and PK when approximately 60 patients in Phase 2 have completed at least 2 cycles of 
study treatment.  Patient enrollment will continue along with the interim analyses.  The Phase 2 
interim analyses will be conducted using unblinded data under the guidance of an internal 
assessment committee.
Unblinding procedures are specified in the Statistical Analysis Plan.


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13. Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study, and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICF
prior to the performance of any protocol procedures and prior to the administration of study drug.
As used in this protocol, the term “informed consent” includes all consent and assent given by 
patients or their legal representatives.
13.2. Ethical Review
Lilly must agree with all ICFs before they are submitted to the ERB and are used at investigative 
sites(s).  All ICFs must be compliant with the International Conference on Harmonisation (ICH) 
guideline on GCP.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).
Any member of the ERB who is directly affiliated with this study as an investigator or as site 
personnel must abstain from the ERB’s vote on the approval of the protocol.
The study site’s ERB(s) should be provided with the following:

The current IB or package labeling and updates during the course of the study

ICF

Relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:

Consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines 

The International Conference on Harmonization Good Clinical Practices Guideline [E6]

Applicable laws and regulations.


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The investigator or designee will promptly submit the protocol to applicable ERB(s).
All or some of the obligations of the sponsor will be assigned to a TPO.
An identification code assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting AEs and/or other trial-related data.
13.3.1. Investigator Information
Licensed physicians with a specialty in oncology will participate as investigators in this clinical 
trial.
13.3.2. Protocol Signatures
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.
13.3.3. 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 sponsor’s responsible medical officer and responsible 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.


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14. References
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet.
2001;357(9255):539-545.
Barakat RR, Markham M, Randall ME. Principles and Practice of Gynecologic Oncology, 5th 
ed. 2009:763-836.
Basen-Engquist K, Bodurka-Bevers D, Fitzgerald MA, Webster K, Cella D, Hu S, Gershenson 
DM. Reliability and validity of the functional assessment of cancer therapy – ovarian. J Clin 
Oncol. 2001;19(6):1809-1817.
Calvert AH, Newell DR, Gumbrell LA, O'Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, 
Gore ME, Wiltshaw E. Carboplatin dosage: prospective evaluation of a simple formula based 
on renal function. J Clin Oncol. 1989;7(11):1748-1756.
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, 
Version 4.0, DCTD, NCI, NIH, DHHS. Bethesda, MD: National Cancer Institute; 2009. 
Cella D, ed. Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) 
Measurement System, Version 4.1. Evanston, IL: Center on Outcomes, Research and 
Education (CORE), Evanston Northwestern Health Care and Northwestern University; 2004.
Cockcroft DW, Gault MD. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16:31-41.
Cox DR. Regression models and life-tables. J Royal Stat Soc Ser B. 1972;74(2):187-220.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging 
Handbook: From the AJCC Cancer Staging Manual, 7th Ed. New York: Springer; 2009.
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2) 228-247.
Food and Drug Administration. 2012.  Available at: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
292362.pdf (Accessed: 20 January 2015)
Han B, Enas NH, McEntegart D. Randomization by minimization for unbalanced treatment 
allocation. Stat Med. 2009;28:3329-3346.
Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary 
CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, 
Cronin KA, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2008. Available at: 
http://seer.cancer.gov/csr/1975_2008/. Accessed December 20, 2011.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer Statistics, 2009. CA: A Cancer 
Journal for Clinicians. 2009;59:225-249.
Jemal A, Siegel R, Xu J, Ward E. Cancer Statistics, 2010. CA: A Cancer Journal for Clinicians.
2010;60:277-300.


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Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Statist Assn.
1958;53:457-481.
Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The use of nitrogen mustards in the 
palliative treatment of carcinoma with particular reference to bronchogenic carcinoma. 
Cancer. 1948;1:634-669.
Leemis LM, Trivedi KS. A comparison of approximate interval estimators for the Bernoulli 
parameter. American Statistician. 1996;50:63-68.
Lewis AM, Varghese S, Xu H, Alexander HR. 2006. Interleukin-1 and cancer progression: the 
emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer 
treatment. J Transl Med. 2006;4:48.
Murray PT, Ratain MJ. Estimation of the glomerular filtration rate in cancer patients: a new 
formula for new drugs. J Clin Oncol. 2003;21(14):2633-2635.
Odicino F, Pecorelli S, Zigliani L, Creasman WT. History of the FIGO cancer staging system. Int 
J Gynaecol Obstet. 2008; 101:205-210.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 1982;5:649-
655.
Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ, Wagner U, Stahle A, Stuart G, R 
Kimmig R, Olbricht S, Le T, Emerich J, Kuhn W, Bentley J, Jackisch C, Luck HJ, Rochon J, 
Zimmermann AM, Eisenhauer E. Gemcitabine plus carboplatin compared with carboplatin in 
patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-
OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006;24:4699-4707.
Pocock S, Simon R. Sequential treatment assignment with balancing of prognostic factors in 
controlled clinical trials. Biometrics. 1975;31:103-115.
Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, Cella DF, 
Djulbegovic B, Goode MJ, Jakubowski AA, Rarick MU, Regan DH, Lichtin AE.Use of 
epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical 
Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol.
2007;26(1):132-149. 
Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO,Spivak JL, Bennett CL, Bohlius,J, 
Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MR. American Society of 
Clinical Oncology/American Society of Hematology clinical practice guideline update on the 
use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. 2010;28(33):4996-
5010.
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, Cantor 
SB, Crawford J, Cross SJ, Demetri G, Desch CE, Pizzo PA, Schiffer CA, Schwartzberg L, 
Somerfield MR, Somlo G, Wade JC, Wade JL, Winn RJ, Wozniak AJ, Wolff AC. Update of 
recommendations for the use of white blood cell growth factors: an evidence-based clinical 
practice guideline. J Clin Oncol. 2006;24:3187-3205.


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Smith BP, Vandenhende FR, DeSante KA, Fraid NA, Welch PA, Callaghan JT, Forgue ST. 
2000. Confidence interval criteria for assessment of dose proportionality. Pharm Res. 17:1278-
1283.
Yost KJ, Eton DT. Combining distribution- and anchor-based approaches to determine 
minimally important differences: the FACIT experience. Eval Health Prof. 2005;28(2):172-
191.


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Attachment 1.Protocol JIAE Study Schedule


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Study Schedule, Baseline Assessments, Protocol I1D-MC-JIAE(c) 
 
 
Study Period 
Baseline 
 
 
 
Cycle 
BL 
 
 
Visit 
0 
 
 
Duration 
28 days 
 
 
Relative day within 
a cycle 
28 
14 
7 
Procedure 
Category 
Procedure 
 
Comments 
Study 
Entry/ 
Enrollment 
Informed Consent Form signed  
X 
Prior to performance of any protocol-specific tests / procedures. 
Inclusion/Exclusion evaluation 
  
X 
 
 
Medical 
History 
 
 
Initial history/preexisting conditions 
  
X 
 
 
Historical illnesses 
  
X 
 
 
Habits assessment 
  
X 
 
 
Physical 
Examination 
Height 
  
X 
 
 
Weight 
  
X 
 
 
Blood pressure/pulse/ respiration rate/temperature 
  
X 
 
 
ECOG performance status 
  
X 
 
 
Calculated creatinine clearance 
  
X 
  
Calculate using the Cockcroft and Gault formula (Attachment 6). 
Tumor 
Assessment 
 
Tumor measurement (palpable or visible) 
X 
Must be completed at least 24 hours prior to Cycle 1 Day 1. 
Radiologic imaging according to RECIST 
X 
Baseline radiological tumor assessment per RECIST version 1.1 should be 
done during screening.  Radiologic assessments obtained previously as part of 
routine clinical care may be used as the baseline assessment if performed 
within 28 days of receiving the first dose of study drug on Day 1of Cycle 1.  
Baseline radiologic assessments must be completed at least 24 hours prior to 
Cycle 1 Day 1. 
 
 


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Study Schedule, Baseline Assessments, Protocol I1D-MC-JIAE(c), continued
Study Period
Baseline
Cycle
BL
Visit
0
Duration
≤28 days
Relative Day
≤28
≤14
≤7
Procedure 
Category
Procedure
Comments
Adverse Events
Adverse Events Collection/CTCAE Grading
X
Must be completed at least 24 hours prior to Cycle 1 Day 1.
Concomitant
Meds
Concomitant Medication Notation
X
Must be completed at least 24 hours prior to Cycle 1 Day 1.
Lab/
Diagnostic 
Tests
Local hematology
X
Must be completed at least 24 hours prior to Cycle 1 Day 1.
Central chemistry
X
At the discretion of the investigator, local chemistry may be collected for safety 
and dosing calculations.  This central chemistry collection is distinct from the 
Cycle 1 Day 1 collection and must be completed at least 24 hours prior to 
Cycle 1 Day1.
Local serum pregnancy test
X
Must be completed at least 24 hours prior to Cycle 1 Day 1.
Local ECG
X
Must be completed at least 24 hours prior to Cycle 1 Day 1.
Stored samples for pharmacogenomics
X
One-time only sample collection. Must be completed at least 24 hours prior to 
Cycle 1 Day 1.  Sample may be sent to Sponsor at any time during study once 
patient has signed informed consent document. 
CA-125
X
Must be completed at least 24 hours prior to Cycle 1 Day 1.
Circulating plasma proteins
X
This sample is distinct from the predose sample on Day 1 of Cycle 1 and must 
be completed at least 24 hours prior to Cycle 1 Day 1.
FACT-O
X
Protocol Attachment 10.  Must be completed at least 24 hours prior to Cycle 1 
Day 1.
Archived tumor sample
X
Must be completed at least 24 hours prior to Cycle 1 Day 1.
Stored sample for germline DNA
X
Must be completed at least 24 hours prior to Cycle 1 Day 1.


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Study Schedule, Treatment Period, Protocol I1D-MC-JIAE(c)
Study Period
Study Treatment Period
Comments
Cycle
1
2-6
7 and Beyond
Visit
1
2-6
7-X
Duration
21
21
28
Relative day within a 
cycle
1
3
10
11
12-21
1
3
10
11
12-21
1
3
4-14
15-28
Procedure 
Category
Procedure
Physical Examination
Weight
X
X
X
X
X
Obtain prior to infusion on-therapy cycles.  May be 
obtained on Day 1 if necessary.
Blood pressure/pulse/ 
respiratory rate/temperature
X
X
X
X
X
Obtain prior to infusion on-therapy cycles.  May be 
obtained on Day 1 if necessary.
ECOG performance status
X
X
X
Obtain prior to infusion on-therapy cycles.  May be 
obtained on Day 1 if necessary.
Calculated creatinine 
clearance
X
X
Obtain prior to infusion on-therapy cycles.  Calculate 
using the Cockcroft and Gault formula (Attachment 6).
Tumor Assessment
Tumor measurement 
(palpable or visible)
X
X
Perform at the same time as radiologic imaging.
Radiologic imaging 
according to RECIST
X
X
Perform between Days 11 through 21 (during induction 
therapy) and Days 15 through 28 (during maintenance 
therapy) of every even cycle. Radiologic assessment can 
be performed at any time if there is evidence of disease 
progression.  Radiological exams should be performed 
using the same imaging method for each assessment 
whenever possible. 
Adver
se 
Events
Adverse event 
collection/CTCAE grading
X
X
X
Concomitant
Medications
Concomitant medication 
notation
X
X
X


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Study Schedule, Treatment Period, Protocol I1D-MC-JIAE(c), continued
Study Period
Study Treatment Period
Comments
Cycle
1
2-6
7 and Beyond
Visit
1
2-6
7-X
Duration
21
21
28
Relative day within a cycle
1
3
10
11
12-21
1
3
10
11
12-21
1
3
4-14
15-28
Procedure
Lab/Diagnostic Tests
Local hematology
X
X
X
X
X
May be performed ≤24 hours in advance of Day 1 of 
each cycle.
Central chemistry
X
X
X
X
X
May be performed ≤24 hours in advance of Day 1 of 
each cycle.
Local ECG
X
X
Obtain on Day10 of Cycle 1 and Cycle 2 only.
Phase 1b (Intensive) PK 
sampling
X
X
X
X
X
X
X
Refer to PK and PD Sampling Schedule (Attachment 3) 
for detailed instructions about collection of these 
samples.
Phase 2 (Intensive) PK 
sampling
X
X
X
X
X
Refer to PK and PD Sampling Schedule (Attachment 3) 
for detailed instructions about collection of these 
samples.
Phase 2 (Standard) PK 
sampling
X
X
PK samples to be collected pre-dose on Day 3 for 
Cycles 1, 2 and 3 only when in clinic for 
gemcitabine/carboplatin IV treatment.  Refer to PK and 
PD Sampling Schedule (Attachment 3) for detailed 
instructions about collection of these samples.
Circulating plasma proteins
X
X
X
Refer to PK and PD Sampling Schedule (Attachment 3) 
for detailed instructions about collection of these 
samples.
CA-125
X
X


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Study Schedule, Treatment Period, Protocol I1D-MC-JIAE(c), continued
Study Period
Study Treatment Period
Comments
Cycle
1
2-6
7 and Beyond
Visit
1
2-6
7-X
Duration
21
21
28
Relative day within a cycle
1
3
10
11
12-21
1
3
10
11
12-21
1
3
4-14
15-28
Procedure
PRO
FACT-O
X
X
Protocol Attachment 10.
Study Therapy
LY2228820 or Placebo
X
Days 1 to 10
X
Days 1 to 10
X
Days 1 to 14
Patients should not consume food beginning 1 hour 
before and ending 1 hour after taking LY2228820 (or 
placebo).  Doses of LY2228820 (or placebo) should 
be taken at the same time of the day with a full glass 
of water, 12 3 hours apart.
Gemcitabine
X
X
X
X
Administer IV over 30 (+15) minutes.
Carboplatin
X
X
Administer IV over 30 (+15) minutes.  Carboplatin 
should be administered after gemcitabine.
Abbreviations: AE = adverse events; Con Meds = Concomitant Medications; CTCAE = Common Terminology Criteria for Adverse Events; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; PK = pharmacokinetics; PRO = patient-reported outcomes; IV = intravenously;
RECIST = Response Evaluation Criteria in Solid Tumors.


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Study Schedule, Follow-Up Period, Protocol I1D-MC-JIAE(c)
Study Period
Post-Discontinuation Follow-Up
Comments
Cycle
Short Term Follow-Up
Long Term Follow-Up
Visit
801
802-XXX
Duration
Approximately 30 days
84 days (14 days)
Relative day 
within a 
cycle
Period begins the day after 
stopping of study treatment 
and lasts approximately 
30 days
Period begins 1 day after short-
term follow-up period is completed 
and continues until death or until 
the patient is lost to follow-up
Procedure 
category
Procedure
Physical 
Examination
Blood 
pressure/pulse/respiratory 
rate/temperature
X
ECOG performance status
X
Adverse 
Events
Adverse events 
collection/CTCAE grading
X
X
Con Meds
Concomitant medication 
notation
X
Lab
Local hematology
X
Local chemistry
X
CA-125
X
PRO
FACT-O
X
Tumor 
Assessment
Radiologic imaging 
according to RECIST
X
X
Radiologic assessments during the 
follow-up phase of the trial should be 
done according to the institutional 
standard of care frequency and by the 
same method used at baseline and 
throughout the study.
Follow-Up
Survival assessment
X
Approximately every 84 (±14) days 
(telephone assessment is acceptable).
Abbreviations: Con Meds = Concomitant Medications; CTCAE = Common Terminology Criteria for Adverse Events; ECOG = Eastern Cooperative Oncology 
Group; PRO = patient-reported outcomes; RECIST = Response Evaluation Criteria in Solid Tumors.


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Attachment 2.Protocol JIAE Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologyb
Clinical Chemistrya
Hemoglobin
  Serum Concentrations of:
Hematocrit
Sodium
Potassium
Erythrocyte count (RBC)
Magnesium
Mean cell volume (MCV)
Total bilirubin
Mean cell hemoglobin concentration (MCHC)
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented and bands
Alanine aminotransferase (ALT/SGPT)
Aspartate Aminotransferase (AST/SGOT)
Lymphocytes
Blood urea nitrogen (BUN)
Monocytes
Creatininec
Eosinophils
Uric acid
Basophils
Calcium
Platelets
Glucose, random
Albumin
Cholesterol
Tumor Markera
Creatine kinase (CK)
CA125
Serum Pregnancy Testb
Abbreviations:  RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated central laboratory.  At the discretion of the investigator, local chemistry may be 
collected for safety and dosing calculations.
b
Local or investigator-designated laboratory.
c
IDMS for US sites.  OUS sites should use IDMS if available.  If IDMS not available OUS, the site should 
continue to utilize the method that has been used historically at the site and should follow the guidance in Section 
9.1.1 about capping the dose.


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Attachment 3.PK and PD Sampling Schedule


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Intensive PK sampling will be performed during Phase 1b induction therapy (Cycles 1-3 only) and maintenance therapy (Cycle 7 
only) for all patients. On PK sampling days, the dose of LY2228820 should be held until after the pre-dose PK sample has been 
drawn. 
Phase 1b Intensive PK Sampling:  Induction Therapy (Cycles 1-3 only) and Maintenance Therapy (Cycle 7 only)
Cycle
Day
Dosing Schedule
Sampling Time for PK (LY2228820)
Sampling Time for PD
Induction Therapy
1
Baseline
At baseline (14 days)
1
1
LY q 12 hr for 10 days between Day1 and Day10
Predose
Predose on Day 1 of Cycle 1
1
1
0.5 hr +/-5 min post LY dose
1
1
1 hr +/-15 min post LY dose
1
1
2 hr +/-15 min post LY dose
1
1
4 hr +/-15 min post LY dose
1
1
6 hr +/-15 min post LY dose
1
1
8 hr +/-15 min post LY dose
1
10
LY q 12 hr
Predose
Predose
1
10
Gemcitabine: 1000 mg/m2,  IV over 30 (+15) min
1
10
(Sample collected at the end of the gemcitabine 
infusion)
0.5 hr +/-5 min post LY dose
1
10
(30 min after the end of the gemcitabine infusion)
1 hr +/-15 min post LY dose
1
10
2 hr +/-15 min post LY dose


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Phase 1b Intensive PK Sampling:  Induction Therapy (Cycles 1-3 only) and Maintenance Therapy (Cycle 7 only)
Cycle
Day
Dosing Schedule
Sampling Time for PK (LY2228820)
Sampling Time for PD
1
10
8 hr +/-15 min post LY dose
1
11
No drug
12 hr ±2 hr after Day 10 evening LYdose
2
1
LY q 12 hr
Predose (276 hr ±2 hr after Day 10 
evening LY dose
2
10
LY2228820 morning dose 
Predose
Predose
2
10
Gemcitabine 1000 mg/m2 over 30 (+15) min
2
10
(Sample collected at the end of the gemcitabine 
infusion)
0.5 hr +/-5 min post LY dose
2
10
(30 mins after the end of the gemcitabine infusion)
1 hr +/-15 min post LY dose
2
10
2 hr +/-15 min post LY dose
2
10
4 hr +/-15 min post LY dose
4hr +/-15 min post LY dose
2
10
6 hr +/-15 min post LY dose
2
10
8 hr +/-15 min post LY dose
2
11
No drug
12 hr (±2 hr) after Day 10 evening LYdose
3
1
LY q 12 hr
Predose (276 hr ±2 hr after Day 10 
evening LY dose


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Phase 1b Intensive PK Sampling:  Induction Therapy (Cycles 1-3 only) and Maintenance Therapy (Cycle 7 only)
Maintenance Therapy
Cycle
Day
Dosing Schedule
Sampling Time for PK (LY2228820)
Sampling Time for PD
7
3
LY or placebo q 12 hr for 10 days between Day1 
and Day10
7
3
Predose
7
3
0.5 hr +/-5 min post LY dose
7
3
1 hr +/-15 min post LY dose
7
3
2 hr+/-15 min post LY dose
7
3
4 hr +/-15min post LY dose
7
3
6 hr +/-15min post LY dose
Abbreviations:  hr = hour, LY = LY2228820, min(s) = minute(s), q = every, PD = pharmacodynamics; PK = pharmacokinetics.


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Intensive PK sampling will be performed during Phase 2 induction therapy (Cycles 1-2 only) and maintenance therapy (Cycle 7 only) 
for approximately 20 patients (10 patients/arm). On PK sampling days, the dose of LY2228820 (or placebo) should be held until after 
the pre-dose PK sample has been drawn. 
Phase 2 Intensive PK Sampling:  Induction Therapy (Cycles 1-2 only) and Maintenance Therapy (Cycle 7 only)
Cycle
Day
Dosing Schedule
PK Sampling Time for 
LY2228820  
PK Sampling Time for
Gemcitabine and dFdU
PK Sampling Time for 
Carboplatin 
PD Sampling Time
Induction Therapy
1
Baseline
At baseline (14 days)
1
1
LY or placebo q 12
hr for 10 days  
between Day 1 and 
Day 10
Predose on Day 1 of 
Cycle 1
1
3
Predose
1
3
Gemcitabine 1000
mg/m2 over 30 (+15)
min
1
3
(Collected at end of 
Gem infusion)
0.5 hr +/-5 min  post LY 
dose
Immediately prior to end 
of infusion (<5 min)
1
3
1 hr +/-15 min post LY 
dose
1 hr after start of infusion 
(±5 min)
1
3
Carboplatin AUC4 
over 30 (+15) min
(1hr after start of 


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gemcitabine infusion)
Phase 2 Intensive PK Sampling:  Induction Therapy (Cycles 1-2 only) and Maintenance Therapy (Cycle 7 only)
Cycl
e
Day
Dosing Schedule
PK Sampling Time for 
LY2228820  
PK Sampling Time for 
Gemcitabine and dFdU
PK Sampling Time for 
Carboplatin
PD Sampling Time
1
3
Immediately prior to end 
of infusion (<5 min)
1
3
2 hr +/-15 min post LY 
dose
2 hr after start of infusion 
(±10 min)
1 hr after start of infusion 
(±5 min)
1
3
1.5 hr after start of 
infusion (±10 min)
1
3
4 hr +/-15 min  post LY 
dose
4 hr after start of infusion 
(±15 min)
3 hr after start of infusion 
(±15 min)
1
3
6 hr +/-15 min post LY 
dose
6 hr after start of infusion 
(±15 min)
5 hr after start of infusion 
(±15 min)
1
3
8 hr +/-15 min post LY 
dose
8 hr after start of infusion 
(±15 min)
1
10
Predose
Predose
1
10
Gemcitabine 1000 mg/m2
over 30 (+15) min
1
10
(Sample collected at the end 
of the gemcitabine infusion)
0.5 hr +/-5 min post LY
dose
Immediately prior to end 
of infusion (<5 min)


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Phase 2 Intensive PK Sampling:  Induction Therapy (Cycles 1-2 only) and Maintenance Therapy (Cycle 7 only)
Cycl
e
Da
y
Dosing Schedule
PK Sampling Time for 
LY2228820  
PK Sampling Time for 
Gemcitabine and dFdU
PK Sampling Time for 
Carboplatin
PD Sampling Time
1
10
(30 min after the end of the 
gemcitabine infusion)
1 hr +/-15 min post LY 
dose
1hr after start of infusion 
(±5 min)
1
10
2 hr +/-15min post LY 
dose
2 hr after start of infusion 
(±10 min)
1
10
4 hr +/-15 min  post LY 
dose
4 hr after start of infusion 
(±15 min)
4hr +/-15 min post LY 
dose
1
10
6 hr +/-15 mi post LY 
dose
6 hr after start of infusion 
(±15 min)
1
10
8 hr +/-15 min post LY 
dose
8 hr after start of infusion 
(±15 min)
1
11
No drug
12 hr (± 2 hr) after Day 
10 evening dose of LY
2
1
LY or placebo - morning 
dose 
Predose
Maintenance Therapy
7
3
LY or placebo q 12 hr for 
10 days between Day1 and 
Day10
7
3
Predose
7
3
0.5 hr +/-5 min post LY 
dose


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Phase 2 Intensive PK Sampling:  Induction Therapy (Cycles 1-2 only) and Maintenance Therapy (Cycle 7 only)
Cycle
Day
Dosing Schedule
PK Sampling Time for 
LY2228820  
PK Sampling Time for 
Gemcitabine and dFdU
PK Sampling Time for 
Carboplatin
PD Sampling Time
7
3
1 hr +/-15 min post LY 
dose
7
3
2 hr+/-15 min post LY 
dose
7
3
4 hr +/-15min post LY 
dose
7
3
6 hr +/-15min post LY 
dose
7
3
8 hr +/-15min post LY 
dose
Abbreviations:  hr = hour, LY = LY2228820, min = minute, q = every, PD = pharmacodynamics; PK = pharmacokinetics.


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Standard PK sampling will be performed during Phase 2 induction therapy for all patients who 
do not have intensive PK sampling.
On PK sampling days, the dose of LY2228820 (or placebo) should be held until after the pre-
dose PK sample has been drawn. 
Phase 2 Standard PK Sampling:  Induction Therapy (Cycles 1-3 only)
Cycle
Day
Dosing 
Schedule
PK Sampling Time for 
LY2228820
PD Sampling Time for 
LY2228820
LY2228820 or 
placebo po q 12 
hr for 10 days 
between Day 1 
and Day 10
1
1
Pre-dose
1
3
Pre-dose
1
10
Pre-dose
1
10
4hr  +/-15 min post LY 
dose
2
3
Pre-dose
3
3
Pre-dose
Abbreviations:  hr = hours; PD = pharmacodynamics; PK = pharmacokinetics; po = by mouth; 
q = every 


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Attachment 4.International Federation of Gynecology and 
Obstetrics (FIGO) Staging
STAGES
I
Tumour confined to ovaries
IA
Tumour limited to one ovary, capsule intact
No tumour on ovarian surface
No malignant cells in the ascites or peritoneal washings
IB
Tumour limited to both ovaries, capsules intact
No tumour on ovarian surface
No malignant cells in the ascites or peritoneal washings
IC
Tumour limited to one or both ovaries, with any of the following:
Capsule ruptured, tumour on ovarian surface, positive malignant
Cells in the ascites or positive peritoneal washings
II
Tumour involves one or both ovaries with pelvic extension
IIA
Extension and/or implants in uterus and/or tubes
No malignant cells in the ascites or peritoneal washings
IIB
Extensions to other pelvic organ
No malignant cells in the ascites or peritoneal washings
IIC
IIA/B with positive malignant cells in the ascites or positive peritoneal washings
III
Tumour involves one or both ovaries with microscopically confirmed peritoneal
metastasis outside the pelvis and/or regional lymph nodes metastasis
IIIA
Microscopic peritoneal metastasis beyond the pelvis
IIIB
Macroscopic peritoneal metastasis beyond the pelvis 2 cm or less in greatest dimension
IIIC
Peritoneal metastasis beyond pelvis more than 2 cm in greatest dimension and/or regional 
lymph nodes metastasis
IV
Distant metastasis beyond the peritoneal cavity


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Attachment 5.ECOG Performance Status
ECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance 
without restriction
1
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self care but unable to 
carry out any work activities. Up and about more than 
50% of waking hours
3
Capable of only limited self care, confined to bed or 
chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self care. 
Totally confined to bed or chair
5
Dead.
Source:  Oken et al. 1982.


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Attachment 6.Formula for Calculating Creatinine Clearance
Note:  This formula should be used to calculate creatinine clearance (CrCl) during screening and 
for all subsequent cycles of induction therapy.  Only local laboratory values should be used in 
the calculation.  
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 mol/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.
Reference:  Cockcroft and Gault 1976.


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Attachment 7.
Formula for Calculating Carboplatin Dose
The Calvert formula must be used for the calculation of the carboplatin dose in this study.
Calvert Formula:
Total Dose (mg) = (target AUC) (GFR + 25) 
Maximum carboplatin dose (mg) = target AUC 4 (mg•min/mL) (125 + 25) = 4 150 mL/min 
= 600 mg.
Reference:  Calvert et al. 1989.


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Attachment 8.RECIST Criteria 1.1
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumors (RECIST): Revised RECIST 
Guideline (version 1.1; Eisenhauer et al. 2009).  
Measurability of Tumor at Baseline
Tumor lesions/lymph nodes will be categorized at baseline as measurable or nonmeasurable.  
Measurable disease is defined by the presence of at least 1 measurable lesion.
Measurable 
Tumor lesions:  Measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of:

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (slice thickness 5 mm) 

10 mm caliper measurement by clinical exam (non-measurable lesions if cannot 
be accurately measured with calipers)

20 mm by chest X-ray.
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan thickness recommended 
to be 5 mm).
Nonmeasurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly nonmeasurable lesions.  Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis,  inflammatory breast disease, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measureable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone lesions:  

Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.


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
Blastic bone lesions are non-measurable.
Cystic lesions:  

Simple cysts should not be considered as malignant lesions (neither measurable 
nor nonmeasurable) 

Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability.  If noncystic 
lesions are presented in the same patients, these are preferred for selection as 
target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated at a previously irradiated area, or in an area subjected 
to other loco-regional therapy, are non-measurable unless there has been 
demonstrated progression in the lesion.  
Baseline Documentation of Target and Non-Target Lesion
Target Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 5 
lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline. Non-nodal Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and can be reproduced in repeated measurements.  
Measurable lymph nodes are target lesions if they meet the criteria of a short axis of 15 mm by 
CT scan.  All measurements are to be recorded in the case record form (CRF) in millimeters (or 
decimal fractions of centimeters [cm]).
Nontarget Lesions
All other lesions (or sites of disease) are identified as nontarget lesions (chosen based on their 
representativeness of involved organs and the ability to be reproduced in repeated measurements) 
and should be recorded at baseline.  Measurement of these lesions are not required but  should be 
followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’.  In addition, it is 
possible to record multiple nontarget lesions involving the same organ as a single item on the 
CRF (for example, multiple liver metastases recorded as one liver lesion).
Lymph nodes with short axis 10 mm but <15 mm should be considered nontarget lesions.  
Nodes that have a short axis <10 mm are considered nonpathological and are not recorded or 
followed.
Specifications by Methods of Measurement
All measurements should be recorded in metric notation, using a ruler or calipers if clinically 
assessed.  All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.


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The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessed by clinical exam.  
An adequate volume of a suitable contrast agent should be given so that the metastases are 
demonstrated to best effect and a consistent method is used on subsequent examinations for any 
given patient.  If prior to enrollment it is known a patient is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or 
MRI (with or without IV contrast) should be used to evaluate the patient at baseline and follow-
up should be guided by the tumour type under investigation and the anatomic location of the 
disease.
Clinical Lesions:  Clinical lesions will only be considered measurable when they are superficial 
and 10 mm diameter as assessed using calipers (for example, skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size of the 
lesion is recommended.  When lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may be reviewed at the 
end of the study.
Chest X-ray:  Chest CT is preferred over chest X-ray when progression is an important endpoint.  
Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung.
CT and MRI:  CT scan is the best currently available and reproducible method to measure lesions 
selected for response assessment.  Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 5 mm.  When CT scan have slice thickness >5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (for example, for body scans).  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances.  
Ultrasound:  Ultrasound should not be used to measure lesion size.  Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a later date and, because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in the course 
of the study, confirmation by CT or MRI is advised.
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques can be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint.
Tumor Markers:  Tumor markers alone cannot be used to assess tumor response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete response (CR).  Specific guidelines for both prostate-specific antigen (PSA) response 


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(in recurrent prostate cancer) and CA-125 response (in recurrent ovarian cancer) have been 
published.  
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete response (CR) in rare cases if required by protocol (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors can 
remain).  When effusions are known to be a potential adverse effect of treatment (for example, 
with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be considered if 
the measurable tumor has met criteria for response or stable disease (SD) in order to differentiate 
between response (or SD) and progressive disease.
Pet Scan (FDG-PET, PET CT):  PET is not recommended for lesion assessment. If a new lesion 
is found by PET, another assessment must be done by CT, unless the PET CT is of diagnostic 
quality.  If CT is done to confirm the results of the earlier PET scan, the date of progression must 
be reported as the earlier date of the PET scan. 
Bone Scan:  If lesions measured by bone scan are reported at baseline, it is necessary to repeat 
the bone scan when trying to identify a complete response (CR) or partial response (PR) in target 
disease or when progression in bone is suspected. 
Response Criteria
Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.  Tumor marker 
results must have normalized.
Partial Response (PR):  At least a 30% decrease in the sum of diameter of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease:  At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest sum on study (including the baseline sum if that is the smallest).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm. The appearance of one or more new lesions is also considered progression.
For equivocal findings of progression (for example, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for progressive disease, taking as reference the smallest sum diameters while on study.
Not Evaluable:  When an incomplete radiologic assessment of target lesions is performed or 
there is a change in the method of measurement from baseline. 


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Evaluation of Nontarget Lesions
Complete Response:  Disappearance of all nontarget lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological or normal in size (<10mm short axis).
Non-CR/ non-progressive disease:  Persistence of 1 or more nontarget lesions and/or 
maintenance of tumor marker level above the normal limits.
Progressive Disease:  Unequivocal progression of existing nontarget lesions.  The appearance of 
1 or more new lesions is also considered progression.
Not Evaluable: When a change in method of measurement from baseline occurs.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the earliest of objective progression or start of new anticancer therapy, taking into account any 
requirement for confirmation.  The patient’s best overall response assignment will depend on the 
findings of both target and nontarget disease and will also take into consideration the appearance 
of new lesions.  The Best Overall Response will be calculated via an algorithm using the 
assessment responses provided by the investigator over the course of the trial.   
Time Point Response
It is assumed that at each protocol-specified time point, a response assessment occurs.  (When no 
imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point.) Table 1 provides a summary of the overall response status calculation at each 
time point for patients who have measurable disease at baseline.
Table 1.
Time Point Response: Patients with Target (Nontarget) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-progressive 
disease
No
PR
CR
Not evaluated
No
PR
PR
Non-progressive disease or 
not all evaluated
No
PR
SD
Non-progressive disease or 
not all evaluated
No
SD
Not all evaluated
Non-progressive disease
No
NE
Progressive 
disease
Any
Yes or No
Progressive disease
Any
Progressive disease
Yes or No
Progressive disease
Any
Any
Yes
Progressive disease
Abbreviations:  CR = complete response; PR = partial response; SD = stable disease.; NE = not evaluable. 


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Table 2 is to be used when patients have nonmeasurable disease only.
Table 2.
Time Point Response: Patients with Nontarget Disease Only
Nontarget Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-progressive 
disease
No
Non-CR/non-progressive diseasea
Not all evaluated
No
NE
Unequivocal progressive 
disease
Yes or No
Progressive disease
Any
Yes
Progressive disease
Abbreviations:  CR = complete response; NE = not evaluable.
a
non-CR/non-progressive disease is preferred over SD for nontarget disease. 
Frequency of Tumor Re-Evaluation
A baseline tumor-evaluation must be performed within 4 weeks before patient begins study 
treatment. Frequency of tumor re-evaluation while on and adapted to treatment should be 
protocol-specific and adapted to the type and schedule of treatment.  In the context of Phase 2 
studies where the beneficial effect therapy is not known, follow-up every 6-8 weeks is 
reasonable.  Normally, all target and non-target sites are evaluated at each assessment using the 
same method.  However, bone scans may need to be repeated only when CR is identified in 
target disease or when progression in bone is suspected.  
Confirmatory Measurement/Duration of Response
Confirmation:
The main goal of confirmation of objective response in clinical trials is to avoid overestimating 
the response rate observed. The confirmation of response is particularly important in 
nonrandomized trials where response (CR/PR) is the primary end point.  In this setting, to be 
assigned a status of PR/CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first 
met.  To confirm a response of CR, a full assessment of all target and nontarget lesions that were 
present at baseline must occur, including those measured by bone scan.  To confirm a PR or SD, 
a full assessment of target lesions that were present at baseline must occur;  assessment of 
nontargets is not required.  
However, in randomized trial (Phase 2 or 3) or studies where SD or progression is the primary 
endpoints, confirmation of response is not required.  But, elimination of the requirement may 
increase the importance of central review to protect against bias, in particular of studies which 
are not blinded.
In the case of SD, follow-up measurements must have met the SD criteria at least once after start 
of treatment at a minimum interval not less than 6 weeks measured from first dose.


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Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective 
progression is observed (taking as reference for progressive disease the smallest measurements 
recorded on study).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, that is the reference for calculation of 
progressive disease).  
Independent Review of Response and Progression
When objective response (CR + PR) is the primary end point, and when key drug development 
decisions are based on the observation of a minimum number of responders, it is recommended 
that all claimed responses be reviewed by an expert(s) independent of the study.  If the study is a 
randomized trial, ideally reviewers should be blinded to treatment assignment.  


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Attachment 9.Protocol JIAE Sampling Summary
This table summarizes the maximum number of samples and volumes for all sampling and tests 
during the study.  Fewer samples may actually be taken, but this will not require a protocol 
amendment.
Protocol I1D-MC-JIAE(c) Sampling Summary
Purpose
Sample 
Type
Maximum Amount 
per Sample 
Maximum 
Number Samples
Maximum Total 
Amount
Screening testsa
Blood
9 mL
1
9 mL
Standard laboratory testsa
Chemistry
Blood
5 mL
8
40 mL
Hematology
Blood
4 mL
10
40 mL
CA125
Blood
5 ml
Circulating plasma proteins
Blood
5 ml
Drug concentration
Blood
6 mL
24
144 mL
Pharmacogenetic samples
Blood
10 mL
1
10 mL
Stored sample for germline 
DNA
Blood
10 mL
1
10 mL
Other exploratory samples
archival tissue 
Block or 
Slides
Total blood
54 mL
45
253 mL
Abbreviations:  mL = milliliters.
a
Additional samples may be drawn if needed for safety purposes.


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Attachment 10.
FACT-Ovarian (FACT-O) Instrument


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CCI
CCI
CCI
CCI
CCI
CCI
CCI


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CCI
CCI
CCI
CCICCI
CCI
CCI


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CCI
CCI
CCI
CCI
CCI


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Attachment 11.
Protocol JIAE Amendment (c) Summary
Overview
Protocol I1D-MC-JIAE, A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Study of 
LY2228820, a p38 MAPK Inhibitor, plus Gemcitabine and Carboplatin versus Gemcitabine and 
Carboplatin for Women with Platinum-Sensitive Ovarian Cancer, has been amended.  The new 
protocol is indicated by amendment (c) and will be used to conduct the study in place of any 
preceding version of the protocol.
The rationale for the amendment was as follows: 
Metabolic clearance analysis has recently been completed which revealed that CYP3A mediated 
metabolism is not the primary clearance pathway of LY2228820.  This allows for the restriction 
of the CYP3A inhibitors, inducers, or substrates to be removed and for the use of dexamethasone 
and other anti-emetics during treatment with LY2228820. 
Based on the available preclinical data, there is a possible risk of clinical drug–drug interaction 
when LY2228820 is administered with inhibitors or inducers of UGT enzymes.  In the absence 
of clinical data to refine the risk of interaction, caution is warranted in the concomitant use of 
UGT enzyme inhibitors such as valproic acid and probenecid and inducers such as 
carbamazepine, phenytoin and rifampin.  When, in the clinical investigator's opinion, 
concomitant use of valproic acid or probenecid is indicated, LY2228820-related DLTs of ataxia, 
dizziness and rash should be carefully monitored.
The ovarian cancer landscape has changed during the course of this study.  Maintenance therapy 
as a part of or after a first line platinum regimen has become more prevalent.  Several studies are 
examining the effect of maintenance after patients achieve a CR with the first line platinum 
regimen.  In order to balance these patients between the placebo and LY2228820 arms, prior 
maintenance therapy has been added as a randomization factor. 
The original sample size calculation for the Phase 2 portion of the study included a censoring 
rate assumption of 6% with 103 PFS events needed from 110 patients.  Upon reflection, Lilly 
considers that this assumed censoring rate is too low.  If just 8 or more patients are lost to follow 
up, the actual censoring rate would be higher.  With this protocol amendment, the censoring rate 
estimate has been increased to 28% resulting in a reduction in the number of PFS events needed 
to 79.  The hazard ratio of 0.7 has been maintained but the power has been reduced to 77% from 
83%.  These assumptions are consistent with enrollment and censoring experience in this phase 
of development.  
In addition, the interim analyses for the study have been updated as follows:

The third interim analysis will be performed when approximately 60 patients in the Phase 
2 portion of the study have completed 2 cycles of treatment, and will examine safety and 


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PK only.  Futility has been eliminated as Lilly does not expect that enough PFS events 
will have been observed to allow a futility analysis to occur at that time.  

The fourth interim analysis has been removed as all patients will have been enrolled and 
the PFS data will be immature.  This interim would not be informative for futility or 
efficacy.  Trial level safety will continue to be monitored throughout the study. 
The overall changes made to this protocol are as follows:


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.


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Global changes:
Protocol ID:  I1D-MC-JIAE(bc)
2. Synopsis
Length of Study:  40 months
Planned first patient visit:  April 2012
Planned last patient visit:  August 2015
Planned interim analyses: 
1.
All patients in Phase 1b have received at least 1 cycle:  safety and pharmacokinetics (PK) 
2.
Approximately 30 patients in Phase 2 have received at least 1 cycle:  safety and PK
3.
Approximately 60 patients in Phase  2 have received at least 2 cycles:  safety, PK, and PKfutility
4.
All patients in Phase 2 have received at least 2 cycles:  safety, PK, futility, and efficacy
Diagnosis and Main Criteria for Inclusion and Exclusions:
Main exclusion criteria for study entry are: 

Are currently enrolled in, or discontinued <14 days from, a clinical trial involving an investigational drug 
or device 

Have previously completed or withdrawn from this study or any other study investigating LY2228820

Have previously been treated with gemcitabine for epithelial ovarian cancer, fallopian tube cancer, or 
primary peritoneal cancer

Receiving concomitant cytotoxic or other antineoplastic treatment

Have had, in the judgment of the investigator, a major bowel resection that would alter oral drug absorption

Have received, within 7 days of the initial dose of study drug, either grapefruit juice or treatment with a 
drug that is a known inducer or moderate/strong inhibitor of CYP3A4

Are receiving, in the judgment of the investigator, concurrent administration of immunosuppressive therapy

Have, in the judgment of the investigator, serious concomitant systemic disorders (e.g., acute myocardial 
infarction within 6 months of study entry, uncontrolled hypertension) incompatible with the study
Test Product, Dose, and Mode of Administration:  
Study drugs are administered on a 21-day cycle during induction therapy (Cycles 1 through 6) 
and on a 28-day cycle during maintenance therapy (Cycle 7 and beyond).  LY2228820 is 
administered orally every 12 hours on Days 1 through 10 of a 21-day cycle during induction 
therapy and on Days 1 through 14 of a 28-day cycle during maintenance therapy.  Gemcitabine 
(1000 mg/m2) is administered intravenously (IV) over 30 minutes (+15 min) on Days 3 and 10 
of induction therapy only.  Carboplatin (area under the plasma concentration–time curve [AUC] 
4 with maximum dose of 600 mg) is administered IV over 30 minutes (+15 min) on Day 3 of 
induction therapy only.
Reference Therapy, Dose, and Mode of Administration:  
Study drugs are administered on a 21-day cycle during induction therapy (Cycles 1-6) and on a 
28-day cycle during maintenance therapy (Cycle 7 and beyond).  Placebo is administered orally 
every 12 hours on Days 1 through 10 of a 21-day cycle during induction therapy and on Days 1 


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through 14 of a 28-day cycle during maintenance therapy.  Gemcitabine (1000 mg/m2) is 
administered IV over 30 (+15) minutes on Days 3 and 10 of induction therapy only.  Carboplatin 
(AUC4 with maximum dose of 600 mg) is administered IV over 30 (+15) minutes on Day 3 of 
induction therapy only.
4.
Abbreviations and Definitions
evaluable patient (for Phase 2)
any randomized patient who receives at least one dose of study treatment
5.
Introduction
5.8.
Interaction with Cytochrome P450 (CYP) Enzymes and Enzymes Responsible for 
the Metabolism of LY2228820
The effect of LY2228820 on drug-metabolizing enzymes has been studied in vitro using human 
liver microsomes.  LY2228820 was found to competitively inhibit the biotransformation of 
midazolam to 1′-hydroxy-midazolam with an estimated Ki of 1.2 µM (0.5 µg/mL).  LY2228820 
was also shown to inhibit CYP3A in a time-dependent manner with a kinact of 0.069 min-1 and 
KI of 9.5 µM (3.99 µg/mL).  These data suggested the possibility that LY2228820 might 
modulate clearance of drugs that are metabolized by CYP3A in vivo.
The ability of LY2228820 to induce catalytic activities associated with CYP1A2, CYP2B6, and 
CYP3A was examined in primary cultures of fresh human hepatocytes. prepared from three 
separate donors.  LY2228820 was found unlikely to cause in vivo induction of the above CYP 
isoforms within the concentration range examined (0.01 to 10 µM).
The effect of LY2228820 on the activity of CYP3A in vivo has beenis being evaluated in the 
dose confirmation phase of Study JIAD (Part B) in which patients wereare administered a 2-mg 
oral dose of midazolam in the absence or presence of 420 mg LY2228820 administered every 12 
hours (after fourteen doses).  Results showedPreliminary results from 9 patients indicate that 
mean PK parameters (Cmax and AUC) of midazolam administered with LY2228820 were no 
higher than those of midazolam administered alone, indicating.  These data indicate that 
LY2228820 may not inhibit the CYP3A activity up to the dose level investigated (18 patients at 
420 mg given every 12 hours).
In vitro studies using human liver microsomes indicated that the metabolic clearance of 
LY2228820 is primarily mediated by the UDP-glucuronosyltransferase (UGT) pathway 
(87%), with CYP-mediated pathway contributing to only 13%.  Further CYP phenotyping 
studies using recombinant human CYPs indicated that CYP3A contributed to 72% of the 
CYP-mediated metabolic clearance of LY2228820.  Taken together, the contribution of 
CYP3A to the total metabolic clearance of LY2228820 is estimated to be less than 10%.  
The regulatory guidance suggests that any enzyme contributing <25% to the systemic 
clearance of the drug is not clinically significant (FDA 2012).


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Collectively, the above in vitro and in vivo data suggest that clinical interactions are 
unlikely when LY2228820 is coadministered with substrates, inhibitors and or inducers of 
CYP3A.  When coadministered, inhibitors of UGT may increase the plasma concentrations 
of LY2228820 and inducers of UGT may decrease the plasma concentrations of 
LY2228820.
Refer to Section 9.8, Concomitant Therapy, for more information regarding inducers and 
moderate/strong inhibitors and inducers of UGTCYP3A4.
5.12.
Rationale for Amendment (c)
Metabolic clearance analysis has recently been completed which revealed that CYP3A 
mediated metabolism is not the primary clearance pathway of LY2228820.  This allows for 
the restriction of the CYP3A inhibitors, inducers, or substrates to be removed and for the 
use of dexamethasone and other anti-emetics during treatment with LY2228820. 
Based on the available preclinical data, there is a possible risk of clinical drug–drug 
interaction when LY2228820 is administered with inhibitors or inducers of UGT enzymes.  
In the absence of clinical data to refine the risk of interaction, caution is warranted in the 
concomitant use of UGT enzyme inhibitors such as valproic acid and probenecid and 
inducers such as carbamazepine, phenytoin and rifampin.  When, in the clinical 
investigator's opinion, concomitant use of valproic acid or probenecid is indicated, 
LY2228820-related DLTs of ataxia, dizziness and rash should be carefully monitored.
The ovarian cancer landscape has changed during the course of this study. Maintenance 
therapy as a part of or after a first line platinum regimen has become more prevalent.  
Several studies are examining the effect of maintenance after patients achieve a CR with 
the first line platinum regimen.  In order to balance these patients between the placebo and 
LY2228820 arms, prior maintenance therapy has been added as a randomization factor. 
The original sample size calculation for the Phase 2 portion of the study included a 
censoring rate assumption of 6% with 103 PFS events needed from 110 patients. Upon 
reflection, Lilly considers that this assumed censoring rate is too low. If just 8 or more 
patients are lost to follow up, the actual censoring rate would be higher. With this protocol 
amendment, the censoring rate estimate has been increased to 28% resulting in a reduction 
in the number of PFS events needed to 79. The hazard ratio of 0.7 has been maintained but 
the power has been reduced to 77% from 83%. These assumptions are consistent with 
enrollment and censoring experience in this phase of development.  
In addition, the interim analyses for the study have been updated as follows:

The third interim analysis will be performed when approximately 60 patients in the 
Phase 2 portion of the study have completed 2 cycles of treatment, and will examine 
safety and PK only. Futility has been eliminated as Lilly does not expect that enough 
PFS events will have been observed to allow a futility analysis to occur at that time.  


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
The fourth interim analysis has been removed as all patients will have been enrolled 
and the PFS data will be immature. This interim would not be informative for 
futility or efficacy. Trial level safety will continue to be monitored throughout the 
study. 
7.
Study Population
7.1.
Inclusion Criteria
[6]
Have adequate organ function, including:

Hematologic:  absolute neutrophil count  1.5 × 109/L, platelets 100 × 
109/L, and hemoglobin 8 g/dL.  Patients may receive erythrocyte 
transfusions to achieve this hemoglobin level at the discretion of the 
investigator.  Initial treatment must not begin until 1 day after the 
erythrocyte transfusion.

Hepatic:  bilirubin 1.5 times upper limits of normal and alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST)and
2.5 times upper limits of normal.
7.2.
Exclusion Criteria
[15] Have a diagnosis of inflammatory bowel disease (Crohn’s disease or 
ulcerative colitis).
[16] Exclusion criterion [16] has been deleted
[16] Have received, within 7 days of the initial dose of study drug, either grapefruit 
juice or treatment with a drug that is a known inducer or moderate/strong 
inhibitor of CYP3A4 (refer to Attachment 10). In addition, patients should 
not receive grapefruit juice or treatment with a known inducer or 
moderate/strong inhibitor of CYP3A4 during the study.
[17] Require concurrent administration of immunosuppressive therapy such as 
corticosteroids (prednisone >10 mg/day, or equivalent).  Intermittent 
corticosteroids usedFor corticosteroid use as part of an antiemetic regimen 
are permitted.agents, see Section 9.8.
7.3.1. Discontinuation of Patients
The reason and date for discontinuation will be collected for all patients.  All patients who 
discontinue but receive at least one dose of study treatment will have procedures performed as 
shown in the Study Schedule (Attachment 1).


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Patients who withdraw from the study before receiving study treatment will be replaced and will 
not be included in the safety or efficacy assessments.
For Phase 1b, any patient who experiences a dose-limiting toxicity or receives at least 75% of 
planned doses of LY2228820 in Cycle 1 will be deemed evaluable for safety assessment at that 
dose level.  Non-evaluableNonevaluable patients may be replaced to ensure at least 3 evaluable 
patients at each dose level, unless accrual to that cohort has stopped because 2 or more patients at 
that dose level have experienced a DLT.  In no case should patients be replaced if they were 
discontinued from the study due to toxicity. Patients who are evaluable for safety assessment at a 
dose level but have insufficient PK sampling may be replaced upon consultation with the 
investigator(s) and the Lilly Clinical Research Physician (CRP) to ensure adequate PK data, 
unless accrual to that cohort has stopped because 2 or more patients at that dose level have 
experienced a DLT.
For Phase 2, any randomized patient who receives at least one dose of study treatment will be 
deemed evaluable for efficacy assessment.  Nonevaluable patients may be replaced. Patients who 
are evaluable for efficacy assessment but have insufficient PK sampling may be replaced upon 
consultation with the investigator(s) and the Lilly CRP to ensure adequate PK data.
8.
Investigational Plan
8.1.2. Phase 2
Approximately 110 patients will be randomized 1:1 to provide 83% power for identifying a 
hazard ratio of 0.7 (LY2228820 arm to placebo arm) with a false-positive rate of 0.2 (one-sided) 
(refer to Section 12 for additional details regarding the sample size description).  Patients will be 
randomized with a minimization method (Pocock and Simon 1975) using the following factors:  
time from completion of first line platinum-based therapy to relapse (6 to 12 months versus over 
12 months) and ECOG performance status (0 and 1 versus 2).
Starting from protocol (c), randomization scheme is updated by adding another 
randomization factor. Patients who consent to protocol (c) will be randomized using 
following factors: time from completion of first line platinum-based therapy to relapse (6 to 
12 months versus over 12 months), ECOG performance status (0 and 1 versus 2) and 
maintenance therapy as a part of or after a first line platinum regimen (yes versus no).
8.1.4. Interim Analyses
The first interim analysis will be conducted to assess safety and PK; it will be performed when 
all evaluable patients in the Phase 1b portion of the study have received at least 1 cycle of study 
treatment.


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The second interim analysis will be conducted to assess safety and PK; it will be performed 
when approximately 30 patients in the Phase 2 portion of the study have received at least 1 cycle 
of study treatment.
The third interim analysis will be conducted to assess safety, PK, and PKfutility; it will be 
performed when approximately 60 patients in the Phase 2 portion of the study have received at 
least 2 cycles of study treatment.
The fourth interim analysis will be conducted to assess safety, PK, futility, and efficacy; it will 
be performed when enrollment in the study is complete and all evaluable patients in the Phase 2 
portion of the study have received at least 2 cycles of study treatment.
9.
Treatment
9.3.
Method of Assignment to Treatment
In the Phase 2 portion of the study, approximately 110 patients will be randomized 1:1 in a 
double-blind manner by an interactive voice-response system (IVRS) to either Arm A 
(LY2228820 plus gemcitabine and carboplatin) or Arm B (placebo plus gemcitabine and 
carboplatin). Randomization will minimize imbalance between treatment arms according to the 
following factors:  time from completion of first line platinum-based therapy to relapse (6 to 12 
months versus over 12 months) and ECOG performance status (0 and 1 versus 2).
Starting from protocol (c), the randomization scheme is updated by adding another 
randomization factor. Patients who consent to protocol (c) will be randomized using 
following the factors: time from completion of first line platinum-based therapy to relapse 
(6 to 12 months versus over 12 months), ECOG performance status (0 and 1 versus 2) and 
maintenance therapy as a part of or after a first line platinum regimen (yes versus no).
This procedure is based on a well-defined algorithm (Pocock and Simon 1975). The 
randomization probability factor will be set at 0.75.
9.4.2.1.
Induction Therapy
Gemcitabine, 1000 mg/m2, will be administered IV over approximately 30 (+15) minutes on 
Days 3 and 10 of a 21-day cycle.  The gemcitabine infusion will be started following the 
morning dose of LY2228820.
Carboplatin, AUC 4 (maximum dose, 600 mg), will be administered IV over approximately 30 
(+15) minutes on Day 3 of a 21-day cycle.  The carboplatin infusion will follow the gemcitabine 
infusion.  Antiemetics should be administered according to institutional standard procedures.  
Patients may receive a single dose of dexamethasone as part of the antiemetic regimen prior to 
administration of intravenous chemotherapy (refer to Section 9.8).


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9.4.3.1.1.
LY2228820 Dose Adjustments
Table JIAE.9.2.
IntercycleIntracycle Dose Adjustments for LY2228820 or Placebo
9.5.1. Dose-Limiting Toxicity Determination and Maximum Tolerated Dose Definition
All toxicities should be graded according to CTCAE Version 4.0.
Nausea/vomiting should be treated promptly with antiemetics (for example, prochlorperazine, 
and metoclopramide). Diarrhea should be treated with antidiarrheals (for example, loperamide). 
Supportive interventions should not involve treatment with medications that are inducers or 
moderate/strong inhibitors of CYP3A4 (refer to Attachment 10).
9.8.
Concomitant Therapy
With the exceptions listed in the following sections, no other chemotherapy, experimental 
medications, other anticancer therapy, immunotherapy, hormonal cancer therapy, radiation, 
surgery for cancer, or experimental medications will be permitted while patients are on study 
treatment.  The need for any form of radiotherapy (including palliative) will be cause for early 
discontinuation from study treatment.  In addition any disease progression requiring other forms 
of specific antitumor therapy will also necessitate early discontinuation from study treatment.  
Appropriate documentation of all forms of premedication’s, supportive care, and concomitant 
medications must be captured at each visit in the case report form (CRF).  Concomitant 
medications and supportive care therapies must be documented at the time of discontinuation and 
also at the 30-day follow-up visit.
Based on the available preclinical data, there is a possible risk of clinical drug–drug 
interaction when LY2228820 is administered with inhibitors or inducers of UGT enzymes.  
In the absence of clinical data to refine the risk of interaction, caution is warranted in the 
concomitant use of UGT enzyme inhibitors such as valproic acid and probenecid and 
inducers such as carbamazepine, phenytoin and rifampin.  When, in the clinical 
investigator's opinion, concomitant use of valproic acid or probenecid is indicated, 
LY2228820-related DLTs of ataxia, dizziness and rash should be carefully monitored.
Patients are not allowed to consume grapefruit juice and/or drugs that are inducers or 
moderate/strong inhibitors of CYP3A4 (see Attachment 10).  Patients will have to discontinue 
these medications or will be discontinued from study treatment if unwilling to stop drugs that are 
inducers or moderate/strong inhibitors of CYP3A4.  The only exception to this requirement is 
that patients may receive a single dose of dexamethasone (an inducer of CYP3A4) as part of the 
antiemetic regimen prior to administration of intravenous chemotherapy.
To avoid potential drug-drug interactions with LY2228820, antiemetics that are not CYP3A4-
inducers or inhibitors should be used, such as prochlorperazine or metoclopramide.


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10.
Efficacy, Health Outcome/Quality of Life Measures, Safety Evaluations, Sample 
Collection and Testing, and Appropriateness of Measurements
10.3.1.1.
Serious Adverse Events
Previously planned (prior to signing the ICF) surgeries should not be reported as SAEs unless the 
underlying medical condition has worsened during the course of the study.
Serious adverse eventsDeath due to disease progression, including death, should not be 
reported as an SAE unless the investigator also deems themthere to be possiblya possible 
contribution related to the study drug.
10.4.2. Archival Tumor Tissue Sample
Pretreatment formalin-fixed, paraffin-embedded tumor tissue obtained at the time of original 
diagnosis should be in a whole block, partial block, or unstained slides.  Stored samples will 
retain the patient identifier and therefore, will not be stored indefinitely.  Any blocks or 
slideswhole block submitted will either be returned to the site or discarded within 15 years 
after last patient visit for the trial.  If archival tissue is not available for a specific patient, it 
will not constitute a protocol violation.
For p53 and PTEN mutation analyses comparing tumor to germline DNA, a single whole-blood 
sample will be collected one time to isolate DNA from PBMCs.  Samples will be identified by 
the patient number (coded) and stored for up to 15 years after the last patient visit for the 
study at a facility selected by the sponsor.  The sample and any data generated from it can 
only be linked back to the patient by investigator site personnel.
Supplies required for the collection and shipment of the patients stored samples will be supplied 
by the sponsor.  Sample handling and shipment to the central laboratory will occur according to 
instructions given to the study sites.
10.4.4. Samples for Drug Concentration Measurements 
Pharmacokinetics/Pharmacodynamics
Pharmacodynamic samples will be collected as specified in the PK and PD Sampling Schedule 
(Attachment 3).  Circulating plasma proteins regulated by p38 MAPK (such as such as TNF, 
IL-1, IL-6, and IL-8) will be measured.  Supplies required for the collection and shipment of the 
patients stored samples will be supplied by the sponsor.  Sample handling and shipment to the 
central laboratory will occur per instructions given to the study sites.  Pharmacodynamic 
samples collected to measure circulating plasma proteins will be retained for a maximum 
of 15 years after the last patient visit for the study.
12.
Sample Size and Statistical Methods


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12.1.
Determination of Sample Size
The primary objective of the Phase 2 portion of this study is to compare the progression-free 
survival in patients treated with LY2228820 plus gemcitabine and carboplatin versus placebo 
plus gemcitabine and carboplatin.  A group sequential design will be used to control type 1 
error across the interim analyses and the final PFS analysis in Phase 2 (see Section 12.2.11
for details). The primary analysis will be performed after 79total of 103 PFS events have 
occurred. Assumingprovide 83% power for identifying a hazard ratio (HR) of 0.7, this sample 
size yield at least 77% power with a false-positive rate of 0.2 (1-sided) using a log-rank test.
This assumes exponentially distributed PFS times, median PFS of 8.6 months for the control 
arm, enrollment duration of 12 months, and follow-up time of 18 months after the last patient is 
enrolled.  Assuming 286% censoring rate of the PFS, a total of 110 patients will be randomized 
(55 patients in each arm) to achieve 79103 PFS events at the primary analysis.
12.2.
Statistical and Analytical Plans
All tests of treatment effects will be conducted at a 1-sided alpha level of 0.2 unless otherwise 
stated.  All CIs will be given at a 2-sided 90% level unless otherwise stated.
Starting from protocol (c), an additional factor is included during patient enrollment as 
randomization factor (see Section 8.1.2). For patients who randomized to phase 2 before 
the approval of protocol (c), the value of maintenance therapy as a part of or after a first 
line platinum regimen for these patients will be imputed as “not collected”.
12.2.5. Primary Outcome and Methodology
For the primary endpoint of PFS, the HR will be estimated from survival data on all randomized 
patients using a Cox proportional hazards model with assigned study treatment arm as fixed 
effect along with cofactors forand time from completion of first line platinum-based therapy to 
relapse (6 to 12 months versus over 12 months),) and ECOG performance status (0 and 1 versus 
2) and maintenance therapy as a part of or after a first line platinum regimen (yes versus 
no versus not collected).as covariates.
The Kaplan-Meier method (Kaplan and Meier 1958) will be used to estimate the survival curve 
as well as survival rates at various time points for each treatment group.  The log-rank test will 
be used to compare PFS distributions between treatment groups in phase 2.
12.2.6. Efficacy Analyses
CA125 data will be log-transformed first and analyzed using a mixed-effect model repeated 
measures analysis with treatment, time, and treatment byand time interaction as fixed effect, 
along with cofactors for time from completion of first line platinum-based therapy to relapse (6 
to 12 months versus over 12 months),) and ECOG performance status (0 and 1 versus 2) and 


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maintenance therapy as a part of or after a first line platinum regimen (yes versus no 
versus not collected).as covariates.
The log ratio of tumor size at the end of Cycle 2 to tumor size at baseline will be calculated for 
each patient. This measure follows a normal distribution and will be compared between 
treatment groups using a t-test.  Analysis of variance will be used to assess the effect of baseline 
factors on the change in tumor size.
The overall response rate is estimated as the total number of CRs and PRs, based on RECIST 
version 1.1, divided by the total number of randomized patients.  The efficacy endpoint of 
overall response rate and its exact 90% confidence interval will be estimated for each treatment 
arm.  The proportion in each treatment arm will be compared using the Chi-square test.
The efficacy analysis on OS will be conducted after all the patients have been followed for at 
least 2 years. The HR will be estimated from survival data on all randomized patients using a 
Cox proportional hazards model using assigned study treatment arm as fixed effect with time 
from completion of first line platinum-based therapy to relapse (6 to 12 months versus over 
12 months),) and ECOG performance status (0 and 1 versus 2) and maintenance therapy as a 
part of or after a first line platinum regimen (yes versus no versus not collected).as 
covariates.
Additional exploratory analyses may be performed as deemed appropriate.
12.2.11.2.
Interim Analyses for Phase 2
TwoThree interim analyses are planned for the Phase 2 portion of the study.  The first analysis 
will be conducted for safety and pharmacokinetics when approximately 30 patients in Phase 2 
have completed at least 1 cycle of study treatment.  The second interim analysis will be 
conducted for safety and PK when approximately 60, PK, and futility when approximately 60 
patients in Phase 2 have completed at least 2 cycles of study treatment.  The third interim 
analysis will be conducted for safety, PK, futility, and efficacy when all patients in Phase 2 have 
completed at least 2 cycles of study treatment.  Patient enrollment will continue along with the 
interim analyses. The Phase 2 interim analyses will be conducted using unblinded data under the 
guidance of an internal assessment committee.
Futility analyses using PFS will be performed at interim analyses 2 and 3 in the Phase 2 portion 
of the study.  The study could be terminated if the posterior probability of the HR less than 0.7 is 
less than 15%.
Unblinding procedures are specified in the Statistical Analysis Plan.
14.
References


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Food and Drug Administration. 2012.  
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances
/ucm292362.pdf (Last accessed: 20 January 2015)
Attachment 3.
PK and PD Sampling Schedule
Phase 2 Standard PK Sampling:  Induction Therapy (Cycles 1-3 only)
Cycle
Day
Dosing Schedule
PK Sampling Time for 
LY2228820
PD Sampling Time for 
LY2228820
LY2228820 or 
placebo po q 12 hr for 
10 days between Day 
1 and Day 10
1
1
Pre-dose
1
3
Pre-dose
1
10
Pre-dose
1
10
4hr  +/-15 min post LY 
Post-dose
2
3
Pre-dose
3
3
Pre-dose
Abbreviations:  hr = hours; PD = pharmacodynamics; PK = pharmacokinetics; po = by mouth; 
q = every 


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Attachment 10.
Inducers and Moderate/Strong Inhibitors of CYP3A4
Inducers of CYP3A4
Carbamazepine 
Dexamethasone*
Phenobarbital/phenobarbitone 
Phenytoin 
Rifapentine
Rifampin 
Rifabutin
St. John’s wort
Strong inhibitors of CYP3A4
All HIV protease inhibitors  
Clarithromycin  
Itraconazole  
Ketoconazole  
Nefazodone  
Moderate inhibitors of CYP3A4
Aprepitant
Diltiazem  
Erythromycin  
Fluconazole  
Fluvoxamine  
Fosamprenavir
Grapefruit juice  
Mibefradil
Verapamil
*Important exception:  Patients may receive a single dose of dexamethasone as part of the 
antiemetic regimen prior to administration of intravenous chemotherapy.

SAP_001.pdf: 
Statistical Analysis Plan I1D-MC-JIAE v4 
 
A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Study of LY2228820, a p38 MAPK Inhibitor, plus 
Gemcitabine and Carboplatin versus Gemcitabine and Carboplatin for Women with Platinum-Sensitive Ovarian 
Cancer 
 
 
NCT01663857 
 
Approval date: 21-Sep-2017 


I1D-MC-JIAE Statistical Analysis Plan Version 4
Page 1
LY2228820
1.
Statistical Analysis Plan for Protocol I1D-MC-JIAE:
A Randomized, Double-Blind, Placebo-Controlled Phase 
Ib/2 Study of LY2228820, a p38 MAPK Inhibitor, plus 
Gemcitabine and Carboplatin versus Gemcitabine and 
Carboplatin for Women with Platinum-Sensitive Ovarian 
Cancer
Confidential Information
The information contained in this Statistical Analysis Plan (SAP) 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.  This document and its associated 
attachments or appendices are subject to United States Freedom of Information Act 
Exemption 4.
p38 Mitogen-Activated Protein Kinase (MAPK) Inhibitor (LY2228820)
This trial is a Phase Ib dose escalation study followed by a randomized, double-blind, 
placebo-controlled  Phase II study of a p38 MAPK inhibitor administered in combination 
with gemcitabine/carboplatin to patients with platinum-sensitive ovarian cancer.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I1D-MC-JIAE
Phase 1b/2
Statistical Analysis Plan Version 1 electronically approved by Lilly on 
30 March 2012
Statistical Analysis Plan Version 2 electronically approved by Lilly on
06 April 2015
Statistical Analysis Plan Version 3 electronically signed and approved by Lilly on
16 June 2017
Statistical Analysis Plan Version 4 electronically signed and approved by Lilly on date 
provided below
Approval Date: 21-Sep-2017 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan for Protocol I1D-MC-JIAE: A Randomized, 
Double-Blind, Placebo-Controlled Phase Ib/2 Study of LY2228820, 
a p38 MAPK Inhibitor, plus Gemcitabine and Carboplatin versus 
Gemcitabine and Carboplatin for Women with Platinum-Sensitive 
Ovarian Cancer ...................................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................4
4.
Study Objectives.................................................................................................................5
4.1.
Primary Objective ..........................................................................................................5
4.2.
Secondary Objectives.....................................................................................................5
5.
A Priori Statistical Methods ................................................................................................6
5.1.
General Considerations ..................................................................................................6
5.1.1.
Primary Endpoints..................................................................................................7
5.1.2.
Secondary Endpoints..............................................................................................7
5.1.3.
Safety Endpoints....................................................................................................7
5.1.4.
Health Outcomes....................................................................................................8
5.2.
Patient Disposition .........................................................................................................8
5.3.
Patient Characteristics ....................................................................................................8
5.4.
Concomitant Therapy.....................................................................................................8
5.5.
Treatment Compliance ...................................................................................................8
5.6.
Primary Analyses...........................................................................................................9
5.6.1.
Sensitivity Analysis................................................................................................9
5.7.
Efficacy Analyses ..........................................................................................................9
5.8.
Pharmacokinetic/Pharmacodynamic Analyses..............................................................10
5.8.1.
Pharmacokinetic Analyses....................................................................................10
5.8.2.
Pharmacodynamic Analysis .................................................................................11
5.9.
Health Outcome/Quality of Life Analyses....................................................................11
5.10. Safety Analyses............................................................................................................12
5.11. Subgroup Analyses.......................................................................................................13
5.12. Interim Analysis...........................................................................................................13
5.12.1.
Interim Analysis for Phase Ib ...............................................................................13
5.12.2.
Interim Analysis for Phase 2 ................................................................................13
5.12.2.1.
The Third Interim Analysis for Phase 2 ..........................................................13
5.13. Determination of Sample Size ......................................................................................14
6.
Unblinding Plan................................................................................................................15


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7.
References ........................................................................................................................17


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior to unblinding.
Statistical Analysis Plan (SAP) Version 2 was updated per protocol (c) and approved before the 
first interim analysis in Phase 2.
The overall changes and rationale for the changes incorporated in Version 2 are as follows:  

Randomization scheme updated:  another randomization factor was added.

Interim analysis for Phase 2 updated:  the third interim will examine safety 
and PK only, and the fourth interim was removed.

Determination of sample size updated.
Statistical Analysis Plan (SAP) Version 3 was updated and approved before the primary outcome 
lock and any aggregated unblinding of efficacy data. 
The overall change and rationale for the changes incorporated in Version 3 are as follows:  

Added a sensitivity analysis of PFS, with patients who start new anticancer 
therapy censored at their last assessment prior to doing so.

Specified that the analysis of OS that will be conducted at the time of final 
analysis of PFS will serve as a futility interim analysis to inform further 
conduct of the study, and provided the statistical assumptions for the interim 
analysis.  
Statistical Analysis Plan (SAP) Version 4 was updated and approved after the primary outcome 
lock and before the final analysis.

Added a statement in the unblinding plan that topline result from the primary 
outcome analysis may be shared with sponsor personnel, patients, and site personnel. 


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4.
Study Objectives
4.1.
Primary Objective
The primary objective of the Phase 1b portion of this study is to determine the recommended 
Phase 2 dose of LY2228820 that can be safely administered in combination with gemcitabine 
and carboplatin.
The primary objective of the Phase 2 portion of this study is to compare the progression-free 
survival (PFS) in patients treated with LY2228820 plus gemcitabine and carboplatin versus 
placebo plus gemcitabine and carboplatin.
4.2.
Secondary Objectives
The secondary objectives of the study are to evaluate:

Change in tumor size, CA125 (serum biomarker for ovarian cancer), overall 
response rate, and overall survival (OS)

Safety and tolerability of the combination:  LY2228820 plus gemcitabine and 
carboplatin

Pharmacokinetics (PK) of LY2228820, gemcitabine and its metabolite 
(dFdU), and carboplatin

Biomarkers related to p38 MAPK pathway activity and the pathogenesis of 
ovarian cancer

Patient-reported outcomes for patients enrolled in the Phase 2 portion of the 
study.


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5.
A Priori Statistical Methods
5.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (Lilly) or its 
designated third party organization (TPO).
No formal statistical analysis will be performed on the Phase 1b portion of the study in which the
primary objective is to assess safety and tolerability of LY2228820 plus gemcitabine and 
carboplatin.  Efficacy analyses for the Phase 2 portion of the study will be conducted on the full 
analysis set.  The analysis populations are defined as below.

The full analysis population includes patients from Phase 2 portion receiving 
at least 1 dose of LY2228820/placebo. 

Safety population is defined as all patients who receive at least 1 dose of 
LY2228820/placebo. 

The PK population consists of patients who have received at least 1 dose of 
study drug and have had sufficient post-dose samples collected to allow 
estimation of the PK parameters.

The pharmacodynamics (PD) population consists of patients who have 
received at least 1 dose of study drug and have undergone PD assessments at 
baseline and at least 1 post-baseline visit.
All tests of treatment effects will be conducted at a 1-sided alpha level of 0.2, unless otherwise 
stated.  All confidence intervals (CIs) will be given at a 2-sided 90% level, unless otherwise 
stated.
Starting from protocol (c), an additional stratification factor is included for patient randomization 
(see Section 8.1.2 of the protocol). For patients who were randomized to Phase 2 before the
approval of protocol (c), the value of maintenance therapy as a part of or after a first line
platinum regimen for these patients will be derived to “not collected.” Patients who consent to 
protocol (c) will be randomized using the following stratification factors: time from completion 
of first line platinum-based therapy to relapse (6 to 12 months versus over 12 months), Eastern 
Cooperative Oncology Group (ECOG) performance status (0 and 1 versus 2) and maintenance 
therapy as a part of or after a first line platinum regimen (yes versus no).
Any change to the data analysis methods described in the protocol will require a protocol
amendment ONLY if it changes a principal feature of the protocol.
Before unblinding of the aggregate database, minor modifications or clarifications to the data 
analysis methods may be justified and described in this plan. Any other change to the data 
analysis methods described in the protocol, and the justification for making the change, will be 
described in the clinical study report (CSR).  
Additional exploratory analyses of the data will be conducted as deemed appropriate.


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This study will be considered complete following final validation and authorization to “lock” the 
database after the protocol-specified objectives have been met.  The Lilly clinical research 
physician (CRP) will notify investigators in the event of study closure.
The following definitions for endpoints only applies to the Phase 2 part of the study, other than 
safety endpoints.
5.1.1. Primary Endpoints
The primary outcome of this trial is PFS, which is the time from the date of randomization to the 
date of objective progression or the date of death due to any cause, whichever is earlier.  The 
censoring is taken in the following order:

If a patient does not have a complete baseline disease assessment, then the 
PFS time will be censored at the enrollment date, regardless of whether or not 
objectively determined disease progression or death has been observed for the 
patient; otherwise,

If a patient is not known to have died or have objective progression as of the 
data inclusion cutoff date for the analysis, the PFS time will be censored at the 
last complete objective progression-free disease assessment date.
5.1.2. Secondary Endpoints
Secondary endpoints in this trial include change in tumor size (CTS), CA125 (ovary cancer 
serum biomarker), response rate (RR), and overall survival (OS).
Change in tumor size: the log ratio of tumor size at the end of Cycle 2 to tumor size at baseline 
will be calculated for each patient. Tumor size is the sum of tumor measurements across all 
target tumors at a given evaluation (Response Evaluation Criteria In Solid Tumors [RECIST]
criteria).
CA125: log-transformed CA125 data will be analyzed using a mixed-effect model repeated 
measures analysis.
Overall survival:  the time from the date of randomization to the date of death from any cause.  
For each patient who is not known to have died as of the data-inclusion cutoff date for the 
analysis, OS will be censored for that analysis at the date the patient was last known to be alive.
Response rate: the total number of patients with a best response of confirmed complete response 
(CR) or partial response (PR), based on RECIST version 1.1, divided by the total number of 
randomized patients. 
5.1.3. Safety Endpoints
Safety measures that will be used in this trial include adverse events (AEs) from the time of 
study entry until at least 30 days after discontinuation of study therapy.  
Any clinically significant findings from electrocardiograms (ECGs), labs, vital sign 
measurements, or other procedures that result in a diagnosis should be reported by the 
investigator as AEs.  All AEs will be graded at each visit  according to Common Terminology 


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Criteria for Adverse Events (CTCAE) Version 4.0, along with the investigator's assessment of 
the potential relatedness of each AE to protocol procedure, studied disease state, study drug, 
and/or drug delivery system.
5.1.4. Health Outcomes
Both time to worsening (TTW) and changes from baseline in dimensions of the health-related 
quality of life (HRQoL) using FACT-O will be assessed in this trial. 
5.2.
Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients completing the study, or discontinuing (overall and by 
reason for discontinuation).  The patient-level completion is defined as follows: Phase 1b:
patient who experiences a dose-limiting toxicity, or completes PK sampling set. Phase 2: 
patient who is dead due to any cause, or patient who is alive and on study at conclusion, but off 
treatment. Reasons for patients who are not completed will be summarized. A summary of all 
important protocol violations will be provided. Important violations from the protocol will 
include protocol inclusion/exclusion criteria violations, informed consent violations, prohibited 
concomitant medications and initiation of post-study drug therapy prior to documented, 
confirmed disease progression.  Number and percentage for each category will be summarized
for each treatment arm.
5.3.
Patient Characteristics
Patient demographics including age, gender, screening height and weight will be summarized 
using descriptive statistics.  Other baseline disease characteristics that will be summarized 
include:

Time from first-line platinum-based therapy to relapse

Pathological diagnosis

Disease stage at the time of initial diagnosis

Pre-existing conditions

Prior cancer therapies

Concomitant drugs

Eastern Cooperative Oncology Group performance status
5.4.
Concomitant Therapy 
Concomitant medications will be listed and summarized for the safety population.
5.5.
Treatment Compliance
The number of dose omissions, reductions, delays, the number of cycles received, and dose 
intensity will be summarized for all treated patients per treatment arm. 


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5.6.
Primary Analyses
For the primary endpoint of PFS, the hazard ratio (HR) will be estimated from survival data on 
all randomized patients using a Cox proportional hazards model with assigned study treatment 
arm as fixed effect along with cofactors for time from completion of first line platinum-based
therapy to relapse (6 to 12 months versus over 12 months), ECOG performance status (0 and 1 
versus 2) and maintenance therapy as a part of or after a first line platinum regimen (yes versus 
no versus not collected). 
The Kaplan-Meier method (Kaplan and Meier 1958) will be used to estimate the survival curve 
as well as survival rates at various time points for each treatment group. The stratified log-rank 
test will be used to compare PFS distributions between treatment groups in Phase 2, using the 
three randomization factors described above as the stratification factors.
5.6.1. Sensitivity Analysis
A sensitivity analysis using the same statistical methods as the primary analysis will be 
conducted, with patients who do not have documented progressive disease per RECIST 1.1 
criteria prior to the initiation of post-study treatment therapy censored at the last adequate 
radiological assessment date prior to start of new anticancer therapy or the enrollment date, 
whichever is later.  
5.7.
Efficacy Analyses 
The primary objective of the Phase 1b portion of this study is to determine the recommended 
Phase 2 dose of LY2228820 that can be safely administered in combination with gemcitabine 
and carboplatin. Thus, no formal efficacy analysis is planned for this part of the trial. Any 
antitumor activity observed will be reported.
The primary objective of the Phase 2 portion of this study is to compare the PFS in patients 
treated with LY2228820 plus gemcitabine and carboplatin versus placebo plus gemcitabine and 
carboplatin.  To support the primary efficacy analysis, additional efficacy analyses will be 
performed on change in tumor size, CA125 (serum biomarker for ovarian cancer), overall 
response rate, and OS. 
CA125 data will be log-transformed first and analyzed using a mixed-effect model repeated 
measures analysis with treatment, time, and treatment-by-time interaction as fixed effects, along 
with cofactors for time from completion of first line platinum-based therapy to relapse (6 to 
12 months versus over 12 months), ECOG performance status (0 and 1 versus 2), and 
maintenance therapy as a part of or after a first line platinum regimen (yes versus no versus not 
collected). The baseline will be modeled as an observation with a single treatment group.
The log ratio of tumor size at the end of Cycle 2 to tumor size at baseline will be calculated for 
each patient. Patients who discontinue early but have a post-baseline assessment will not be 
included. This measure presumably follows a normal distribution and will be compared between 
treatment groups using a t-test. Analysis of variance will be used to assess the effect of baseline 
factors on the change in tumor size.


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The overall response rate (ORR) is estimated as the total number of patients with a best response 
of CR or PR, based on RECIST version 1.1, divided by the total number of randomized patients.  
The efficacy endpoint of overall response rate and its exact 90% confidence interval will be 
estimated for each treatment arm.  The proportion in each treatment arm will be compared using 
the Chi-square test.  
The efficacy analysis on OS will be conducted after all the patients have had the opportunity to 
have been followed for at least 2 years. The HR will be estimated from survival data on all 
randomized patients using a Cox proportional hazards model using assigned study treatment arm
as fixed effect, along with cofactors for time from completion of first line platinum-based 
therapy to relapse (6 to 12 months versus over 12 months), ECOG performance status (0 and 1 
versus 2) and maintenance therapy as a part of or after a first line platinum regimen (yes versus 
no versus not collected).  
Additional exploratory analyses may be performed as deemed appropriate.
5.8.
Pharmacokinetic/Pharmacodynamic Analyses
5.8.1. Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on the pharmacokinetic population as mentioned in 
section 5.1.  
The PK parameters for LY2228820 will be computed by standard noncompartmental methods.   
The Cmax, AUC, half-life, apparent volume of distribution (Vd/F), apparent clearance (CL/F), 
and other relevant parameters (such as intercycle accumulation) that can be calculated from the 
data will be reported.  Parameters will be calculated following administration on Day 1 and on 
Day 10 of Cycle 1 as well as on Day 10 of Cycle 2 for the Phase 1b portion; on Day 3 and on 
Day 10 of Cycle 1 for the induction part of the Phase 2 portion, and on Day 3 of Cycle 7 for the 
maintenance part of the Phase 2 portion.
The version of any software used for the analysis will be documented and the program will meet 
the Lilly requirements of software validation.  It is possible that other validated equivalent PK 
software programs may be used if appropriate, warranted, and approved by Global 
Pharmacokinetic management.
Providing that data allow in the Phase 1b portion, the pharmacokinetic parameter estimates 
(Cmax and AUC) for LY2228820 will be evaluated statistically to delineate the effects of dose 
proportionality using the methods described previously (Smith et al. 2000).  Least-square 
estimates of geometric means and their corresponding 90% confidence intervals will be provided 
by dose and with the dose-normalized ratio of geometric means and confidence interval. 
The primary PK parameters for gemcitabine, its metabolite (dFdU), and carboplatin that will be 
used to detect potential drug–drug interaction are the maximum plasma concentration (Cmax), 
area under the plasma concentration-time curve from zero to the last measurable time [AUC(0-
tlast)], area under the plasma concentration-time curve from 0 to 24 hours [AUC(0-24hr)], and area 
under the plasma concentration-time curve from time 0 to infinity [AUC(0-)].  The AUC 


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values will be calculated by the linear/log trapezoidal method, in which the linear trapezoidal 
method will be employed up to the tmax, and the log trapezoidal rule will be used for 
concentrations beyond tmax.  Descriptive statistics will be reported for other secondary PK
parameters (for example, tmax, CL/F, Vd/F, and terminal elimination half-life). 
The 90% CI for the AUC and Cmax ratios will be computed to assess the potential effect of 
LY2228820 on gemcitabine and carboplatin. The ratios will be calculated for the Phase 2
portion for gemcitabine, its metabolite (dFdU), and carboplatin on Day 3 of Cycle 1 in the 
LY2228820 arm versus the placebo arms.
The 90% confidence interval for the AUC and Cmax ratios will be computed to assess the 
potential effect of gemcitabine and carboplatin on LY2228820. The ratios will be calculated for 
the Phase 2 portion for LY2228820 on Day 3 of Cycle 1 versus Day 3 of Cycle 7.
In addition to a standard noncompartmental assessment, the plasma LY2228820 data will also be 
analyzed using nonlinear mixed effect modeling (as implemented in nonlinear mixed effects 
model [NONMEM]).  
All available plasma data from all patients may be analyzed to determine the compartmental 
pharmacokinetics parameters and between and within patient variability.  The drug–drug
interaction may also be assessed using this approach using the typical covariates approach. 
5.8.2. Pharmacodynamic Analysis
The pharmacodynamic population will be analyzed as mentioned in Section 5.1.  
Pharmacodynamic data will be documented in the study report by dose.  Absolute and
percentage change from baseline for PD markers may be summarized by providing the mean, 
standard deviation, median, minimum, and maximum for each cohort.  Data may be log-
transformed prior to summarizing if necessary.  The interpatient variability in human PD 
response may also be assessed where appropriate.
5.9.
Health Outcome/Quality of Life Analyses 
Findings of the FACT-O and compliance with completing the questionnaire will be summarized 
for all treated patients for the given time points: baseline, each treatment cycle, and 
discontinuation visit. Frequency distributions, including measures of central tendency and 
variability, will be calculated for individual items and for the total scale. The TTW variables, 
including TTW in TOI, will be analyzed using the same methods utilized for other time-to-event 
variables.  All randomized patients with a baseline assessment will be included in the TTW 
analysis.  Clinically important difference thresholds will be used to define the proportion of 
patients that improve, remain stable, or worsen. The FACT-O scores will be summed at baseline 
and for each visit in order to calculate changes from baseline mean scores. These data will be 
compared between the 2 treatment arms. The scores will include the FACT-O total and subscale 
scores and TOI-O. All randomized patients with baseline and at least 1 post-baseline measure 
will be included in the change from baseline analysis.  Other exploratory analyses may be 
performed, including longitudinal modeling (for example, repeated measures models and the 
impact of covariates) and subgroup analysis (for example, age ≤70 versus >70 years, and 


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subgroups based on ECOG performance status, tumor response status, PFS, and OS). Individual 
responses, using an a priori responder definition (that is, the individual patient PRO score change 
over a predetermined time period that should be interpreted as a treatment benefit) will be 
displayed using the cumulative distribution function of responses between treatment groups.   
Exploratory analysis may be performed to assess potential relationships between patient reported 
symptoms and endpoints of interest such as OS and PFS.  Compliance with completing the 
FACT-O will be summarized.
5.10. Safety Analyses
All safety summaries and analyses will be based upon the Safety Population as defined in 
Section 5.1. 
Overall exposure to study drug, the numbers of patients completing each cycle, and the dose 
intensity will be summarized using descriptive statistics.  The number of patients with any dose 
adjustment will be presented for entire treatment period as well as for each cycle.  The number of 
patients with dose reductions, dose delays, or dose omissions will also be summarized, as will
the reasons for dose adjustments. 
An overall summary of AEs will be provided for AEs deemed by the investigator to be possibly 
related to study medication, and repeated for events regardless of study drug causality.  Incidence 
rates of these events will be compared between treatment arms using Fisher’s exact test. 
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened in severity after baseline or within 30 days of treatment discontinuation.  
The number of patients who experienced a TEAE, SAE, or AE related to study drug, as well as 
those who died or discontinued from the study due to an AE will be summarized by treatment.
Common Terminology Criteria for Adverse Events version 4.0 will be used to report AEs by 
CTCAE system organ class, terms, and grades.
Laboratory and nonlaboratory CTCAEs will be summarized by CTCAE term and maximum 
CTCAE grade, including the total for maximum Grade 3 or higher.  These summaries will be 
provided for events regardless of study drug causality, and repeated for events deemed by the 
investigator to be possibly related to study medication.
Reasons for death will be summarized separately for on-therapy and within 30 days of last dose 
of study drug/last visit.  All SAEs will be summarized by preferred term. 
Hospitalizations and transfusions during the study treatment period or during the 30-day post-
discontinuation follow-up period will be summarized by treatment group.
Hematology and chemistry lab results will be summarized and presented using Spotfire. Listings 
will also be provided for abnormal lab results. Listings and summary tables, or Spotfire outputs
of the key ECG parameters will be provided for each day/time combination (heart rate, QTcF, 
QTcB, RR). Changes from baseline and maximal change from baseline will also be 
summarized. Listing of vital signs will be provided.


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5.11. Subgroup Analyses
There are no planned subgroup analyses.  However, exploratory analyses may be performed to 
generate hypotheses about the efficacy of study therapy in certain subgroups tested in future 
clinical trials.  
5.12. Interim Analysis
All interim analyses for Phase 2 will be conducted under the guidance of an internal assessment 
committee.  The study team will assess data continuously during Phase 1b.
5.12.1. Interim Analysis for Phase Ib
Safety data for all patients will be reviewed continuously throughout this component of the
study.  One interim analysis is planned for the Phase 1b portion of the study and will be 
conducted for safety and pharmacokinetics after all patients in Phase 1b have completed at least 
1 cycle of study treatment.  If the combination maximum tolerated dose (MTD) has been 
identified prior to completion of the interim analysis and patients are available for Phase 2, with 
investigator and Lilly CRP approval, those patients will be randomized into the Phase 2
component of the study without delay.
5.12.2. Interim Analysis for Phase 2
Three interim analyses are planned for the Phase 2 portion of the study. The first analysis will be 
conducted for safety and pharmacokinetics when approximately 30 patients in Phase 2 have 
completed at least 1 cycle of study treatment. The second interim analysis will be conducted for 
safety and PK when approximately 60 patients in Phase 2 have completed at least 2 cycles of 
study treatment. Patient enrollment will continue along with the interim analyses. The third 
interim analysis will be the futility analysis of OS, which will be conducted at the time of the 
final analysis of PFS, to inform further conduct of the study.
The Phase 2 interim analyses will be conducted using unblinded data under the guidance of an 
internal assessment committee.
5.12.2.1. The Third Interim Analysis for Phase 2
Assuming an OS hazard ratio of 0.70 (a median OS of 18 months for the control arm [Pfisterer, 
et al]), it is predicted that approximately a total of 47 OS events would be observed at the time of 
the futility interim analysis of OS, and approximately a total of 70 OS events would be observed
at the time of final analysis of OS.  These numbers of events will provide an approximately 70% 
statistical power to detect superiority of investigational treatment arm (Arm A) over control arm 
(Arm B) in OS with the use of a log-rank test and a 1-sided type I error rate of 0.20.  
If 47 OS events were actually observed and the observed hazard ratio were greater than 0.88 at 
the time of the futility interim analysis of OS, then the futility boundary would be crossed and 
the study could be stopped for futility. A Lan-DeMets spending function will be used to control 
Type II error rate, which has the flexibility to adjust futility boundary according to the actual 
number of OS events observed at interim analysis, even if that number is different than the 
predicted one.  


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5.13. Determination of Sample Size
The primary objective of the Phase 1b portion of this study is to determine the recommended 
Phase 2 dose of LY2228820 that can be safely administered in combination with gemcitabine 
and carboplatin.  The sample size for this part of the study is customary and not subject to 
statistical calculations. 
The primary objective of the Phase 2 portion of this study is to compare the progression-free 
survival in patients treated with LY2228820 plus gemcitabine and carboplatin versus placebo 
plus gemcitabine and carboplatin. The primary analysis will be performed after 79 PFS events
have occurred. Assuming a HR of 0.7, this sample size yields at least 77% power with a false-
positive rate of 0.2 (1-sided) using a log-rank test. This assumes exponentially distributed PFS 
times, median PFS of 8.6 months for the control arm, enrollment duration of 12 months, and 
follow-up time of 18 months after the last patient is enrolled.  Assuming 28% censoring rate of 
the PFS, a total of 110 patients will be randomized (55 patients in each arm) to achieve 79 PFS 
events at the primary analysis.


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6.
Unblinding Plan
The purpose of this unblinding plan is to maintain the scientific integrity of the study.  Access to 
study data will be strictly controlled until the final database lock occurs.
The Phase 1b portion of this study is open-label whereas the Phase 2 portion of this study is 
double-blind.
Randomization during Phase 2 will occur at each patient’s baseline visit using an interactive 
voice response system (IVRS).  Assignment to treatment groups will be determined by dynamic 
allocation using the method of Pocock and Simon.  Only a minimum number of Lilly personnel 
with the IVRS group will have access to the randomization algorithm and treatment assignments 
before the study is complete.
To preserve blinding of the study, a minimum number of sponsor personnel will see treatment 
assignments before PFS and OS analyses are completed. A designated study team member in 
collaboration with the statistician will be responsible for keeping a running log of individuals 
given access to any unblinded study data.  This log will include the person’s name, title, date of 
unblinding, level of unblinding (that is, group or patient), and purpose of unblinding.
Emergency unblinding for AEs may be performed through an IVRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used only if the patient’s well-being requires knowledge of the patient’s treatment
assignment.  All calls resulting in an unblinding event are recorded and reported by the IVRS.
The investigator should make every effort to contact the Lilly CRP prior to unblinding a patient’s 
treatment assignment.  If a patient’s treatment assignment is unblinded, Lilly must be notified 
immediately by telephone.
Every effort will be made to blind both the patient and the investigator to the treatment 
assignment, but the inadvertent unblinding of a patient may occur.  A double-blind study design 
is known to be imperfect because the potential for individual unblinding exists due to treatment-
related signs and symptoms.  If a patient or investigator is unblinded, the unblinding will not 
alone be sufficient cause for that patient to be discontinued from study treatment or excluded 
from any safety or efficacy analyses.
Additionally, there may be ethical reasons to have the patient remain on study treatment.  For 
patients to continue on study treatment in the event of unblinding, the investigator must obtain 
specific approval from a Lilly CRP for the patient to continue in the study.  
Patients and investigators will remain blinded to study treatment with no sharing of efficacy 
information with sites until PFS analyses are completed.  Treatment assignment will be blinded 
in the reporting database except for a minimum number of sponsor personnel required to perform 
the interim and final analyses.  This will ensure unblinded aggregate efficacy results are not 
available outside of the Assessment Committee until the time of final data analysis of the 
primary outcome (PFS). The topline result from the primary outcome analysis, stating whether 
the primary objective of the study was met as determined by the assessment committee, is 


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documented in the assessment committee meeting minutes and may be shared with sponsor 
personnel, patients, and site personnel, given that doing so will induce negligible bias to study 
conduct and data analyses.  Patients and investigators may be unblinded to individual treatment 
assignments after both PFS and OS analyses are completed.  
For this study, there are four planned interim analyses (1 for Phase 1b and 3 for Phase 2).  
During Phase 2, internal procedures require that interim analyses be conducted under the 
guidance of an Assessment Committee.


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7.
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