Phase 2 Study of LY2157299 in Patients With Hepatocellular Carcinoma
Phase: PHASE2
Conditions: Carcinoma, Hepatocellular
Sponsor: Eli Lilly and Company

JBAK Protocol (e) 
 
Phase 2 Study of LY2157299 in Patients with Hepatocellular Cancer 
 
NCT01246986 
 
Approval date: 18-Aug-2016 
 

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1. Protocol H9H-MC-JBAK(e)
Phase 2 Study of LY2157299 in Patients with 
Hepatocellular Carcinoma
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 
LY2157299, 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.
LY2157299
This is an open-label, multicenter, multicountry, Phase 2 study of LY2157299 in patients 
with hepatocellular carcinoma. The study design consists of 5parts.  In Part A, patients 
with a
lpha-fetoprotein (AFP)1.5xULN will be randomized to 2cohorts based on initial 
dose of LY2157299 to be received (160 or 300 mg/day). In PartB, patients with AFP <1.5x
ULN will receive LY2157299 300 mg/day. In Part C, patients with no prior systemic 
treatment will receive LY2157299 in combination with sorafenib. In Part D, patients will 
receive LY2157299 in combination with ramucirumab.  In Part E, patients who have 
received at least one prior line of systemic therapyor whohave not received prior treatment 
and are ineligible for sorafenib treatmentwill receive LY2157299 150 mg BID accordingto 
a 21 days on/7 days off schedule.
Approval Date: 18-Aug-2016 GMT
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Approved by Lilly:27 October 2010
Amendment (a) Electronically Signed and Approved by Lilly:  27February2012
Amendment (b) Electronically Signed and Approved by Lilly:  05July 2012
Amendment (c) Electronically Signed and Approved by Lilly:  02 July 2013
Amendment (d) Electronically Signed and Approved by Lilly:10 December 2014
Amendment (e) Electronically Signed and Approved by Lilly ondate provided below.

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2.
Synopsis
Study Rationale
Transforming growth factor beta (TGF-) is an important protein that regulates the immune 
response to tumor cells and metastatic spread of tumor cells.  TGF-also is an important 
regulator of neoangiogenesis.  LY2157299 is a small molecule designed to inhibit selectively the 
serine/threonine kinase of the TGF-receptor type I (TGF-RI).  Thus, the antitumor effect of 
LY2157299 is expected to result in an increased tumor immune surveillance, reduced metastatic 
spread, and decreased tumor-associated neoangiogenesis.  The role of TGF-β inhibitors in 
hepatocellular carcinoma (HCC) was investigated in several in vitro and in vivo studies.  
TGF-β R1 inhibition by LY2109761 produced several different antitumor activities in HCC 
preclinical models.  The spread of HCC cells in the surrounding tissue is inhibited by the 
up-regulation of E-cadherin (Fransvea et al. 2008).  LY2109761 inhibits invasion of HCC cells 
(Fransvea et al. 2009) and also inhibits tumor growth thanks to inhibiting neoangiogenesis by 
reducing vascular endothelial growth factor (VEGF) production (Mazzocca et al. 2009).  These 
effects are selectively dependent on the TGF-1/SMAD-2 pathway (Zhang 2009; Melisi et al. 
2008).  Finally, LY2109761 inhibits the production of connective tissue growth factor, interrupts 
the cross talk between tumor and stroma, and blocks the progression of HCC (Mazzocca et al. 
2010).  Inhibition of TGF-β RI activation using LY364947 inhibits TGF-β-dependent cell 
signaling and reduces cell motility and invasion in parental and multikinase-resistant HCC cells 
(Garbay et al. 2010).  Given the chemical and biological similarities of LY2109761 and 
LY364947 with the clinical candidate LY2157299, it is expected that LY2157299 will also have 
significant antitumor activity in HCC.  The present Phase 2 study is a proof of concept to 
evaluate the quality and quantity of the anti-tumor effect of LY2157299 in patients with HCC.

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Clinical Protocol Synopsis:  Study H9H-MC-JBAK
Name of Investigational Product:
LY2157299
Title of Study:  Phase 2 Study of LY2157299 in Patients with Hepatocellular Carcinoma 
Number of Planned Patients/Subjects:
Enrolled/Randomized: approximately 235
Phase of Development: Phase 2
Length of Study:  7.5 years
Planned first patient visit:  Q1 2011               Planned last patient visit:  July 2018
Objectives: The primary objective of this study is to characterize both the time-to-progression (TTP) 
distributions and the effect on transforming growth factor beta (TGF--associated serum biomarkers (for 
example, TGF-, alpha-fetoprotein [AFP], E-cadherin) of study treatment in patients with hepatocellular 
carcinoma (HCC).
The secondary objectives of the study are:

To evaluate the safety of LY2157299 as monotherapy and in combination with sorafenib or 
ramucirumab in HCC patients

To evaluate the population pharmacokinetics (PK) of LY2157299 as monotherapy and in combination 
with sorafenib or ramucirumab

To recommend which doses of LY2157299 as monotherapy and in combination with sorafenib or 
ramucirumab to use in future trials recruiting HCC patients

To evaluate the safety and tolerability, pharmacokinetics and efficacy of LY2157299 as monotherapy 
administered according to a 21 days on/7 days off schedule

To characterize other time-to-event distributions, such as progression-free survival (PFS, based on 
Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 and modified RECIST [mRECIST], for 
HCC) and overall survival (OS)

To estimate antitumor efficacy using response rate (RR, based on RECIST 1.1 and mRECIST, for 
HCC)

To assess patient-reported outcome (PRO) measures of disease-specific symptoms and health-related 
quality of life (Functional Assessment of Cancer Therapy Hepatobiliary [FACT-Hep])

To explore E-cadherin, pSMAD, and -integrin (and other markers associated with 
epithelial-to-mesenchymal transition [EMT] transformation and the TGF--associated signaling 
pathway) presence in the original diagnostic tumor tissue and optional posttreatment tumor tissue and 
the correlation of this with both clinical efficacy endpoints and biomarker response

To explore the utility of exploratory imaging techniques (for example, positron emission tomography 
[PET] scan, contrast echography) to assess treatment effect with LY2157299 as monotherapy and in 
combination with sorafenib when possible

To explore fibrosis-related biomarkers, such as Fibrotest
Study Design: This is an open-label, multicenter, multicountry, Phase 2 study of LY2157299 in patients with 
hepatocellular carcinoma.  The study design consists of 5 parts.  In Part A, patients with AFP 1.5x upper limit 
of normal (ULN) will be randomly assigned to 2 cohorts based on initial dose of LY2157299 to be received (160 
or 300 mg/day).  In Part B, patients with AFP <1.5x ULN will receive LY2157299 300 mg/day.  In Part C, 
patients with no prior systemic treatment will receive LY2157299 (160 or 300 mg/day) in combination with 
sorafenib 400 mg twice daily (BID).  In Part D, patients with Child-Pugh A liver disease will receive treatment 
with LY2157299 (160 or 300 mg/day) in combination with ramucirumab (8 mg/kg IV on Days 1 and 15 of each 
cycle).  In Part E, patients with Child-Pugh Class A liver disease and any AFP who have received at least one 
prior line of systemic therapy or who have not received prior treatment and are ineligible for sorafenib treatment 
will receive LY2157299 150 mg BID according to a 21 days on/7 days off schedule.

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Diagnosis and Main Criteria for Inclusion and Exclusions:
Inclusion Criteria:  
[1] Have histological evidence of a diagnosis of HCC not amenable to curative surgery.
[2] Have Child-Pugh Class:
Parts A and B: A or B7
Parts C and D: A
Part E:  A
[3] Have serum AFP:
- Part A: ≥1.5x ULN
- Part B: <1.5x ULN
Criterion [3] applies for Parts A and B only.
[4] Have the presence of measurable disease as defined by the RECIST 1.1.  A lesion that has been 
previously treated by local therapy will qualify as a measurable or evaluable lesion if there was 
demonstrable progression following locoregional therapy.
[5] Age 18 years
[6] Have given written informed consent prior to any study-specific procedures
[7] Have adequate organ function including:
- Hematologic: absolute neutrophil count (ANC) 1.5 x 109/L, platelets 50 x 109/L, and hemoglobin 8 
g/dL.
- Hepatic: bilirubin 2.5 times ULN; alanine aminotransaminase (ALT) and aspartate aminotransaminase 
(AST) 5 times ULN.  Prothrombin time international normalized ratio 2.3; or prothrombin time limit is 6 
seconds above control.
- Renal:  Serum creatinine 1.5 times ULN or calculated creatinine clearance >45 mL/min.
Note:  Small differences from the outlined laboratory values will be deemed as consistent with 
the protocol requirements provided that the following criteria are met:  they are isolated, 
are transient, and are not reflective of a medical condition in the opinion of the 
investigator.  Such differences are often a result of biological or laboratory equipment 
variability.  To confirm that these results are within biological or laboratory equipment 
variability, repeat laboratory/hematological tests should be done prior to dosing the 
patient on Cycle 1 Day 1.
[8] Have a performance status of 1 on the Eastern Cooperative Oncology Group (ECOG) scale.
[9] Have:
In Parts A and B:
- received sorafenib and have progressed or were intolerant to sorafenib, or
- are ineligible for sorafenib treatment (at the investigator’s discretion).
In Part C:  not received previous systemic treatment.
In Part D:  
- received sorafenib and have progressed or were intolerant to sorafenib, or
- are ineligible for sorafenib treatment (at the investigator’s discretion), or 
- have not received prior systemic treatment (at the investigator’s discretion).
In Part E:  
- received at least one prior line of systemic therapy, or
- not received prior treatment and are ineligible for sorafenib treatment (at the investigator’s discretion).
[10] In Parts A, B, D and E:  have discontinued sorafenib for at least 2 weeks.
Exclusion Criteria:
[15] Are currently enrolled in, or discontinued within the last 28 days from a clinical trial involving an 
investigational drug or device or not approved use of a drug or device, or concurrently enrolled in any other 
type of medical research judged not to be scientifically or medically compatible with this study.
[16] Known HCC with fibro-lamellar or mixed histology.
[17] Presence of clinically relevant ascites.

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[18] Liver transplant requiring increased immunosuppressive therapy.  (Patients on maintenance 
immunosuppressive therapy after liver transplant are eligible for Parts A and B.  Rapamycin analogues are 
not allowed.)
[19] Have received >1 line of systemic treatment in Parts A, B, and D.
[20] Have moderate or severe cardiac disease.
[21] Have serious preexisting medical conditions that, in the opinion of the investigator, cannot be adequately 
controlled with appropriate therapy or would preclude participation in this study.
[22] Females who are pregnant or lactating.
[23] Have a history of any other cancer (except nonmelanoma skin cancer or carcinoma in situ of the cervix) 
unless in complete remission and off all therapy for that disease for a minimum of 3 years.
At the discretion of the investigator, hormone-refractory prostate cancer patients who are stable on 
gonadotropin-releasing hormone (GnRH) agonist therapy and breast cancer patients who are stable on 
antiestrogen therapy (for example, an aromatase inhibitor) may have that treatment continued while they are 
enrolled in this study.
[24] Have active infection that would interfere with the study objectives or influence study compliance.
[25] For Part C, have a known hypersensitivity to sorafenib or its excipients.
[26] For Part D, have a serious illness or medical condition(s), including but not limited to the following:
a)
The patient has undergone major surgery within 28 days prior to randomization or has undergone 
central venous access device placement within 7 days prior to randomization.
b)
The patient has uncontrolled arterial hypertension ≥150 / ≥90 mm Hg despite standard medical 
management.
c)
The patient is receiving ongoing therapy with nonsteroidal anti-inflammatory agents (NSAIDs) (eg, 
indomethacin, ibuprofen, naproxen, nimesulide, celecoxib, etoricoxib, or similar agents) or other 
antiplatelet agents (eg, clopidogrel, ticlopidine, prasugrel, dipyridamole, picotamide, indobufen, 
anagrelide, triflusal, or similar agents).  Aspirin at dosages up to 100 mg/day is permitted.
d)
The patient is receiving therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or 
similar agents.  Patients receiving prophylactic, low-dose anticoagulation therapy are eligible provided 
that the coagulation parameters defined in the inclusion criteria are met.
e)
Uncontrolled thrombosis (including myocardial infarction, unstable angina, cerebrovascular accident, or 
transient ischemic attack within 6 months prior to randomization) or bleeding.
f)
The patient has experienced any Grade 3 or 4 gastrointestinal bleeding or any variceal bleeding episode 
in the 3 months prior to randomization requiring transfusion, endoscopic or operative intervention 
(patients with any bleeding episode considered life-threatening during the 3 months prior to 
randomization are excluded, regardless of transfusion or intervention status). Patients who have 
esophageal or gastric varices that require immediate intervention or represent a high bleeding risk in the 
opinion of the investigator or consulting gastroenterologist or hepatologist are excluded.
g)
Elective or planned major surgery to be performed during the course of the clinical trial.
h)
Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to randomization.
i)
Known allergy or hypersensitivity to monoclonal antibody treatment or any components used in the 
ramucirumab drug product preparation.
j)
The patient's urinary protein is >1+ on dipstick or routine urinalysis.  If urine dipstick or routine 
analysis indicates ≥2+ proteinuria, then a 24-hour urine must be collected and must demonstrate <1000 
mg of protein in 24 hours to allow participation in the study.
k)
The patient has either a history of or current hepatic encephalopathy or current clinically meaningful 
ascites.  Clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring 
ongoing treatment with diuretics and/or paracentesis.

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Test Product, Dosage, and Mode of Administration:
Parts A and B: LY2157299 is administered orally by daily dosing morning and evening (BID) at either 80 or 
150 mg per dose (total dosage of 160 or 300 mg daily) for 14 days, followed by 14 days with no study drug.  
(The exception is for patients who will have a Day 15 PK sample taken, who will omit the evening dose on Day 
14.)  This on/off schedule constitutes a cycle of 28 days.  In extenuating circumstances, the “on study drug”
window is allowable from Day 10 to Day 14.  
Part C: LY2157299 is administered orally by daily dosing morning and evening (BID) at either 80 or 150 mg 
per dose (total dosage of 160 or 300 mg daily) for 14 days, followed by 14 days with no study drug.  Sorafenib is 
administered orally by daily dosing morning and evening (BID) at 400 mg per dose (total dosage of 800 mg 
daily) for 28 days. This constitutes a cycle of 28 days.
Part D:  LY2157299 is administered orally by daily dosing morning and evening (BID) at either 80 or 150 mg 
per dose (total dosage of 160 or 300 mg daily) for 14 days, followed by 14 days with no study drug.  
Ramucirumab is administered intravenously at 8 mg/kg on Days 1 and 15 of every cycle.  This constitutes a 
cycle of 28 days.
Part E:  LY2157299 is administered orally by daily dosing morning and evening (BID) at 150 mg per dose (total 
dosage of 300 mg daily) for 21 days, followed by 7 days with no study drug.
Planned Duration of Treatment Per Patient: Per patient, the screening period is no more than 4 weeks or 28 
days before the first dose of LY2157299; the planned treatment duration is 6 cycles or approximately 24 weeks.  
However, patients may receive LY2157299 until their disease has progressed, the patient has died, or the patient 
discontinues for adverse events, investigator’s judgment, or other reasons.  Wash-out period:  none.
Planned Follow-Up Observation Period Per Patient:  Follow-up visits consist of a visit approximately 30 
days after the last study treatment and any subsequent follow-up approximately every 60 days (approximately 2 
months) (±7 days).  Patients who have discontinued study treatment without progression will continue to be 
followed for progression.  Every attempt should be made to gather all information every 2 months (radiological 
scans and survival), even if a patient starts a new anticancer therapy.  All patients will be followed until death.
Patients who have entered the treatment extension period will be followed for just 30 days after treatment 
discontinuation.  
Reference Therapy, Dose and Mode of Administration: Not applicable
Criteria for Evaluation:
Efficacy: RECIST 1.1 and mRECIST, (mRECIST for HCC) for RR, TTP and PFS
Safety:  International Common Terminology Criteria for Adverse Events (CTCAE), version 4.0
Health Outcomes: PRO measures of disease-specific symptoms and health-related quality of life (FACT-Hep)
Bioanalytical: Plasma LY2157299/sorafenib/ramucirumab concentrations will be analyzed by liquid 
chromatography/mass spectrometry/mass spectrometry

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Statistical Methods:  
Outline of Design: Approximately 235 Child-Pugh Class A or B7 patients with HCC will be enrolled into this 
study. In Parts A and B, patients were initially randomly assigned onto 1 of 2 doses, balanced based on AFP 
levels (≤400 ng/mL and >400 ng/mL), etiology, and whether sorafenib-naïve or not. A planned interim analysis 
after approximately 10 (for PK and acute safety) patients enrolled into each dose and completed 1 cycle was 
carried out. The second interim analysis for futility of 1 or both doses was not carried out but, as part of the 
continuous monitoring of safety, PK, and laboratory markers in patients with HCC, the sponsor noted that 
patients in both cohorts were staying on study beyond 4 months. An additional data review was carried out 
based on 64 enrolled patients, and a decision was made to stop enrollment to the 160 mg/day dose and continue 
enrollment to the 300 mg/day dose until 70 patients were treated. The protocol was amended (Amendment [b]) 
to have 3 parts.  The 2 cohorts planned in the original protocol and in Amendment (a) were designated as Part A.  
Part B enrolled approximately 40 patients with AFP levels <1.5x ULN and treated them with 300 mg/day 
intermittent dosing. Two interim analyses were planned for Part B – one after the last of 70 patients with 
elevated AFP levels in Cohort 2 started Cycle 1, and the second after 18 patients enrolled into Part B and were 
actively followed for at least 3 months or discontinued from study treatment. Part C enrolled approximately 47
Child-Pugh Class A patients and consisted of a safety lead-in of 2 dose-escalation cohorts followed by an 
expansion cohort where the selected dose(s) of the combination treatment were evaluated. Part D will enroll 
approximately 18 Child-Pugh Class A patients into 2 dose-escalation cohorts.  Part E will initially enroll up to
approximately 23 patients. This would give a total of approximately 235 patients enrolled.
Safety: Summary statistics, plots, and listings for all safety data collected will be provided in aggregate and by 
dose in Part A and Part C, and in aggregate for Part B separately.  Comparisons between doses and parts will be 
summarized for Part A and Part B, and may be compared to Part C. Data from Part D and Part E will be 
summarized separately from the data in Parts A, B, and C.
Clinical Efficacy: Time-to-event distributions will be characterized for each dose in each part (where data 
allow) using Kaplan-Meier methods, and various time-to-event parameters, such as median TTP, PFS, and OS 
and their rates at specified time points, will be estimated from their respective distributions. The hazard ratios
between doses for patients with elevated AFP levels and between groups of patients with elevated AFP and AFP 
levels <1.5x ULN at 300 mg/day will be estimated. Sensitivity analyses using alternative models may also be 
performed. RR will be summarized by dose and part. Stratification factors used in the randomization of Part A 
may be included as covariates in analyses between doses. Beginning with Amendment (b), patients will no 
longer be randomized onto treatment, but the same covariates may be considered in analyses of clinical 
endpoints. Data from Part D and Part E will be summarized separately from the data in Parts A, B, and C.

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Health Outcomes:  Summary descriptive statistics by study part will be provided for the PRO data (FACT-Hep) 
at each time point and change from baseline.  Time to worsening of symptoms will also be evaluated.
Pharmacokinetics:  A population PK analysis will be performed on all patients receiving LY2157299.  A PK 
analysis will be performed for sorafenib as well for some patients enrolled in Part C.  This analysis will explore 
the impact of covariates such as demographic factors and markers on the relevant PK parameters.  In Part D, the 
LY2157299 and ramucirumab PK administered in combination will be characterized. In Part E, the PK of 
LY2157299, when administered according to a 21 days on /7 days off treatment schedule, will be characterized.
Pharmacodynamics: Changes in response biomarkers, such as pSMAD in tumor tissue (or other TGF--related 
biomarkers) and lactate dehydrogenase, AFP, E-cadherin in serum will be estimated and may be correlated with 
clinical efficacy.  Exploratory population PK/pharmacodynamic analyses may be conducted to identify the 
exposure-biomarker response relationship.  

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3.
Table of Contents
Phase 2 Study of LY2157299 in Patients with Hepatocellular 
Carcinoma 
Section
Page
1.
Protocol H9H-MC-JBAK(e) Phase 2 Study of LY2157299 in 
Patients with Hepatocellular Carcinoma..............................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................9
4.
Abbreviations and Definitions...........................................................................................16
5.
Introduction ......................................................................................................................22
5.1.
LY2157299 – Nonclinical and Clinical Experience ......................................................25
5.1.1.
Nonclinical Pharmacokinetics of LY2157299.......................................................25
5.1.2.
Nonclinical Pharmacokinetic/Pharmacodynamic Model.......................................26
5.1.3.
Clinical Pharmacokinetics of LY2157299 ............................................................26
5.1.4.
Nonclinical Toxicology of LY2157299 ................................................................27
5.1.4.1.
Overall Conclusions .......................................................................................29
5.1.5.
Clinical Experience..............................................................................................31
5.1.5.1.
Safety.............................................................................................................31
5.1.5.2.
JBAK:  Brief Summary of Results to Date......................................................32
5.1.5.3.
Rationale for the Study...................................................................................33
5.1.6.
Rationale for Amendment (a)...............................................................................33
5.1.7.
Rationale for Amendment (b)...............................................................................34
5.1.8.
Rationale for Amendment (c)...............................................................................36
5.1.9.
Rationale for Amendment (d)...............................................................................36
5.1.10.
Rationale for Amendment (e)...............................................................................37
6.
Objectives.........................................................................................................................39
6.1.
Primary Objective ........................................................................................................39
6.2.
Secondary Objectives...................................................................................................39
7.
Investigational Plan...........................................................................................................40
7.1.
Summary of Study Design............................................................................................40
7.1.1.
Extension Period..................................................................................................45
7.2.
Discussion of Design and Control ................................................................................46
8.
Study Population...............................................................................................................47
8.1.
Inclusion Criteria..........................................................................................................47
8.2.
Exclusion Criteria ........................................................................................................48
8.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................50

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8.3.
Discontinuations ..........................................................................................................51
8.3.1.
Discontinuation of Patients...................................................................................51
8.3.2.
Discontinuation of Study Sites .............................................................................52
8.3.3.
Discontinuation of the Study................................................................................52
9.
Treatment..........................................................................................................................53
9.1.
Treatments Administered .............................................................................................53
9.1.1.
Parts A and B.......................................................................................................53
9.1.2.
Part C...................................................................................................................53
9.1.3.
Part D...................................................................................................................54
9.1.4.
Part E...................................................................................................................55
9.1.5.
Criteria for Dose Escalation (Parts C and D) ........................................................55
9.1.5.1.
Dose-Limiting Toxicity Determination and Maximum 
Tolerated Dose Definition (Parts C, D and E) .................................................56
9.2.
Selection and Timing of Doses.....................................................................................57
9.3.
Materials and Supplies .................................................................................................57
9.3.1.
LY2157299..........................................................................................................57
9.3.2.
Sorafenib..............................................................................................................58
9.3.3.
Ramucirumab.......................................................................................................58
9.4.
Method of Assignment to Treatment ............................................................................58
9.5.
Dose Adjustments ........................................................................................................59
9.5.1.
LY2157299..........................................................................................................59
9.5.2.
Sorafenib..............................................................................................................60
9.5.3.
Ramucirumab.......................................................................................................61
9.5.3.1.
Infusion-Related Reactions.............................................................................62
9.5.3.2.
Hypertension ..................................................................................................62
9.5.3.3.
Proteinuria......................................................................................................62
9.5.3.4.
Hepatic Encephalopathy .................................................................................62
9.6.
Continued Access to Study Drug..................................................................................62
9.7.
Blinding .......................................................................................................................63
9.8.
Concomitant Therapy...................................................................................................63
9.9.
Treatment Compliance .................................................................................................63
10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing (Standard Laboratory 
Testing, Pharmacokinetics, Biomarker Analysis), and 
Appropriateness of Measurements.....................................................................................65
10.1. Efficacy Measures........................................................................................................65
10.1.1.
Clinical Efficacy Measures...................................................................................66
10.2. Safety Evaluations........................................................................................................67
10.2.1.
Adverse Events ....................................................................................................67

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10.2.1.1.
Serious Adverse Events ..................................................................................68
10.2.2.
Summary of Adverse Event/Serious Adverse Event 
Reporting Guidelines ...........................................................................................69
10.2.3.
Electrocardiography.............................................................................................70
10.2.4.
Echocardiograms with Doppler and Chest CT Scans ............................................71
10.2.5.
Safety Monitoring ................................................................................................71
10.2.6.
Complaint Handling.............................................................................................72
10.3. Sample Collection and Testing.....................................................................................72
10.3.1.
Samples for Standard Laboratory Testing.............................................................72
10.3.2.
Samples for Drug Concentration Measurements -
Pharmacokinetics/Pharmacodynamics..................................................................73
10.3.3.
Samples for Biomarker Analysis ..........................................................................73
10.3.3.1.
Pharmacogenomic Evaluations .......................................................................73
10.3.4.
Nonpharmacogenetic Biomarker Evaluation and Patient 
Tailoring ..............................................................................................................74
10.3.4.1.
Sample Requirements and Preparation............................................................74
10.3.4.2.
Sample Labeling.............................................................................................75
10.3.4.3.
Sample Shipping and Handling.......................................................................75
10.4. Appropriateness of Measurements................................................................................75
11.
Data Quality Assurance.....................................................................................................76
11.1. Data Capture System....................................................................................................76
12.
Sample Size and Statistical Methods .................................................................................77
12.1. Determination of Sample Size ......................................................................................77
12.2. Statistical and Analytical Plans.....................................................................................79
12.2.1.
General Considerations ........................................................................................79
12.2.2.
Definition of Clinical Efficacy Measures..............................................................80
12.2.3.
Definition of Pharmacodynamic Efficacy Measures .............................................81
12.2.4.
Patient Disposition...............................................................................................82
12.2.5.
Patient Characteristics..........................................................................................82
12.2.6.
Concomitant Therapy...........................................................................................82
12.2.7.
Treatment Compliance .........................................................................................82
12.2.8.
Clinical Efficacy Analyses ...................................................................................82
12.2.9.
Pharmacodynamic Efficacy Analyses...................................................................83
12.2.10. Pharmacokinetic/Pharmacodynamic Analyses......................................................84
12.2.11. Health Outcome/Quality of Life Analyses............................................................85
12.2.12. Safety Analyses....................................................................................................85
12.2.13. Exploratory Analyses...........................................................................................86
12.2.14. Interim Analyses..................................................................................................86

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12.2.15. Criteria for Study Termination .............................................................................89
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................90
13.1. Informed Consent.........................................................................................................90
13.2. Ethical Review.............................................................................................................90
13.3. Regulatory Considerations ...........................................................................................91
13.3.1.
Investigator Information.......................................................................................91
13.3.2.
Protocol Signatures ..............................................................................................91
13.3.3.
Final Report Signature .........................................................................................91
14.
References ........................................................................................................................92

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List of Tables
Table
Page
Table JBAK.1.
Examples of Experimental Treatments as Second-Line Therapy in 
Patients with Hepatocellular Carcinoma .................................................23
Table JBAK.2.
Margin of Safety Based on NOEL to Cardiovascular Effects..................31
Table JBAK.3.
Treatment Regimens for Parts A and B...................................................53
Table JBAK.4.
Treatment Regimens for Part C...............................................................54
Table JBAK.5.
Treatment Regimens for Part D ..............................................................55
Table JBAK.6.
Treatment Regimen for Part E ................................................................55
Table JBAK.7.
Sorafenib Dose Modifications for Hematologic and 
Nonhematologic Toxicities.....................................................................60
Table JBAK.8.
Suggested Sorafenib Dose Modifications for Skin Toxicity ....................61
Table JBAK.9.
Ramucirumab Dose Reductions for Proteinuria ......................................62
Table JBAK.10.
Assessment Guide for Adverse Events and Serious Adverse Events .......70

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List of Figures
Figure
Page
Figure JBAK.1.
Illustration of study design for Protocol H9H-MC-JBAK Parts A 
and B......................................................................................................41
Figure JBAK.2.
Illustration of study design for Protocol H9H-MC-JBAK Part C.............42
Figure JBAK.3.
Illustration of study design for Protocol H9H-MC-JBAK Part D.............43
Figure JBAK.4.
Illustration of study design for Protocol H9H-MC-JBAK Part E.............44

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JBAK Study Schedule ..............................................................97
Attachment 2.
Protocol JBAK Clinical Laboratory Tests.............................................121
Attachment 3.
Protocol JBAK ECOG Performance Status...........................................123
Attachment 4.
Protocol JBAK Pharmacokinetic Sampling Instructions........................124
Attachment 5.
Protocol JBAK Child-Pugh Score.........................................................129
Attachment 6.
Protocol JBAK Barcelona Clinic Liver Cancer Classification Table .....130
Attachment 7.
Protocol JBAK Cancer of the Liver Italian Program (CLIP) 
Scoring System.....................................................................................131
Attachment 8.
Protocol JBAK RECIST Criteria 1.1.....................................................132
Attachment 9.
Protocol JBAK Creatinine Clearance Formula......................................139
Attachment 10.
Protocol JBAK FACT-Hep...................................................................140
Attachment 11.
Protocol JBAK New York Heart Association Functional 
Classification........................................................................................144
Attachment 12.
Protocol JBAK Echocardiography........................................................145
Attachment 13.
Protocol JBAK Qualitative and Quantitative Parameters for 
Grading Valvular Regurgitation............................................................152
Attachment 14.
Protocol JBAK Guidance for Sorafenib Eligibility................................153
Attachment 15.
Modified RECIST Assessment for Hepatocellular Carcinoma ..............155
Attachment 16.
Sorafenib Adverse Events.....................................................................165
Attachment 17.
Protocol JBAK Amendment (e) Summary 
Phase 2 Study of LY2157299 in Patients with Hepatocellular 
Carcinoma............................................................................................167

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4.
Abbreviations and Definitions
Term
Definition
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.
ADME
absorption, distribution, metabolism, excretion
AFP
alpha-fetoprotein
ALT
alanine aminotransaminase
ANC
absolute neutrophil count
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]).  
AST
aspartate aminotransaminase
AUC(0-∞)
area under the concentration-time curve, zero to infinity
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).
BID
twice a day
BNP
brain natriuretic peptide
blinding/masking
A procedure in which one or more parties to the trial are kept unaware of the 
treatment assignment(s).  Single-blinding usually refers to the subject(s) being 
unaware, and double-blinding usually refers to the subject(s), investigator(s), 
monitor(s), and in some cases, select sponsor personnel being unaware of the 
treatment assignment(s).
CART
classification and regression tree
case report form 
(CRF) and 
electronic case 
report form (eCRF)
Sometimes referred to as clinical report form:  A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the 
protocol.
CI
confidence interval
CL
clearance

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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.
CLss/F
apparent clearance at steady state
Cmax,ss
maximum observed drug concentration at steady state
complaint
A complaint is 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.
confirmation
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that Lilly is 
confident that results are accurate.  Confirmation will either occur immediately 
after initial testing or will require that samples be held to be retested at some 
defined time point, depending on the steps required to obtain confirmed results.
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.  
CR
complete response
CrCL
creatinine clearance
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EF
ejection fraction
EIAED
enzyme-inducing anti-epileptic drug
EMT
epithelial-to-mesenchymal transition
end of study (trial)
End of study (trial) is the date of the last visit or last scheduled procedure shown 
in the Study Schedule for the last active subject in the study.  
The European Union has additional reporting requirements associated with the 
end of study.  Consult regional SOPs for further information.

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EU
European Union
F344
Fischer 344 
FACT-Hep
Functional Assessment of Cancer Therapy, Hepatobiliary
FACIT
Functional Assessment of Chronic Illness Therapy 
FFPE
formalin-fixed paraffin-embedded
FHD
first-into-human dose
FHSI-8
Focal High Signal Intensity 8
GBM
glioblastoma multiforme
GCP
good clinical practice
GLP
good laboratory practice 
GnRH
gonadotropin-releasing hormone
HCC
hepatocellular carcinoma
HR
hazard ratio
HRQoL
health-related quality of life
IB
investigator brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IND
investigational new drug
INR
International Normalized Ratio
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.
IRR
infusion-related reaction
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 interim analysis is an analysis of clinical trial data, separated into treatment 
groups, that is conducted before the final reporting database is created/locked.

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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
IWRS
interactive web response system
Ki
inhibition constant
LD
longest diameter
LA
left atrial
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 trial.
LV
left ventricular
LVEF
left ventricular ejection fraction
MAP
multi-analyte panel
MOS
margin of safety
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NE
not evaluable 
NOEL
no observed effect level
NONMEM
nonlinear mixed-effect modeling
NSAID
nonsteroidal anti-inflammatory drug
ORR
overall response rate
OS
overall survival
patient
A study participant who has the disease or condition for which the 
investigational product is targeted.
PBMC
peripheral blood mononuclear cells
PD
pharmacodynamic or progressive disease
per protocol set 
The set of data generated by the subset of patients who sufficiently complied 

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(PPS)
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
PK
pharmacokinetic(s)
PPI
proton pump inhibitor
PR
partial response
PRF
pulse repetition frequency
PRO
patient-reported outcome
PS
performance status
PSA
prostate-specific antigen
PT
prothrombin time
RA
accumulation ratio
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.
RECIST, mRECIST
Response Evaluation Criteria in Solid Tumors, modified RECIST
RR
response rate
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become 
part of a pool of potential candidates for participation in a clinical trial.  In this 
study, screening involves invasive or diagnostic procedures and/or tests (for 
example, x-rays, blood draws).  For this type of screening, informed consent for 
these screening procedures and/or tests shall be obtained; this consent may be 
separate from obtaining consent for the study.
SD
stable disease
SLD
sum of the longest diameter
SOP
standard operating procedure
subject
An individual who is or becomes a participant in clinical research, either as a 
recipient of the investigational product(s) or as a control.  A subject may be 
either a healthy human or a patient.
t1/2
half life

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TGF-β
transforming growth factor beta
TGF-β RI
transforming growth factor beta receptor type I
tmax,ss
time to maximum concentration at steady state
treatment-
emergent adverse 
event (TEAE)
Any untoward medical occurrence that either occurs or worsens at any time 
after treatment baseline and which does not necessarily have to have a causal 
relationship with this treatment (also called treatment-emergent signs and 
symptoms [TESS]).
TTP
time-to-tumor progression
ULN
upper limit of normal
US
United States
Vss
volume of distribution at steady state
WHO
World Health Organization

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Phase 2 Study of LY2157299 in Patients with Hepatocellular 
Carcinoma 
5.
Introduction
Hepatocellular carcinoma (HCC) represents the sixth most common cancer worldwide with a 
still increasing incidence (Parkin et al. 2005).  Patients with chronic liver disease and cirrhosis 
are at high risk for HCC; thus the prognosis, which is usually poor, is related to underlying liver 
function in addition to disease stage.
Patients with HCC considered to have noncurable disease include those for whom liver 
transplant, resection, tumor embolization, or other percutaneous ablation are not suitable.  For 
these patients, the median survival time with no treatment ranges from 40 months for patients 
with multinodular asymptomatic tumors to about 5 months for those with cancer-related 
symptoms, vascular disease, or extrahepatic spread.  For this patient population, tumor 
chemoembolization and recently sorafenib are the only options with survival impact.  In the 
recently presented SHARP trial (Phase 3), which compared sorafenib with placebo in patients 
with advanced liver cancer with no prior systemic treatment, performance status (PS) 0 to 2, and 
a Child-Pugh status A, the hazard ratio (HR) for overall survival (OS) was 0.69 (95% confidence 
interval [CI]:  0.55, 0.87; p=.0006) in favor of sorafenib, representing a 44% improvement in OS 
compared with placebo.  The median OS was 10.7 and 7.9 months with an HR for time-to-tumor 
progression (TTP) of 0.58 (95% CI:  0.45, 0.74; p=.000007). The median TTP was longer 
(5.5 versus 2.8 months) with sorafenib than with placebo (Llovet et al. 2008).  Given these 
results, sorafenib is the first-line standard of care for patients with advanced liver cancer who are 
not candidates for surgical or local treatment. However, if the treatment with sorafenib failed, 
there is no approved second-line therapy.  In patients with Child-Pugh B status, the benefit of 
sorafenib treatment over best supportive care is not proven. TTP after sorafenib treatment in 
patients with moderate to advanced cirrhosis is estimated to be 2.8 months (Pinter et al. 2009).
Different agents have been tested as second-line therapy in HCC patients (Table JBAK.1). Time 
to progression without any treatment is estimated to be 2.7 months (Llovet et al. 2012). 

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Table JBAK.1.
Examples of Experimental Treatments as Second-Line Therapy in Patients with Hepatocellular 
Carcinoma
Study
Patient 
(n)
Treatment
Time to Progression 
or Time to 
Treatment Failure
(median months)
Method
Response 
Rate
OS
(median, 
months)
Reference
Phase II
46
Brivanib
2.7
mWHO (assessed by PI)
4.3%
9.7
Finn et al. 2012
1.77 
(95% CI, 1.38–4.01)
mWHO (assessed by 
IRRC)
4.3%
6.9
(95% CI, 3.9–NR)
mRECIST (assessed by 
independent radiologist)
10.9%
Phase III
263
Brivanib
4.2
mRECIST
11.5%
9.4
Llovet et al. 2012
132
Placebo
2.7
mRECIST
1.9%
8.2
Phase I/II
28
Everolimus
3.9
(95% CI, 2.1-5.5)
RECIST
4%
8.4
Zhu et al. 2011 
Phase II
38
Sunitinib
2.9
(95% CI, 0.5-15)
-
6%
Yau et al. 2011
Phase II
11
Sunitinib
3.2 
RECIST
8.4
Wörns et al. 2010 
Phase II
18
Gemcitabine 
Oxaliplatin
PFS 3.2
(95 % CI, 2.3–3.9)
4.7
Mir et al. 2012 
Phase III
283
Ramucirumab
3.48
RECIST
7.1%
9.17
Zhu et al. 2015
Phase III
573
Regorafenib
3.2
mRECIST
10.6%
10.6
Bruix et al. 2016
Abbreviations:  CI = confidence interval; IRRC= independent response review committee; mRECIST = modified Response Evaluation Criterial in Solid Tumors; 
mWHO = modified World Health Organization; NR = not reached; OS = overall survival; PFS = progression free survival; PI – principal investigator.

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Transforming growth factor beta (TGF-) has been shown to be a tumor promoter in advanced, 
metastatic cancer, while in normal tissue, TGF-inhibits epithelial cell proliferation 
(de Caestecker et al. 2000; Massagué et al. 2000; Derynck et al. 2001; Wakefield and Roberts 
2002). Because of this tumor-promoting activity, TGF-inhibition is currently being considered 
as a treatment option in patients with advanced cancer (Yingling et al. 2004).
TGF-signals into the cell by engaging TGF-Type I and Type II receptors and inducing 
phosphorylation of the TGF-receptor kinases (Shi and Massagué 2003).  The Type I receptor 
kinase phosphorylates SMAD2 and SMAD3 resulting in the formation of SMAD complexes, 
which are subsequently translocated into the nucleus to stimulate gene transcription of TGF-
responsive genes (Derynck et al. 2001).  Therefore, assessment of phosphorylated SMAD 
(pSMAD) after TGF-activation can be used to determine the ability of the host to respond to 
TGF-activation.
Several mechanisms have been proposed to explain the tumor-promoting activity of TGF-such
as increased neovascularization of the tumor causing increased nourishment to the tumor cells, 
immunosuppression leading to the escape of tumor immune surveillance, and increased 
migration and invasion resulting in metastasis (Akhurst and Derynck 2001; Derynck et al. 2001; 
Siegel and Massagué 2003).  These combined effects on the tumor microenvironment by TGF-
promote tumor progression, and therefore a TGF-receptor type I (TGF-RI) kinase inhibitor is 
expected to cause arrest of tumor growth and metastasis in patients.
It has been reported that TGF-β1 is increased in HCC patients and correlates with worst 
prognosis.  In addition, plasma TGF-β1 levels are elevated in HCC patients with 
alpha-fetoprotein (AFP) levels above 10 IU/mL (Sacco et al. 2000).
TGF-β is a pro-fibrotic cytokine and induces HCC progression through a paracrine mechanism, 
which is abrogated by inhibition of TGF-β/SMAD signaling in hepatocytes (Gressner et al. 2002; 
Mikula et al. 2006).  HCC progression is also frequently associated with an epithelial-to-
mesenchymal transition (EMT) of hepatocytes that may be caused by the cooperation of 
laminin 5 and TGF-β (Giannelli et al. 2005).  TGF-β stimulation induces EMT and invasion in 
HCC while its inhibition is association with decrease of invasion (van Zijl 2009)
A recent review integrating the gene expression data from 9 different human genetic expression 
studies across various geographies and stages of HCC was able to propose 3 distinct genetic 
patterns associated with disease outcome (Hoshida et al. 2009).  In this genetic expression 
assessment, the -catenin and TGF--induced gene expression was associated with poor 
survival.  AFP was found to differentiate between the proposed 3 clusters (S1 to S3).
Although the clinical candidate LY2157299 has not yet been investigated in HCC models, 
surrogate compounds, such as LY2109761, have been used to elucidate the antitumor effect of 
the TGF-inhibition in several in vitro and in vivo studies.  TGF-β R1 inhibition by LY2109761 
produced several different antitumor activities in HCC preclinical models.  The spread of HCC 
cells in the surrounding tissue is inhibited by the up-regulation of E-cadherin (Fransvea et al. 
2008).  LY2109761 inhibits invasion of HCC cells (Fransvea et al. 2009) and also inhibits tumor 
growth thanks to inhibiting neoangiogenesis by reducing vascular endothelial growth factor 

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(VEGF) production (Mozzacca 2009).  These effects are selectively dependent on the 
TGF-1/SMAD-2 pathway (Zhang 2009; Melisi et al. 2008).  Finally, LY2109761 inhibits the 
production of connective tissue growth factor, interrupts the cross-talk between tumor and 
stroma, and blocks the progression of HCC (Mazzocca et al. 2010).  Inhibition of TGF-β RI 
activation using another surrogate compound, LY364947, also inhibits TGF-β-dependent cell 
signaling and reduces cell motility and invasion in parental and multikinase-resistant HCC cells 
(Garbay et al. 2010).
These data support the study of TGF-β inhibitors in HCC.  LY2157299 is a small molecule 
designed to inhibit selectively the serine/threonine kinase of the TGF-RI.  Thus, the antitumor 
effect of LY2157299 is expected to result in an increased tumor immune surveillance, reduced 
metastatic spread, and decreased tumor-associated neoangiogenesis.
5.1.
LY2157299 – Nonclinical and Clinical Experience
5.1.1. Nonclinical Pharmacokinetics of LY2157299
Nonclinical pharmacokinetic (PK) studies were performed in 2 species, rat and dog.  LY2157299 
exposure was examined in rats following daily oral doses of 15, 50, and 150 mg/kg after 1 dose 
and 28 doses.  The PK of LY2157299 were linear, but female rats had a consistently higher 
(approximately 2-fold) exposure over the course of the study.  LY2157299 is rapidly absorbed 
and eliminated with a half-life (t1/2) of approximately 4 to 8 hours.
As determined by metabolism studies in rats, most of LY2157299 was excreted in feces.  Three 
metabolites have thus far been identified.  The function and activity of these metabolites have not 
been defined at this time.
In the nonrodent studies using dogs, a gastric pH-dependent variability was observed suggesting 
that at acidic pH, LY2157299 had a less variable exposure.  To reduce possible PK variability, 
LY2157299 will be administered on an empty stomach.
Male and female Fischer 344 (F344) rats were given daily oral doses of LY2157299 
monohydrate at 0, 15, 50, or 150 mg/kg for 1 month.  Male and female beagle dogs were given 
daily oral doses of LY2157299 monohydrate at 0, 50, 250, or 500 mg/kg for 1 month.  The 
potential for induction of hepatic microsomal drug-metabolizing enzymes was evaluated by 
quantitating total cytochrome P450 (CYP) content in liver samples collected at necropsies.  
Slight but variable changes in total CYP content were observed in treated male rats, while no 
significant changes were observed in treated female rats.  No statistically significant changes in 
total CYP content were observed in treated beagle dogs.  The magnitude of the changes observed 
in male rats and the lack of significant change in female rats and male and female dogs suggest 
that LY2157299 is not an inducer of overall CYP content under the conditions of these studies.
The ability of LY2157299 to inhibit CYP-mediated metabolism in vitro was examined.  The data 
show that LY2157299 would not be expected to inhibit metabolism mediated by CYP2D6, 
CYP2C19, CYP2C9, and CYP1A2.  LY2157299 was found to competitively inhibit the 
biotransformation of midazolam to 1'-hydroxymidazolam, a marker activity for CYP3A4, 

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yielding an inhibition constant (Ki) value of 44 M.  LY2157299 was found to competitively 
inhibit the biotransformation of testosterone to 6-hydroxytestosterone, a marker activity for 
CYP3A4, yielding a Ki value of 290 M.  
Based on the nonclinical metabolism studies, LY2157299 is not anticipated to have the potential 
to accumulate in patients or have a risk of high hepatic metabolism.
For details on the nonclinical PK of LY2157299, please see the Investigator’s Brochure (IB).
5.1.2. Nonclinical Pharmacokinetic/Pharmacodynamic Model
Because regular assessment of pSMAD in tumor tissue in patients is both too invasive and likely 
to produce variable results given the heterogeneous nature of tumor tissue, a specific bioassay 
was developed to determine pSMAD levels in a surrogate tissue, peripheral blood mononuclear 
cells (PBMC) (data on file, Eli Lilly; Farrington et al. 2007).  To compare the effect of 
LY2157299 between the surrogate and tumor tissue, the pSMAD level changes measured in both 
PBMC and 4T1 tumor tissue in rats treated with LY2157299 was investigated.  A significant 
relationship between pSMAD modulation in tumor cells and in peripheral blood was observed at 
30- and 300-mg/kg doses (p-values were 0.002 and 0.059 in the 30- and 300-mg/kg groups, 
respectively, and <.0001 for the combined data) which suggests that the pSMAD modulation in 
human PBMC should be a useful surrogate of the pharmacodynamic (PD) effect of LY2157299.  
A PK/PD model was developed to characterize the relationship between drug concentrations and 
pSMAD levels.  This PK/PD model integrated the time course of the PK of the compound, the 
inhibition of pSMAD in tumor and PBMC, as well as the nonclinical tumor growth delay of 
3 tumor animal models.  This model was used to predict an anticipated dose range that is likely 
to be biologically effective in patients with cancer.  The simulations from the rat and the mouse 
suggest that a range of 200 to 500 mg (total daily doses), administered twice daily are expected 
to produce the required percentage inhibition of pSMAD that has been associated with 
tumor-growth delay in the preclinical studies.
For details refer to the IB.
5.1.3. Clinical Pharmacokinetics of LY2157299
As of 19 August 2011, 39 patients have been treated with LY2157299 in an ongoing study, 
Study H9H-MC-JBAH (JBAH).  Of 39 patients, noncompartmental PK analysis has been 
performed on 37 patients.
Results from all 5 cohorts showed rapid absorption of LY2157299, as demonstrated by 
measurable plasma concentrations at the first sampling time (0.5 to 2 hours).  At steady state, on 
Day 14, the median time to maximum concentration (tmax,ss) ranged from 0.5 to 2 hours 
postdose, independent of dose.  Both the maximum observed concentration at steady state 
(Cmax,ss) and exposure increased with dose.  The geometric mean of the apparent clearance at 
steady state (CLss/F) was similar across Cohorts 3, 4, and 5, whereas for the first 2 cohorts the 
scheduled sampling time was only up to 8 hours post dose and the parameter could not be 
estimated with any degree of certainty.  No accumulation of LY2157299 in the 5 cohorts was 

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observed over the 14-day twice-daily (BID) dosing regimen, with accumulation ratio (RA) 
observed to be approximately 1.  A population PK model, based on Cohorts 1 through 5 data, 
was developed.  A first order absorption linear 2-compartment model, with elimination from the 
central compartment provided the best fit to the plasma data.  The mean population clearance of 
LY2157299 was 38.4 L/h with standard error, expressed as a percentage coefficient of variation 
of 8% and the steady state volume of distribution (Vss) was 193 L.  From the population PK 
analysis of all 5 cohorts’ data, the between-patient variance was estimated to be 46% on the 
population apparent clearance.  The between-occasion variability on apparent CL was estimated 
at 18%.  
The dose-proportionality analysis was performed for the PK parameters area under the plasma 
concentration-time curve from 0 to infinity (AUC[0-∞]) and Cmax,ss (Day 15) using results from 
30 patients from all 5 cohorts (pooled across Cycles 1 and 2 for Cohorts 3, 4, and 5).  From this 
analysis, there was no evidence of a difference between Cycles 1 and 2 for Cohorts 3, 4, and 5.  
The estimated ratios of geometric means for AUC(0-∞) and Cmax,ss between 150 mg BID and 
20 mg BID were estimated as 7.90 (90% CI:  2.85, 22.0) and 3.56 (90% CI:  2.09, 6.06), 
respectively.  For a doubling of dose, the fold increases for AUC(0-∞) and Cmax,ss are 2.04-fold 
with corresponding 90% confidence limits (1.43, 2.89) and 1.55-fold with 90% confidence limits 
(1.29, 1.86), respectively.  Within- and between-patient coefficients of variation were estimated 
as 26% and 40% for AUC(0-∞) at steady state, respectively, and 34% and 56% for Cmax,ss, 
pooled across the 5 cohorts from the dose-proportionality analysis.
For additional information see Section 6.1 in the IB.
5.1.4. Nonclinical Toxicology of LY2157299
The toxicity of LY2157299 has been characterized in repeat- and intermittent-dose nonclinical 
safety studies up to 6 months duration in the rat and dog.  The following paragraphs summarize 
the major findings in rats and dogs.  
The heart and great vessels are major target organs for toxicity in both F344 rats and beagle dogs 
following treatment with LY2157299.  These effects include valvulopathy and vascular lesions 
of multiple blood vessels at the base of the heart in rat and dog, which in the rat appear to be 
partially reversible.  In the rat, a continuum of changes in the gastrointestinal tract have been 
described, including inflammation of the mucosa, simple mucosal hyperplasia, and 
adenocarcinoma following 6 months of continuous treatment.  Based on safety pharmacology 
studies, administration of LY2157299 produced increases in hexobarbital-induced sleep time.  
Administration of LY2157299 may produce dose-dependent hemodynamic side effects, 
measured by decreased blood pressure and increases in heart rate, which can be easily monitored 
in the clinic and are reversible upon cessation of treatment.  The nonclinical data do not reveal 
any substantive clinical risk of QT/QTc prolongation at doses that result in total plasma 
concentrations of at least 3.3 g/mL.  
LY2157299 was negative in a bacterial mutation test (Ames test) and an in vivo mammalian test 
(mouse micronucleus).  However, LY2157299 was positive in an in vitro mammalian test 

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LY2157299
(chromosome aberration) with and without S9 activation.  This positive finding is considered 
acceptable in the intended patient population.
Rats were dosed up to 3 months intermittently or 6 months continuously at 50, 150, and 
250 mg/kg.  Dogs have been dosed with up to 500 mg/kg for 1 month and 8, 20, and 60 mg/kg 
daily for 6 months.  LY2157299 caused mortality in the rat at progressively lower doses as the 
duration of treatment increased.  In shorter-duration studies, mortality was observed in rats 
administered 1200 mg/kg of LY2157299 in a 14-day pilot study and in the 3- and 6-month rat 
studies, mortality occurred in animals receiving daily doses of 150 (6-month study) and 
250 mg/kg (3- and 6-month study) beginning on Days 83 and 54, respectively.  All preterminal 
deaths in rats were attributed to compound-related inflammation of the aorta and distributing 
arteries at or near the base of the heart, except for 1 male for which the cause of death was 
undetermined and 1 male that died of an intestinal adenocarcinoma (6-month study).  One female 
dog in the high-dose reversibility group (500 mg/kg) died shortly after the treatment phase ended 
in the 1-month study; death was attributed to bile peritonitis.  There was no mortality observed in 
the 6-month dog study.  Vascular lesions in the rat were characterized by minimal-to-severe 
inflammation of multiple blood vessels at the base of the heart including the ascending aorta, 
coronary arteries, and distributing arteries of the aortic arch.  These changes were described in 
the 3-month (150 and 250 mg/kg) and 6-month (≥50 mg/kg) continuous-dose groups.  The 
vascular damage in rats administered ≥150 mg/kg continuously for 3 and 6 months and 2 weeks 
on/2 weeks off correlated with serum chemistry and hematologic responses typical of chronic 
hemorrhage and inflammation.  In rats given 150 and 250 mg/kg (mid and high dose, 6 months 
and ≥3 months, respectively), vascular inflammation was, in some animals, associated with 
vascular rupture resulting in acute hemorrhage into the thoracic cavity and death.  
The no-observed-effect level (NOEL) for vascular damage in the rat is 50 mg/kg administered on 
a 2-weeks-on/2-weeks-off schedule.  Changes in the base of the ascending aorta, characterized 
by minimal-to-marked degeneration, disorganization, and separation of intramural elastic 
laminae without an accompanying inflammatory response, were observed in the dog 
administered daily doses of 8, 20, or 60 mg/kg for 6 months.  The aortic mural degeneration was 
focally extensive or multifocal with no compound-related microscopic changes in the descending 
aorta.  Although the microscopic changes likely compromised regional aortic structural integrity, 
there were no diagnostic changes of an aortic aneurysm – no gross dilation, no effects in the 
intimal layer, and a lack of free blood within the wall of the aorta.  A cardiac valvulopathy, 
characterized by endothelial/stromal cell proliferation, inflammation, and increases in smooth 
muscle actin immunolabeling and hemorrhage was identified in rats and dogs given high doses 
of LY2157299 for ≤30 days.  In the 3- and 6-month studies, compound-related valvulopathy of 
similar character occurred at lower doses than previously described in studies ≤30 days in 
duration (150 and 250 mg/kg [intermittent 2 weeks on/2 weeks off and continuous groups] in the 
3-month study and at all doses [50, 150, and 250 mg/kg] in the rat 6-month study and at the mid 
and high doses [20 and 60 mg/kg] in the dog).  The cardiac valvulopathy observed in rats and 
dogs given LY2157299 were observed but have not been associated with extracardiac evidence 
of valvular insufficiency or dysfunction.  The NOEL for valvulopathy in the rat is 50 mg/kg 
administered on a 2-weeks-on/2-weeks-off schedule and 8 mg/kg in the dog in the 6-month 

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LY2157299
study.  In an effort to characterize the reversibility of cardiovascular lesions, a non-good 
laboratory practice (GLP) study in rats administered 250 mg/kg daily for 8 weeks followed by a 
6-week recovery period was conducted.  Data indicate that vascular lesions are partially 
reversible when rats are administered a dose known to induce a high incidence of cardiovascular 
lesions (vasculitis and valvulopathy) with daily dosing.  After the 6-week recovery period, a 
decrease in both incidences in severity of cardiovascular lesions was observed.  However, at the 
end of this recovery period, a few animals still were observed with minimal-to-moderate 
inflammation at the base of the aorta, coronary arteries or valves, and minimal stromal 
hyperplasia of the atrioventricular valves.  These lesions were still considered adverse.
Treatment with LY2157299 results in a continuum of changes characterized by inflammation in 
the mucosa of mid- and high-dose (150 and 250 mg/kg) rats dosed either daily or intermittently 
for 3 months to proliferative changes at the mid and high dose (150 and 250 mg/kg) in the 
6-month daily-dosing rat study.  The proliferative changes included simple mucosal hyperplasia 
that progressed to include adenomatous hyperplasia, adenoma, and, in 2 males at the high dose, 
adenocarcinoma.
In the rat, additional important compound-related findings affecting the skeletal system, 
consisting of proliferation of trabecular bone or sternal cartilage, altered endochondral 
ossification, and slightly increased degeneration of articular cartilage were observed.  Consistent 
with literature predictions (Lahn et al. 2005), administration of LY2157299 in a pilot 
embryo-fetal study resulted in increased resorptions and fetal skeletal morphology at 20 and 
200 mg/kg.  A no effect level for embryo-fetal effects was established at 2 mg/kg in this pilot 
study.  In the dog, corneal edema and episcleritis were noted in the eyes of dogs at the high dose 
(60 mg/kg) during a scheduled ophthalmologic examination of all dogs on Day 176.  Corneal 
endothelitis (inflammation of the most posterior cell layer of the cornea) was considered to be 
the primary change.  Histologic evaluation of the eye was unremarkable.  Additional important 
compound-related findings in the dog consisted of atrophy and/or inflammation of the mucosa of 
the stomach and large intestine, proliferation of sterna cartilage, and gallbladder mucification.  
For additional information, see Section 5 in the IB.
5.1.4.1.
Overall Conclusions
Collectively, the findings in the continuous 3- and 6-month daily-dosing toxicity studies, 
particularly the degeneration of the large blood vessels, imply that long-term, daily dosing of 
LY2157299 may carry a risk in patients for developing aneurysms.  Reversibility was not 
assessed in the 3- or 6-month toxicity studies, but in a non-GLP reversibility study in rat, data 
indicate the cardiovascular lesions are partially reversible, but those that are still present 
following the recovery period are still adverse.  The intermittent-dosing regimen in patients is 
based on the safety demonstrated in the rat and dog following 1 month of continuous daily 
dosing in which the NOEL for any effects in the heart was 150 and 20 mg/kg in the rat and dog, 
respectively, and a 3-month intermittent-dosing study in the rat in which the NOEL for any 
effects in the heart was 50 mg/kg (see Table JBAK.2 for margin-of-safety [MOS] calculations).  
Although the likelihood of occurrence or the extent and timing of such a risk observed after daily 

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LY2157299
dosing is not known in humans, LY2157299 will be administered as an intermittent-dosing 
regimen in this patient population which has a poor prognosis and rapidly advancing cancer.

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Table JBAK.2.
Margin of Safety Based on NOEL to Cardiovascular Effects 
Clinical Dose (mg/day)
160
300
Measured AUC0-24hr (ghr/mL) at steady state BID 
2.2
4.3
Simulated AUC0-24 hr (ghr/mL) at steady state QDa
4.1
7.7
Rat NOELb (150 mg/kg) (30 days; daily dosing)
AUC0-24 h (ghr/mL)c
36.3
Measured
(Steady State BID)
16.5
8.4
Simulateda
(Steady State QD)
8.9
4.7
Rat NOELb (50 mg/kg) (3-months intermittent; 2 weeks on/2 weeks off)
AUC0-24 h (ghr/mL)c
8.0
Measured 
(Steady State BID)
3.6
1.9
Simulateda
(Steady State QD)
2.0
1.0
Rat LOEL (150 mg/kg) (3-months intermittent; 2 weeks on/2 weeks off)
AUC0-24 h (ghr/mL)c
24.2
Measured 
(Steady State BID)
11
5.6
Simulateda
(Steady State QD)
5.9
3.1
Dog NOELb (20 mg/kg) (30 days; daily dosing)
AUC0-24 h (ghr/mL)d
23.9
Measured (Steady 
State BID)
10.9
5.6
Simulateda
(Steady State QD)
5.8
3.1
Margin of safety based on NOEL to cardiovascular effects in 30 day daily and 3-month intermittent dosing GLP 
toxicology studies in rat and dog and measured clinical AUC (shaded row indicates the relevant MOS for 
LY2157299) or exposure multiple to an effect dose (LOEL) for cardiac lesions in the rat in a 3-month 
intermittent dosing GLP toxicology study.
Abbreviations:  AUC = area under the concentration curve; BID = twice daily; GLP = good laboratory practice; 
LOEL = lowest-observed-effect level; MOS = margin of safety; NOEL = no-observed-effect level; QD = daily.
a
Simulations based on all clinical data from Study JBAH (Cohorts 1 to 5) assuming QD dosing.
b
NOEL is based on absence of any cardiovascular changes at this dose.
c
AUC from males were used to calculate MOS or exposure multiple to the LOEL.
d
AUC from males and females was averaged since no exposure differences were noted.
5.1.5. Clinical Experience
5.1.5.1.
Safety
As of 15 September 2015, approximately 696 patients and 20 healthy subjects have received 
treatment with LY2157299, either in monotherapy or in combination with chemotherapy.  These 
include clinical trial patients with advanced/metastatic cancer, solid tumors, glioblastoma, 
pancreatic cancer, HCC and myelodysplastic syndromes (MDS).
Overall, few SAEs deemed by investigators to be associated with drug treatment have been 
reported.  Most treatment-related SAEs have been reported in 1 patient except anemia (2 patients 

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with HCC), cardiac failure (2 patients with MDS), neutropenia (1 patient with glioblastoma and 
1 patient with HCC), thrombocytopenia (2 patients with glioblastoma), peritoneal hemorrhage 
(2 patients with HCC), and diarrhea (1 patient with glioblastoma and 1 patient with HCC).  The 
SAE profile seems to differ when LY2157299 is used in patients with glioblastoma, MDS, and 
HCC, indicating a possibility that reporting rates are influenced by the underlying disease and 
there have been no trends or signals noted in the reported SAEs.  
The most common TEAEs (≥10%) for LY2157299 monotherapy are fatigue (19%), anemia 
(18%), abdominal pain (18%), edema peripheral (15%), nausea (15%), asthenia (14%), diarrhea 
(14%), vomiting (14%), abdominal pain (12%), headache (12%), constipation (10%), decreased 
appetite (10%), and pruritus (10%).  Most of these AEs were of mild or moderate severity.
The addition of LY2157299 to standard cancer treatments appeared to have no effect on the 
established toxicity profile of these standard therapies.
Extensive cardiac safety monitoring has been conducted in all clinical studies, and available data 
has shown no indication of a LY2157299-related cardiac toxicity.  
The intermittent dosing regimen of 14 days on treatment with LY2157299 followed by 14 days 
off treatment (1 cycle = 28 days) that has been used in clinical development to date appears to be 
well tolerated with no clinically significant valvulopathies or aneurysms reported or observed at 
dosages of up to 300 mg/day. 
For additional details, please refer to the LY2157299 IB, Section 6.
5.1.5.2.
JBAK:  Brief Summary of Results to Date
At the time of Amendment (e), Part A and Part B of the study have completed.  A total of 149 
patients were enrolled (109 in Part A and 40 in Part B). Eighty-five percent of patients were 
male and the median age was 65 years.  Fifty-six percent of patients had an ECOG performance 
status (PS) of 0 and 44% had a PS of 1. Eighty-six percent of patients had a Child-Pugh Class A
score and 14% had a Class B score.  Etiology of disease was a follows: hepatitis C 24%, 
hepatitis B 20%, alcohol 20%; multiple 9.4%. Overall, 83% of patients had received prior 
sorafenib.  Eleven patients discontinued treatment due to AEs: 8 were considered related to 
study treatment. Grade 3/4 AEs possibly related to treatment were observed in 26 (17%) 
patients. Of these AEs, neutrophil count decrease was observed in 4 patients.  Anemia, 
hypoalbuminemia, decreased bilirubin, fatigue and embolism were observed in 2 patients each.
All other AEs occurred in just 1 patient. Median TTP was 11.9 weeks (95% CI:  6.3, 12.6) in 
Part A and 18.0 weeks (95% CI:  10.0, 24.0) in Part B. Median OS was 31.4 weeks (95% CI:  
22.9, 40.6) in Part A and 73.0 weeks (95% CI:  45.4, 104.7) in Part B. The median OS for the 
overall population was estimated as 40.4 weeks (95% CI:  31.1, 52.4) (Giannelli et al. 2016).
Enrollment into Part C has completed and maturation of the data is awaited.  Enrollment is 
ongoing in Part D of the study.

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LY2157299
5.1.5.3.
Rationale for the Study
The scientific justification of investigating LY2157299 in HCC is compelling based on the role 
of TGF-β in the process of fibrosis and cirrhosis leading to HCC.  The evidence of antitumor 
effects in several models with TGF-β inhibitors, such as LY2109761 and LY364947, suggest 
that LY2157299 will have activity in HCC.  Also, the relatively favorable toxicity profile 
differentiates LY2157299 from other kinase inhibitors with their characteristic cardiovascular 
and cutaneous toxicity.  Therefore, it is anticipated that LY2157299 will:  

Increase immunecompetence in HCC patients 

Show increased antitumor activity due to a reduction in fibrogenesis, 
remodeling, neoangiogenesis, and invasiveness
In addition to the scientific rationale and the expected improvements, the study is justified 
because of the following reasons:

LY2157299 has shown a favorable short- and long-term toxicity profile in 
Study JBAH.

No indication of cardiac insufficiency.

Three Grade 3 to 4 events (CTCAE v 3.0) (thrombocytopenia, 
thromboembolism, ischemic stroke) possibly related to study drug occurred in 
Study JBAH in patients who received LY2157299 treatment.

Evidence of tumor responses while patients were treated with single-agent 
LY2157299 in Study JBAH, the study in GBM patients.
o
Two patients had complete responses (CRs) and 3 patients had partial 
responses (PRs).  Three patients were treated for more than 20 cycles 
(updated information in the IB).

Clinical exposures achieved in Study JBAH are 1.9-fold below a 
no-observed-effect level for cardiac toxicity in the rat (most sensitive species 
for cardiac effects) suggesting clinical activity can be achieved at exposures 
lower than those required to elicit toxicity in nonclinical species.
The proposed immunomodulatory as well as anti-invasive properties of LY2157299 suggest that 
a clinical investigation in the first-line setting of patients with HCC is promising.  Hence, it may 
be acceptable to treat patients with LY2157299 even before they are considered to receive 
sorafenib or other antivascular agents.  
In summary, the combination of a well-tolerated agent such as LY2157299 in a disease with high 
unmet medical need, justifies the evaluation of this agent in the first- and second-line treatment 
of HCC.  Thus, the overall benefit/risk profile is acceptable in this setting.
5.1.6. Rationale for Amendment (a)
The protocol is amended for the following reasons:

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LY2157299

Modification and clarification of inclusion/exclusion criteria taking into account 
updated safety information of LY2157299 and the patient population with 
hepatocellular carcinoma:
o
Expand inclusion criteria to Child–Pugh Class B7 as these patients are similar to 
Child-Pugh A patients and the current bilirubin limits for inclusion criteria 
include B7 patients.
o
Allow previous liver transplant patients because of the favorable safety profile of 
LY2157299 and because the absence of drug-drug interaction as determined with 
enzyme-inducing anti-epileptic drugs (EIAEDs) and proton pump inhibitors 
(PPIs).
o
Allow patients with lower platelet levels due the favorable safety profile of 
LY2157299. 
o
Allow patients with hormone-refractory prostate cancer stable on 
gonadotropin-releasing hormone (GnRH), and patients with breast cancer stable 
on antiestrogen therapy to continue treatment while enrolled in the study, as these 
patients have their disease controlled and their condition is unlikely to interfere 
with the aim of the present study.

To help investigators decide who may be considered sorafenib ineligible patients, a 
tool is provided (Attachment 14).

Addition of serum markers for hepatocellular carcinoma and hematology subset for 
T cell on T regulatory cells.

To remove the requirement for administration of Functional Assessment of Cancer 
Therapy, Hepatobiliary (FACT-Hep) questionnaire on Cycle 1, Day 1 as this 
procedure was considered redundant.

To add the requirement for patients who are to have Day 15 PK to omit the evening 
dose on Day 14, so as to allow for a 24-hour time period between the Day 14 morning 
dose and the Day 15 PK sample.  This was omitted from the original protocol version 
in error.

To clarify and update the details of the supplied clinical trial material.

To add confirmation that local laboratory results may be used to determine patients’
eligibility.

To clarify that the second interim analysis is planned after 40 patients have been 
enrolled into each dose cohort and have been actively followed for 3 months or until 
progressive disease or death have been observed.

To provide corrections and clarifications within the Study Schedule (Attachment 1).
5.1.7. Rationale for Amendment (b)
The protocol is amended for the following reasons:

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LY2157299
As part of the continuous monitoring of safety, PK, and laboratory markers in patients with 
HCC, the sponsor noted that patients are staying on study beyond 4 months.  Furthermore, the 
300 mg/day dose appears to have no evidence of increased toxicity.  There appears to be no 
difference in the number of patients at the 160-mg/day and the 300-mg/day dose who stayed 
beyond 4 months.  In addition, in all other ongoing trials with LY2157299, the dose of 
300 mg/day was selected for future clinical development.
Preliminary PK data from the first interim analysis (n=20 patients) suggest that patients 
administered 300 mg/day have higher exposures than previously observed for the same dose 
level (Study JBAH) during the treatment period. LY2157299 appears to be fully eliminated after 
the 14-days off period of a cycle (additional PK sampling is added to study the clearance of 
LY2157299). The lowest exposure level (ie, most conservative) in the most sensitive nonclinical 
species administered LY2157299 in a clinically relevant dosing schedule (2 weeks on/2 weeks 
off) in which cardiac effects were observed was 24 μg*hr/mL (Table JBAK.2). The findings at 
this dose level (150 mg/kg) consisted of a single male rat (n=10/group) with minimal 
inflammation in the aortic valve and ascending aorta.  Administration of 300 mg/day to patients 
with HCC may result in higher than anticipated exposures; however, due to the clinical safety 
profile observed thus far and the benefit:risk in this patient population, this approach is 
considered acceptable.  
Because of these reasons and the lack of substantial evidence that the 160-mg/day dose is 
superior to the 300-mg/day dose, the dose of 300 mg/day is selected for the continuation of this 
trial.  
For Part B, it was decided to evaluate the effects of LY2157299 in patients with AFP <1.5x
upper limit of normal (ULN) to have an overall assessment of LY2157299 efficacy in all HCC 
patients. At the time of the decision to focus on the 300-mg/day dose, 74 patients were 
randomized.
The study design will be modified as follows:

Part A: Evaluation of LY2157299 in Child-Pugh A or B7 patients with AFP ≥1.5x ULN. 
After stopping the 160-mg/day dose arm, all newly enrolled patients will be treated at the 
300-mg/day dose.

Part B: Evaluation of LY2157299 in Child-Pugh A or B7 patients with AFP <1.5x ULN
For Part C, patients with Child-Pugh B7 or B8 status do not have any therapeutic options. 
Sorafenib approval in HCC was granted after evaluation in patients with Child-Pugh A status 
(Llovet et al. 2008).  Given the safety profile of LY2157299, the assessment of LY2157299 in 
Child-Pugh B7 or B8 patients is justified to assess potential new agents in this population.
For all patients, treatment discontinuation for progressive disease is not solely based on 
radiological assessments, but also considers whether the patient is clinically asymptomatic and 
their biomarker responses.

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LY2157299
5.1.8. Rationale for Amendment (c)
The protocol is being amended for the following reasons:

Based on the second interim analysis and preclinical data, Part C is being modified to 
evaluate the safety of sorafenib (currently the only approved systemic agent in HCC)
when combined with LY2157299 in patients with first-line HCC and Child-Pugh A
status:
o
Preclinical data:
Combination of LY2157299 with sorafenib showed potentiation of sorafenib 
activity in vitro and ex vivo study.  This implies the possibility that this 
combination may be more effective than LY2157299 alone.  
o
Safety:
The favorable safety and PK profile of LY2157299 thus far observed in HCC 
suggest that a combination with sorafenib may not add additional toxicity to the 
known toxicity of sorafenib. Furthermore, the PK profile for LY2157299 will be 
documented for patients receiving the combination treatment and compared with
the PK profile for patients who received the monotherapy.
o
Antitumor activity of LY2157299 in first-line patients:
Preliminary results from 20 sorafenib-naive patients (3 of whom had received 
brivanib as a first-line treatment and 17 who have not received any systemic 
treatment) treated with LY2157299 monotherapy estimated that the median TTP 
was 18.3 weeks, higher than TTP in second-line HCC patients.  Together with the 
preclinical information, this justifies the evaluation of the combination in first-line 
HCC.
An exploratory evaluation will compare the potential increase of TTP in patients 
receiving the combination therapy (LY2157299 + sorafenib) to the TTP observed 
in sorafenib-naive patients enrolled in the monotherapy part.

Adding a treatment extension period to allow patients who are benefiting from study 
treatment to continue the same study treatment once study endpoint is met.

To provide corrections and clarifications within the follow-up safety assessments and 
Study Schedule.
5.1.9. Rationale for Amendment (d)
The protocol is being amended to add a Part D that will allow for safety assessment of 
LY2157299 in combination with ramucirumab.  This combination is being studied for the 
following reasons:

Based on recent data, ramucirumab showed antitumor activity in HCC, including an 
improvement in OS for second-line HCC patients with AFP levels ≥400 ng/mL (median 

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LY2157299
OS = 7.8 months for ramucirumab versus 4.2 months for placebo; OS hazard 
ratio = 0.67 [95% CI, 0.51–0.90]) (Zhu et al. 2014).

Antiangiogenic treatment, such as ramucirumab, polarizes tumor-associated macrophages 
to reduce immune-regulatory signals and, thereby, creates an immune-supportive 
microenvironment to recruit and activate CD8+ T cells (Huang et al. 2012).

Targeting the vasculature and TGF-β together may lead to greater antitumor activity by 
reducing angiogenesis and, at the same time, promoting antitumor immunity via TGF-β.
5.1.10. Rationale for Amendment (e)
The protocol is being amended to add a Part E that will allow the evaluation of the safety and 
tolerability, pharmacokinetics and efficacy of LY2157299 administered according to a 21 days 
on/7 days off schedule.
Across the clinical development program at the time of Amendment (e), LY2157299 has shown 
a favorable short- and long-term toxicity profile in different studies and activity in different 
tumor types.
In light of cardiotoxicity observed in nonclinical trials of LY2157299, comprehensive cardiac 
safety monitoring was implemented in all clinical trials of LY2157299, including Study JBAK, 
and has been ongoing until the time of this amendment.
Using a data cut-off date of 15 September 2015, Lilly has performed a cross-study
cardiovascular (CV) safety analysis of 745 patients from 10 completed and ongoing unblinded 
studies of LY2157299, including patients assigned to standard of care control arms who did not 
receive LY2157299.  This analysis included a review of CV-related TEAEs and SAEs (with a 
focus on patients with increased valvular insufficiency and vascular-related 
hemorrhage/aneurysm, as well as patients with events of heart failure) and a correlation of 
TEAE/SAE data with central echocardiography findings, chest CT scan and/or MRI findings, 
cardiac laboratory markers (BNP, cystatin C, and troponin I) and central ECG findings.  The 
cumulative results of this cross-study analysis did not identify any concerning trends in AEs, in 
particular those related to valvulopathies or aneurysms.  
As described in Section 5.1.4, nonclinical toxicology data have determined a no-effect level for 
CV lesions that is higher than the observed and anticipated exposures in Study JBAK and other 
clinical trials.  There is also no evidence of accumulation in patients given multiple doses of 
LY2157299 at 150 mg BID, suggesting that daily exposures on a schedule with increased days of 
dosing will remain lower than the no-effect-level for CV lesions characterized in toxicology 
studies.
In view of  these clinical and nonclinical observations, Lilly has proposed and received 
endorsement from the United States (US) Food and Drug Administration to explore a new 
treatment schedule for LY2157299 in Part E of amended Study JBAK.  This schedule will dose 
LY215729 at 150 mg twice daily for 21 days, followed by 7 days off drug (cycle length= 28 
days).  The goal is to improve upon the efficacy that has been observed in patients receiving 

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LY2157299 on a 14 days on/14 days off schedule by increasing time on target and thereby 
limiting chances for tumor regrowth and resistance.
Amendment (e) also includes the provision that Part D of Study JBAK will be conducted outside 
of the European Union (EU) and clarification on how Part D expansion will be conducted. 
Attachment 17 lists changes made in protocol amendment (e).

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LY2157299
6.
Objectives
6.1.
Primary Objective
The primary objective of this study is to characterize both the TTP distributions and the effect on 
TGF--associated serum biomarkers (for example, TGF-, AFP, E-cadherin) of study treatment 
in patients with HCC.
6.2.
Secondary Objectives
The secondary objectives of the study are as follows:

To evaluate the safety of LY2157299 as monotherapy and in combination 
with sorafenib or ramucirumab in HCC patients

To evaluate the population PK of LY2157299 as monotherapy and in 
combination with sorafenib or ramucirumab

To recommend which doses of LY2157299 as monotherapy and in 
combination with sorafenib or ramucirumab to use in future trials recruiting 
HCC patients

To evaluate the safety and tolerability, pharmacokinetics and efficacy of 
LY2157299 as monotherapy administered according to a 21 days on/7 days 
off schedule

To characterize other time-to-event distributions, such as progression-free 
survival (PFS, based on Response Evaluation Criteria in Solid Tumors
[RECIST] 1.1 and modified RECIST [mRECIST], for HCC) and OS

To estimate antitumor efficacy using response rate (RR, based on RECIST 
1.1. and mRECIST, for HCC)

To assess patient-reported outcome (PRO) measures of disease-specific 
symptoms and health-related quality of life (FACT-Hep)  

To explore E-cadherin, pSMAD, and -integrin (and other markers associated 
with EMT transformation and the TGF--associated signaling pathway) 
presence in the original diagnostic tumor tissue and optional posttreatment 
tumor tissue and the correlation of this with both clinical efficacy endpoints 
and biomarker response

To explore the utility of exploratory imaging techniques (for example, 
positron emission tomography [PET] scan, contrast echography) to assess 
treatment effect with LY2157299 as monotherapy and in combination with 
sorafenib when possible

To explore fibrosis-related biomarkers, such as Fibrotest

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7.
Investigational Plan
7.1.
Summary of Study Design
Study JBAK is a multicenter, randomized trial characterizing the TTP distribution of 2 dose 
levels of LY2157299 in patients with Child-Pugh Class A or B HCC.
Approximately 235 patients will be enrolled into the study:  109 have been enrolled into Part A, 
40 into Part B, 47 into Part C, approximately 18 into Part D and approximately 23 into Part E.
Starting with Amendment (e), there are 5 parts to this study:
Parts A and B
Part A and Part B enrolled patients with Child-Pugh Class A and B7 status HCC, distinguished
by baseline AFP levels, who had either progressed on sorafenib or were ineligible to receive 
sorafenib.  Enrollment is complete with 109 patients enrolled into Part A and 40 into Part B.
In Part A, patients with AFP ≥1.5x ULN were randomized to 2 cohorts based on initial dose of 
LY2157299 to be received (160 or 300 mg/day).  Eligible patients were randomized to 1 of these 
cohorts (the 2 cohorts being balanced as far as possible for AFP levels, etiology, and whether or 
not sorafenib-naïve) and received LY2157299 for 14 days followed by 14 days of rest (Figure 
JBAK.1).
A first interim analysis for safety was planned and carried out after 10 patients per dose had
enrolled and completed 1 cycle of treatment.  A PK interim analysis occurred after the PK 
sample on Day 15 had been collected from 20 patients.  The decision to continue enrollment on 
the 300-mg/day dose only occurred after a data review prior to the planned second interim 
analysis in protocol Amendment (a).  Patients who were still on study treatment when this 
decision was made remained on their original dose unless there were safety or efficacy reasons to 
change their dose. For the purposes of data collection and analysis, patients whose dose was 
changed remained in the original cohort to which they were assigned.
At this point, Amendment (b) was implemented to continue enrolling into Cohort 2 of Part A and 
to initiate enrollment into Part B and included changes to the planned interim analyses.
The second planned interim analysis for Part A (based on N=106 patients, Cohorts 1 and 2) was 
completed after the last patient had enrolled into Cohort 2 (n=69) and started Cycle 1.  Detailed 
information is given in Section 12.2.14 (Interim Analyses).  Enrollment continued during all data 
reviews and interim analyses.
In Part B, patients with AFP <1.5x ULN received LY2157299 300 mg/day for 14 days followed 
by 14 days of rest (Figure JBAK.1).  The third interim analysis occurred after 18 patients had
been treated and completed 3 cycles or discontinued from study treatment.  Detailed information 
is given in Section 12.2.14 (Interim Analyses).

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Abbreviations:  AFP = alpha-fetoprotein; PK = pharmacokinetics; ULN = upper limit 
of normal.
Figure JBAK.1.
Illustration of study design for Protocol H9H-MC-JBAK Parts A and 
B.
Part C
Part C evaluated LY2157299 in combination with sorafenib in patients with advanced HCC and 
Child-Pugh Class A status who had not received previous systemic treatment.  Up to 40 patients 
were planned to be enrolled. Enrollment is complete and a total of 47 patients have been treated.  
Part C comprised a safety lead-in of 2 cohorts followed by an expansion phase with selected safe 
dose(s) (Figure JBAK.2). Patients enrolled in Cohort 1 were administered LY2157299 80 mg 
BID on Days 1 to 14 in combination with sorafenib at 400 mg BID on Days 1 to 28 on a 28-day 
cycle.  Three patients were planned to be enrolled in Cohort 1; if no dose-limiting toxicities 
(DLTs) (related to LY2157299 or combination regimen) were observed in Cycle 1, 3 patients 
were to be treated in Cohort 2 at LY2157299 150 mg BID on Days 1 to 14 in combination with 
sorafenib at 400 mg BID on Days 1 to 28 on a 28-day cycle.  If a DLT related to LY2157299 or 
combination regimen was observed in either cohort in the first 3 patients in Cycle 1, then that 
cohort was to be expanded to include an additional 3 patients.  Six to 12 patients were planned to 
be enrolled in the safety lead-in, depending on the observed DLTs.  See Section 9.1.5 for more 
detailed dose escalation and expansion criteria.  PK sampling was conducted in Cycle 1 with the 
intent to assess drug-drug interactions between LY2157299 and sorafenib (Attachment 4).  
Depending on the results from the safety lead-in cohorts and analysis from Parts A and B, the 
expansion cohort was to consist of 1 of the following:

Single treatment group: LY2157299 80 mg BID on Days 1 to 14 in combination with 
sorafenib at 400 mg BID on Days 1 to 28 on a 28-day cycle, or

Single treatment group: LY2157299 150 mg BID on Days 1 to 14 in combination with 
sorafenib at 400 mg BID on Days 1 to 28 on a 28-day cycle, or

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
Two treatment groups: LY2157299 80 mg BID on Days 1 to 14 in combination with 
sorafenib at 400 mg BID on Days 1 to 28 versus LY2157299 150 mg BID on Days 1 to 
14 in combination with sorafenib at 400 mg BID on Days 1 to 28. Both cohorts were to 
be on a 28-day cycle.
Patients enrolled in the safety lead-in cohorts were to continue treatment as per that cohort.  
Figure JBAK.2.
Illustration of study design for Protocol H9H-MC-JBAK Part C.
Part D
Part D will be conducted outside of the EU and will evaluate LY2157299 in combination with 
ramucirumab in patients with advanced HCC and Child-Pugh Class A status.  Part D comprises 2 
cohorts (Figure JBAK.3).  Patients enrolled in Cohort 1 will be administered LY2157299 80 mg 
BID on Days 1 to 14 in combination with ramucirumab administered at 8 mg/kg as an 
intravenous (IV) infusion on Days 1 and 15 of every cycle.  Approximately 18 patients may be 
enrolled to allow the selected dose to be expanded to approximately 15 patients in total.   
Three patients will be initially enrolled on Cohort 1; if no dose-limiting toxicities (DLTs) 
(related to LY2157299 or the combination regimen) are observed in Cycle 1, then 3 patients will 
be treated on Cohort 2 at LY2157299 150 mg BID on Days 1 to 14 in combination with 
ramucirumab 8 mg/kg administered as an IV infusion on Days 1 and 15 of every cycle.  If a DLT 
related to LY2157299 or the combination regimen is observed in the first 3 patients in Cycle 1 of 
Cohort 1, Cohort 1 will enroll an additional 3 patients.  If no further DLTs are observed, Cohort 
2 will be opened. If 1 or more additional DLTs are observed in Cohort 1, Part D will close. If 
Cohort 2 is opened and no DLTs are observed in the first 3 patients, Cohort 2 will be expanded 
until approximately 15 patients have been enrolled. If 1 DLT is observed in Cycle 1 in the first 3 
patients in Cohort 2, another 3 patients will be enrolled. If 2 or more DLTs are observed in the 
first 3 patients OR 1 or more DLTs are observed in the additional 3 patients in Cohort 2, a safety 
review by Lilly and the investigators will occur to decide whether to expand Cohort 1.  If no 
further DLTs are observed in Cohort 2, Cohort 2 will be expanded until a total of approximately

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15 patients have been enrolled at this dose. See Section 9.1.5 for more detailed dose escalation 
and expansion criteria.
PK sampling will be conducted in Cycles 1 and 2 with the intent to assess changes in 
LY2157299 and ramucirumab exposure when administered in combination (Attachment 4).  
Abbreviations:  BID = twice daily; IV = intravenous.
Figure JBAK.3.
Illustration of study design for Protocol H9H-MC-JBAK Part D.
Part E
Part E will evaluate the safety, tolerability, pharmacokinetics and efficacy of LY2157299 given 
according to a 21 days on/7 days off schedule in patients with Child-Pugh Class A HCC who 
have received at least one prior line of systemic treatment or who have not received prior 
treatment and are ineligible for sorafenib treatment (at the investigator’s discretion).  Up to 
approximately 23 patients may be enrolled.  
Figure JBAK.4 shows the Part E study design.
It is planned that Part E will initially enroll up to 3 patients. Enrollment will halt after the first 3 
patients have received their first dose of treatment. If a patient discontinues study treatment 
within the first cycle of therapy for any reason other than a dose-limiting toxicity (DLT), that 
patient may be deemed unevaluable and replaced.  A safety evaluation will occur after the third 
evaluable patient has completed one cycle of therapy.  Dose-limiting toxicities will be as defined 
in Section 9.1.5.1. If DLTs are observed in 2 of the first 3 patients dosed, Part E will close. If 
DLTs are observed in 1 of the 3 patients, a safety assessment will occur after the next 3 
evaluable patients have completed 1 cycle. If the schedule is deemed to be tolerable (<33% 
DLTs in Cycle 1 as well as consideration of the overall safety profile from later cycles), 
additional patients will be enrolled so that data from approximately 20 patients will be available

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to better characterize the safety of the schedule and allow comparison to safety, 
pharmacokinetics and efficacy results in other cohorts. 
Recognizing that potential CV effects may occur after the initial DLT period, patients will be 
regularly monitored according to a stringent schedule and as part of a trial level safety review.  
Trial level safety reviews will occur approximately every 3 months, beginning after the initial 
DLT evaluation period.
Abbreviation:  BID = twice daily.
Figure JBAK.4.
Illustration of study design for Protocol H9H-MC-JBAK Part E.
All Study Parts
One cycle is defined as 28 days (a minimum of 26 days and a maximum of 31 days).  The 
treatment period for LY2157299 must be a minimum of 10 days and a maximum of 14 days (for 
Parts A, B, C and D) and 21 days (for Part E); the “off-treatment” period can vary to ensure an 
overall cycle length of 26 to 31 days).  In extenuating circumstances, the “on study drug”
window for LY2157299 is allowable from Day 10 to Day 14. (In Part C and D safety lead-in 
Cycle 1, patients must have received 14 days of LY2157299 treatment). For Part E Cycle 1, all 
patients must receive 21 days of treatment, followed by 7 days off treatment.  If patients are not 
evaluable for DLT assessment and/or PK in Cycle 1 of Part C or Part D safety lead-in, or Cycle 1 
Part E, the patients will be replaced.
Per patient, the screening period is no more than 4 weeks or 28 days before the first dose of 
LY2157299; the planned treatment duration is 6 cycles or approximately 24 weeks, but patients 
may continue to receive study drug if they are still benefiting from treatment in the opinion of 
the investigator and Lilly physician.  Follow-up visits will occur approximately 30 days after the 
last day of study treatment and subsequently approximately every 60 days (approximately 2 
months [±7 days]).

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In case of the occurrence of severe toxicities in later cycles in patients treated with either 
LY2157299 monotherapy or LY2157299 in combination with ramucirumab or sorafenib, the 
sponsor will review and choose a lower dose or discontinue the patient, if necessary.  
The final analysis for Parts A and B will be conducted after the study objectives for these 2 parts 
have been met.  This is likely to be after approximately 30 deaths have occurred in Part B in 
order to have a reasonable estimate of overall survival in this patient group (AFP <1.5x ULN).  
Part C will be considered complete and the final analysis initiated once 85% of events for 
survival analysis in the expanded cohort in Part C have occurred.  
Part D will be considered complete and the final analysis initiated after the last patient has 
discontinued from study treatment and completed at least the 30-day follow-up visit [Visit 801]. 
Part E will be considered complete and the final analysis initiated after the last patient has 
discontinued from study treatment and completed at least the 30-day follow-up visit [Visit 801].
At the time all parts of the study are considered complete, the study will be considered complete 
and those patients still on treatment may enter the treatment extension period and continue to 
receive the study treatment (see Section 7.1.1).
All patients will be followed for OS until study completion.
End of study (trial) is the date of the last visit or last scheduled procedure shown in the Study 
Schedule for the last active subject in the study (this includes all patients who enter the extension 
period).  The European Union (EU) has additional reporting requirements associated with the 
end of study.  Consult regional standard operating procedures (SOPs) for further information.
7.1.1. Extension Period
After study completion (i.e., study objectives met, see Section 7.1), all patients who are on study 
treatment (LY2157299 alone or LY2157299 with sorafenib in Part C, LY2157299 with 
ramucirumab in Part D, or LY2157299 alone in Part E) and who are eligible for the extension 
period may continue to receive study treatment until one of the criteria for treatment 
discontinuation is met (Section 8.3.1).  Patients who are no longer on study treatment at the time 
of study completion and who have completed at least the 30-day follow-up visit (V801) will be 
discontinued from long-term follow-up and therefore reach the end of the study, unless they are 
being followed due to unresolved safety concerns.  Lilly will notify investigators when the 
extension period begins.  
During the extension period, all AEs and study drug exposure will be reported on the case report 
form (CRF).  SAEs will also be reported on the CRF and to Lilly Global Patient Safety (see 
Section 10.2.1.1).  In the event that an SAE occurs, Lilly may request additional information 
(such as local laboratory results, concomitant medications, and hospitalizations) in order to 
evaluate the reported SAE.

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All patients in the extension period will be treated following the Study Schedule (see 
Attachment 1).  This will ensure that appropriate risk/benefit assessments are conducted for all 
patients.
The patient’s participation in the extension period will end after study drug(s) is discontinued.
The date and reason for treatment discontinuation will be collected on the CRF. Data will be 
collected until 30 days after the patient has been discontinued from study treatment and at this 
point, the patient will have ended the study. If the patient dies within the 30-day follow-up 
period, the reason for study discontinuation will be “Death”, and the cause and date of death 
recorded. Otherwise, the reason for study discontinuation will be noted as “Completed”. There
will be no long-term post-discontinuation follow-up period for these patients, unless any safety 
concerns have not resolved. Requests for updates on survival may occur. 
After the last of the patients in the extension period has completed their 30-day follow-up period, 
an addendum report will be written listing the details of data collected from patients entered in
this phase. The addendum report will not be delayed due to any patients continuing in long-term 
follow-up, but will note those patients still in long-term follow-up due to unresolved safety 
issues.
7.2.
Discussion of Design and Control
Part A of this open-label, multicenter, multi-country Phase 2 study of patients randomized to 
receive 1 of 2 doses of LY2157299 is an appropriate design for assessing antitumor activity and 
tolerability in an HCC patient population with no alternative therapy options, including patients 
who the investigator decides not to give sorafenib based on its toxicity profile, the condition of 
the patient, the institutional practice guidelines (see guidelines in Attachment 15), or other 
reasons that justify not administering sorafenib.
The requirement of including patients with elevated AFP (≥1.5 x ULN) in Part A is based on 
previous studies suggesting that patients with elevated AFP may also have increased levels of 
TGF-1 and thus have an activated TGF-pathway. The enrollment of patients with AFP <1.5 x 
ULN into Part B, will allow a comprehensive assessment of LY2157299 efficacy in all HCC 
patients. Patients will be enrolled into Part A or B based on the local AFP assessment.  For the 
final study assessment, the centrally collected AFP values will be used.  At enrollment, the local 
AFP value may be higher or lower than the centrally-assessed AFP values and this will not 
constitute a protocol violation. 
Part C will allow safety and efficacy assessment of LY2157299 combination with sorafenib as 
first-line treatment for HCC.  Sorafenib is the approved agent for first-line treatment of HCC.  
Part D will allow a safety assessment of LY2157299 in combination with ramucirumab.
Part E will allow assessment of the safety and tolerability, pharmacokinetics and efficacy of 
LY2157299 administered according to a 21 days on/7 days off schedule, as well as comparison 
of these endpoints to that observed in patients on the 14 days on/14 days off schedule.  At least 
approximately 20 patients must complete 21 days of therapy in order to have sufficient 
information to assess tolerability of the regimen.

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8.
Study Population
8.1.
Inclusion Criteria
[1]
Have histological evidence of a diagnosis of HCC not amenable to curative 
surgery.
[2]
Are Child-Pugh Class:
- Parts A and B:
A or B7 (see Attachment 5)
- Parts C and D: 
A
- Part E: A
[3]
Have serum AFP:
- Part A: ≥1.5x ULN
- Part B: <1.5x ULN
Criterion [3] applies for Parts A and B only.
[4]
Have the presence of measurable disease as defined by the RECIST 1.1 
(Eisenhauer et al. 2009) (see Attachment 8).  A lesion that has been previously 
treated by local therapy will qualify as a measurable or evaluable lesion if 
there was demonstrable progression following locoregional therapy.
[5]
Are age 18 years.
[6]
Have given written informed consent prior to any study-specific procedures.
[7]
Have adequate organ function including:
- Hematologic:  absolute neutrophil count (ANC) 1.5 x 109/L, 
platelets 50 x 109/L, and hemoglobin 8 g/dL.
- Hepatic:  bilirubin 2.5x ULN; alanine transaminase (ALT) and aspartate 
transaminase (AST) 5x ULN.  Prothrombin time (PT) international 
normalized ratio (INR) 2.3; or PT limit is 6 seconds above control
- Renal:  serum creatinine 1.5x ULN or calculated creatinine clearance 
(CrCL) >45 mL/min (see Attachment 9).
Note:  Small differences from the outlined laboratory values will be deemed 
as consistent with the protocol requirements provided that the following 
criteria are met:  are isolated, are transient, and are not reflective of a 
medical condition in the opinion of the investigator.  Such differences 
are often a result of biological or laboratory equipment variability.  To 
confirm that these results are within biological or laboratory equipment 
variability, repeat laboratory/hematological tests should be done prior to 
dosing the patient on Cycle 1 Day 1.

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[8]
Have a performance status of ≤1 on the Eastern Cooperative Oncology Group 
(ECOG) scale (see Attachment 3).
[9]
Have:
In Parts A and B:
- received sorafenib and have progressed or were intolerant to sorafenib, or
- are ineligible for sorafenib treatment (at the investigator’s discretion).
In Part C:  not received previous systemic treatment.
In Part D:  
- received sorafenib and have progressed or were intolerant to sorafenib, or
- are ineligible for sorafenib treatment (at the investigator’s discretion), or 
- have not received prior systemic treatment (at the investigator’s discretion).
In Part E: 
- received at least one prior line of systemic therapy, or
- not received prior treatment and are ineligible for sorafenib treatment (at the
investigator’s discretion).
[10] In Parts A, B, and D and E: have discontinued sorafenib for at least 2 weeks.
[11] Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[12] Males and females with reproductive potential must agree to use medically 
approved contraceptive precautions during the trial and for 3 months 
following the last dose of study drug.
[13] Females with childbearing potential must have had a negative serum 
pregnancy test 7 days prior to the first dose of study drug.
[14] Are able to swallow capsules or tablets.
8.2.
Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply:
[15] Are currently enrolled in, or discontinued within the last 28 days from, a 
clinical trial involving an investigational drug or device or not approved use of 
a drug or device, or concurrently enrolled in any other type of medical 
research judged not to be scientifically or medically compatible with this 
study.
[16] Known HCC with fibro-lamellar or mixed histology.
[17] Presence of clinically relevant ascites.

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[18] Liver transplant requiring increased immunosuppressive therapy.  (Patients on 
maintenance immunosuppressive therapy after liver transplant are eligible for 
Parts A and B.  Rapamycin analogues are not allowed.)
[19] Have received >1 line of systemic treatment in Parts A, B, and D.
[20] Have moderate or severe cardiac disease:
a) Have the presence of cardiac disease, including a myocardial infarction 
within 6 months prior to study entry, unstable angina pectoris, New York 
Heart Association Class III/IV congestive heart failure, or uncontrolled 
hypertension (see Attachment 11).
b) Have documented major ECG abnormalities at the investigator’s 
discretion (for example, symptomatic or sustained atrial or ventricular 
arrhythmias, second- or third-degree atrioventricular block, bundle-branch 
blocks, ventricular hypertrophy, or recent myocardial infarction).
c) Have major abnormalities documented by echocardiography with Doppler 
(for example, moderate or severe heart-valve-function defect and/or left 
ventricular ejection fraction [LVEF] <50%, evaluation based on the 
institutional lower limit of normal).  For additional details, refer to 
echocardiography protocol (see Attachment 12).
d) Have predisposing conditions that are consistent with development of 
aneurysms of the ascending aorta or aortic stress (for example, family 
history of aneurysms, Marfan Syndrome, bicuspid aortic valve, evidence 
of damage to the large vessels of the heart documented by computerized 
tomography [CT] scan with contrast).
[21] Have serious preexisting medical conditions that, in the opinion of the 
investigator, cannot be adequately controlled with appropriate therapy or 
would preclude participation in this study.
[22] Females who are pregnant or lactating.
[23] Have a history of any other cancer (except nonmelanoma skin cancer or 
carcinoma in situ of the cervix) unless in complete remission and off all 
therapy for that disease for a minimum of 3 years.
At the discretion of the investigator, hormone-refractory prostate cancer 
patients who are stable on GnRH agonist therapy and breast cancer patients 
who are stable on antiestrogen therapy (for example, an aromatase inhibitor) 
may have that treatment continued while they are enrolled in this study.
[24] Have active infection that would interfere with the study objectives or 
influence study compliance.
[25] For Part C, have a known hypersensitivity to sorafenib or its excipients.
[26] For Part D, have a serious illness or medical condition(s), including but not 
limited to the following:

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a) The patient has undergone major surgery within 28 days prior to randomization or 
has undergone central venous access device placement within 7 days prior to 
randomization.
b) The patient has uncontrolled arterial hypertension ≥150 / ≥90 mm Hg despite 
standard medical management.
c) The patient is receiving ongoing therapy with nonsteroidal anti-inflammatory 
agents (NSAIDs) (eg, indomethacin, ibuprofen, naproxen, nimesulide, celecoxib, 
etoricoxib, or similar agents) or other antiplatelet agents (eg, clopidogrel, 
ticlopidine, prasugrel, dipyridamole, picotamide, indobufen, anagrelide, triflusal, 
or similar agents).  Aspirin at dosages up to 100 mg/day is permitted.
d) The patient is receiving therapeutic anticoagulation with warfarin, 
low-molecular-weight heparin, or similar agents.  Patients receiving prophylactic, 
low-dose anticoagulation therapy are eligible provided that the coagulation 
parameters defined in the inclusion criteria are met.  
e) Uncontrolled thrombosis (including myocardial infarction, unstable angina, 
cerebrovascular accident, or transient ischemic attack within 6 months prior to 
randomization) or bleeding.
f)
The patient has experienced any Grade 3 or 4 gastrointestinal bleeding or any 
variceal bleeding episode in the 3 months prior to randomization requiring 
transfusion, endoscopic or operative intervention (patients with any bleeding 
episode considered life-threatening during the 3 months prior to randomization 
are excluded, regardless of transfusion or intervention status). Patients who have 
esophageal or gastric varices that require immediate intervention or represent a 
high bleeding risk in the opinion of the investigator or consulting 
gastroenterologist or hepatologist are excluded.
g) Elective or planned major surgery to be performed during the course of the 
clinical trial.
h) Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to 
randomization.
i)
Known allergy or hypersensitivity to monoclonal antibody treatment or any 
components used in the ramucirumab drug product preparation.
j)
The patient's urinary protein is >1+ on dipstick or routine urinalysis.  If urine 
dipstick or routine analysis indicates ≥2+ proteinuria, then a 24-hour urine must 
be collected and must demonstrate <1000 mg of protein in 24 hours to allow 
participation in the study.
k) The patient has either a history of or current hepatic encephalopathy or current 
clinically meaningful ascites.  Clinically meaningful ascites is defined as ascites 
resulting from cirrhosis and requiring ongoing treatment with diuretics and/or 
paracentesis.
8.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion Criterion [15] eliminates drugs that cannot be mapped to a standard drug dictionary or 
for which little data are known to analyze the potential relationship of AEs or drug interactions.

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Exclusion Criterion [20] excludes patients with compromised cardiac function that could be at 
risk when receiving LY2157299.  Based on the nonclinical toxicology assessment, patients with 
cardiac insufficiency or damage to large vessels of the heart will be carefully screened.  All 
moderate and severe cases of cardiac insufficiency will be excluded.  Because of the average age 
of most patients eligible for this study, mild or minimal cardiac disease is commonly present, and 
therefore these patients will not be excluded (Singh et al. 1999).  If CT scan of the chest cannot 
be performed, MRI can be used as an alternative imaging procedure.
Inclusion Criterion [14] ensures that patients are able to swallow the study medication 
LY2157299.
Exclusion Criterion [22] excludes patients who are pregnant or breast feeding.  This is 
appropriate as there are no data available that can provide safety estimates for fetal development 
or the impact of LY2157299 on infants.
Exclusion Criteria [23], [24], and [25] provide for patient safety.
Exclusion Criterion [26] incorporates exclusions for ramucirumab for Part D based on clinical 
experience.  
8.3.
Discontinuations
8.3.1. Discontinuation of Patients
The criteria for enrollment must be followed explicitly.  If a patient who does not meet 
enrollment criteria is inadvertently enrolled, that patient is discontinued from the study drug but 
can be allowed to continue in the study in order to provide the follow-up data needed for the 
analysis of the entire intention-to-treat (ITT) population.  An exception may be granted in rare 
circumstances because HCC patients have a serious or life-threatening condition for which there 
is no effective alternative therapy and, in the opinion of the investigator, is receiving benefit 
from study drug.  In these rare 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 drug in the following circumstances.

The patient has evidence of objective progressive disease (radiological 
assessments by RECIST v1.1 or mRECIST and/or is clinically symptomatic).  
The important decision in determining whether or not a patient can continue on 
study drug could be based on their clinical symptoms, even if the patient has 
progressive disease based on radiological evidence. The investigator may also 
take into consideration biomarker responses.

Enrollment in any other clinical trial involving use of an investigational product 
or enrollment in any other type of medical research judged not to be scientifically 
or medically compatible with this study.

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
The investigator decides that the patient should be withdrawn.  If this decision is 
made because of an SAE or a clinically significant laboratory value related to the 
study drug, the study drug is to be discontinued and appropriate measures are to 
be taken.  Lilly or its designee is to be alerted immediately.  

The patient requests that he/she be withdrawn from the study drug.

The study drug has shown unacceptable toxicity.

The patient becomes pregnant or fails to use adequate birth control (for women 
with reproductive potential).  

The patient is noncompliant with study procedures, including being noncompliant 
with respect to taking study drug (see Section 9 on compliance).

The patient for any reason requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication.  In 
this case, discontinuation from the study occurs prior to introduction of the new 
agent.

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 (GCP).
8.3.2. 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, or other reasons 
consistent with applicable laws, regulations, and GCP.
8.3.3. Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.

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9.
Treatment
9.1.
Treatments Administered
The investigator or his/her designee is responsible for explaining the correct use of the 
investigational agent to the patient, verifying that instructions are followed properly, maintaining 
accurate records of study-drug dispensing and collection, and returning or destroying all unused 
medication to Lilly or its designee at the end of the study as requested.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study drug so that the situation can be assessed.
Patients will keep a study diary to document that they are taking LY2157299 (Parts C, D and E)
and sorafenib (Part C only) correctly.
A treatment delay at the start of a cycle (Day 1) of no more than 3 days, because of holidays, 
weekends, inclement weather, or other justifiable events, will be permitted and not counted as a 
protocol violation.
9.1.1. Parts A and B
These parts involve characterization of 160 mg LY2157299/daily and 300 mg LY2157299/daily 
administered orally in Child-Pugh Class A or B7 HCC patients.  Table JBAK.3 shows the 
treatment regimens.
Table JBAK.3.
Treatment Regimens for Parts A and B
LY2157299
Daily Dose
Schedule
Time of Day
Part A (Cohort 1) 
80 mg BID LY
Daily
14 days on/14 days off
Morning and evening for 
14 days and then paused for 
14 days.
Part A (Cohort 2) and Part B
150 mg BID LY
Daily
14 days on/14 days off
Morning and evening for 
14 days and then paused for 
14 days.
Abbreviations:  BID = twice daily; LY = LY2157299; PK = pharmacokinetic.
Note:  For patients who will have a Day 15 PK sample taken, the evening dose on Day 14 will be omitted to allow 
for a 24-hour time period between the Day 14 morning dose and the Day 15 PK sample.
In extenuating circumstances, the ‘on study drug’ window is allowable from Day 10 to Day 14.  
9.1.2. Part C
Part C comprises a safety lead-in of 2 dose-escalation cohorts followed by an expansion phase 
with selected dose(s).  This part involves characterization of LY2157299 administered at either 
80 mg BID or 150 mg BID for 14 days followed by 14 days off and sorafenib 400 mg BID for 
28 days administered orally to Child-Pugh Class A HCC patients.  LY2157299 and sorafenib 
need to be taken at the same time, within a 15-minute window. A cycle is defined as 28 days. 
Table JBAK.4 shows the proposed dose levels and schedule for Part C.  

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Depending on the results from the safety lead-in cohorts and analysis from Parts A and B, the 
expansion cohort will consist of one of the following:

Single treatment group: LY2157299 80 mg BID on Days 1 to 14 in combination with 
sorafenib at 400 mg BID on Days 1 to 28 on a 28-day cycle, or

Single treatment group: LY2157299 150 mg BID on Days 1 to 14 in combination with 
sorafenib at 400 mg BID on Days 1 to 28 on a 28-day cycle, or

Two treatment groups: LY2157299 80 mg BID on Days 1 to 14 in combination with 
sorafenib at 400 mg BID on Days 1 to 28 versus LY2157299 150 mg BID on Days 1 to 
14 in combination with sorafenib at 400 mg BID on Days 1 to 28. Both cohorts will be
on a 28-day cycle.
This decision will be made by the sponsor. Patients enrolled in the safety lead-in cohorts may 
continue treatment as per that cohort.
Table JBAK.4.
Treatment Regimens for Part C
Daily Dose
Schedule
Time of Day
Safety lead-in Cohort 1 
80 mg BID LY
plus 
400 mg BID sorafenib 
Daily
14 days on/14 days off
Daily 
Morning and evening for 
14 days and then paused for 
14 days.
Take in the morning and 
evening with LY dose
Safety lead-in Cohort 2 
150 mg BID LY
plus 
400 mg BID sorafenib
Daily
14 days on/14 days off
Daily
Morning and evening for 
14 days and then paused for 
14 days.
Take in the morning and 
evening with LY dose 
Expansion cohort
Recommended LY 
dose(s) from safety 
lead-in
plus 
400 mg BID sorafenib
Daily
14 days on/14 days off
Daily
Morning and evening for 
14 days and then paused for 
14 days.
Take in the morning and 
evening with LY dose
Note:  For patients who will have a Day 15 PK sample taken, the evening dose on Day 14 will be omitted to allow 
for a 24-hour time period between the Day 14 morning dose and the Day 15 PK sample.
In extenuating circumstances, the “on study drug” window for LY2157299 is allowable from Day 10 to Day 14.
Abbreviations:  BID = twice daily; LY = LY2157299; PK = pharmacokinetic.
9.1.3. Part D
Part D comprises 2 dose-escalation cohorts and involves characterization of LY2157299 
administered at either 80 mg BID or 150 mg BID for 14 days followed by 14 days off and 
ramucirumab 8 mg/kg on Days 1 and 15 of each cycle administered as an IV infusion over 
approximately 60 minutes (maximum infusion rate: 25 mg/min).  On Day 1 of each cycle, 
LY2157299 should be taken within 30 minutes before the start of ramucirumab treatment.  

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LY2157299 should be taken mornings and evening approximately 12 hours apart; ramucirumab 
should be given in the mornings.
A cycle is defined as 28 days.  Table JBAK.5 shows the proposed dose levels and schedule for 
Part D.  
Table JBAK.5.
Treatment Regimens for Part D
Dose
Schedule
Time of Day
Cohort 1 
80 mg BID LY
plus 
8 mg/kg ramucirumab
Daily by oral administration
14 days on/14 days off
Days 1 and 15 each cycle by IV 
administration
(given over 60 min)
Morning and evening for 
14 days and then paused for 14 days.
On Day 1 of each cycle, morning within 
30 min of LY2157299 administration; on 
Day 15 of each cycle, morning
Cohort 2 
150 mg BID LY
plus 
8 mg/kg ramucirumab
Daily by oral administration
14 days on/14 days off
Days 1 and 15 each cycle by IV 
administration 
(given over 60 min)
Morning and evening for 
14 days and then paused for 14 days.
On Day 1 of each cycle, morning within 
30 min of LY2157299 administration; on 
Day 15 of each cycle, morning
Note:  For patients who will have a Day 15 PK sample taken, the evening dose on Day 14 will be omitted to allow 
for a 24-hour time period between the Day 14 morning dose and the Day 15 PK sample.
In extenuating circumstances, the on-study-drug window for LY2157299 is allowable from Day 10 to Day 14.
Abbreviations:  BID = twice daily; IV = intravenous; LY = LY2157299; min = minutes; PK = pharmacokinetic.
9.1.4. Part E
In Part E, LY2157299 will be administered orally at 150 mg BID for 21 days followed by 7 days 
off.  A cycle is defined as 28 days. Section 9.1.5.1 details the DLT criteria that will be used.
Table JBAK.6 shows the proposed dose level and schedule for Part E.  
Table JBAK.6.
Treatment Regimen for Part E
Dose
Schedule
Time of Day
LY2157299 150 mg BID Daily by oral administration
21 days on/7days off
Morning and evening for 
21 days and then paused for 7 days
Abbreviations:  BID = twice daily.
9.1.5. Criteria for Dose Escalation (Parts C and D)
Dose escalation will be driven by safety using the 3+3 method.  Both cohorts will have a 
minimum of 3 patients enrolled.  If 1 patient in either dose level experiences a DLT within the 
first cycle of LY2157299 and sorafenib or ramucirumab, then up to 3 additional patients will be 
enrolled at that dose level.  If a DLT is observed in 2 or more patients at either dose level in the 
first cycle, dose escalation will cease and either the previous dose level will be declared the 
maximum tolerated dose (MTD) or, following discussions between the sponsor and 

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investigators, additional patients may be treated at intermediate doses between the previous and 
current dose levels.
By nature of being a dose-escalation safety assessment, data will be evaluated on an ongoing 
basis until the MTD is determined, as defined in Section 9.1.5.1.  The maximum dose of 
LY2157299 will be 150 mg BID.  Safety data, in particular AEs, will be the primary criteria for 
the dose escalation.  The dose will be escalated following assessment of toxicity using the 
standard scoring system, CTCAE version 4.0, established by the National Cancer Institute (NCI).  
Any AEs related to LY2157299 or sorafenib (Part C) or ramucirumab (Part D) will be 
considered as toxicities.
In addition, if available at the time of dose-escalation decision, PK (eg, maximum plasma drug 
concentration, area under the curve, and apparent systemic clearance) results will be used as 
secondary/supporting data for dose escalation.
Additional patients may be enrolled at a specific dose level to characterize PK/PD.
Intermediate doses levels will be explored if deemed necessary after discussion between the 
sponsor and investigators.
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 
clinical research physician (CRP).  The decision will be documented in writing.
9.1.5.1.
Dose-Limiting Toxicity Determination and Maximum Tolerated Dose 
Definition (Parts C, D and E)
A DLT is defined as an AE during Cycle 1 in Cohorts 1 or 2 that is related to the LY2157299 
and sorafenib combination regimen in Part C, to the LY2157299 and ramucirumab combination 
regimen in Part D, or to LY2157299 administered on a 21 days on / 7 days off schedule in Part E
and fulfills any 1 of the following criteria using NCI CTCAE v 4.0:

CTCAE Grade 3 nonhematological toxicity.  Exceptions will be made for:

Nausea, vomiting, constipation, diarrhea ≤72 hours, or electrolyte 
disturbance that can be controlled with treatment or optimal supportive 
care

Transient (<7 days) Grade 3 elevations of ALT and/or AST, without 
evidence of other hepatic injury, in the setting of preexisting hepatic 
metastasis may not be considered a DLT if agreed by the study 
investigator and Lilly CRP/clinical research scientist

Hand-foot syndrome attributed to sorafenib only 

Hypertension attributed to sorafenib or ramucirumab only that cannot be 
adequately controlled

CTCAE Grade 4 hematological toxicity of >5 days duration

Any febrile neutropenia

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
Grade 3 or 4 thrombocytopenia with bleeding

Any other significant toxicity deemed by the primary investigator and Lilly 
clinical research personnel to be dose limiting (for example, any toxicity that is 
possibly related to the combination regimen that requires the withdrawal of the 
patient from the study during Cycle 1)
As a guidance of toxicity relationship for sorafenib, please refer to Attachment 16 (safety profile 
for sorafenib). 
For the purpose of this study, the MTD is defined as the highest tested dose in each part that has 
<33% probability of causing a DLT during Cycle 1.
As patients receive more cycles of treatment, investigators, together with the Lilly CRP, can 
declare a DLT-equivalent toxicity if a patient is experiencing increasing toxicity during treatment
in later cycles (ie, other than Cycle 1), and it becomes clear that it will not be possible to 
complete the treatment without exposing the patient to excessive risk.
Once the MTD has been defined, that dose level will be expanded in Parts C, D and E.  
If toxicities are observed in the first cycle that would meet the DLT criteria defined above for 
Cohorts 1 and 2 or DLT-equivalent toxicities occur in 33% or more of patients within the cohort 
expansions in Part C, D and E, then investigators and the Lilly CRP will assess the nature and 
severity of these toxicities.  The safety review and decision will be documented in writing.
9.2.
Selection and Timing of Doses
Room-temperature storage condition is recommended for both the tablet drug products.  The 
tablets should remain in the primary packaging until just prior to administration.
At the discretion of the investigator, if a patient vomits within 30 minutes of taking a dose of 
LY2157299, the LY2157299 dose should be repeated 1 time only that same day, if 
nausea/vomiting permits.
LY2157299 and sorafenib (for Part C) should be taken at approximately the same time every 
day.  Patients should take the agent preferably 1 hour before breakfast and 1 hour before dinner.
For Part D and Part E, LY2157299 should be taken mornings and evening approximately 12 
hours apart.  Patients should take the agent preferably 1 hour before a meal.
In Part D, ramucirumab should be given in the mornings.  On Day 1 of each cycle, LY2157299 
should be taken within 30 minutes before the start of ramucirumab treatment.  
Tablets should be swallowed whole and not split, crushed, or dissolved for administration.  
9.3.
Materials and Supplies
9.3.1. LY2157299
LY2157299 will be provided as tablets in blister packs.  All materials must be stored at room 
temperature within temperature range specified on the material label.  The material will be 

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labeled according to regulatory requirements of the country.  Should the type of clinical trial 
material packaging change, it will adhere to country-specific regulations.  
The tablet should remain in the blister pack until just prior to administration.
9.3.2. Sorafenib
Sorafenib will be supplied in commercially available dosage forms and provided according to the 
country’s regulatory requirements.
9.3.3. Ramucirumab
Ramucirumab will be supplied in commercially available dosage forms and provided according 
to the country’s regulatory requirements.
9.4.
Method of Assignment to Treatment
In Part A, patients who meet all criteria for enrollment will be randomized to receive 1 of 2 doses 
of LY2157299 after completing the screening at Visit 0.  Assignment to dose cohorts will be 
determined by a computer-generated random sequence using an interactive voice response 
system (IVRS).  The randomization method used should result in approximately equal numbers 
of patients in each dose cohort (no more than a difference of 4 patients between the 2 dose 
cohorts at any planned analysis while enrollment into both cohorts occurs).  To achieve 
between-cohort comparability for stratification factors, the randomization should ensure as much 
balance as possible between AFP levels (≤400 ng/mL and >400 ng/mL), etiology (alcohol, viral 
hepatitis, other), and whether sorafenib naive or not, both at interim (after 20 and 80 patients 
have been randomized) and final analyses, the order of priority being as listed.  It is important to 
implement a system such that treatment of eligible patients is not delayed.  
The decision to stop enrolling into Cohort 1 was made based on the results from the additional 
data review. The remaining patients that were to be assigned to Cohort 1 (until 70 patients have 
been treated) who have elevated AFP levels and who meet all criteria for enrollment will be 
assigned by the IVRS to receive the LY2157299 300-mg/day dose (ie, transferred to Cohort 2)
after completing the screening at Visit 0.  
In Part B, patients who have a AFP level <1.5x ULN and who meet all criteria for enrollment 
will be assigned by the IVRS to receive the LY2157299 300-mg/day dose after completing the 
screening at Visit 0.
Enrollment into Part B will continue during the interim analysis of Part B.
In Part C, patients who have not received prior systemic treatment and who meet all criteria for 
enrollment will be assigned by the IVRS to receive either the LY2157299 80 mg BID or the 
LY2157299 150-mg BID dose after completing the screening at Visit 0.
In Part D, patients who meet all criteria for enrollment will be assigned by the IVRS to receive 
either the LY2157299 80-mg BID or the LY2157299 150-mg BID dosage after completing the 
screening visit.

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In Part E, patients who have received at least one prior line of systemic therapy or who have not 
received prior treatment and are ineligible for sorafenib treatment (at the investigator’s 
discretion) and who meet all criteria for enrollment will be assigned by the IWRS to receive 
LY2157299 150 mg BID dosage after completing the screening visit.
The IVRS will be used to assign LY2157299 clinical trial material (eg, blister packs) containing 
study drug to each patient.  Site personnel will confirm that they have located the correct clinical 
trial material by entering a confirmation number found on the packaging into the IVRS.  
9.5.
Dose Adjustments
9.5.1. LY2157299
If a patient experiences any of the following events that are considered possibly related to 
LY2157299, LY2157299 will be omitted until the event resolves:
ANC <0.5 x 109/L for longer than 7 days, or ANC <1.0 x 109/L with a single 
temperature of >101F/38.3C or a sustained temperature of >100.4F/38C for 
more than 1 hour or platelet count <25 x 109/L
CTCAE Grade 3 or 4 nonhematologic toxicity
Nonhematological toxicity must resolve to CTCAE Grade 0, 1, or baseline (with the exception of 
alopecia, fatigue, skin rash, nausea, vomiting, constipation, or diarrhea that can be controlled 
with treatment).  
Hematologic toxicity must resolve to a level that, in the opinion of the investigator, is reasonable 
to allow for continuation of treatment.  
If dosing is delayed for more than 2 weeks, the patient should be withdrawn from the study.  
For Parts A and B, patients who do recover within the 2-week time frame may have the dose 
reduced to 160 mg for 300-mg dose arm and to 100 mg for 160-mg dose arm.
For Parts C and D: in case of a dose delay of LY2157299, patients can continue sorafenib or 
ramucirumab treatment (at investigator discretion).
For Part E, patients who do recover within the 2-week time frame may have the dose reduced to 
160 mg or their schedule altered after discussion between the investigator and Lilly CRP. 
No patient will have his/her dose reduced more than once.  Re-escalation to the previous dose is 
acceptable in the absence of continuing or cardiac toxicities.  If subsequent dose reduction is 
required after re-escalation, the patient must be maintained at the reduced dose level for all 
remaining cycles.  
If moderate or severe heart valve toxicities are observed, the patient must immediately be 
discontinued from the treatment (for definitions see Attachment 12, including references on the 
echocardiographic assessment based on the Guidelines of the American and European Societies 
of Cardiac Echocardiography).  Exceptions to this rule must be approved by the ERBs.

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9.5.2. Sorafenib
Doses will be delayed or reduced for clinically significant hematologic and other toxicities 
(Table JBAK.7; see Table JBAK.8 for modifications due to skin toxicity) that are related to 
sorafenib. In case of a dose delay of sorafenib, patient can continue LY2157299 treatment (at 
investigator discretion).  
When dose reduction is necessary, sorafenib dosage may be reduced using the predefined dose 
levels:  

Dose level 1 (no reduction): 400 mg (2 x 200 mg) administered orally BID daily

Dose level 2: 400 mg (2 x 200 mg) daily

Dose level 3: 400 mg (2 x 200 mg) every other day

If further dose reduction is required, the patient should be discontinued from the study.  
At the discretion of the investigator, the dose may be re-escalated to the previous dose level
400 mg BID after the resolution of the AE.
Table JBAK.7.
Sorafenib Dose Modifications for Hematologic and 
Nonhematologic Toxicities
Grade
Dose Delay
Dose Modification
Hematologic toxicities
Grade 0-2
Treat on time
No change
Grade 3
Treat on time
Decrease 1 dose level
Grade 4
Delaya until Grade 2
Decrease 1 dose level
Nonhematologic toxicities (except skin toxicity)b
Grade 0-2
Treat on time
No change
Grade 3
Delaya until Grade 2
Decrease 1 dose levelc
Grade 4
Off protocol therapy
Off protocol therapy
Source: Llovet et al. 2008 supplementary material.
a
If no recovery after 30-day delay, treatment will be discontinued unless patient is deriving clinical benefit.
b
Also excludes nausea/vomiting that has not been premedicated, and diarrhea.
c
If >2 dose reductions are required, treatment will be discontinued.

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Table JBAK.8.
Suggested Sorafenib Dose Modifications for Skin Toxicity
Skin Toxicity Grade
Occurrence
Suggested Dose Modifications
Grade 1:  Numbness, dysesthesia, 
paresthesia, tingling, painless 
swelling, erythema or discomfort of 
the hands or feet that does not 
disrupt the patient’s normal 
activities
Any occurrence
Continue treatment with sorafenib and 
consider topical therapy for symptomatic 
relief
Grade 2:  Painful erythema and 
swelling of the hands or feet and/or 
discomfort affecting the patient’s 
normal activities
1st occurrence
Continue treatment with sorafenib and 
consider topical therapy for symptomatic 
relief.  If no improvement within 7 days, see 
below
No improvement within 
7 days or 2nd or 3rd 
occurrence
Interrupt sorafenib treatment until toxicity 
resolves to Grade 0-1.  When resuming 
treatment, decrease sorafenib dose by 1 dose 
level (400 mg daily or 400 mg every other
day)
4th occurrence
Discontinue sorafenib treatment
Grade 3:  Moist desquamation, 
ulceration, blistering or severe pain 
of the hands or feet, or severe 
discomfort that causes the patient to 
be unable to work or perform 
activities of daily living
1st or 2nd occurrence
Interrupt sorafenib treatment until toxicity 
resolves to Grade 0-1.  When resuming 
treatment, decrease sorafenib dose by 1 dose 
level (400 mg daily or 400 mg every other 
day
3rd occurrence
Discontinue sorafenib treatment
Source:  FDA, 2011 (sorafenib prescribing information).  
Suggested Management of Hypertension (adapted from Izzedine et al. 2009)

Blood pressure should be checked regularly on sorafenib therapy. Hypertension should 
be managed in accordance with standard medical practice for sorafenib individualized to 
the patient's clinical circumstances (refer to local institutional guidance, other available 
guidelines, or Izzedine et al. 2009).

For hypertension >140/90 and ≤160/100: Continue sorafenib.  Consider adding or 
adjusting anti-hypertensive medications.

For persistent (>160/100) or symptomatic hypertension: Interrupt sorafenib.  Resume 
when blood pressure improves to ≤160/100. If persistent hypertension with optimal 
treatment consider decrease sorafenib by 1 dose level.

In case of hypertension crisis (Grade 4), sorafenib should be withheld.
9.5.3. Ramucirumab
Doses will be delayed or reduced for clinically significant toxicities that are related to 
ramucirumab.  In case of a dose delay of ramucirumab, patients can continue LY2157299 
treatment (at the investigator’s discretion).  

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9.5.3.1.
Infusion-Related Reactions
Reduce the ramucirumab infusion rate by 50% for the duration of the infusion and all subsequent 
infusions if the patient experiences a Grade 1 or 2 infusion-related reaction (IRR) (per the NCI 
CTCAE). Premedication is recommended with an IV histamine H1 antagonist (eg, 
diphenhydramine) prior to administration of ramucirumab.
If a patient experiences a Grade 1 or 2 IRR, premedication must be given for all subsequent 
infusions. If a patient has a second Grade 1 or 2 IRR, administer dexamethasone (or equivalent); 
then, for subsequent infusions, premedicate with the following or equivalent medications: 
diphenhydramine hydrochloride (intravenously), acetaminophen, and dexamethasone.
Immediately and permanently discontinue ramucirumab for Grade 3 or 4 IRRs.
9.5.3.2.
Hypertension
Monitor blood pressure during treatment with ramucirumab and treat as clinically indicated. 
Temporarily suspend ramucirumab for severe hypertension until controlled with medical 
management.
9.5.3.3.
Proteinuria
Monitor for the development or worsening of proteinuria during ramucirumab therapy. If the 
urine protein level is ≥2+, perform a 24-hour urine collection. Temporarily discontinue 
ramucirumab administration if the urine protein level is ≥2 g/24 hours. Resume treatment at a 
reduced dose level (see Table JBAK.9) once the urine protein level returns to <2 g/24 hours. A 
second dose reduction (see Table JBAK.9) is recommended if a urine protein level ≥2 g/24 hours 
reoccurs.
Permanently discontinue ramucirumab therapy if the urine protein level is >3 g/24 hours or in the 
setting of nephrotic syndrome.
Table JBAK.9.
Ramucirumab Dose Reductions for Proteinuria
Initial Ramucirumab 
Dose
First Dose Reduction 
to:
Second Dose Reduction 
to:
8 mg/kg
6 mg/kg
5 mg/kg
9.5.3.4.
Hepatic Encephalopathy
In the case of a new occurrence of hepatic encephalopathy and/or hepatorenal syndrome, 
ramucirumab will be discontinued.  
9.6.
Continued Access to Study Drug
Because LY2157299 is an investigational agent, patients cannot receive LY2157299 without 
being in a clinical trial. Ramucirumab is commercially available for other indications, but 
patients with HCC cannot receive ramucirumab without being in a clinical trial. Sorafenib is 
commercially available within the studied indication and will not be provided by the Sponsor 
outside of this clinical trial.

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9.7.
Blinding
This is an open-label study.
9.8.
Concomitant Therapy
No other anticancer therapy, immunotherapy, hormonal cancer therapy, or experimental 
medications will be permitted while the patients are participating in this study. Palliative 
radiation therapy to nontarget lesions is allowed.  Any disease progression requiring other forms 
of specific antitumor therapy will be cause for early discontinuation of study therapy.
Immunosuppressive agents for patients who have received a liver transplant are allowed if the 
patient is receiving these drugs as a maintenance treatment after transplant (Perry and Neuberger 
2005).  Rapamycin analogues are not allowed.
During the first-in-human Study JBAH, patients received EIAEDs, such as carbamazepine, 
phenobarbital, or phenytoin.  No apparent drug-drug interaction has been observed, consistent 
with the nonclinical absorption, distribution, metabolism, excretion (ADME) properties of this 
agent.  
When sorafenib is administered, avoid concomitant use of strong CYP3A4 inducers (such as, 
carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, rifabutin, St. John’s wort), 
when possible, because inducers can decrease the systemic exposure to sorafenib. Warfarin is 
not recommended in coadministration with sorafenib.
For Part D, patients may not receive chronic antiplatelet therapy, including NSAIDs (eg, 
indomethacin, ibuprofen, naproxen, nimesulide, celecoxib, etoricoxib, or similar agents) or other 
antiplatelet agents (eg, clopidogrel, ticlopidine, prasugrel, dipyridamole, picotamide, indobufen, 
anagrelide, triflusal, or similar agents). Patients receiving therapeutic anticoagulation with 
warfarin, low-molecular-weight heparin, or similar agents are excluded from participation.  
Anticoagulant therapy may be instituted during the course of treatment on study (following an 
asymptomatic or treatable deep vein thrombosis or pulmonary embolism), provided that no 
evidence of portal hypertension (including splenomegaly) or any prior history of variceal 
bleeding exists.  Aspirin at dosages up to 100 mg/day is permitted.
9.9.
Treatment Compliance
Patient compliance with study medication will be assessed at each visit.  Compliance will be 
assessed by direct questioning, review of diary, and counting returned tablets.  Deviations from 
the prescribed dosage regimen should be recorded in the “Study treatment:  modifications” form.  
For patients who are significantly noncompliant (<80% or >120% of expected study drug taken 
in a visit interval), investigative sites must counsel patients on the importance of study drug 
compliance and drug accountability.  Patients who are consistently out of the compliance range 
may be discontinued.  A Lilly representative should be contacted upon the second instance of 
treatment noncompliance.
The following procedures will be employed to assure appropriate drug accountability:

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
Drug accountability will be emphasized at the start-up meeting.

Drug accountability will be monitored throughout the study.

Each patient should be instructed to return all study-drug packaging and unused 
material to the study site at each visit.  The study site will keep a record of all 
drug dispensed to and returned by the patients throughout the study.  Study site 
personnel will return or destroy (as requested) all unused study drug for all 
patients.

Patients will keep a study diary to document that they are taking LY2157299 and 
sorafenib (if applicable) correctly.
Ramucirumab in Part D will be administered intravenously at the investigational site, under the 
direction of the investigator.  As a result, a patient’s compliance with study drug administration 
is ensured.  

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10. Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing (Standard 
Laboratory Testing, Pharmacokinetics, Biomarker 
Analysis), and Appropriateness of Measurements
Refer to the Study Schedule in Attachment 1 for study procedures and their timing.
Terms used to describe the study periods are defined below:

Baseline/Visit 0:  From the time of screening to first study treatment (or 
discontinuation, if no treatment is given)

Treatment Start:  First day of study treatment

Study Treatment Period:  Time from treatment start to discontinuation from 
study treatment

Discontinuation from Study Treatment:  The day the patient discontinues study 
treatment (summary visit)
•
Applies to patients in extension period, too

Postdiscontinuation from Study Drug 30-day Follow-up Period:  The time 
after the patient discontinues study treatment during which follow-up data are 
collected.  Visit 801 starts 1 day after discontinuation from study treatment and 
lasts 30 days (±3 days).
•
Applies to patients in extension period, too. However, for patients in the 
extension period, the end of the 30-day follow-up period is also the end of 
their study participation (unless further follow-up is required for safety 
reasons).

Long-Term Follow-up Period:  All subsequent long-term follow-up visits will 
occur at 60-day intervals (7 days) (for example, Visit 802, Visit 803, etc.) until 
the patient meets the requirements to discontinue from the study.  These are the 
preferred windows for follow-up visits (Visit 802 and beyond); however, if some 
information cannot be obtained at all or not within the specified window for Visit 
802 and beyond, it will not result in a protocol violation if no cardiac toxicity
requiring further cardiac monitoring was observed at V801.
•
Not required for patients in extension period (unless required for safety 
follow-up)
10.1. Efficacy Measures
All patients will be followed for progression and OS.  Patients who come off therapy due to 
objective progressive disease will be followed for survival every 2 months. From 
Amendment (b), patients may continue on study treatment even if they have objective 
progression if they are clinically asymptomatic (see Section 8.3). However, it is important that 
the cycle response records objective progressive disease in the cycle that it occurred in order to 

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estimate time to tumor progression, progression free survival, and response rate without bias.
These patients will then be discontinued from study treatment because of overall symptomatic 
deterioration (including biomarker response) or other causes. Patients who come off therapy and 
do not have objective progressive disease should be followed every 2 months after 
discontinuation from study treatment until death, including 6-weekly radiologic examinations
until objective progressive disease is determined (using the same radiological scans as at 
baseline). Patients who progress should then be followed for survival every 2 months.  Every 
attempt should be made to gather all information every 2 months (radiological scans and 
survival), even if a patient starts a new anticancer therapy.  Evaluation of survival can be 
accomplished by telephone contact if necessary.  The date any new anticancer therapy starts, 
either during the 30-day poststudy drug discontinuation period or long-term follow-up periods, 
needs to be collected.  This will enable a better estimate of time-to-event data to inform future 
decisions in this indication as it will be based on more mature data.
It is important that protocol procedures related to collection of these data, both during the active 
study treatment phase and follow-up period, are followed and that dates of data collection are 
recorded accurately.
10.1.1. Clinical Efficacy Measures
The clinical efficacy endpoint of this study is to determine the TTP for each patient. 
The primary method used for objective progressive disease is determined by RECIST 1.1 
(see Attachment 8), but is also assessed by mRECIST (RECIST modified for HCC) (see 
Attachment 15).  
Please note:  The mRECIST assessments should be performed according to the guidelines 
recommended by the American Association for the Study of Liver Diseases-Journal of the 
National Cancer Institute, AASLD-JNCI (Lencioni and Lovett 2010).  
Each patient will be assessed by 1 or more of the following radiologic tests for tumor 
measurement at the times specified in the Study Schedule (Attachment 1):  CT scan or MRI.  In 
addition, for final study report analyses, a central review of all radiographic examinations will be 
conducted, and assessments of progression will be based on RECIST 1.1 and if applicable 
mRECIST.
Other clinical efficacy measures include other time-to-event variables and also RRs that will be 
determined by both RECIST 1.1 and mRECIST; although, the primary method will be RECIST 
1.1.  
Radiological assessments will be collected at the times shown in the Study Schedule. MRI 
and/or CT scans will be collected and stored centrally; if necessary, independent review of all or 
a representative sample of scans may be considered following study completion.
Changes in biomarkers’ (collected as specified in the schedule of events and detailed in 
Section 10.3.3) response are measures of progressive disease response, and the relationship to 
clinical efficacy measures will be explored.  These biomarkers are further defined in 
Section 12.2.3.

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Health Outcome/Quality of Life Measures 
The assessment of PROs, including disease-specific symptoms and health-related quality of life 
(HRQoL), will be assessed using the FACT-Hep (Attachment 10).  
The FACT-Hep is a validated and reliable self-administered questionnaire with 45 items, which 
includes the 27-item FACT-G to assess general HRQoL and an 18-item hepatobiliary section 
with disease specific issues (Heffernan et al. 2002).  FACT subscales, total score, trial-outcome 
index, and symptoms (Focal High Signal Intensity 8 [FHSI-8]) will be assessed.  The FHSI-8 has 
a specific focus regarding the most frequent and concerning symptoms experienced by patients 
with hepatobiliary malignancies (jaundice, stomach pain/discomfort) and some that are 
associated with generalized advanced/metastatic malignancy (weight loss, fatigue) (Yount et al. 
2002; Cella et al. 2000).  These items were selected based on relative clinical importance ratings 
provided by a multinational group of 95 hepatobiliary cancer specialists.  
The FACT-Hep will be administered at baseline, at every cycle starting from Cycle 2, and at 
discontinuation (see Study Schedule for details [Attachment 1]).
Patient-reported outcomes (PROs) instruments should be completed at the beginning of office 
visits, before any extensive contact and consultation with the clinician/study investigator or staff.  
Consultation with the clinician may bias perceptions about quality of life and symptoms and thus 
affect assessments.
The FACT-Hep will only be completed by patients for whom there is a validated translation in 
which the patient is fluent.
10.2. 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.
10.2.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.
Lack of drug effect is not an AE in clinical trials because the purpose of the clinical trial is to 
establish drug effect.

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Cases of pregnancy that occur during maternal or paternal 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 preexisting 
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 in the electronic case 
report form (eCRF) 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 via eCRF.
In addition, all AEs occurring after the patient receives the first dose of study drug must be 
reported to Lilly or its designee via eCRF.
Any clinically significant findings from ECGs, labs, vital-sign measurements, other procedures, 
and so on that result in a diagnosis should be reported to Lilly or its designee via eCRF.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, studied disease state, study drug, and/or drug 
delivery system via eCRF.
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 eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
Events leading to the clinical outcome of death due to progressive disease will be included as 
part of the safety and efficacy analyses for this study and will not be reported to Lilly or its 
designee as AEs via eCRF, unless the investigator believes the event may have been caused by 
the study drug or drug delivery system.
10.2.1.1. Serious Adverse Events
Serious adverse event (SAE) 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.
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.

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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.  An SAE is any AE from this study that results in one of the following outcomes:

death 

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

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 or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.
Serious adverse events (SAEs) occurring after a patient has taken the last dose of study drug will
be collected for 30 days after the discontinuation from study treatment, regardless of the 
investigator’s opinion of causation.  Thereafter, SAEs are not required to be reported unless the 
investigator feels the events were related to either study drug, or drug delivery system, or a 
protocol procedure.
Any SAE occurring prior to enrollment that the investigator believes may have been caused by a 
protocol procedure must be reported to Lilly or its designee within 24 hours of investigator 
awareness of the event and recorded on the eCRF.
Study-specific clinical outcomes of death from progressive disease should be reported as SAEs 
only if the investigator deems them related to use of the study drug.
10.2.2. Summary of Adverse Event/Serious Adverse Event Reporting 
Guidelines
Table JBAK.10 presents the reporting schedule for AEs and SAEs.  

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Table JBAK.10.
Assessment Guide for Adverse Events and Serious Adverse 
Events
Timing
Types of AEs/SAEs Reported
Prestudy 
(Starts at the signing of informed consent 
and ends at the first dose of study drug)

Preexisting conditions

All AEs/SAEs (except for patients who do NOT enroll). For 
enrolled patients, only AEs/SAEs related to protocol 
procedures should be reported.
On therapy
(Starts at first dose of study drug[s] and 
ends at last dose of study drug[s])

All AEs and clinically significant lab values regardless of 
relatedness

All SAEs regardless of relatedness (except death due to 
progressive disease unless the investigator also deems there to 
be a possible contribution related to study drug)
Initial follow-up Visit (V801)
(Starts at discontinuation from study 
treatment and ends when end of study safety 
assessments are completed [30 days, ±3 
days, after discontinuation from study 
treatment]) 

All AEs and clinically significant lab values regardless of 
relatedness

All SAEs regardless of relatedness (except death due to 
progressive disease unless the investigator also deems there to 
be a possible relation with study drug)
Subsequent follow-up visits, if necessary

Ongoing or new AEs/SAEs possibly related to study drug(s) 
or protocol procedures
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
10.2.3. Electrocardiography
For each subject, 12-lead digital ECGs will be obtained as single ECGs according to the Study 
Schedule (Attachment 1).  Patients must be supine for approximately 5 to 10 minutes before 
ECG collection and remain supine during ECG collection.  ECGs 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.
ECGs 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 patient is still 
present, to determine whether the patient meets entry criteria and for immediate patient 
management, should any clinically relevant findings be identified.
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) and to determine if the patient can continue in the study.  The investigator or 
qualified designee is responsible for determining if any change in patient management is needed 
and must document his/her review of the ECG printed at the time of evaluation.
All digital ECGs will be electronically transmitted to a central ECG laboratory designated by 
Lilly.  A cardiologist at the central ECG laboratory will then conduct a full overread on the ECG 
(including all intervals); a report based on data from this analysis will be issued to the 
investigative site.  All data from the overreads will be placed in the Lilly database for analytical 
and study-report purposes.

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It is recognized that ECG interpretations by the investigator (or qualified designee) and by the 
cardiologist at the central ECG laboratory may be different.  When there are differences in ECG 
interpretation between the investigator (or qualified designee) and the cardiologist at the central 
ECG laboratory, the investigator (or qualified designee) interpretation will be used for study 
entry and immediate subject management.  Interpretations from the cardiologist at the central 
ECG laboratory will be used for data analysis and report-writing purposes.
The investigator (or qualified designee) must document his/her review of the ECG printed at the 
time of evaluation, the final overread ECG report issued by the central ECG laboratory, and any 
alert reports.
Other safety measures include assessments of physical examinations, preexisting conditions, 
transfusions and hospitalizations, and AEs.  Patients will be assessed before each visit by using 
the CTCAE v4.0.
10.2.4. Echocardiograms with Doppler and Chest CT Scans
Because of the cardiotoxicity monitoring in this study, echocardiographs with Doppler and chest 
CT scans are being performed (see Attachment 1, Attachment 12, and Attachment 13).  
Echocardiography with Doppler will be locally assessed at screening for enrollment and 
throughout the study according to the Study Schedule (Attachment 1) for safety decisions by a 
physician or a person who is qualified by experience or training.  The individual must be 
identified at each site.  A central reading will be performed for the data used in the study report.  
Chest CT scan with contrast of thorax and abdomen to evaluate the large vessels of the heart will 
be locally assessed at screening for enrollment and throughout the study according to the 
schedule of events (Attachment 1) for safety decisions by a physician or a person who is 
qualified by experience or training.  Alternatively, chest and/or abdomen MRI are allowed.
If the patient has clinically significant cardiac findings at discontinuation (Visit 801), 
echocardiography, ECG and ECG chemistry will be repeated every 2 months for 6 months 
(Visits 803, 804, and 805).
If there are no clinically significant cardiac findings at discontinuation (Visit 801), 1 more 
echocardiography, ECG, and ECG chemistry will be performed after 2 months (Visit 802).  If a 
patient receives another treatment, Visit 802 cardiac assessments will not be performed.
The monitoring described in the above 2 paragraphs also applies to patients in the extension 
period.  Therefore, for these cases, the patient does not discontinue from the study at the end of 
the 30-day follow-up period but after the cardiac findings have either resolved or, if not resolved 
after 6 months, after discussions between the Lilly CRP and investigator.
10.2.5. 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 is appropriate, consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical scientist and review trends and laboratory analytes.  
10.2.6. 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 concomitant drugs/drug delivery systems are reported directly to the 
manufacturers of those drugs/devices in accordance with the package insert.
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.
10.3. Sample Collection and Testing
Protocol JBAK Study Schedule (Attachment 1) lists the schedule for the specific tests performed 
for this study.  With the exception of samples for PK testing, all samples should be collected 
prior to the LY2157299 dose unless otherwise specified in Attachment 1 or Attachment 4.  In 
extenuating circumstances, blood can be drawn up to 3 days before Day 1, but the appropriate 
central laboratory kit for the respective new visit must be used.
10.3.1. Samples for Standard Laboratory Testing
Standard laboratory tests, including chemistry, hematology, and urinalysis panels, will be 
performed.  A serum pregnancy test will be performed (if applicable).  Other clinical laboratory 
tests will be analyzed by central and local laboratories.  Protocol JBAK Clinical Laboratory 
Tests (Attachment 2) lists the specific tests that will be performed for this study.  Patient 
eligibility is based on local laboratory results only, unless the investigator chooses to use the 
central laboratory for such a purpose.  Central laboratory results are used for study report 
purposes and where appropriate for safety analyses.
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.  Certain samples may be retained for a longer period, if necessary, to 
comply with applicable laws, regulations, or laboratory certification standards.

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10.3.2. Samples for Drug Concentration Measurements -
Pharmacokinetics/Pharmacodynamics
Sparse samples for PK evaluation will be collected from all patients in the study as indicated in 
Attachment 4.  The actual time of dosing on the day of sampling and the actual time of sampling 
for each of the samples must be collected.  Dose information (dose time and amount of dose) 
must be collected for the day of sampling and the 2 days prior to the sampling day.  This 
information can be obtained from the patient at the visit for blood sampling.
The sampling times in the schedule are approximate and the actual sampling time should be 
recorded.  Instructions for the collection and handling of blood samples will be provided by the 
sponsor.
Plasma samples will be analyzed for LY2157299 using a validated method.
Bioanalytical samples collected to measure study-drug concentration will be retained for a 
maximum of 2 years following last patient visit for the study.
Additional samples will be collected for progressive disease analysis as indicated in 
Attachment 1.
For Cycle 1 safety assessment during the Part C safety lead-in cohorts, PK samples for both 
LY2157299 and sorafenib will be collected on Days 1 and 14.  One morning PK sample 
(Day 15) will then be taken to evaluate the elimination-phase kinetics of LY2157299 during the 
nondosing phase of Cycle 1 (see Attachment 4). On Days 22 and 23, PK samples will be taken 
for evaluation of whether there was any change in sorafenib PK profile after monotherapy 
compared with sorafenib in combination with LY2157299.  In Cycle 2, sparse PK sampling for 
LY2157299 and sorafenib will be performed as indicated in Attachment 4. From Cycle 3 
onwards, only predose Day 1 samples will be taken.
For Cycles 1 and 2 safety assessments during Part D, PK samples for LY2157299 will be 
collected on Days 1, 14 and 15, and samples for ramucirumab will be collected on Days 1 and 
15.  One morning PK sample (Day 15 before ramucirumab dosing) to evaluate the elimination-
phase kinetics of LY2157299 during the nondosing phase of Cycles 1 and 2 and one 
ramucirumab PK sample at end of infusion will be taken.  From Cycle 3 onwards, only predose 
Day 1 samples will be taken.  
For Part E, PK samples for LY2157299 will be collected on Days 1, 21 and 22 (Attachment 4).
10.3.3. Samples for Biomarker Analysis
10.3.3.1. Pharmacogenomic Evaluations
There is growing evidence that deoxyribonucleic acid (DNA) variation may impact a patient’s 
response to therapy.  Variable response to therapy may be due to genetic determinants that 
impact drug ADME, 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 

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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 HCC and targets related to LY2157299 and other administered medicines including, but not 
limited to, genetic changes associated with metabolism and response genes to evaluate their 
association with observed response to LY2157299.  
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 
LY2157299.  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.
The sample 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.  
Blood samples will be collected at the times specified in the Study Schedule (Attachment 1).  
Supplies required for the collection, handling, and shipment of the patients’ samples will be 
provided by the sponsor.  Samples will be stored at a facility selected by the sponsor in the US.  
Collection of a blood sample for genetic testing is a mandatory part of this study where local 
regulations allow.  The blood sample for pharmacogenomics evaluation will be a 1-time 
collection unless the sample does not yield adequate DNA for use.  It is recommended that the 
blood sample be taken at the baseline visit but may be taken at any time while the patient is 
participating in the clinical study.  Genes related to safety, efficacy, PK, and/or the mechanism of 
action of LY2157299 may be tested.  Patients will not have the option to request test results and 
will not receive the genetic test results.
10.3.4. Nonpharmacogenetic Biomarker Evaluation and Patient 
Tailoring
10.3.4.1. Sample Requirements and Preparation
Collection of samples for biomarker research is required for this study.  Refer to the Study 
Schedule (Attachment 1) for timing of sample collection.
The research on stored samples from this study may look at the proteins or other biochemical 
markers to learn more about compound-specific disease states or how patients respond to or 
tolerate treatment with LY2157299 or other compounds/medications administered during this 
study.  Stored samples may also be used in validating diagnostic tools or assay(s) related to 
patient tailoring and disease state.  
At baseline, before the patient receives study drug, the following samples will be collected:

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
pretreatment formalin-fixed paraffin-embedded (FFPE) tumor tissue taken from 
the original diagnostic tumor specimen if available (paraffin blocks or 
approximately 10 unstained slides cut from that block, for correlation studies of 
molecular markers

optional tumor biopsy 

plasma
At Cycle 1, the following samples will be collected:

plasma
At Cycle 2, an optional tumor biopsy will be collected.
After Cycle 2, at the time of disease progression and only if the patient is on study therapy, the 
following samples will be collected:

plasma
10.3.4.2. Sample Labeling
All samples will be labeled with the same identification code assigned to the patient.  This code 
will be used in lieu of the patient’s name to protect the patient’s identity.
Blood, serum, and plasma samples must be collected and shipped according to instructions 
provided in the central laboratory manual.
10.3.4.3. Sample Shipping and Handling
Samples will be shipped by the local laboratory to the designated research laboratories, 
according to the instructions in the central laboratory manual  Designated research laboratories 
are associated with Lilly and are located in the US and EU.
10.4. Appropriateness of Measurements
There are no surrogate endpoints used in this study.  All efficacy and safety assessments used in 
this study are standard and appropriate for an oncology study.

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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.  
CRF data will be encoded and stored in a clinical trial database.  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 to the 
Lilly generic labs system.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a daily dosing schedule.
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
This study is a Phase 2 proof-of-concept study which attempts to characterize the quality and 
quantity of antitumor activity of inhibiting the novel target of TGF-signaling in HCC; dose and 
dose schedule determination will not be exclusively dependent on the clinical response measures, 
but rather the clinical response measures will be used to interpret the progressive disease 
responses appropriately.  These include safety, PK, a number of important progressive disease 
measures (such as AFP, plasma TGF-1, plasma E-cadherin, and levels of cytokines, 
chemokines, and fibrosis-associated biomarkers) as well as clinical response measures.  
Since the objectives of this study are composite in nature, it was important to ensure that the 
sample size was large enough for the parameters of each measure (safety, clinical response, 
progressive disease responses) to be estimated with sufficient precision.  In addition, the sample 
size should allow for possible identification of subgroups of patients who may benefit from 
treatment with LY2157299 and those who may not, particularly with respect to using the 
treatment effect on the progressive disease efficacy markers. 
12.1. Determination of Sample Size
This section describes how amendments to the protocol have affected the determination in 
sample size.
The original protocol and Amendment (a) planned to enroll 140 Child-Pugh Class A or B7 
patients with HCC in this study.  Each patient was randomized into 1 of 2 cohorts to receive 
either 160 or 300 mg/day of LY2157299.  Both cohorts were proportionately balanced for 
3 factors:  baseline AFP levels (≤400 ng/mL, >400 ng/mL), etiology (alcohol, viral, other), and 
sorafenib-naive or not.
This sample size meant that if the study had completed to its maximum enrollment, there would 
be approximately 80% power to detect a HR of 1.5 as statistically significant at the 20% level 
(2-sided) between the 2 doses.  This was assuming an exponential survival distribution, a 
24-month accrual period, 6-month observation period after the last patient enrolled, and no loss 
to follow-up, and anticipation of around 129 events being observed.
There were 2 planned interim analyses.  The first interim analysis assessed safety after 
10 patients enrolled in each dose cohort (20 total patients) and completed 1 cycle of treatment 
and assessed PK when 10 patients/dose were eligible for PK assessments (all samples including 
the Day 15 sample).  After the first interim analysis, it was decided that enrollment into both 
doses should continue.  The second interim analysis was planned after 40 patients had enrolled 
into each dose cohort (80 total patients) and actively followed for 3 months or until progressive 
disease or death had been observed to further investigate safety and to compare the progressive 
disease efficacy measures between the 2 dose cohorts.
Consideration was also to be given to the number of patients who were free from progression at 
3 months at the second interim analysis.  Given that some of the patients included in this study 
may have previously progressed on sorafenib, a median TTP of 4.5 months would have been

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considered promising, representing a 60% improvement over best supportive care of these 
patients (median TTP of 3 months).  If the true median TTP in any dose group is 4.5 months or 
3 months, then 63% or 50%, respectively, are expected to be free from disease progression at 
3 months.
Details of the decision criteria for each of the planned interim analyses are provided in 
Section 12.2.14.
The first interim analysis was completed. However, an additional data review was carried out 
prior to the planned second interim analysis, and this was when 64 patients had received at least 
1 dose of study drug and were reported in the clinical database. Of these, 44 patients had 
completed at least 3 cycles of treatment or discontinued from study treatment.  The decision from 
this review was to stop enrollment into Cohort 1 (at 37 patients) and to complete enrollment of 
Cohort 2 (n=70 patients).  In addition, the protocol was amended (Amendment [b]) to have 2, 
and possibly 3, parts in this study.  The 2 cohorts planned in the original protocol and in the 
Amendment (a) were designated as Part A.  Part B was to enroll 40 Child-Pugh Class A or B7 
patients with HCC with AFP levels<1.5x ULN. Part C was to enroll approximately 40 Child-
Pugh B7 or B8 status patients.
Therefore, the study (Amendment [b]) planned to enroll a total of 147 patients, and possibly 
187 patients: 107 in Part A (37 in Cohort 1, 70 in Cohort 2), 40 in Part B, and 40 in Part C (if 
implemented).  Given these changes, the primary objective of the study is now restricted to 
characterize both the TTP distributions and the effect on TGF--associated serum biomarkers 
(for example, TGF-, AFP, E-cadherin) of the 2 doses of LY2157299 in patients with HCC with 
elevated AFP levels and in patients with normal AFP levels dosed at 300 mg/day, and not to 
carry out any formal comparisons. Rather, estimates of treatment differences between the 
2 doses in Part A, and between Part A 300 mg/day and Part B and Part C patients would be 
provided.
Two interim analyses were planned for Amendment (b) – one after the 70 patients with elevated 
AFP levels had enrolled into Cohort 2 and started Cycle 1, and the second after 18 patients had 
enrolled into Part B and had been actively followed for at least 3 months or had discontinued 
from study treatment. If Part C was implemented, 1 interim analysis was planned after 18 
patients had been enrolled and had been actively followed for at least 3 months or had 
discontinued from study treatment.  Details of the decision criteria for the planned interim 
analyses are provided in Section 12.2.14.  
The 2 planned interim analyses described for Parts A and B in Amendment (b) have been 
completed (December 2012 and June 2013).  
With Amendment (c), the study planned to enroll approximately 190 patients: 109 patients have 
been enrolled in Part A (37 in Cohort 1, 72 in Cohort 2); 40 are planned for Part B, and 40 for
Part C (amended to enroll Child Pugh A patients who had not received any prior systemic 
therapy and were to be treated with LY2157299 plus sorafenib in a safety lead-in followed by an 
expansion at the selected dose).

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With Amendment (d) and the addition of Part D, an additional 15 patients may be enrolled.  With 
Amendment (e) and the addition of Part E, approximately 23 additional patients may be enrolled.
The primary objective of the study now is to characterize the TTP distributions, the effect on 
TGF--associated serum biomarkers (for example, TGF-, AFP, E-cadherin) and the 
relationship between biomarker response and efficacy endpoints of:
1) Each of the 2 doses of LY2157299 in second-line patients or patients 
ineligible to receive sorafenib with HCC who have elevated AFP levels 
(Part A, Cohorts 1 and 2), 
2) In second-line patients or patients ineligible to receive sorafenib with HCC 
who have AFP levels <1.5x ULN dosed at 300 mg/day (Part B),
3) In first-line patients with HCC treated with 2 doses of LY2157299 in 
combination with sorafenib.  If the decision in Part C is to use only 
1 treatment group in the expansion cohort, the results from patients at the 
other dose will simply be listed.
4) In second-line patients with HCC treated with LY2157299 given for 21 days on 
followed by 7 days off (Part E).
For efficacy endpoints, no formal hypothesis testing based on a priori power calculations is 
planned; rather differences in various endpoints (eg, hazard ratios for TTP, OS) between 
appropriate treatment groups will be estimated. Since Part C patients are different in 2 ways 
from patients in Parts A and B (first-line versus second-line and treated with LY2157299 in 
combination with sorafenib compared to LY2157299 monotherapy, respectively), the only 
estimate of differences between Parts A and/or B with Part C will be between Part C and the 
sorafenib-naive patients from Parts A and B. The interpretation of any estimate will be 
considered in light of the size of this subgroup.
Data from patients from Part D and E will be summarized separately from the data in Parts A, B,
and C.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company.
All patients who receive at least 1 dose of study drug will be evaluated for safety, efficacy, 
toxicity, and progressive disease endpoints.  The progressive disease responses will especially 
focus on the AFP kinetics and the TGF-β1 levels but also include the assessments of 
EMT-associated markers (for example, E-cadherin) and fibrosis-related blood markers.
Patients with measurable disease will be included in summaries of tumor response.  Tumor 
response will only be tabulated for patients who received at least 1 dose of study drug and have 
measurable disease at baseline.

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After Amendment (b), patients are allowed to continue on study treatment at the investigator’s 
discretion, even when objective progression is determined by radiological measurements, if they 
do not have overall symptomatic deterioration as well. This change should not affect the primary 
objective (estimation of TTP), PFS, or response rate. However, bias may be introduced in the 
assessment of OS, since patients prior to Amendment (b) will have discontinued based on 
objective progression alone. It is therefore important to capture patients enrolled in each 
amendment.
Patients from all sites will be pooled for the purposes of analysis.  All confidence intervals of 
treatment effects will be provided at a 2-sided alpha level of 0.10, unless otherwise stated.
Patients with Child-Pugh Class A and B7 will be considered as 1 group of patients, given the 
similarity of Class B7 patients to Class A patients. If all patients in Part A and Part B are 
second-line, Part C patients will be analyzed as a separate group.  If there are some first-line 
patients in Part A or Part B, different subgroups may be required. Part D will be conducted 
outside of the EU.  Data from patients from Parts D and E will be analyzed separately from Parts
A, B, C.
Any change to the data-analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data-analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report.  Additional exploratory analyses of the data will be conducted as 
deemed appropriate.
12.2.2. Definition of Clinical Efficacy Measures
Anticancer therapy is considered any treatment after failure or discontinuation on LY2157299.
Best response is determined from the sequence of cycle responses assessed.  For complete 
response (CR) or partial response (PR), best response must be confirmed.  A second assessment 
should be performed ≥28 days after the first documentation 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 start of study treatment.  
Evidence of progression is as defined in the RECIST 1.1 criteria (primary method) and 
mRECIST for both determining clinical response and time-to-event endpoints except for OS.
The following definitions for time-to-event measures will apply:

OS duration is measured 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 cut-off date for a particular analysis, OS duration will be censored for 
that analysis at the date of last prior contact.

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
PFS duration is measured from the date of randomization to the first date of 
progression of disease or of death from any cause.  For each patient who is not 
known to have died or to have had a progression of disease as of the 
data-inclusion cut-off date for a particular analysis, PFS will be censored at the 
date of last prior contact.  PFS duration will be calculated and analyzed twice:  
(1) including clinical progressions of disease not based on lesion measurements, 
and (2) excluding clinical progressions.

Time to progressive disease is measured from the date of randomization to the 
first date of progression of disease.  For each patient who is not known to have 
had a progression of disease as of the data-inclusion cut-off date for a particular 
analysis, or who has died without progression of disease, time to progressive 
disease will be censored for that analysis at the date of the patient’s last tumor 
assessment prior to that cut-off date.  Time to progressive disease will be 
calculated and analyzed twice:  (1) including clinical progressions of disease not 
based on lesion measurements, and (2) excluding clinical progressions.

Duration of tumor response is measured from the date of the first objective status 
assessment of a CR or PR to the first date of progression of disease or death from 
any cause.  For each patient who is not known to have died or to have had a 
progression of disease as of the data-inclusion cut-off date for a particular 
analysis, duration of tumor response will be censored at the date of last prior 
contact.

Time to treatment failure is measured from the date of randomization until the 
date of discontinuation of study treatment due to AE, progression of disease, or 
death from any cause.  For each patient who has discontinued study treatment for 
any other reason, time to treatment failure will be censored at the date of 
discontinuation of study treatment.  If a patient is still on study treatment as of the 
data-inclusion cut-off date for the particular analysis, time to treatment failure will 
be censored for that patient at that cut-off date.
12.2.3. Definition of Pharmacodynamic Efficacy Measures
AFP elevation is an important marker of disease progression in HCC.  Hence, a treatment effect 
can be measured by following the kinetics of AFP reduction during the treatment period.  It is 
estimated that a reduction of 50% over 3 months is a relevant change suggesting a treatment 
effect.
Less validated is the increase of TGF-β1 levels in HCC patients.  However, there is a body of 
studies suggesting that levels above 800 ng/mL are correlated with poor clinical outcome.  
Hence, a reduction in TGF-1 levels is another marker of activity of a beneficial treatment 
effect.  Given that LY2157299 is specifically designed to reduce TGF--related pathology, a 
change in the TGF-1 kinetics is an important proof-of-concept for the activity of LY2157299.
Finally, E-cadherin is a protein associated with the EMT.  Its levels were found to be increased 
in aggressively growing HCC.  Hence, a change in kinetics of its levels may reflect treatment 
effects.

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12.2.4. Patient Disposition
A detailed description of patient disposition will be provided.  It will include the following:

a summary of data on patient discontinuation

a summary of data on overall qualification status of all patients

an account of all identified protocol violations
All patients entered in the study will be accounted for in the summary.  The number of patients 
who do not qualify for analysis, who die, or who discontinue before treatment begins will be 
specified.
12.2.5. Patient Characteristics
Patient characteristics will include a summary of the following:

patient demographics

baseline disease characteristics

preexisting conditions

historical illness

prior therapies

concomitant drugs
Other patient characteristics will be summarized as deemed appropriate.  
12.2.6. Concomitant Therapy 
Concomitant medications will be listed and may be summarized by World Health Organization 
(WHO) preferred name.
12.2.7. Treatment Compliance 
A summary of treatment compliance will be generated using information from drug 
accountability records and the patient diary.  A patient will be considered compliant with the 
study-therapy protocol if pill counts indicate the patient took at least 80% of LY2157299 during 
the preceding cycle of study therapy (refer to Section 9.9).
An attempt may be made to determine how compliance to study treatment relates to observed 
study-related outcome.
12.2.8. Clinical Efficacy Analyses
Kaplan-Meier analysis will be performed on the observed distribution of TTP (Kaplan and Meier 
1958) for each dose in Part A, Part B, Part C, Part D and Part E, with parameter estimates of the 
TTP median and quartiles being reported.  All parameter estimates will be quoted together with 
their 90% confidence limits.  The hazard ratio between the observed TTP distributions of each 
cohort in Part A will be estimated, recognizing that since 1 dose cohort did not enroll to its full 

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complement, the precision of the HR will be lower than originally planned. The hazard ratios 
between the 300 mg/day cohort in Part A and Part B cohort will also be estimated. In addition, 
the hazard ratio between a subgroup of sorafenib-naive patients in Parts A and B and patients in 
Part C may be estimated. The interpretation of any estimate will be considered in light of the 
size of this subgroup.
Alternative distributions of TTP times, such as exponential Weibull (estimating a shape 
parameter may also be considered) where median TTP and its 90% CIs will be reported.  
Individual parameters, such as TTP rate after specific time points (for example, after 12 months 
on treatment) will be estimated from the TTP distribution.  
Secondary efficacy measures include other time-to-event parameters, and these will follow the 
same analyses as described above.  
The overall response rate (ORR) for each cohort in Part A, Part B, Part C, Part D and Part E will 
be estimated by dividing the total number of confirmed responders by the number of patients 
who received at least 1 dose of study treatment.  The clinical benefit rate will be estimated for 
each treatment group by dividing the total number of patients experiencing benefit by the number 
of patients who received at least 1 dose of study treatment.  A patient is considered to have 
received benefit if they achieve a confirmed response, CR or PR, or SD per RECIST v1.1 or 
mRECIST.  Both mean and exact confidence limits will be provided for each group (Cohort 1 
and Cohort 2 in Part A, Part B, Part C, Part D and Part E, as well as estimates of differences 
between 2 cohorts in Part A, between Parts A and B at 300 mg/day, and between sorafenib-naive 
patients in Part A and Part B with those in Part C. The interpretation of any estimate in the latter 
comparison will be considered in light of the size of this subgroup.
Additional exploratory analyses of efficacy endpoints will be performed to assess the effect of 
important prognostic factors on the outcome, including, but not exclusively, baseline AFP levels 
(either as a continuous factor and/or categorical factor), etiology, and whether sorafenib-naïve or 
not.  Analyses using subgroup identification methods, such as classification and regression tree
(CART) (classification and regression tool) may also be carried out. The only difference 
between Part A and Part B patients is their baseline AFP levels, and therefore results from 
Cohort 2 in Part A and Part B will be combined in these analyses. Similar analyses for patients 
in Parts C, D and E may be carried out.
The original statistical analysis plan (SAP) was finalized prior to the first patient in the study 
being dosed. The amended SAP was finalized prior to the first patient in Part B being dosed. 
The amended SAP (version 2) was finalized prior to the first patient in Part C being dosed. The 
amended SAP (version 3) will be finalized prior to the first patient in Part D being dosed. An 
amended SAP (version 4) will be finalised prior to the first patient in Part E being dosed.
12.2.9. Pharmacodynamic Efficacy Analyses
Pharmacodynamic (PD) parameters (for example, AFP, E-cadherin, TGF-β1) will be analyzed 
using a mixed-effects model with patient as a random effect and dose, time of sample, and 
baseline values as fixed effects.  Two effects of LY2157299 are of interest for changes in AFP 

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levels:  first, whether there is evidence of a reasonably sustained (2 months) 50% or greater 
reduction from baseline (as this is considered indicative of clinical benefit) in either dose. 
Second, whether there is a difference of 20% in the percentage change from baseline between the 
2 doses (eg, 50% reduction at 300 mg/day and 30% reduction at 160 mg/day).  
Comparisons between subgroups of interest (baseline AFP [as a continuous covariate and 
subgroups categorized by cutoff values], etiology, and whether sorafenib-naive or not) will be 
carried out by either including these terms as fixed effects, including interaction terms if needed) 
in the above model or as separate analyses.  The decision will be in part based on whether there 
is any evidence that the variability of data differ between the different subgroups and the actual 
number of patients enrolled in each subgroup. A variance-covariance structure will be added to 
the model as appropriate.  Serum concentrations will be log transformed prior to analysis as 
concentration data are typically log normally distributed, and the comparisons of interest are fold 
differences between different groups as opposed to absolute differences. In addition to the above 
2 analyses, the percentage of patients who have at least 2 cycles of reductions of at least 25% 
AFP levels will be provided. Percentages of patients for other cutoff values may also be 
provided.  With the early closure of Cohort 1 in Part A and addition of Part B, the above effects 
of interest will be investigated by providing summary statistics and estimating differences 
between study Parts A and B for patients on 300 mg/day.  
The association between changes in PD parameters and clinical endpoints will be explored to 
determine their value as predictive biomarkers of drug effect on clinical outcome.
Summary statistics for each parameter will be provided by dose, time, and subgroup of interest.  
Estimates of fold differences from the model (between doses for each subgroup of interest and 
also between subgroups of interest within each dose) will be provided together with their 95% 
CIs.  Visual presentation of the results will be provided where meaningful.
12.2.10.
Pharmacokinetic/Pharmacodynamic Analyses
The plasma concentration versus time data together with information on dosing and patient 
characteristics will be pooled and analyzed using a population PK analysis approach.  Nonlinear 
mixed-effect modeling (NONMEM) will be used for the estimation of the population PK 
parameters of LY2157299.  
All patients who have completed at least 2 days of sampling will be included in the PK analysis.  
LY2157299 PK will be modeled using NONMEM.  These population parameters describe the 
average dose-concentration relationship in the target population, the influence of fixed effects 
(such as weight or age) on a PK parameter of interest, the interindividual variation in the PK 
parameter, and the residual variation in the observed concentration.
For the purposes of the JBAK study report, plasma-concentration data will be illustrated 
graphically and summarized descriptively.  If data are sufficient, then data from patients in this 
study will be modeled using the population approach for characterizing LY2157299 PK.  In 
addition, if appropriate, data from patients in this study will be combined in a PK database with 
data from Study JBAH and other completed studies, for population PK analysis. In Part C, 
Cycle 1 assessment on possible sorafenib exposure change during monotherapy and combination 

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will be made.  In Part D, Cycle 1 and 2 assessment of the possible LY2157299 exposure and/or 
ramucirumab change when in administered in combination will be evaluated. In Part E, Cycle 1 
LY2157299 PK profile of patients dosed for 21 days on treatment and 7 days off treatment will 
be characterized.
Exploratory PK/PD analyses will be conducted to identify the exposure-response (biomarker) 
relationship in this study.  The PK and PK/PD analyses may be reported as separate stand-alone 
reports for this study.  Additional analyses such as exposure-response using TTP and/or other 
appropriate clinical endpoints may be explored, if data warrant.  
The version of any software used for the analysis will be documented, and the program will meet 
Lilly requirements of software validation.  It is possible that other validated equivalent PK 
software programs may be utilized if appropriate, warranted, and approved by global PK 
management.
12.2.11.
Health Outcome/Quality of Life Analyses
The following will be carried out for each part separately.
Questionnaire compliance rates will be ascertained at each measurement time point until the end 
of study therapy including at discontinuation (Visit 801).
Summary descriptive statistics will be provided for the PRO data (FACT-Hep) at each 
assessment.  This summary will include mean, standard deviation, median, minimum, maximum, 
and change from baseline.  Scores will be evaluated both in aggregate (that is, median values for 
each study arm at a given time point) and individually, in which each patient’s score on study is 
evaluated relative to his/her baseline score.  Time to worsening of symptoms will also be 
evaluated, and longitudinal analyses, such as repeated measures, will be performed.  FACT 
subscales, total score, trial-outcome index, and symptoms (FHSI-8) will be assessed per the 
established scoring algorithm.
Other exploratory longitudinal analyses may be performed.
12.2.12.
Safety Analyses
Adverse event (AE) terms and severity grades will be assigned by the investigator using
CTCAE v4.0.  AE terms will also be derived from verbatims using the Medical Dictionary of 
Regulatory Activities.
All patients who received LY2157299 will be evaluated for safety.  Safety analyses will include, 
but are not limited to, the following:

all reported AEs, including seriousness, severity, and possible relationship to 
study drug, using CTCAE terminology and grades

TEAEs, including seriousness, severity, and possible relationship to study drug, 
using CTCAE terminology and grades

dose adjustments for any study therapy

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
physical exam and other safety observations, including those specifically targeting 
monitoring for cardiac safety

laboratory measures
Safety analysis may also estimate the difference in the incidence of AEs between the 2 doses and 
study parts, adjusting as necessary for baseline AFP levels or other important covariates.
12.2.13.
Exploratory Analyses
Exploratory analyses/data mining will be carried out on imaging data, Fibrotest data, 
gene-expression data, rules-based medicine multi-analyte panel (MAP) data and tumor-tissue 
data as appropriate, investigating links between these data and clinical and PD efficacy 
endpoints.  Other TGF-β-signaling pathway biomarkers will also be included in this analysis.
After Amendment (a), both Child-Pugh Class A patients and Child-Pugh Class B7 patients are 
eligible and are being treated as 1 group given the similarity between these groups of patients, 
but additional analyses will look at the contribution of both classes to the clinical endpoints.  In 
addition, as of Amendment (a), patients with liver transplant on maintenance immunosuppressive 
therapy are eligible, and possible differences in safety and efficacy endpoints between patients 
with and without liver transplant will be investigated.
After Amendment (c), first-line Child Pugh A patients are included in the study. Similar 
analyses to those conducted for patients in Parts A and B will be carried out for patients in 
Part C.
Given the more limited number of patients to be enrolled in Part D and E, exploratory analyses 
will be carried out as appropriate.
12.2.14.
Interim Analyses
There were 2 planned interim analyses in Amendment (a).  The first interim analysis reviewed 
both safety and PK of LY2157299.  Safety was assessed after 20 patients (10 patients/dose) had 
enrolled and completed 1 cycle of treatment.  The PK interim analysis occurred after the PK 
sample on Day 15 had been collected from 20 patients (this was carried out after the safety 
review).  
For enrollment to continue in either dose level, there had to be no evidence of cardiotoxicity in 
any patient at that dose level and no drug-related CTCAE Grade 3/4 toxicity that was not 
manageable.  The PK of LY2157299 in HCC patients were compared to those of patients with 
glioblastoma observed in Study JBAH.  Since only sparse sampling was performed in Study 
JBAK (Parts A and B), comparisons between the 2 populations were carried out by simulations 
(median and 20th and 80th percentiles) using the population PK model from Study JBAH.  
The decision to continue was based on the following:
1.  If neither dose was considered tolerable, then the study would be terminated.
2.  If only 1 dose was considered tolerable, then enrollment would continue into this dose 
cohort, and the other dose cohort would close.

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3.  If the predicted 80th percentile of the distribution of AUC exceeded 10.96 (mg.h/L) 
for either dose, enrollment into this dose cohort may have been ceased.
Enrollment after the first interim analysis continued in both dose cohorts, and a second interim 
analysis was planned when an additional 30 patients had been enrolled in each arm (i.e., total of 
40 patients in each arm) and had been actively followed for 3 months or progressive disease or 
death had been observed.  This was to be after the second planned radiological assessment 
(planned every 6 weeks) and after the collection of biomarker (specifically AFP) samples for all 
patients.  Any patient who was lost to follow-up or started a new anticancer therapy before 
3 months had elapsed without an event being observed was not eligible for inclusion in the 
interim analysis.  
The decision for dropping 1 of the 2 dose cohorts was to be based on a composite endpoint, 
including the number of patients who were free from progression at 3 months, amount reduction 
in AFP and other TGF-related biomarkers from baseline (adjusting for baseline levels if 
needed), and safety.
For example:
1.  If the observed mean percentage reduction from baseline in AFP concentrations in 
either cohort was more than 50%, enrollment into the dose cohort may continue.
2.  If the difference in mean percentage change from baseline in AFP concentrations 
between the 2 doses is >20%, then the dose with the lowest reduction from baseline 
may be dropped after taking into consideration the observed results for E-cadherin and 
other TGF-β related biomarkers.
3.  Either dose or both doses will be dropped if there is evidence of cardiotoxicity and/or 
drug-related CTCAE Grade 3/4 toxicity that is not manageable in any patient.
4.  If the number of patients who are free from progression at 3 months in either dose is 
21 or less, then the dose level may be discontinued.
o
This cut-off represents a risk of continuing when the true median TTP is not 
considered clinically meaningful over no intervention (that is, median TTP = 
3 months) is 32% and of deciding not to continue when the true median TTP is 
considered meaningful (that is, median TTP = 4.5 months) is 11%.  (Information 
for risks of an incorrect decision using other cutoff values will be provided in the 
SAP.)
Two effects of LY2157299 are of interest for changes in AFP levels – whether there is evidence 
of a reasonably sustained 50% or greater reduction from baseline (as this is considered indicative 
of clinical benefit) in either dose and whether there is a difference of 20% in the percentage
change from baseline between the 2 doses (for example, 50% reduction at 300 mg/day and 30% 
reduction at 160 mg/day).  With 40 patients enrolled at each dose cohort and an assumed 
within-patient coefficient of variation of 44% (data on file), there is at least 95% probability that 
treatment effect of 50% within a dose group will be detected as significant at the 5% significance 

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level.  The more sensitive situation concerns the probability of detecting a difference of 20% in 
the percentage reduction in pre and postdose concentrations between the 2 dose groups in order 
to choose a dose at this stage.  The power to detect a 20% difference in percentage reduction 
between the 2 doses is approximately 80%, at the 20% 2-sided significance level.
Analysis of the mean fold change from baseline of biomarker concentrations levels were to be 
estimated from a mixed-effects model with sampling time, dose and their interaction as fixed 
effects, baseline levels (either as a continuous variable or categorical [AFP:  ≤400 ng/mL or 
>400 ng/mL]) as a covariate and patient as a random effect.  The choice of variance-covariance 
structure was to have depended on the data.  Biomarker concentrations were to be log 
transformed prior to analysis.  Specific details of these analyses will be provided in the SAP.
If at the second interim analysis, when a total of 40 patients had been enrolled at each dose and 
followed as described, results of the comparison between the doses were still inconclusive, the 
decision to either continue enrollment into both doses or to choose 1 dose was to be made after 
discussions between the investigator, Lilly, and study statistician.
However, the planned second interim analysis described in Amendment (a) was not carried out,
but an additional data review was conducted. Based on this review, the decision was to close 
Cohort 1 and continue enrollment until 70 patients enrolled into Cohort 2. At the time of the 
decision, 64 patients had been treated.
As part of Amendment (b), the second interim analysis for Part A was changed and planned to be 
after the 70th patient enrolled into Cohort 2 and started Cycle 1.  The purpose of this analysis 
was to help inform the decision to prepare for further development of the compound in patients 
with HCC with elevated AFP levels.  This analysis was completed in December 2012 (Faivre et 
al. 2013).
The purpose of the interim analyses in Part B (interim analysis 3) and Part C (interim analysis 4)
was to prepare for further development of the compound and to inform the decision as to whether
all second-line HCC patients, irrespective of baseline AFP levels (Part B), and Child-Pugh B7 or 
B8 status (Part C) patients may benefit from treatment with LY2157299.  
The timing of the interim analyses for Parts B and C was based on assuming Parts B and C are
designed as a Simon’s 2-stage design with the same characteristics as used in the original 
protocol:  where the assumption of a poor treatment is if the proportion free from disease 
progression is 50% at 3 months (assumes median TTP = 3 months) and a good treatment is if the 
proportion free from disease progression at 3 months is 63% (assumes median TTP = 
4.5 months).  The operating characteristics of this design are as follows:  The null hypothesis is 
that the true response rate is 50%.  In the first stage, 18 patients will be accrued and actively 
followed for at least 3 months or until they have discontinued.  If there are 8 or fewer patients 
free from disease progression in these 18 patients, this may be indicative that patients with 
normal AFP levels are not benefiting from the treatment.  The additional 22 patients will be 
accrued for a total of 40.  The null hypothesis will be ‘rejected’ at the end of Parts B and C if 
22 or more patients out of 40 patients in each part are observed to be free from disease

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progression at 3 months.  This design yields a type I error rate of 15% and power of 78% when
the true response rate is 63%.
From Amendment (c), the above calculations now only applied to the third interim analysis (for 
Part B, completed June 2013). Given the change in strategy for Part C to enroll and treat first 
line Child Pugh A or B7 patients in amendment (c), only safety reviews are planned while the 
study is ongoing. An additional analysis may be carried out if needed to help with clinical 
planning of the compound for treating first-line patients.
Safety reviews for Part D are planned to determine the LY2157299 dose in combination with 
ramucirumab. This will be after 3 patients have completed 1 cycle of treatment in Cohort 1
(LY2157299 80 mg BID) prior to escalating to Cohort 2 (LY2157299 150 mg BID).  A further 
safety review will be carried out after 3 patients have completed 1 cycle in Cohort 2.
In Part E, safety data will be reviewed after 3 patients have completed one cycle. If the schedule 
is deemed to be tolerable (<33% DLTs in Cycle 1 and consideration of the overall safety profile 
in later cycles), an additional 20 patients will be enrolled in order to better characterize the safety 
of the schedule and allow comparison to safety, pharmacokinetics and efficacy seen in other 
cohorts. No additional interim analyses are planned for Part E.
The timing of the final analyses for each study parts’ clinical study reports and the final database 
lock is provided in Section 7.1.
12.2.15.
Criteria for Study Termination
This Phase 2 study will be considered complete following the completion of all data collection 
and/or study objectives have been met (including any possible long-term “follow-up” survival 
analysis).  The Lilly CRP will notify investigators in the event of study closure and the decision 
to stop collecting data.

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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 patients entered into the study and to document that the 
patients 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.
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.  Informed consent obtained under special circumstances may occur only if 
allowed by local laws and regulations and performed in accordance with a written process 
approved by Lilly.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly.  The 
ERB(s) will review the protocol as required.
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

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13.3. Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical
Sciences International Ethical Guidelines
2) the International Conference on Harmonisation (ICH) GCP Guideline [E6]
3) applicable laws and regulations
The investigator or designee will promptly submit the protocol to applicable ERB(s).
This study is being conducted under an active US Investigational New Drug (IND) application.  
The US IND number is 116167.
All or some of the obligations of the sponsor will be assigned to several third-party 
organizations.  These responsibilities include (1) ensuring that the study is conducted in 
accordance with Study Protocol JBAK, and (2) shipping study drug to the investigative sites.
An identification code assigned by the investigator 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
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 will sign 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
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LeBerre M-A, Baumhauer A, Meinhardt G, Han G on behalf of the RESORCE Investigators. 
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de Caestecker MP, Piek E, Roberts AB. Role of transforming growth factor-β signaling in 
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Derynck R, Akhurst RJ, Balmain A. TGF-β signaling in tumor suppression and cancer 
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J.  
New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). 
Euro J Cancer. 2009;45:228-247. 
Faivre SJ, Santoro A, Kelley RK, Merle P, Gane E, Douillard J-Y, Waldschmidt D, Mulcahy 
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MMF, Murray N, Benhadji KA, Raymond E, Giannelli G. Randomized dose comparison 
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Finn RS, Kang YK, Mulcahy M, Polite BN, Lim HY, Walters I, Baudelet C, Manekas D, 
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Fransvea E, Angelotti U, Antonaci S, Giannelli G. Blocking transforming growth factor–beta up-
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Fransvea E, Mazzocca A, Antonaci S, Giannelli G. Targeting transforming growth factor 
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Garbay D, Serova M, Serrate C, Bieche I, Riveiro ME, Raymond E, Faivre S. Specific TGF-beta 
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Giannelli G, Faivre S, Santoro A, Kelley RK, Merle P, Gane E, Douillard J-Y, Waldschmidt D, 
Mulcahy M, Costentin C, Minguez B, Papappicco PP, Gueorguieva I, Cleverly A, Desaiah D, 
Lahn MM, Ameryckx S, Benhadji KA, Raymond E. Evaluation of LY2157299 monohydrate, 
a TGF-β receptor l kinase inhibitor, in patients with advanced hepatocellular carcinoma: phase 
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European Association for the Study of the Liver; April 9-13, 2014; London, United Kingdom.
Giannelli G, Santoro A, Kelley RK, Gane E, Paradis V,  Cleverly A, Estrem S, Man M, Liu J, 
Desaiah D, Lahn MM, Raymond E, Benhadji KA, Faivre S. Final results of a phase 2 study of 
galunisertib, a transforming growth factor-beta (TGFβ) receptor I kinase inhibitor, in patients 
with advanced hepatocellular carcinoma (HCC) [abstract]. In: International Liver Cancer 
Association 10th annual meeting program; Sept 9-11, 2016; Vancouver, Canada. Abstract 
ABSSUB-380.
Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-beta in hepatic fibrosis. 
Front Biosci. 2002;7:d793-807.
Heffernan N, Cella D, Webster K, Odom L, Marone M, Passik S, Bookbinder M, Fong Y, 
Jarnagin W, Blumgart L. Measuring health-related quality of life in patients with hepatobiliary 
cancers: The Functional Assessment of Cancer Therapy - Hepatobiliary (FACT-Hep) 
questionnaire. J Clin Oncol. 2002;20(9):2229-2239.
Hoshida Y, Nijman SMB, Kobayashi M, Chan JA, Brunet JP, Chiang DY, Villanueva A, Newell 
P, Ikeda K, Hashimoto M, Watanabe G, Gabriel S, Friedman SL, Kumada H, Llovet JM, 
Golub TR. Integrative transcriptome analysis reveals common molecular subclasses of human 
hepatocellular carcinoma. Cancer Res. 2009;69(18):7385-7392.
Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, Santosuosso M, Martin JD, 
Martin MR, Vianello F, Leblanc P, Munn LL, Huang P, Duda DG, Fukumura D, Jain RK, 
Poznansky MC. Vascular normalizing doses of antiangiogenic treatment reprogram the 
immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad 
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Izzedine H, Ederhy S, Goldwasser F, Soria JC, Milano G, Cohen A, Khayat D, Spano JP. 
Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol.
2009;20(5):807-815.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Statist
Assoc. 1958;53:457-481.
Lahn M, Kloeker S, Berry BS. TGF-beta inhibitors for the treatment of cancer. Expert Opin 
Investig Drugs. 2005;14(6):629-643.
Lencioni R, Lovett RM. Modified RECIST (mRECIST) Assessment for Hepatocellular 
Carcinoma. Semin Liver Dis. 2010;30:52-60.
Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, 
Boige V, Mathurin P, Fartoux L, Lin DY, Bruix J, Poon RT, Sherman M, Blanc JF, Finn R, 
Tak WY, Chao Y, Ezzeddine R, Liu D, Walters I, Park JW.  Brivanib versus placebo in 
patients with advanced hepatocellular carcinoma (HCC) who failed or were intolerant to 
sorafenib: results from the phase 3 brisk-Ps study [abstract].  In: The International Liver 
Congress 2012 47th Annual Meeting of the European Association for the Study of the Liver; 
April 18-22, 2012; Barcelona, Spain.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, Cosme de Oliveira A, Santoro 
A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, 
Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Jordi Bruix 
J, for the SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. 
New Engl J Med. 2008;359:378-390.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, Cosme de Oliveira A, Santoro 
A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, 
Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Jordi Bruix 
J, for the SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. 
New Engl J Med. 2008;359 supplementary material. Available at:
http://www.nejm.org/action/showSupplements?doi=10.1056%2FNEJMoa0708857&viewType
=Popup&viewClass=Suppl. Accessed June 27, 2013.
Massagué J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable 
disorders. Cell. 2000;103:295-309.
Mazzocca A, Fransvea E, Lavezzari G, Antonaci S, Giannelli G. Inhibition of transforming 
growth factor beta receptor I kinase blocks hepatocellular carcinoma growth through 
neo-angiogenesis regulation. Hepatology. 2009;50(4):1140-1151.
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patients with hepatocellular carcinoma pre-treated with sorafenib. Med Oncol.
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Attachment 1.Protocol JBAK Study Schedule

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Parts A and B
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, nl
Extension
Period
Visit 
801
Follow-
upf
Comments
Relative Day 
Within a Cycle
28
14
7
1i
8i
14i
15
22
1i
14i,
k
1i
14i,k
Procedures
Informed 
Consent 
X
Informed consent must be signed prior 
to performing any study procedures.
Medical History
X
Child-Pugh, 
Barcelona Clinic 
Liver Cancer 
(BCLC), and 
CLIP staging
Xh
Pregnancy Test
X
Physical Exam
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be performed 
once per cycle. Perform predose on 
Day 1 of each cycle in extension 
period. 
Vital Signs (heart 
rate, blood 
pressure)
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be performed 
once per cycle. Perform predose on 
Day 1 of each cycle in extension 
period.
CTCAE Grading
X
X
X
X
X
X
X
X
Xa
Starting in Cycle 3, to be performed 
once per cycle. Perform predose on 
Day 1 of each cycle in extension 
period.
Concomitant 
Medications 
X
X
X
X
X
X
X
Perform predose on Day 1 of each 
cycle in extension period.
Performance 
Status
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be performed 
once per cycle. Perform predose on 
Day 1 of each cycle in extension 
period.

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Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension
Period
Visit 801
Follow-upf
Comments
Relative Day 
Within a Cycle
28
14
7
1i
8i
14i
15
22
1i
14
i,k
1i
14i,k
Tumor
Assessment, 
Physical (Palpable 
or Visible)
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
Imaging 
Procedures 
Echocardiography 
with Dopplerg
X
X
X
X
Xb
Xb
Cycle 2, 3, 4, and every other 
cycle (C6, C8,…etc). Perform 
predose on Day 1 of each cycle 
in extension period
Chest CT Scan or 
Chest MRI
X
X
Xc
CT scan or MRI every 6 
months
Tumor
Assessment, 
Radiological
X
X
X
Xd
Xd
Tumor assessment every 6 
weeks starting Cycle 2, Day 14. 
May be performed 3 days 
around the scheduled date. 
Optional during the extension 
period (including extension 
period V801)
ECG
X
X
X
X
Xb
Xb
Cycle 2, 3, 4, and every other 
cycle (C6, C8,…etc). Perform 
predose on Day 1 of each cycle 
in extension period

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Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow-upf
Comments
Relative Day 
Within a Cycle
28
14
7
1i
8i
14i
15
22
1i
14i,
k
1i
14i,
k
Laboratory
/Diagnostic Tests
ECG chemistry
X
X
X
X
Xb
Xb
Cycle 2, 3, 4, and every other 
cycle (C6, C8,…etc). Perform 
predose on Day 1 of each cycle 
in extension period.  Can be 
done at local labs during the 
extension period
Special chemistry
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs during 
the extension period
Hematology
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs during 
the extension period
Serum chemistry
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs during 
the extension period
Urinalysis
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
Urine C-terminal 
telopeptides of 
Type 1 collagen
X
X
X
Optional during the extension 
period

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Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow-upf
Comments
Relative Day 
Within a Cycle
28
14
7
1i
8i
14i
15
22
1i
14i,
k
1i
14i,
k
PK samplinge
X
X
X
X
X
X
Timed with ECG 
Serum markers 
(AFP, AFP L3, E-
cadherin, PIVKA 
II)
X
X
X
X
X
X
X
AFP only
X
Perform predose on Day 1 of 
each cycle in extension period.  
Can be done at local labs 
during the extension period
Immuno-
phenotype
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
TGF-β+PF4
X
X
X
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
MAP panel
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
Fibrotest
X
X
X
X
aPTT/PT/
INR
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period
Patient-Reported 
Outcomes
FACT-Hep
X
X
X
X
Optional during the extension 
period (including extension 
period V801)

H9H-MC-JBAK(e) Clinical Protocol
Page 102
LY2157299
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow-upf
Comments
Relative Day Within 
a Cycle
28
14
7
1i
8i
14i
15
22
1i
14i,k 1i 14i,k
Translational 
Research
Whole blood for PGx
X
Obtained diagnostic 
tumor tissue, when 
available 
X
Optional tumor 
biopsy
X
X
+/- 3 days after end of 
treatment with LY2157299
Abbreviations:  AFP = alpha-fetoprotein; aPTT = activated partial prothrombin time; C = cycle; CLIP = Cancer of the Liver Italian Program; CT = computerized 
tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; FACT = Functional Assessment of Cancer Therapy; 
INR = international normalized ratio; MAP = multi-analyte panel; MRI = magnetic resonance imaging; PGx = pharmacogenomics; PIVKA II = prothrombin 
induced by vitamin K absence; PK = pharmacokinetic; PT = prothrombin time; TGF-β = transforming growth factor beta.
a
If drug-related toxicity is present 30 days after last cycle of study drug, patients must be followed up approximately every 30 days until toxicity resolution, 
stabilization, another therapy is initiated, or death.
b If the patient has clinically significant cardiac findings at discontinuation (V801), echocardiography with Doppler, ECG, and ECG chemistry will be repeated 
every 2 months for 6 months (V803, V804, and V805).  If there are no cardiac findings at discontinuation (V801), 1 more echocardiography with Doppler, 
ECG, and ECG chemistry will be performed after 2 months (V802) unless a patient is receiving another treatment (see Section 10.2.4).  
c
If there were no clinically significant findings at the last assessment conducted within the 30 days following discontinuation and the patient has started 
another treatment, Visit 801 CT scan or chest MRI with contrast will not be performed.
d Repeat radiological scans at study discontinuation may be omitted if a patient has objective disease progression or if imaging has been performed in the 
previous 3 to 6 weeks.
e
For details, see Attachment 4.  PK sampling will be performed on Cycle 1, with a predose sample on Day 1 of Cycle 2 and all subsequent cycles.
f
Follow-up consists of Visit 802 and all subsequent visits (60 days ±7 days)
g Echocardiography with Doppler can be performed up to 3 days prior to Day 1.
h Child-Pugh, BCLC, and CLIP assessment procedures can be found in Attachment 5, Attachment 6, and Attachment 7, respectively.  
i
To be performed predose LY2157299.
j
A delay at the start of a cycle (Day 1) of no more than 3 days, because of holidays, weekends, inclement weather, or other justifiable events, will be permitted 
and not counted as a protocol violation.
k In extenuating circumstances, the ‘on study drug’ window is allowable from Day 10 to Day 14.  
l
Patients on study for more than 1 year (before entering extension phase) only need tests to be performed on Day 1 of each cycle.  

H9H-MC-JBAK(e) Clinical Protocol
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LY2157299
Part C
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow
-upf
Comments
Relative Day 
Within a Cycle
28 14 7
1i
8i 14i 15 22 23
27
1i
14i,k
15
22
1i
14i,
k
Procedures
Informed Consent 
X
Informed consent must be 
signed prior to performing any 
study procedures.
Medical History
X
Child-Pugh, 
Barcelona Clinic 
Liver Cancer 
(BCLC), and 
CLIP staging
Xh
Pregnancy Test
X
Physical Exam
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be 
performed once per cycle. 
Perform predose on Day 1 of 
each cycle in extension period.
Vital Signs (heart 
rate, blood 
pressure)
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be 
performed once per cycle. 
Perform predose on Day 1 of 
each cycle in extension period.
CTCAE Grading
X
X
X
X
X
X
X
X
Xa
Starting in Cycle 3, to be 
performed once per cycle. 
Perform predose on Day 1 of 
each cycle in extension period.
DLT assessment 
X
Safety lead-in cohorts 1 and 2 
only
Concomitant 
Medications 
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period.

H9H-MC-JBAK(e) Clinical Protocol
Page 104
LY2157299
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
period
Visit 
801
Follow
-upf
Comments
Relative Day 
Within a Cycle
28 14 7
1i
8i 14i
15
22 23
27
1i
14i,k
15
22
1i
14
i,k
Performance 
Status
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be 
performed once per cycle. 
Perform predose on Day 1 of 
each cycle in extension period.
Tumor 
Assessment, 
Physical (Palpable 
or Visible)
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801).
Imaging 
Procedures 
Echocardiography 
with Dopplerg
X
X
X
X
Xb
Xb
Cycle 2, 3, 4, and every other 
cycle (C6, C8…etc).  Perform 
predose on Day 1 of each cycle 
in extension period.
Chest CT Scan or 
Chest MRI
X
X
Xc
CT scan or MRI every 6 
months
Tumor 
Assessment, 
Radiological
X
X
X
Xd
Xd
Tumor assessment every 6 
weeks starting Cycle 2, Day 14. 
May be performed 3 days 
around the scheduled date.
Optional during the extension 
period (including extension 
period V801).
ECG
X
X
X
X
Xb
Xb
Cycle 2, 3, 4, and every other 
cycle (C6, C8,…etc)  Perform 
predose on Day 1 of each cycle 
in extension period.
Optional PET 
scan
At discretion of the 
investigator.

H9H-MC-JBAK(e) Clinical Protocol
Page 105
LY2157299
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
period
Visit 
801
Follow
-upf
Comments
Relative Day 
Within a Cycle
28 14 7
1i
8i 14i
15
22 23
27
1i
14i,k
15
22
1i
14
i,k
Laboratory
/Diagnostic Tests
ECG Chemistry
X
X
X
X
Xb
Xb
Cycle 2, 3, 4, and every other 
cycle (C6, C8,…etc). Perform 
predose on Day 1 of each cycle 
in extension period.  Can be 
done at local labs during the 
extension period.
Special Chemistry
X
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period.  
Can be done at local labs during 
the extension period.
Hematology
X
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period.  
Can be done at local labs during 
the extension period.
Serum Chemistry
X
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period.  
Can be done at local labs during 
the extension period.
Urinalysis
X
X
X
X
Optional during the extension 
period (including extension 
period V801).
Urine C-terminal 
telopeptides of 
Type 1 Collagen
X
X
X
Optional during the extension 
period. 
PK sampling (Part 
C Lead-in cohorts 
only)
X
X
X
X
X
X
X
X
X
X
See Attachment 4 for timing of 
samples.

H9H-MC-JBAK(e) Clinical Protocol
Page 106
LY2157299
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
period
Visit 
801
Follow
-upf
Comments
Relative Day 
Within a Cycle
28 14 7
1i
8i
14i 15 22 23
27
1i
14i,k
15
22
1i
14
i,k
PK sampling (Part 
C expansion phase 
only)
X
X
X
X
X
X
See Attachment 4 for timing of 
samples.
Serum markers 
(AFP, AFP L3, E-
cadherin, PIVKA 
II)
X
X
X
X
X
X
X
AFP only
X
Perform predose on Day 1 of 
each cycle in extension period.  
Can be done at local labs during 
the extension period.  
Immunopheno-
type
X
X
X
X
Optional during the extension 
period (including extension 
period V801).
TGF-β+PF4
X
X
X
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801).
MAP Panel
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801).
Fibrotest
X
X
X
X
aPTT/PT/
INR
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs during 
the extension period.

H9H-MC-JBAK(e) Clinical Protocol
Page 107
LY2157299
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, nl
Exten-
sion 
Period
Visit 
801
Follow
- upf
Comments
Relative Day 
Within a Cycle
28 14 7
1i
8i 14i
15
22 23
27
1i
14i,k
15
22
1i
14i,k
Patient-Reported 
Outcomes
FACT-Hep
X
X
X
X
Optional during the extension 
period (including extension 
period V801).
Translational 
Research
Whole blood for 
PGx
X
Obtain diagnostic 
tumor tissue
X
Optional tumor 
biopsy
X
X
+/- 3 days after end of treatment 
with LY2157299
Abbreviations:  AFP = alpha-fetoprotein; aPTT = activated partial prothrombin time; C = cycle; CLIP = Cancer of the Liver Italian Program; CT = computerized 
tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; FACT = Functional Assessment of Cancer Therapy; 
INR = international normalized ratio; MAP = multi-analyte panel; MRI = magnetic resonance imaging; PGx = pharmacogenomics; PIVKA II = prothrombin 
induced by vitamin K absence; PK = pharmacokinetic; PT = prothrombin time; RT-PCR = reverse transcriptase-polymerase chain reaction; TGF-β = 
transforming growth factor beta.
a
If drug-related toxicity is present 30 days after last cycle of study drug, patients must be followed up approximately every 30 days until toxicity resolution, 
stabilization, another therapy is initiated, or death.
b If the patient has clinically significant cardiac findings at discontinuation (V801), echocardiography with Doppler and ECG and ECG chemistry will be 
repeated every 2 months for 6 months (V803, 804 and V805).  If there are no cardiac findings at discontinuation (V801), 1 more echocardiography with 
Doppler, ECG, and ECG chemistry will be performed after 2 months (V802) unless a patient is receiving another treatment (see Section 10.2.4).  
c
If there were no clinically significant findings at the last assessment conducted within the 30 days following discontinuation and the patient has started 
another treatment, Visit 801 CT scan or chest MRI with contrast will not be performed.
d Repeat radiological scans at study discontinuation may be omitted if a patient has objective disease progression or if imaging has been performed in the 
previous 3 to 6 weeks.
e
For details, see Attachment 4. 
f
Follow-up consists of Visit 802 and all subsequent visits (60 days ±7 days).  For the patients in the extension phase, long-term follow up will not be 
conducted unless there are cardiac toxicities (Section 10.2.4).

H9H-MC-JBAK(e) Clinical Protocol
Page 108
LY2157299
g Echocardiography with Doppler can be performed up to 3 days prior to Day 1.
h Child-Pugh, BCLC, and CLIP assessment procedures can be found in Attachment 5, Attachment 6, and Attachment 7, respectively.  
i
To be performed predose LY2157299 or sorafenib.
j
A delay at the start of a cycle (Day 1) of no more than 3 days, because of holidays, weekends, inclement weather, or other justifiable events, will be permitted 
and not counted as a protocol violation.
k In extenuating circumstances, the “on study drug” window for LY2157299 is allowable from Day 10 to Day 14.  
l
Patients on study for more than 1 year (before entering extension phase) only need tests to be performed on Day 1 of each cycle.  

H9H-MC-JBAK(e) Clinical Protocol
Page 109
LY2157299
Part D
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow
-Upf
Comments
Relative Day 
Within a Cycle
28 14 7
1i
8i 14i 15 22 23
27
1i
14i,k
15
22
1i
14i,
k
Procedures
Informed consent 
X
Informed consent must be 
signed prior to performing any 
study procedures
Medical history
X
Child-Pugh, 
Barcelona Clinic 
Liver Cancer 
(BCLC), and 
CLIP staging
Xh
Pregnancy test
X
Physical exam
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be 
performed once per cycle. 
Perform predose on Day 1 of 
each cycle in extension period
Vital signs (heart 
rate, blood 
pressure)
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be 
performed once per cycle. 
Perform predose on Day 1 of 
each cycle in extension period
CTCAE grading
X
X
X
X
X
X
X
X
Xa
Starting in Cycle 3, to be 
performed once per cycle. 
Perform predose on Day 1 of 
each cycle in extension period
DLT assessment 
X
Concomitant 
medications
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period

H9H-MC-JBAK(e) Clinical Protocol
Page 110
LY2157299
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow
-Upf
Comments
Relative Day 
Within a Cycle
28 14 7
1i
8i
14i 15
22 23
27
1i
14i,k
15
22
1i
14
i,k
Performance 
status
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be 
performed once per cycle. 
Perform predose on Day 1 of 
each cycle in extension period
Tumor 
assessment, 
physical (palpable 
or visible)
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
Imaging 
Procedures 
Echocardiography 
with Dopplerg
X
X
X
X
Xb
Xb
Cycles 2, 3, 4, and every other 
cycle (C6, C8…etc).  Perform 
predose on Day 1 of each cycle 
in extension period
Chest CT scan or 
chest MRI
X
X
Xc
CT scan or MRI every 6 
months
Tumor 
assessment, 
radiological
X
X
X
Xd
Xd
Tumor assessment every 6 
weeks starting Cycle 2, Day 
14. May be performed 3 days 
around the scheduled date. 
Optional during the extension 
period (including extension 
period V801)
ECG
X
X
X
X
Xb
Xb
Cycles 2, 3, 4, and every other 
cycle (C6, C8,…etc). Perform 
predose on Day 1 of each cycle 
in extension period
Optional PET 
scan
At discretion of the 
investigator

H9H-MC-JBAK(e) Clinical Protocol
Page 111
LY2157299
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow
-Upf
Comments
Relative Day 
Within a Cycle
28 14 7
1i
8i
14i 15
22 23
27
1i
14i,k
15
22
1i
14
i,k
Laboratory
/Diagnostic Tests
ECG chemistry
X
X
X
X
Xb
Xb
Cycles 2, 3, 4, and every other 
cycle (C6, C8,…etc). Perform 
predose on Day 1 of each cycle 
in extension period. Can be 
done at local labs during the 
extension period
Special chemistry
X
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period
Hematology
X
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period
Urinalysis
Xm
X
X
X
Optional during the extension 
period (including extension 
period V801)
Urine C-terminal 
telopeptides of 
Type 1 collagen
X
X
X
Optional during the extension 
period
PK sampling
X
X
X
X
X
X
X
See Attachment 4 for timing of 
samples

H9H-MC-JBAK(e) Clinical Protocol
Page 112
LY2157299
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow
-Upf
Comments
Relative Day 
Within a Cycle
28 14 7
1i
8i
14i 15
22 23
27
1i
14i,k
15
22
1i
14
i,k
Serum markers 
(AFP, AFP L3, 
E-cadherin, 
PIVKA II)
X
X
X
X
X
X
X
AFP only
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period
Immunopheno-
type
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
TGF-β+PF4
X
X
X
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
MAP panel
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
Fibrotest
X
X
X
X
aPTT/PT/
INR
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period

H9H-MC-JBAK(e) Clinical Protocol
Page 113
LY2157299
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, nl
Exten-
sion 
Period
Visit 
801
Follow
-Upf
Comments
Relative Day 
Within a Cycle
28 14 7
1i
8i 14i
15
22 23
27
1i
14i,k
15
22
1i
14i,k
Patient-Reported 
Outcomes
FACT-Hep
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
Translational 
Research
Whole blood for 
PGx
X
Obtain diagnostic 
tumor tissue
X
Optional tumor 
biopsy
X
X
+/- 3 days after end of 
treatment with LY2157299
Abbreviations:  AFP = alpha-fetoprotein; aPTT = activated partial prothrombin time; C = cycle; CLIP = Cancer of the Liver Italian Program; CT = computerized 
tomography; CTCAE = Common Terminology Criteria for Adverse Events; DLT = dose-limiting toxicity; ECG = electrocardiogram; exam = examination; 
FACT = Functional Assessment of Cancer Therapy; INR = international normalized ratio; labs = laboratories; MAP = multi-analyte panel; MRI = magnetic 
resonance imaging; PET = positron emission tomography; PGx = pharmacogenomics; PIVKA II = prothrombin induced by vitamin K absence; 
PK = pharmacokinetic; PT = prothrombin time; TGF-β = transforming growth factor beta; V = visit.
a
If drug-related toxicity is present 30 days after the last cycle of study drug, patients must be followed up with approximately every 30 days until toxicity 
resolution, stabilization, initiation of another therapy, or death.
b If the patient has clinically significant cardiac findings at discontinuation (V801), echocardiography with Doppler, ECG, and ECG chemistry will be repeated 
every 2 months for 6 months (V803, V804, and V805).  If there are no cardiac findings at discontinuation (V801), 1 more echocardiography with Doppler, 
ECG, and ECG chemistry will be performed after 2 months (V802) unless a patient is receiving another treatment (see Section 10.2.4).  
c
If there were no clinically significant findings at the last assessment conducted within the 30 days following discontinuation and the patient has started 
another treatment, Visit 801 CT scan or chest MRI with contrast will not be performed.
d Repeat radiological scans at study discontinuation may be omitted if a patient has objective disease progression or if imaging has been performed in the 
previous 3 to 6 weeks.
e
For details, see Attachment 4.  
f
Follow-up consists of Visit 802 and all subsequent visits (60 days ±7 days).  For the patients in the extension phase, long-term follow-up will not be 
conducted unless there are cardiac toxicities (Section 10.2.4).

H9H-MC-JBAK(e) Clinical Protocol
Page 114
LY2157299
g Echocardiography with Doppler can be performed up to 3 days prior to Day 1.
h Child-Pugh, Barcelona Clinic Liver Classification, and CLIP assessment procedures can be found in Attachment 5, Attachment 6, and Attachment 7, 
respectively.  
i
To be performed predose LY2157299 or ramucirumab.
j
A delay at the start of a cycle (Day 1) of no more than 3 days, because of holidays, weekends, inclement weather, or other justifiable events, will be permitted 
and not counted as a protocol violation.
k In extenuating circumstances, the “on study drug” window for LY2157299 is allowable from Day 10 to Day 14.  
l
Patients on study for more than 1 year (before entering extension phase) only need tests to be performed on Day 1 of each cycle.  
m Patient will be excluded from the study if the patient's urinary protein is >1+ on dipstick or routine urinalysis.  If urine dipstick or routine analysis indicates 
≥2+ proteinuria, then a 24-hour urine must be collected and must demonstrate <1000 mg of protein in 24 hours to allow participation in the study.

H9H-MC-JBAK(e) Clinical Protocol
Page 115
LY2157299
Part E
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, nl
Extension
Period
Visit 
801
Follow-
upf
Comments
Relative Day 
Within a Cycle
28
14
7
1i
8i
14i
21
22
1i
14i,
k
1i
14i,k
Procedures
Informed 
Consent 
X
Informed consent must be signed prior 
to performing any study procedures.
Medical History
X
Child-Pugh, 
Barcelona Clinic 
Liver Cancer 
(BCLC), and 
CLIP staging
Xh
Pregnancy Test
X
Physical Exam
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be performed 
once per cycle. Perform predose on 
Day 1 of each cycle in extension 
period. 
Vital Signs (heart 
rate, blood 
pressure)
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be performed 
once per cycle. Perform predose on 
Day 1 of each cycle in extension 
period.
CTCAE Grading
X
X
X
X
X
X
X
X
Xa
Starting in Cycle 3, to be performed 
once per cycle. Perform predose on 
Day 1 of each cycle in extension 
period.
DLT Assessment
X
Concomitant 
Medications 
X
X
X
X
X
X
X
Perform predose on Day 1 of each 
cycle in extension period.
Performance 
Status
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be performed 
once per cycle. Perform predose on 
Day 1 of each cycle in extension 
period.

H9H-MC-JBAK(e) Clinical Protocol
Page 116
LY2157299
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension
Period
Visit 801
Follow-upf
Comments
Relative Day 
Within a Cycle
28
14
7
1i
8i
14i
21
22
1i
14
i,k
1i
14i,k
Tumor 
Assessment, 
Physical (Palpable 
or Visible)
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
Imaging 
Procedures 
Echocardiogram
with Dopplerg
X
X
X
X
Xb
Xb
Cycle 2, 3, 4, and every other 
cycle (C6, C8, etc). Perform 
predose on Day 1 of each cycle 
in extension period
Chest CT Scan or 
Chest MRI
X
X
Xc
CT scan or MRI every 6 
months
Tumor 
Assessment, 
Radiological
X
X
X
Xd
Xd
Tumor assessment every 6 
weeks starting Cycle 2, Day 14. 
May be performed 3 days 
around the scheduled date. 
Optional during the extension 
period (including extension 
period V801)
ECG
X
X
X
X
Xb
Xb
Cycle 2, 3, 4, and every other 
cycle (C6, C8, etc). Perform 
predose on Day 1 of each cycle 
in extension period

H9H-MC-JBAK(e) Clinical Protocol
Page 117
LY2157299
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow-upf
Comments
Relative Day 
Within a Cycle
28
14
7
1i
8i
14i
21
22
1i
14i,
k
1i
14i,
k
Laboratory
/Diagnostic Tests
ECG chemistry
X
X
X
X
Xb
Xb
Cycle 2, 3, 4, and every other 
cycle (C6, C8, etc). Perform 
predose on Day 1 of each cycle 
in extension period.  Can be 
done at local labs during the 
extension period
Special chemistry
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period
Hematology
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period
Serum chemistry
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period
Urinalysis
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
Urine C-terminal 
telopeptides of 
Type 1 collagen
X
X
X
Optional during the extension 
period

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Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow-upf
Comments
Relative Day 
Within a Cycle
28
14
7
1i
8i
14i
21
22
1i
14i,
k
1i
14i,
k
PK samplinge
X
X
X
X
X
Timed with ECG.  See 
Attachment 4 for specific 
timepoints.
Serum markers 
(AFP, AFP L3, E-
cadherin, PIVKA 
II)
X
X
X
X
X
AFP only
X
Perform predose on Day 1 of 
each cycle in extension period.  
Can be done at local labs 
during the extension period
Immuno-
phenotype
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
TGF-β+PF4
X
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
MAP panel
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
Fibrotest
X
X
X
X
aPTT/PT/
INR
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period
Patient-Reported 
Outcomes
FACT-Hep
X
X
X
X
Optional during the extension 
period (including extension 
period V801)

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Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow-upf
Comments
Relative Day 
Within a Cycle
28
14

7
1i
8i
14i
21 22
1i
14i,k 1i 14i,k
Translational 
Research
Whole blood for 
PGx
X
Obtained 
diagnostic tumor 
tissue, when 
available 
X
Optional tumor 
biopsy
X
X
+/- 3 days after end of treatment 
with LY2157299
Abbreviations:  AFP = alpha-fetoprotein; aPTT = activated partial prothrombin time; C = cycle; CLIP = Cancer of the Liver Italian Program; CT = computerized 
tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = Day; ECG = electrocardiogram; FACT = Functional Assessment of Cancer 
Therapy; INR = international normalized ratio; MAP = multi-analyte panel; MRI = magnetic resonance imaging; PGx = pharmacogenomics; PIVKA II = 
prothrombin induced by vitamin K absence; PK = pharmacokinetic; PT = prothrombin time; TGF-β = transforming growth factor beta.
a
If drug-related toxicity is present 30 days after last cycle of study drug, patients must be followed up approximately every 30 days until toxicity resolution, 
stabilization, another therapy is initiated, or death.
b If the patient has clinically significant cardiac findings at discontinuation (V801), echocardiography with Doppler, ECG, and ECG chemistry will be repeated 
every 2 months for 6 months (V803, V804, and V805). If there are no cardiac findings at discontinuation (V801), 1 more echocardiography with Doppler, 
ECG, and ECG chemistry will be performed after 2 months (V802) unless a patient is receiving another treatment (see Section 10.2.4).  
c
If there were no clinically significant findings at the last assessment conducted within the 30 days following discontinuation and the patient has started 
another treatment, Visit 801 CT scan or chest MRI with contrast will not be performed.
d Repeat radiological scans at study discontinuation may be omitted if a patient has objective disease progression or if imaging has been performed in the 
previous 3 to 6 weeks.
e
For details, see Attachment 4.  PK sampling will be performed on Cycle 1, with a predose sample on Day 1 of Cycle 2 and all subsequent cycles.
f
Follow-up consists of Visit 802 and all subsequent visits (60 days ±7 days).  All patients will be followed for OS until study completion. 
g Echocardiogram with Doppler can be performed up to 3 days prior to Day 1.
h Child-Pugh, BCLC, and CLIP assessment procedures can be found in Attachment 5, Attachment 6, and Attachment 7, respectively.  
i
To be performed predose LY2157299.
j
A delay at the start of a cycle (Day 1) of no more than 3 days, because of holidays, weekends, inclement weather, or other justifiable events, will be permitted 
and not counted as a protocol violation.

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k In extenuating circumstances, the ‘on study drug’ window is allowable from Day 10 to Day 14.  
l
Patients on study for more than 1 year (before entering extension phase) only need tests to be performed on Day 1 of each cycle.

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Attachment 2.Protocol JBAK Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Hemoglobin
Erythrocyte count (RBC)
Leukocytes (WBC)
Neutrophils, segmented + bands
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Immunophenotypeb
Urinalysisa
Specific gravity
pH
Protein
Glucose
Ketones
Blood
Leukocyte esterase
ECG Chemistryb
Lipase
Thyroid Stimulating Hormone (TSH)
Tri-iodothyronine (T3)
Thyroxine (T4)
Calciumc
Glucose, random (nonfasting) c
Albuminc
Phosphorusc
Sodiumc
Potassiumc
Magnesiumc
Special Chemistryb
Cystatin C 
Troponin I
BNP
High-sensitivity C-reactive protein (hs-CRP)
Clinical Chemistryb
Total bilirubin
Direct bilirubin
Total Protein
Alkaline phosphatase
LDH
Creatinine kinase (CK)
ALT/SGPT
AST/SGOT
Blood urea nitrogen (BUN)
Creatinine
Uric acid
Calcium
Glucose, random (nonfasting)
Albumin
Cholesterol
Phosphorus
Sodium 
Potassium
Magnesium
AFPb
AFP L3b
PIVKA IIb
E-cadherinb
TGF-β+PF4b
aPPT/PT/INRb
Fibrotestb
Urine C-terminal telopeptides of Type 1 Collagenb
Serum Pregnancy Test (females only)a

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Abbreviations:  AFP = alpha-fetoprotein; ALT = alanine aminotransaminase; aPTT = activated partial prothrombin 
time; AST = aspartate aminotransferase; BNP = brain natriuretic peptide; ECG = electrocardiogram; INR = 
international normalized ratio; LDH = Lactate Dehydrogenase; SGOT = serum glutamic oxaloacetic 
transaminase; SGPT = serum glutamic pyruvic transaminase; WBC = white blood cells; PIVKA II = prothrombin 
induced by vitamin K absence.
a
All samples will be discarded within 60 days of validated test results. Validation will occur at the time of initial 
testing. All these tests will be performed at a local or investigator-designated laboratory, with the exception of 
immunophenotype.
b
All samples will be discarded within 60 days of validated test results. Validation will occur at the time of initial 
testing. All these tests will be performed at a Lilly-designated laboratory.  Tests will be performed at a local 
laboratory if performed during the treatment extension period.
c
Test not performed if both chemistry and ECG chemistry are required.  See Attachment 1.

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Attachment 3.Protocol JBAK ECOG Performance Status
ECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all predisease performance 
without restriction
1
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, for example, light 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 MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Am J Clin Oncol.
1982;Dec;5(6):649-655.

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Attachment 4.Protocol JBAK Pharmacokinetic Sampling 
Instructions
Sparse PK Sampling Schedule Parts A and B
Sample Number
Cycle
Day
Sampling Windows for PK
1
1
1
Predosea
2
1
1
0.5-2 hours
3
1
14
Predosea
4
1
14
0.5-2 hours
5b
1
14
3-5 hours
6b
1
15
Morning
7
1
22
Morning
8
2
1
Predosea
9
3, n
1
Predosea
Abbreviations:  n = cycle number ≥Cycle 4; PK = pharmacokinetic.
a
The predose sample has to be taken before receiving any LY2157299.
b
For patients who will have a Day 15 PK sample taken, their evening dose of LY2157299 on Day 14 should be 
omitted.  

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Part C Sampling Schedule for Safety Lead-in Cohorts
Day
LY2157299 + Sorafenib
Dosing Schedule
Sampling Times
Pharmacokinetics
(LY2157299)
Pharmacokinetics
(Sorafenib)
Cycle 1 Day 1
(Day at which sorafenib and
LY2157299 are combined)
Both drugs as per Section 9
Predosea
Predosea
0.5 h after dose
0.5 h after dose
2 h after dose
2 h after dose
3 h after dose
3 h after dose
6 h after dose
6 h after dose
Cycle 1 Day 8
Both drugs as per Section 9
Predosea
Predosea
Cycle 1 Day 14b
(last day of LY2157299 
dosing)
Both drugs as per Section 9
Predosea
Predosea
0.5 h after dose
0.5 h after dose
2 h after dose
2 h after dose
3 h after dose
3 h after dose
6 h after dose
6 h after dose
Cycle 1 Day 15b
Sorafenib only as per Section 9
Morning (before 
sorafenib is taken)
Morning (before 
sorafenib is taken)
Cycle 1 Day 22
Sorafenib only as per Section 9
Predosea
0.5 h after dose
2 h after dose
3 h after dose
6 h after dose
Cycle 1 Day 23
Sorafenib only as per Section 9
Morning PK (predose)
Cycle 2 Day 1
Both drugs as per Section 9
Predosea
Predosea
Cycle 2 Day 1
Both drugs as per Section 9
0.5-2 hours
0.5-2 h
Cycle 2, Day 14b
Both drugs as per Section 9
Predosea
Predosea
Cycle 2, Day 14b
Both drugs as per Section 9
0.5-2 hours
0.5-2 h
Cycle 2, Day 14b
Both drugs as per Section 9
3-5 hours
3-5 h
Cycle 2, Day 15b
Sorafenib only as per Section 9
Morning (before 
sorafenib is taken)
Predosea
Cycle 3, Day 1
Both drugs as per Section 9
Predosea
Predosea
Cycle 4, n, Day 1
Both drugs as per Section 9
Predosea
Predosea
Abbreviations:  h = hour(s); n = cycle number ≥Cycle 4; PK = pharmacokinetic.
a
The predose sample has to be taken before receiving any LY2157299 or sorafenib.
b
For patients who will have a Day 15 PK sample taken, their evening dose of LY2157299 on Day 14 should be 
omitted.

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Part C Sampling Schedule for LY2157299 and Sorafenib in Expansion Cohort
Sample Number
Cycle
Day
Sampling Windows for PK
1
1
1
Predosea
2
1
1
0.5-2 hours
3
1
14
Predosea
4
1
14
0.5-2 hours
5b
1
14
3-5 hours
6b
1
15
Morning
7
1
22
Morning
8
2
1
Predosea
9
3, n
1
Predosea
Abbreviation:  PK = pharmacokinetic.
a
The predose sample has to be taken before receiving any LY2157299 or sorafenib.
b For patients who will have a Day 15 PK sample taken, their evening dose of LY2157299 on Day 14 should be 
omitted.

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Part D Sampling Schedule
Day
LY2157299 + RAM
Dosing Schedule
Pharmacokinetic
Sampling Times
(LY2157299) plasma
Pharmacokinetic
Sampling Times
(RAM) serum
Cycle 1 Day 1
(Day at which RAM and 
LY2157299 are combined)
Both drugs as per Section 9
Predosea
Predosea
1.5-3 h after 
LY2157299 dose 
End of RAM infusion
Cycle 1 Day 14b
(last day of LY2157299 
dosing)
LY2157299 as per Section 9
Predosea
0.5 h after dose
2 h after dose
3 h after dose
6 h after dose
Cycle 1 Day 15b
RAM only as per Section 9
Morning (before RAM 
is taken)
Predose
Cycle 1 Day 15
RAM only as per Section 9
End of RAM infusion
Cycle 2 Day 1
Both drugs as per Section 9
Predosea
Predosea
1.5-3 hours after dose 
(LY)
End of RAM infusion
Cycle 2, Day 14b
LY2157299 as per Section 9
Predosea
0.5-2 hours
3-5 hours
Cycle 2, Day 15b
RAM only as per Section 9
Morning (before RAM 
is taken)
Predose
Cycle 2 Day 15
RAM only as per Section 9
End of RAM infusion
Cycle 3, Day 1
Both drugs as per Section 9
Predosea
Predosea
Cycle 4, n, Day 1
Both drugs as per Section 9
Predosea
Predosea
Abbreviations:  h = hour(s); LY = LY2157299; n = cycle number ≥Cycle 4; PK = pharmacokinetic; 
RAM = ramucirumab.
a
The predose sample has to be taken before receiving any LY2157299 or ramucirumab.
b
For patients who will have a Day 15 PK sample taken, their evening dose of LY2157299 on Day 14 should be 
omitted.

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Part E Sampling Schedule for LY2157299
Sample Number
Cycle
Day
Sampling Windows for PK
1
1
1
Predosea
2
1
1
0.5-2 hours
3
1
21
Predosea
4
1
21
0.5-2 hours
5b
1
21
3-5 hours
6b
1
22
Morning
7
2
1
Predosea
8
3 - n
1
Predosea
Abbreviation:  PK = pharmacokinetic.
a
The predose sample should be taken before the patient receives any LY2157299.
b For patients who will have a Day 22 PK sample taken, the evening dose of LY2157299 on Day 21 should be 
omitted.

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Attachment 5.Protocol JBAK Child-Pugh Score
Child-Pugh Score
Clinical and 
biochemical 
parameters
Points
1
2
3
Bilirubin (mg/dL)
<2
2-3
>3
Albumin (g/dL
>3.5
2.8-3.5
<2.8
Ascites
Absent
Moderate
Tense
Encephalopathy
Absent
Moderate (Stage I-II)
Severe (Stage III-IV)
Prothrombin time
    Sec prolonged
    %
    INRa
<4
>60
<1.7
4-6
40-60
1.7-2.3
>6
<40
>2.3
In case of primary biliary cirrhosis
1
2
3
Bilirubin (mg/dL)
<4
4-10
>10
Total points:

5 to 6:  Child-Pugh class A

7 to 9:  Child-Pugh class B

10 to 15:  Child-Pugh class C
a  INR (International Normalized Ratio) is an expression of prothrombin time, corrected by the sensitivity of the 
reactive to anticoagulants and should be validated as an alternative to prothrombin time in liver insufficiency.
Source: Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for 
bleeding oesophageal varices. Br J Surg. 1973;60:646-649.

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Attachment 6.Protocol JBAK Barcelona Clinic Liver Cancer 
Classification Table
Barcelona Clinic Liver Classification Table
Stage
Performance 
Status Test
Tumor Stage
Okuda Stage
Liver Function 
Status
A
0
Single
I-II
Child-Pugh A-B
B
0
Large multinodular
I-II
Child-Pugh A-B
C
1-2
Vascular invasion/ 
extrahepatic spread
I-II
Child-Pugh A-B
D
3-4
Any
III
Child-Pugh C
Note:  Stages A and B, all criteria should be fulfilled; Stages C and D, at least 1 criterion.
Source: Llovet JM, Burroughs A, Bruix J. Hepatocellular Carcinoma. Lancet. 2003;362:1907.

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Attachment 7.Protocol JBAK Cancer of the Liver Italian 
Program (CLIP) Scoring System
CLIP Scoring System
Variable
Score
Child-Pugh stage
  A
0
  B
1
  C
2
Tumor morphology
  Uninodular and extension ≤50%
0
  Multinodular and extension ≤50%
1
  Massive or extension >50%
2
AFP
  <400
0
  ≥400
1
Portal vein thrombosis
  No
0
  Yes
      1
Abbreviation:  AFP = alpha-fetoprotein.
Source:  The Cancer of the Liver Italian Program (CLIP) Investigators. Hepatology. 2000;31(4):840-845.

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Attachment8.Protocol JBAK RECIST Criteria1.1
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).  
  
 
 
 
 
 
 
 
CCI
 
 
 
  
 
 
 
CCI

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CCI
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
CCI

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CCI
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI

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CCI
 
 
 
 
  
 
 
 
CCI
CCI

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CCI
 
 
CCI
CCI

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CCI
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 

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CCI
 
 
 
 
  

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Attachment 9.Protocol JBAK Creatinine Clearance Formula
Note:  This formula is to be used for calculating creatinine clearance (CrCL) from local 
laboratory results only.  
For serum creatinine 
concentration in 
mg/dL:
CrCl =
(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.
Source:  Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron.
1976;16:31-41. 
-OR-
GFR (mL/min/1.73 m2) = 170 x [PCr]-0.999 x [age]-0.176
x [0.762 if patient is female] x [1.18 if patient is black]
x [SUN]-0.17 x [Alb]+0.318
Abbreviations:  PCr= plasma creatinine, mg/dL; SUN= serum urea nitrogen, mg/dL; Alb= serum albumin, g/dL
Source:  Murray PT, Ratain MJ. Estimation of the glomerular filtration rate in cancer patients:  a new formula for 
new drugs. J Clin Oncol. 2003;21:2664-2672. 

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Attachment 10.
Protocol JBAK FACT-Hep
The FACT-Hep assesses additional concerns for hepatobiliary (liver, bile duct, and pancreas) 
cancer patients.  Score calculations are based on the FACT-Hep scoring guidelines in Section 3 
of the manual of the Functional Assessment of Chronic Illness Therapy (FACIT) Scales, 
Version 4.

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Attachment 11.
Protocol JBAK New York Heart 
Association Functional Classification 
The New York Heart Association Functional Classification classifies the extent of heart failure 
by placing patients in 1 of 4 categories based on how much they are limited during physical 
activity; the limitations/symptoms are in regards to normal breathing and varying degrees in 
shortness of breath and or angina pain:
Class I:  Patients with cardiac disease but without resulting limitation of physical activity.  
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.  
Class II:  Patients with cardiac disease resulting in slight limitation of physical activity.  They 
are comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain.  
Class III:  Patients with cardiac disease resulting in marked limitation of physical activity.  They 
are comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain.  
Class IV:  Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort.  Symptoms of heart failure or the anginal syndrome may be present even at 
rest.  If any physical activity is undertaken, discomfort is increased.
Reference
The Criteria Committee of the New York Heart Association. Nomenclature and criteria for 
diagnosis of diseases of the heart and great vessels. 9th ed. Boston:  Little, Brown & Co; 1994. 

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Attachment 12.
Protocol JBAK Echocardiography
Echocardiography
In this study, echocardiographic images are acquired with the purpose of ascertaining that 
patients enrolled in the study have baseline (and maintain during the study) normal cardiac 
structure and function, normal pulmonary artery pressure and absence of significant valvular 
disease (defined herein as no valvular regurgitation except for mild tricuspid, mild mitral, mild 
aortic regurgitation, and no more than mild mitral or aortic valvular stenosis).  Repeated 
echocardiograms in each subject are performed to establish the cardiac safety of LY2157299 by 
comparison with the initial studies.  Determination of normalcy status requires objective 
evaluation of cardiac chamber size and function and attention to the use of appropriate 
techniques in the performance of the echocardiographic examinations, in particular the use of 
standardized settings during the acquisitions of color-flow Doppler imaging.  Therefore, because 
quantitative echocardiography is the goal, stringent criteria for image quality and reproducibility 
are essential.
In addition to qualitative assessment of valvular regurgitation when or if detected (trace, mild, 
moderate, or severe according to Singh et al. 1999 and Zoghbi et al. 2003 (see below) and 
qualitative/quantitative assessment of valvular stenosis when or if detected (mild, moderate or 
severe, using mean and peak pressure gradient in mm Hg and orifice area in cm2 as applicable), 
other echocardiographic parameters to be serially quantified are left ventricular (LV) cavity size 
(diameters, volumes; assisted by IV injection of left-sided contrast echocardiographic agents).  
LV ejection fraction (EF), LV mass and mass index, diastolic function based on mitral flow 
velocity, mitral deceleration time, pulmonary venous flow pattern, tissue Doppler, extrapolation 
of LV end-diastolic pressure by E/Em, left atrial (LA) volume index, and extrapolation of 
pulmonary artery systolic pressure based on contrast-enhanced tricuspid regurgitation Doppler 
data.
An echocardiogram with no clinically significant abnormalities is one defined specifically as the 
LV internal dimension in diastole should be ≤2.8 cm/M2 (Schiller et al. 1989) the LA 
end-systolic volume should be ≤36 mL/M2 (Tsang et al. 2002), the LVEF should be ≥50% 
without regional wall motion abnormalities (Oh ), 2-dimensional echocardiographic-derived LV 
mass index should be ≤115 g/M2 for males and ≤99 g/M2 for females (Schiller et al. 1989), the 
pulmonary artery pressure should be normal (tricuspid regurgitation jet velocity 2.5 ms and/or 
pulmonary valve flow acceleration time ≥120 ms), the LV diastolic function should be normal 
(screening:  mitral deceleration time ≥150 ms and ≤250 ms, mitral E/A ratio ≥0.75 and ≤1.5, 
mitral E velocity divided by Doppler mitral annular velocity [E/Em] <15) (Khouri et al. 2004), 
and there should be no evidence for pericardial or congenital or heart disease.  In addition, there 
should be no evidence for more than mild mitral or aortic stenosis (mitral valve area should be 
greater than 2 cm2, and aortic valve area should be >1.5 cm2), no evidence of more than mild 
mitral or aortic regurgitation (Singh et al. 1999 and Zoghbi et al. 2003).  Patients enrolled in the 

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study may have evidence for tricuspid (trace or mild), pulmonary, mitral (trace or mild) or aortic 
(trace or mild) regurgitation by Doppler techniques (Singh et al. 1999 and Zoghbi et al. 2003).
References
Khouri SJ, Maly GT, Suh DD, Walsh TE. A practical approach to the echocardiographic 
evaluation of diastolic function.  J Am Soc Echocardiogr. 2004;17:290-297.
Oh JK. The Echo Manual, 2nd ed. Philadelphia: Lippincott, Williams and Wilkins; 2006.
Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Reicheck N, Sahn 
D, Schnittger I, Silverman NH, Tajik AJ. Recommendations for quantitation of the left 
ventricle by two dimensional echocardiography. J Am Soc Echocardiogr. 1989;2:358-367.
Singh JP, Evans JC, Levy D, Larson MG, Freed LA, Fuller DL, Lehman B, Benjamin EJ. 
Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (The 
Framingham Heart Study). Am J Cardiol. 1999;83:897-902.
Tsang TSM, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as 
morphophysiologic expression of left ventricular diastolic dysfunction and relation to 
cardiovascular risk burden. Am J Cardiol. 2002;90:1284-1289.
Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Craft CD, Levine RA, 
Nihoyannopoulos  P, Otto CM, Quinones MA, Rakowski H, Stewart WJ, Waggoner A, 
Weissman NJ.  Recommendations for evaluation of the severity of native valvular 
regurgitation with two dimensional and Doppler echocardiography. J Am Soc Echocardiogr.
2003;16:777-802.
Echocardiographic Certification Process
To ensure protocol adherence, each study center will be required to submit an initial study for 
certification.  The certification study will be performed on the first patient at the study site.  Once 
a certification certificate is received from Biomedical Systems the site may begin seeing 
additional study patients. 
General Instructions for Echocardiography

Allow 1 hour for the performance of the echocardiographic examination in 
each patient.

Do not enter the patient’s name in the initial video screen of the 
echocardiographic imaging system or protocol.  Only the patient’s screen 
and/or randomization number is to be entered and visible during the 
echocardiogram recording.

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
Set the echocardiography imaging system (create preset “Lilly” and use in 
subsequent visits of patients in the study) to acquire and store digital 3 cardiac 
cycles loops for 2-dimensional echocardiographic image per screen and obtain 
at least 3 or more cardiac cycles per each M-Mode or Doppler spectral-image 
screen.

This protocol calls for the use of both, harmonic imaging (for all views; native 
or tissue harmonics, using high [>1.3] mechanical index, with the appropriate 
highest transmitted frequency possible for that transducer) as well as 
fundamental imaging (this for limited views of the aortic and mitral valve on 
parasternal long axis).

Obtain the patient’s height and weight at the time of the examination and 
include with the study data.

Obtain and record with the study data the patient’s arterial blood pressure in 
right arm while undergoing echocardiography in the recumbent left-lateral 
position.

Display the electrocardiogram (ECG) at all times during echocardiographic 
sequence recordings.

Obtain all image sequences at held expiration (for up to 5 seconds at a time).

Record images (2D and color-flow Doppler cine loops, frames for M-Mode 
and Doppler spectral) in digital form and copy to a CD-ROM or MO-disk for 
each patient per visit.

Choose the best transmit gain, TGCs, mechanical index and compression 
setting for each patient.  Record these settings and use them at all future visits 
for each specific patient.

Always obtain all images (except subcostal) at held-end expiration with the 
patient lying on the left side (45 to 60 degrees) at 16-cm depth of field.  In the 
rare instance when the apical view silhouette of the heart (including the atria) 
exceeds 16 cm, then employ a 20-cm depth setting and make a note of this to 
employ 20-cm depth for that patient in subsequent visits.

Employ Doppler color-flow imaging from all views (long axis, short axis, 
apical 4-chamber, apical 2-chamber, and apical long axis) and note presence 
of valvular regurgitation.  For Doppler color flow, employ a Nyquist limit of 
50 to 60 cm/sec, and set the color gain at a level that just eliminates random 
color speckle from nonmoving regions.  Before recording Doppler color-flow 
image data for the first time in each patient at each visit, record continuously 
in videotape while the adjustment of color gain is performed to document in 
the videotaped data that gain settings have been properly obtained.  Avoid 
using very high or very low levels of pulse-repetition frequency (PRF).  Also, 
employ a color sector or color region of interest as narrow as possible for each 
valve examination, and with the least depth, to maximize lateral and temporal 
resolution.  

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
Spectral Doppler and M-Mode echocardiography data are to be recorded at a 
display speed of 50 or 100 mm/s (use discretion considering heart rate; 
videotape) using optimal gain control and minimal filter setting (at least 
3 beats), also at held expiration.

Before starting the second or subsequent visit echocardiogram for a given 
patient:
A. Retrieve the cine loop, from the patient’s first study digital data set, 
2D images of the left ventricle (short axis) as acquired in the original 
study.
B. Utilize this cine loop as part of a split screen to use as a guide to obtain the 
same imaging plane of the short axis again for this and subsequent visits 
of the same patient.
After obtaining the current image, acquire a new image of both, short axis LV images

Keep a set of the digital images of each echocardiogram obtained for that particular 
patient into a “master” file to remain in the site’s echocardiography laboratory and 
send via courier mail a CD-ROM or MO-disk copy of each study to the Core 
Echocardiography Laboratory at Biomedical Systems, St. Louis.  Use the provided 
preprinted shipping forms included with this manual.  If additional forms are 
required, please contact Biomedical Systems Echocardiography Laboratory in 
St. Louis.
Echocardiography Protocol; Required Views
Parasternal Long-Axis View, 16-cm depth

Record 3 beats (held expiration) of the entire 2D image with harmonic 
imaging.

Employ color-flow Doppler to evaluate for aortic and mitral regurgitation 
(using here and at each time that color-flow Doppler is used, the procedures 
described above regarding Nyquist limits, gain, and PRF) and record 3 beats 
(held expiration).

Obtain M-Mode views of the LV as close as possible to the minor axis of the 
ventricle, avoiding the papillary muscle, and obtain a freeze-frame M-Mode 
image (50 to 100 mm/s display).

Switch to fundamental imaging (this is, the only sequence of the protocol that 
requires fundamental imaging) by turning off the harmonic imaging mode; 
then place a small region of 2D sector or region of interest (2D only without 
color flow; at >45 Hz frame rate) that includes both the aortic and mitral valve 
leaflets, and record 3 beats (held expiration).

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Parasternal Short-Axis View, 16-cm depth

Record 2D harmonic imaging views of the aortic, mitral valve, and papillary 
muscle level of the LV and record a sweep sequence of 5 beats. 

Employ color-flow Doppler to evaluate for aortic regurgitation (record 3 beats 
in held expiration), then for mitral regurgitation at the level of the aortic 
root/left atrium (record 3 beats in held expiration).

Obtain pulsed spectral Doppler of the pulmonary valve flow at the level of the 
right-ventricular outflow tract; freeze and record spectral display of 3 to 
5 beats at held expiration.

If this is the second study in this patient, compare to previous image in the 
same patient (loop) to ensure obtaining the same LV papillary muscle level.  
This procedure entails retrieving from digital data of the site’s laboratory 
master storage of the same patient’s previous echocardiogram tape that 
contains the short-axis view 

Once it has been ascertained that the same papillary muscle level is being 
obtained today, as before, acquire (end-expiration) and save “today’s” short 
axis LV papillary muscle level; record both for 3 beats.
Apical 4-Chamber View, 16- or 20-cm depth

Avoid foreshortening of the image by maximizing the length of the LV cavity 
with the transducer placed as lateral and leftward as possible (toward the 
axilla and at a lower interspace in the left chest wall).  Likewise, obtain the 
widest possible LV cavity to ensure optimal assessment of LV volumes.

Pay special attention to optimal visualization of the endocardium of the lateral 
wall and septum and avoid visualization of the papillary muscle in this view.  
Record 5 beats with harmonic imaging at held expiration.

Employ color-flow Doppler to evaluate for mitral and tricuspid regurgitation 
(using procedures described above for settings, etc.) and record 3 beats for 
each valve.

Record at least 3 beats of the pulsed Doppler transmitral-flow velocity with 
the sample volume (smallest size possible) positioned both at the mitral leaflet 
tips and at the mitral annulus level with the left atrium; (displayed at 
100 mm/s).

Then measure the flow velocity across the mitral valve employing continuous-
wave Doppler (3 beats, spectral display recording, 50 to 100 mm/s).

Record at least 3 beats of the pulmonary venous-flow velocities (pulsed 
Doppler spectral) with the sample volume at the right upper pulmonary vein 
entrance into the left atrium.

Record at least 3 beats of the pulsed Doppler transtricuspid-flow velocity with 
the sample volume positioned at the tips of the tricuspid valve.

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
Then measure the flow-velocity spectra across the tricuspid valve employing 
continuous-wave Doppler (tricuspid-regurgitation peak-flow velocity; 3 beats, 
spectral display recording, 50 to 100 mm/s). 

If the tricuspid regurgitation jet is incompletely visualized or truncated 
(examples to be discussed and shown at investigators’ meeting), this calls for 
the use of agitated-saline contrast echocardiography (harmonic imaging, high 
mechanical index) to be employed to enhance the detection of the peak 
velocity of the tricuspid regurgitation jet.  For this purpose, start a 20-gauge or 
larger peripheral IV (antecubital vein preferred).  Draw 9 mL of sterile saline 
into a 10-mL syringe, connect it to a 3-way stopcock, and connect an empty 
10-mL syringe to the other port.  Leave 1 mL of air in the saline syringe.  
Agitate the solution by rapidly transferring the volume from 1 syringe to the 
other.  Expel all visible bubbles from the syringe that will be used for 
injection (for contrast, it is not necessary to inject visible air, and it is 
dangerous and contraindicated to do so).  Before injecting, point the syringe 
with saline downward so any remaining visible bubbles may rise towards the 
plunger (away from the patient).  Inject only 7 mL of the 9 mL of saline on the 
syringe, leaving a residual of 2 mL in that syringe.  This avoids the injection 
of visible bubbles.

For recording of the tricuspid regurgitation peak jet after saline enhancement, 
be prepared to quickly reduce the Doppler spectral gain to avoid noise-artifact 
blooming of the signal once the saline contrast effect is detected at the 
tricuspid-valve inlet.  Using continuous-wave Doppler, obtain at least 3 beats 
with the enhanced Doppler signal; freeze the spectral display, and record for 
5 seconds.

Obtain by tissue-Doppler echocardiography (initially by real-time 2D color 
display to facilitate placement of the sample volume within the LV 
myocardium) the spectral data of myocardial velocities at the level of the 
mitral annulus (lateral wall or interventricular-septum site) and freeze a 
spectral display (50 mm/s; at least 3 to 4 beats, held end expiration) and 
record (apply procedures for specific manufacturers regarding presets with 
optimal settings for map, gain, power, dark background in the display, etc.).  
Ensure that the ECG is displayed above the Doppler tissue spectral data.
Apical 5-Chamber View, 16-cm depth

Record 3 beats of the apical 5-chamber view harmonic imaging color-flow 
Doppler (to evaluate for aortic regurgitation). 

Place a sample volume within 1 cm of the aortic valve in the LV outflow tract 
and record (at held expiration) at least 3 beats of spectral-pulsed Doppler of 
the flow velocity in the outflow tract (displaying the closing [but not the 
opening] valve clicks, at 50 or 100 mm/s spectral-display speed).  

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
Then measure the flow velocity across the aortic valve employing 
continuous-wave Doppler (3 beats, spectral-display recording, 50 to 
100 mm/s) displaying both systolic- and any diastolic-flow velocity spectra 
(held expiration).
Apical 2-Chamber View, 16- or 20-cm depth

Obtain 3 beats at held expiration (or held inspiration, if necessary for this view 
only) of the harmonic imaging apical 2-chamber view.  Avoid foreshortening 
of the view by obtaining the longest possible major-axis length displayed and 
the widest possible cavity. 

Employ color-flow Doppler to evaluate for mitral regurgitation and record 
3 beats.
Apical Long-Axis View, 16- or 20-cm depth

Record 3 beats of the harmonic imaging apical long-axis 2D examination 
employing held expiration.  Again, avoid foreshortening the view by obtaining 
the longest as well as the widest possible LV cavity area.

Employ color-flow Doppler to evaluate for mitral and aortic regurgitation and 
record 3 beats for each valve image.
Subcostal View, 20- or 24-cm depth (if necessary)

Record 3 beats continuously with harmonic imaging of the inferior vena cava 
while asking the patient to abruptly sniff once.

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Attachment 13.
Protocol JBAK Qualitative and 
Quantitative Parameters for Grading Valvular 
Regurgitation
(Mitral and Aortic) Regurgitation Severity
Please refer to references below for information on qualitative and quantitative parameters for 
grading valvular (mitral and aortic) regurgitation severity.
Singh JP, Evans JC, Levy D, Larson MG, Freed LA, Fuller DL, Lehman B, Benjamin EJ. 
Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (The 
Framingham Heart Study). Am J Cardiol. 1999;83:897-902.
Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Craft CD, Levine RA, 
Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski H, Stewart WJ, Waggoner A, 
Weissman NJ. Recommendations for evaluation of the severity of native valvular regurgitation 
with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr. 
2003;16:777-802.

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Attachment 14.
Protocol JBAK Guidance for Sorafenib 
Eligibility
From the UK NHS Guidance
www.medicines.org.uk/guides (Last updated 05 May 11)
Sorafenib tosylate
Sorafenib 200-mg tablets when used in liver carcinoma
Whether this medicine is suitable for you
Sorafenib tosylate is not suitable for everyone and some people should never use it. Other people 
should only use it with special care. It is important that the person prescribing this medicine 
knows your full medical history.
Your prescriber may only prescribe this medicine with special care or may not prescribe it at all 
if you:

are allergic or sensitive to or have had a reaction to any of the ingredients in the 
medicine

are on dialysis

have liver problems

have high blood pressure

have heart problems

have recently had a heart attack

have or have had a stomach ulcer

have a wound that is still healing

are elderly

are about to have surgery

have metabolic problems

have risk factors for developing kidney problems

have taken rifampicin within the last 5 days
Furthermore the prescriber may only prescribe this medicine with special care or may not 
prescribe it at all for someone under the age of 18 years.

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As part of the process of assessing suitability to take this medicine a prescriber may also arrange 
tests:

to check that this medicine is having the desired effect

to check that this medicine is not having any undesired effects
Over time it is possible that Sorafenib tosylate can become unsuitable for some people, or they 
may become unsuitable for it. If at any time it appears that Sorafenib tosylate has become 
unsuitable, it is important that the prescriber is contacted immediately.

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Attachment 15.
Modified RECIST Assessment for 
Hepatocellular Carcinoma

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CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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CCI

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Attachment 16.
Sorafenib Adverse Events
The following drug-related adverse reactions and laboratory abnormalities (very common,
≥10%; common, 1 to <10%; uncommon, 0.1% to <1%) were reported from clinical trials of 
sorafenib (NEXAVAR; Bayer HealthCare Pharmaceuticals Inc., Wayne, New Jersey, USA):  

Cardiovascular
o
Common: congestive heart failure,*† myocardial ischemia and/or 
infarction 
o
Uncommon: hypertensive crisis*
o
Rare: QT prolongation* 

Dermatologic
o
Very common: erythema 
o
Common: exfoliative dermatitis, acne, flushing 
o
Uncommon: folliculitis, eczema, erythema multiforme, 
keratoacanthomas/squamous cell cancer of the skin 

Digestive
o
Very common: increased lipase, increased amylase 
o
Common: mucositis, stomatitis (including dry mouth and glossodynia), 
dyspepsia, dysphagia 
o
Uncommon: pancreatitis, gastrointestinal reflux, gastritis, gastrointestinal 
perforations,* cholecystitis, cholangitis 

Note that elevations in lipase are very common (41%, see 
below); a diagnosis of pancreatitis should not be made solely 
on the basis of abnormal laboratory values 

General disorders
o
Very common: hemorrhage (including gastrointestinal* and respiratory 
tract* and uncommon cases of cerebral hemorrhage*), asthenia, pain 
(including mouth, bone, and tumor pain) 
o
Common: decreased appetite, influenzalike illness, pyrexia 
o
Uncommon: infection 

Hematologic
o
Very common: leukopenia, lymphopenia 
o
Common: anemia, neutropenia, thrombocytopenia 
o
Uncommon: INR abnormal 

Hypersensitivity
o
Uncommon: hypersensitivity reactions (including skin reactions and 
urticaria) 

Metabolic and nutritional
o
Very common: hypophosphatemia 
o
Common: transient increases in transaminases 
o
Uncommon: dehydration, hyponatremia, transient increases in alkaline 
phosphatase, increased bilirubin (including jaundice), hypothyroidism, 
hyperthyroidism 

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
Musculoskeletal
o
Common: arthralgia, myalgia 

Nervous system and psychiatric
o
Common: depression 
o
Uncommon: tinnitus, reversible posterior leukoencephalopathy*

Renal and genitourinary
o
Common: renal failure 

Reproductive
o
Common: erectile dysfunction 
o
Uncommon: gynecomastia 

Respiratory
o
Common: hoarseness 
o
Uncommon: rhinorrhea, interstitial lung disease-like events (includes 
reports of pneumonitis, radiation pneumonitis, acute respiratory distress, 
interstitial pneumonia, pulmonitis, and lung inflammation) 

In addition, the following medically significant adverse reactions were uncommon 
during clinical trials of sorafenib:  
o
transient ischemic attack, 
o
arrhythmia, and
o
thromboembolism. 
For these adverse reactions, the causal relationship to sorafenib has not been 
established.
*
Adverse reactions may have a life-threatening or fatal outcome.  
†
Reported in 1.9% of patients treated with sorafenib (N=2276).
The following adverse drug reactions have been identified during postapproval use of sorafenib. 
Because these reactions are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug 
exposure. 

Dermatologic: Stevens-Johnson syndrome and toxic epidermal necrolysis 

Hypersensitivity: angioedema, anaphylactic reaction 

Hepatobiliary disorders: drug-induced hepatitis, including reports of hepatic failure 
and death
Source:  FDA, 2011.

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Attachment 17.
Protocol JBAK Amendment (e) Summary 
Phase 2 Study of LY2157299 in Patients with 
Hepatocellular Carcinoma 
Overview
Protocol H9H-MC-JBAK Phase 2 Study of LY2157299 in Patients with Hepatocellular 
Carcinoma has been amended.  The new protocol is indicated by Amendment (e) and will be 
used to conduct the study in place of any preceding version of the protocol.  
Amendment (e) revisions are summarized as follows:

Part E will be added to the study to explore LY2157299 given at 150 mg twice daily for 
21 days, followed by 7 days off drug (cycle length= 28 days). This dose will be 
examined in approximately 23 patients.  

Amendment (e) includes the provision that Part D of Study JBAK will be conducted 
outside of the EU and clarification on how Part D expansion will be conducted. The Part 
D PK sampling schedule (Attachment 4) has been revised to include required sampling 
timepoints for ramucirumab PK concentrations.

A reference to the appearance of the LY2157299 tablets has been removed.

Editorial revisions have been made throughout the protocol.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Protocol H9H-MC-JBAK(de) Phase 2 Study of LY2157299 in Patients with
Hepatocellular Carcinoma
This is an open-label, multicenter, multicountry, Phase 2 study of LY2157299 in patients 
with hepatocellular carcinoma.  The study design consists of 3 5 parts.  In Part A, patients 
with alpha-fetoprotein (AFP) 1.5x ULN will be randomized to 2 cohorts based on initial 
dose of LY2157299 to be received (160 or 300 mg/day).  In Part B, patients with AFP <1.5x 
ULN will receive LY2157299 300 mg/day.  In Part C, patients with no prior systemic 
treatment will receive LY2157299 in combination with sorafenib.  In Part D, patients will 
receive LY2157299 in combination with ramucirumab.  In Part E, patients who have 
received at least one prior line of systemic therapy or who have not received prior treatment 
and are ineligible for sorafenib treatment will receive LY2157299 150 mg BID according to 
a 21 days on/7 days off schedule.

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2. Synopsis
Name of Investigational Product:
LY2157299
Title of Study:  Phase 2 Study of LY2157299 in Patients with Hepatocellular Carcinoma 
Number of Planned Patients/Subjects:
Enrolled/Randomized:  approximately 205235
Phase of Development: Phase 2
Length of Study:  57.5 years
Planned first patient visit:  Q1 2011               Planned last patient visit:  October July 2018
Objectives: The primary objective of this study is to characterize both the time-to-progression (TTP) 
distributions and the effect on transforming growth factor beta (TGF--associated serum biomarkers (for 
example, TGF-, alpha-fetoprotein [AFP], E-cadherin) of study treatment in patients with hepatocellular 
carcinoma (HCC).
The secondary objectives of the study are:

To evaluate the safety of LY2157299 as monotherapy and in combination with sorafenib or 
ramucirumab in HCC patients

To evaluate the population pharmacokinetics (PK) of LY2157299 as monotherapy and in combination 
with sorafenib or ramucirumab

To recommend which doses of LY2157299 as monotherapy and in combination with sorafenib or 
ramucirumab to use in future trials recruiting HCC patients

To evaluate the safety and tolerability, pharmacokinetics and efficacy of LY2157299 as monotherapy 
administered according to a 21 days on/7 days off schedule

To characterize other time-to-event distributions, such as progression-free survival (PFS, based on 
Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 and modified RECIST [mRECIST], for 
HCC) and overall survival (OS)

To estimate antitumor efficacy using response rate (RR, based on RECIST 1.1 and mRECIST, for 
HCC)

To assess patient-reported outcome (PRO) measures of disease-specific symptoms and health-related 
quality of life (Functional Assessment of Cancer Therapy Hepatobiliary [FACT-Hep])

To explore E-cadherin, pSMAD, and -integrin (and other markers associated with 
epithelial-to-mesenchymal transition ([EMT)] transformation and the TGF--associated signaling 
pathway) presence in the original diagnostic tumor tissue and optional posttreatment tumor tissue and 
the correlation of this with both clinical efficacy endpoints and biomarker response

To explore the utility of exploratory imaging techniques (for example, positron emission tomography 
[PET] scan, contrast echography) to assess treatment effect with LY2157299 as monotherapy and in 
combination with sorafenib when possible

To explore fibrosis-related biomarkers, such as Fibrotest
Study Design:  This is an open-label, multicenter, multicountry, Phase 2 study of LY2157299 in patients with 
hepatocellular carcinoma.  The study design consists of 45 parts.  In Part A, patients with AFP 1.5x upper limit 
of normal (ULN) will be randomly assigned to 2 cohorts based on initial dose of LY2157299 to be received (160 
or 300 mg/day).  In Part B, patients with AFP <1.5x ULN will receive LY2157299 300 mg/day.  In Part C, 
patients with no prior systemic treatment will receive LY2157299 (160 or 300 mg/day) in combination with 
sorafenib 400 mg twice daily (BID).  In Part D, patients with Child-Pugh A liver disease will receive treatment 
with LY2157299 (160 or 300 mg/day) in combination with ramucirumab (8 mg/kg IV on Days 1 and 15 of each 
cycle).  In Part E, patients with Child-Pugh Class A liver disease and any AFP who have received at least one 
prior line of systemic therapy or who have not received prior treatment and are ineligible for sorafenib treatment 
will receive LY2157299 150 mg BID according to a 21 days on/7 days off schedule.

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Diagnosis and Main Criteria for Inclusion and Exclusions:
Inclusion Criteria:  
[1] Have histological evidence of a diagnosis of HCC not amenable to curative surgery.
[2] Have Child-Pugh Class:
Parts A and B:  A or B7
Parts C and D:  A
Part E:  A
[3] Have serum AFP:
- Part A:  ≥1.5x ULN
- Part B:  <1.5x ULN
Criterion [3] applies for Parts A and B only.
[4] Have the presence of measurable disease as defined by the RECIST 1.1.  A lesion that has been 
previously treated by local therapy will qualify as a measurable or evaluable lesion if there was 
demonstrable progression following locoregional therapy.
[5] Age 18 years
[6] Have given written informed consent prior to any study-specific procedures
[7] Have adequate organ function including:
- Hematologic:  absolute neutrophil count (ANC) 1.5 x 109/L, platelets 50 x 109/L, and hemoglobin 8 
g/dL.
- Hepatic:  bilirubin 2.5 times ULN; alanine aminotransaminase (ALT) and aspartate aminotransaminase 
(AST) 5 times ULN.  Prothrombin time international normalized ratio, 2.3; or prothrombin time limit is
6 seconds above control.
- Renal:  Serum creatinine 1.5 times ULN or calculated creatinine clearance >45 mL/min.
Note:  Small differences from the outlined laboratory values will be deemed as consistent with 
the protocol requirements provided that the following criteria are met:  they are isolated, 
are transient, and are not reflective of a medical condition in the opinion of the
investigator.  Such differences are often a result of biological or laboratory equipment 
variability.  To confirm that these results are within biological or laboratory equipment 
variability, repeat laboratory/hematological tests should be done prior to dosing the 
patient on Cycle 1 Day 1.
[8] Have a performance status of 1 on the Eastern Cooperative Oncology Group (ECOG) scale.
[9] Have either:
In Parts A and B:
- received sorafenib and have progressed or were intolerant to sorafenib, or
- are ineligible for sorafenib treatment (at the investigator’s discretion).
In Part C:  not received previous systemic treatment.
In Part D:  
- received sorafenib and have progressed or were intolerant to sorafenib, or
- are ineligible for sorafenib treatment (at the investigator’s discretion), or 
- have not received prior systemic treatment (at the investigator’s discretion).
In Part E:  
- received at least one prior line of systemic therapy, or
- not received prior treatment and are ineligible for sorafenib treatment (at the investigator’s discretion).
[10] In Parts A, B, and D and E:  have discontinued sorafenib for at least 2 weeks.
Exclusion Criteria:
[15] Are currently enrolled in, or discontinued within the last 28 days from a clinical trial involving an 
investigational drug or device or not approved use of a drug or device, or concurrently enrolled in any other 
type of medical research judged not to be scientifically or medically compatible with this study.
[16] Known HCC with fibro-lamellar or mixed histology.
[17] Presence of clinically relevant ascites.

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[18] Liver transplant requiring increased immunosuppressive therapy.  (Patients on maintenance 
immunosuppressive therapy after liver transplant are eligible for Parts A and B.  Rapamycin analogues are 
not allowed.)
[19] Have received >1 line of systemic treatment in Parts A, B, and D.
[20] Have moderate or severe cardiac disease.
[21] Have serious preexisting medical conditions that, in the opinion of the investigator, cannot be adequately 
controlled with appropriate therapy or would preclude participation in this study.
[22] Females who are pregnant or lactating.
[23] Have a history of any other cancer (except nonmelanoma skin cancer or carcinoma in situ of the cervix) 
unless in complete remission and off all therapy for that disease for a minimum of 3 years.
At the discretion of the investigator, hormone-refractory prostate cancer patients who are stable on 
gonadotropin-releasing hormone (GnRH) agonist therapy and breast cancer patients who are stable on 
antiestrogen therapy (for example, an aromatase inhibitor) may have that treatment continued while they are 
enrolled in this study.
[24] Have active infection that would interfere with the study objectives or influence study compliance.
[25] For Part C, have a known hypersensitivity to sorafenib or its excipients.
[26] For Part D, have a serious illness or medical condition(s), including but not limited to the following:
a)
The patient has undergone major surgery within 28 days prior to randomization or has undergone 
central venous access device placement within 7 days prior to randomization.
b)
The patient has uncontrolled arterial hypertension ≥150 / ≥90 mm Hg despite standard medical 
management.
c)
The patient is receiving ongoing therapy with nonsteroidal anti-inflammatory agents (NSAIDs) (eg, 
indomethacin, ibuprofen, naproxen, nimesulide, celecoxib, etoricoxib, or similar agents) or other 
antiplatelet agents (eg, clopidogrel, ticlopidine, prasugrel, dipyridamole, picotamide, indobufen, 
anagrelide, triflusal, or similar agents).  Aspirin at dosages up to 100 mg/day is permitted.
d)
The patient is receiving therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or 
similar agents.  Patients receiving prophylactic, low-dose anticoagulation therapy are eligible provided 
that the coagulation parameters defined in the inclusion criteria are met.
e)
Uncontrolled thrombosis (including myocardial infarction, unstable angina, cerebrovascular accident, or 
transient ischemic attack within 6 months prior to randomization) or bleeding.
f)
The patient has experienced any Grade 3 or 4 gastrointestinal bleeding or any variceal bleeding episode 
in the 3 months prior to randomization requiring transfusion, endoscopic or operative intervention 
(patients with any bleeding episode considered life-threatening during the 3 months prior to 
randomization are excluded, regardless of transfusion or intervention status).  Patients who have 
esophageal or gastric varices that require immediate intervention or represent a high bleeding risk in the 
opinion of the investigator or consulting gastroenterologist or hepatologist are excluded.
g)
Elective or planned major surgery to be performed during the course of the clinical trial.
h)
Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to randomization.
i)
Known allergy or hypersensitivity to monoclonal antibody treatment or any components used in the 
ramucirumab drug product preparation.
j)
The patient's urinary protein is >1+ on dipstick or routine urinalysis.  If urine dipstick or routine 
analysis indicates ≥2+ proteinuria, then a 24-hour urine must be collected and must demonstrate <1000 
mg of protein in 24 hours to allow participation in the study.
k)
The patient has either a history of or current hepatic encephalopathy or current clinically meaningful 
ascites.  Clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring 
ongoing treatment with diuretics and/or paracentesis.

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Test Product, Dosage, and Mode of Administration:
Parts A and B:  LY2157299 is administered orally by daily dosing morning and evening (BID) at either 80 or 
150 mg per dose (total dosage of 160 or 300 mg daily) for 14 days, followed by 14 days with no study drug.  
(The exception is for patients who will have a Day 15 PK sample taken, who will omit the evening dose on Day 
14.)  This on/off schedule constitutes a cycle of 28 days.  In extenuating circumstances, the “on study drug” 
window is allowable from Day 10 to Day 14.  
Part C:  LY2157299 is administered orally by daily dosing morning and evening (BID) at either 80 or 150 mg 
per dose (total dosage of 160 or 300 mg daily) for 14 days, followed by 14 days with no study drug.  Sorafenib is 
administered orally by daily dosing morning and evening (BID) at 400 mg per dose (total dosage of 800 mg 
daily) for 28 days.  This constitutes a cycle of 28 days.
Part D:  LY2157299 is administered orally by daily dosing morning and evening (BID) at either 80 or 150 mg 
per dose (total dosage of 160 or 300 mg daily) for 14 days, followed by 14 days with no study drug.  
Ramucirumab is administered intravenously at 8 mg/kg on Days 1 and 15 of every cycle.  This constitutes a 
cycle of 28 days.
Part E:  LY2157299 is administered orally by daily dosing morning and evening (BID) at 150 mg per dose (total 
dosage of 300 mg daily) for 21 days, followed by 7 days with no study drug.
Planned Duration of Treatment Per Patient:  Per patient, the screening period is no more than 4 weeks or 28 
days before the first dose of LY2157299; the planned treatment duration is 6 cycles or approximately 24 weeks.  
However, patients may receive LY2157299 until their disease has progressed, the patient has died, or the patient 
discontinues for adverse events, investigator’s judgment, or other reasons.  Wash-out period:  none.
Planned Follow-Up Observation Period Per Patient:  Follow-up visits consist of a visit approximately 30 
days after the last study treatment and any subsequent follow-up approximately every 60 days (approximately 2 
months) (±7 days).  Patients who have discontinued study treatment without progression will continue to be 
followed for progression.  Every attempt should be made to gather all information every 2 months (radiological 
scans and survival), even if a patient starts a new anticancer therapy.  All patients will be followed until death.  
Patients who have entered the treatment extension period will be followed for just 30 days after treatment 
discontinuation.  
Reference Therapy, Dose and Mode of Administration: Not applicable
Criteria for Evaluation:
Efficacy: RECIST 1.1 and mRECIST, (mRECIST for HCC) for RR, TTP and PFS
Safety:  International Common Terminology Criteria for Adverse Events (CTCAE), version 4.0
Health Outcomes: PRO measures of disease-specific symptoms and health-related quality of life (FACT-Hep)
Bioanalytical: Plasma LY2157299/sorafenib/ramucirumab concentrations will be analyzed by liquid 
chromatography/mass spectrometry/mass spectrometry

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Statistical Methods:  
Outline of Design:  Approximately 205235 Child-Pugh Class A or B7 patients with HCC will be enrolled into 
this study.  In Parts A and B, patients were initially randomly assigned onto 1 of 2 doses, balanced based on AFP 
levels (≤400 ng/mL and >400 ng/mL), etiology, and whether sorafenib-naïve or not.  A planned interim analysis 
after approximately 10 (for PK and acute safety) patients enrolled into each dose and completed 1 cycle was 
carried out.  The second interim analysis for futility of 1 or both doses was not carried out but, as part of the 
continuous monitoring of safety, PK, and laboratory markers in patients with HCC, the sponsor noted that 
patients in both cohorts were staying on study beyond 4 months.  An additional data review was carried out 
based on 64 enrolled patients, and thea decision was made to dropstop enrollment to the 160 mg/day dose and to 
continue enrolling into enrollment to the 300 mg/day dose until 70 patients have beenwere treated was made.  
The protocol was amended (Amendment [b]) to have 3 parts.  The 2 cohorts planned in the original protocol and 
in Amendment (a) will bewere designated as Part A.  Part B will enrollenrolled approximately 40 patients with 
AFP levels <1.5x ULN and treattreated them with 300 mg/day intermittent dosing.  Two interim analyses 
arewere planned for Amendment (b) Part B – one after the last of the 70 patients with elevated AFP levels in 
Cohort 2 have started Cycle 1, and the second after 18 patients have enrolled into Part B and were actively 
followed for at least 3 months or have discontinued from study treatment.  Part C will enrollenrolled
approximately 4047 Child-Pugh Class A patients and will consistconsisted of a safety lead-in withof 2 dose-
escalation cohorts followed by an expansion cohort where the selected dose(s) of the combination treatment will 
bewere evaluated.  Part D will enroll approximately 1518 Child-Pugh Class A patients and will consist ofinto 2 
dose-escalation cohorts. Part E will initially enroll up to approximately 23 patients. This would give a total of 
approximately 205235 patients enrolled.
Safety:  Summary statistics, plots, and listings for all safety data collected will be provided in aggregate and by 
dose in Part A and Part C, and in aggregate for Part B separately.  Comparisons between doses and parts will be 
summarized for Part A and Part B, and may be compared to Part C.  Data from Part D and Part E will be 
summarized separately from the data in Parts A, B, and C.
Clinical Efficacy:  Time-to-event distributions will be characterized for each dose in each part (where data 
allow) using Kaplan-Meier methods, and various time-to-event parameters, such as median TTP, PFS, and OS 
and their rates at specified time points, will be estimated from their respective distributions.  The hazard ratios 
between doses for patients with elevated AFP levels and between groups of patients with elevated AFP and AFP 
levels <1.5x ULN at 300 mg/day will be estimated.  Sensitivity analyses using alternative models willmay also 
be performed.  RR will be summarized by dose and part.  Stratification factors used in the randomization willof 
Part A may be included as covariates in analyses between doses.  Beginning with Amendment (b), patients will 
no longer be randomized onto treatment, but the same covariates willmay be considered in analyses of clinical 
endpoints.  Data from Part D and Part E will be summarized separately from the data in Parts A, B, and C.
Health Outcomes:  Summary descriptive statistics by study part will be provided for the PRO data (FACT-Hep) 
at each time point and change from baseline.  Time to worsening of symptoms will also be evaluated.
Pharmacokinetics:  A population PK analysis will be performed on all patients receiving LY2157299.  A PK 
analysis will be performed for sorafenib as well for some patients being enrolled in Part C.  This analysis will 
explore the impact of covariates such as demographic factors and markers on the relevant PK parameters.  The 
LY2157299 PK, when administered in combination with ramucirumab, will be characterized.
Pharmacodynamics: Changes in response biomarkers, such as pSMAD in tumor tissue (or other TGF--related 
biomarkers) and lactate dehydrogenase, AFP, E-cadherin in serum will be estimated and may be correlated with 
clinical efficacy.  Exploratory population PK/pharmacodynamic analyses may be conducted to identify the 
exposure-biomarker response relationship.  

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Health Outcomes:  Summary descriptive statistics by study part will be provided for the PRO data (FACT-Hep) 
at each time point and change from baseline.  Time to worsening of symptoms will also be evaluated.
Pharmacokinetics:  A population PK analysis will be performed on all patients receiving LY2157299.  A PK 
analysis will be performed for sorafenib as well for some patients enrolled in Part C.  This analysis will explore 
the impact of covariates such as demographic factors and markers on the relevant PK parameters.  In Part D, the 
LY2157299 and ramucirumab PK administered in combination will be characterized. In Part E, the PK of 
LY2157299, when administered according to a 21 days on /7 days off treatment schedule, will be characterized.
Pharmacodynamics: Changes in response biomarkers, such as pSMAD in tumor tissue (or other TGF--related 
biomarkers) and lactate dehydrogenase, AFP, E-cadherin in serum will be estimated and may be correlated with 
clinical efficacy.  Exploratory population PK/pharmacodynamic analyses may be conducted to identify the 
exposure-biomarker response relationship.  
4. Abbreviations and Definitions
IWRS
interactive web response system
5. Introduction
Different agents have been tested as second-line therapy in HCC patients (Table JBAK.51).
Time to progression without any treatment is estimated to be 2.7 months (Llovet et al. 2012). 

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Table JBAK.5.1.1.
Examples of Experimental Treatments as Second-Line Therapy in Patients with Hepatocellular 
Carcinoma
Study
Patient 
(n)
Treatment
Time to Progression 
or Time to 
Treatment Failure
(median months)
Method
Response 
Rate
OS 
(median, 
months)
Reference
Phase II
46
Brivanib
2.7
mWHO (assessed by PI)
4.3%
9.7
Finn et al. 2012
1.77 
(95% CI, 1.38–4.01)
mWHO (assessed by 
IRRC)
4.3%
6.9
(95% CI, 3.9–NR)
mRECIST (assessed by 
independent radiologist)
10.9%
Phase III
263
Brivanib
4.2
mRECIST
11.5%
9.4
Llovet et al. 2012
132
Placebo
2.7
mRECIST
1.9%
8.2
Phase I/II
28
Everolimus
3.9
(95% CI, 2.1-5.5)
RECIST
4%
8.4
Zhu et al. 2011 
Phase II
38
Sunitinib
2.9 months 
(95% CI, 0.5-15)
-
6%
Yau et al. 2011
Phase II
11
Sunitinib
3.2 months 
RECIST
8.4
Wörns et al. 2010 
Phase II
18
Gemcitabine 
Oxaliplatin
PFS 3.2
(95 % CI, 2.3–3.9)
4.7
Mir et al. 2012 
Phase III
283
Ramucirumab
3.48
RECIST
7.1%
9.17
Zhu et al. 2015
Phase III
573
Regorafenib
3.2
mRECIST
10.6%
10.6
Bruix et al. 2016
Abbreviations:  CI = confidence interval; IRRC= independent response review committee; mRECIST = modified Response Evaluation Criterial in Solid Tumors; 
mWHO = modified World Health Organization; NR = not reached; OS = overall survival; PFS = progression free survival; PI – principal investigator.

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5.1.4.1. Overall Conclusions
Collectively, the findings in the continuous 3- and 6-month daily-dosing toxicity studies, 
particularly the degeneration of the large blood vessels, imply that long-term, daily dosing of 
LY2157299 may carry a risk in patients for developing aneurysms.  Reversibility was not 
assessed in the 3- or 6-month toxicity studies, but in a non-GLP reversibility study in rat, data 
indicate the cardiovascular lesions are partially reversible, but those that are still present 
following the recovery period are still adverse.  The intermittent-dosing regimen in patients is 
based on the safety demonstrated in the rat and dog following 1 month of continuous daily 
dosing in which the NOEL for any effects in the heart was 150 and 20 mg/kg in the rat and dog, 
respectively, and a 3-month intermittent-dosing study in the rat in which the NOEL for any 
effects in the heart was 50 mg/kg (see Table JBAK.5.2 for margin-of-safety [MOS] calculations).  
Although the likelihood of occurrence or the extent and timing of such a risk observed after daily 
dosing is not known in humans, LY2157299 will be administered as an intermittent-dosing 
regimen in this patient population which has a poor prognosis and rapidly advancing cancer.
Table JBAK.5.2..2.
Margin of Safety Based on NOEL to Cardiovascular Effects 
5.1.5.1. Safety
As of 15 September 2015, approximately 696 patients and 20 healthy subjects have received 
treatment with LY2157299, either in monotherapy or in combination with chemotherapy.  These 
include clinical trial patients with advanced/metastatic cancer, solid tumors, glioblastoma, 
pancreatic cancer, HCC and myelodysplastic syndromes (MDS).
Overall, few SAEs deemed by investigators to be associated with drug treatment have been 
reported.  Most treatment-related SAEs have been reported in 1 patient except anemia (2 patients 
with HCC), cardiac failure (2 patients with MDS), neutropenia (1 patient with glioblastoma and 
1 patient with HCC), thrombocytopenia (2 patients with glioblastoma), peritoneal hemorrhage 
(2 patients with HCC), and diarrhea (1 patient with glioblastoma and 1 patient with HCC).  The 
SAE profile seems to differ when LY2157299 is used in patients with glioblastoma, MDS, and 
HCC, indicating a possibility that reporting rates are influenced by the underlying disease and 
there have been no trends or signals noted in the reported SAEs.  
The most common TEAEs (≥10%) for LY2157299 monotherapy are fatigue (19%), anemia 
(18%), abdominal pain (18%), edema peripheral (15%), nausea (15%), asthenia (14%), diarrhea 
(14%), vomiting (14%), abdominal pain (12%), headache (12%), constipation (10%), decreased 
appetite (10%), and pruritus (10%).  Most of these AEs were of mild or moderate severity.
The addition of LY2157299 to standard cancer treatments appeared to have no effect on the 
established toxicity profile of these standard therapies.
Extensive cardiac safety monitoring has been conducted in all clinical studies, and available data 
has shown no indication of a LY2157299-related cardiac toxicity.  
The intermittent dosing regimen of 14 days on treatment with LY2157299 followed by 14 days 
off treatment (1 cycle = 28 days) that has been used in clinical development to date appears to be 

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well tolerated with no clinically significant valvulopathies or aneurysms reported or observed at 
dosages of up to 300 mg/day. 
For additional details, please refer to the LY2157299 IB, Section 6.
5.1.5.2. JBAK:  Brief Summary of Results to Date
At the time of Amendment (e), Part A and Part B of the study have completed.  A total of 149 
patients were enrolled (109 in Part A and 40 in Part B).  Eighty-five percent of patients were 
male and the median age was 65 years.  Fifty-six percent of patients had an ECOG performance 
status (PS) of 0 and 44% had a PS of 1.  Eighty-six percent of patients had a Child-Pugh Class A 
score and 14% had a Class B score.  Etiology of disease was a follows:  hepatitis C 24%, 
hepatitis B 20%, alcohol 20%; multiple 9.4%.  Overall, 83% of patients had received prior 
sorafenib.  Eleven patients discontinued treatment due to AEs:  8 were considered related to 
study treatment.  Grade 3/4 AEs possibly related to treatment were observed in 26 (17%) 
patients.  Of these AEs, neutrophil count decrease was observed in 4 patients.  Anemia, 
hypoalbuminemia, decreased bilirubin, fatigue and embolism were observed in 2 patients each.  
All other AEs occurred in just 1 patient.  Median TTP was 11.9 weeks (95% CI:  6.3, 12.6) in 
Part A and 18.0 weeks (95% CI:  10.0, 24.0) in Part B.  Median OS was 31.4 weeks (95% CI:  
22.9, 40.6) in Part A and 73.0 weeks (95% CI:  45.4, 104.7) in Part B.  The median OS for the 
overall population was estimated as 40.4 weeks (95% CI:  31.1, 52.4) (Giannelli et al. 2016).
Enrollment into Part C has completed and maturation of the data is awaited.  Enrollment is 
ongoing in Part D of the study.
5.1.7. Rationale for Amendment (b)
Preliminary PK data from the first interim analysis (n=20 patients) suggest that patients 
administered 300 mg/day have higher exposures than previously observed for the same dose 
level (Study JBAH) during the treatment period.  LY2157299 appears to be fully eliminated after 
the 14-days off period of a cycle (additional PK sampling is added to study the clearance of 
LY2157299).  The lowest exposure level (ie, most conservative) in the most sensitive nonclinical 
species administered LY2157299 in a clinically relevant dosing schedule (2 weeks on/2 weeks 
off) in which cardiac effects were observed was 24 μg*hr/mL (Table JBAK.5.2).  The findings at 
this dose level (150 mg/kg) consisted of a single male rat (n=10/group) with minimal 
inflammation in the aortic valve and ascending aorta.  Administration of 300 mg/day to patients 
with HCC may result in higher than anticipated exposures; however, due to the clinical safety 
profile observed thus far and the benefit:risk in this patient population, this approach is 
considered acceptable.  
5.1.10. Rationale for Amendment (e)
The protocol is being amended to add a Part E that will allow the evaluation of the safety and 
tolerability, pharmacokinetics and efficacy of LY2157299 administered according to a 21 days 
on/7 days off schedule.

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Across the clinical development program at the time of Amendment (e), LY2157299 has shown 
a favorable short- and long-term toxicity profile in different studies and activity in different 
tumor types.
In light of cardiotoxicity observed in nonclinical trials of LY2157299, comprehensive cardiac 
safety monitoring was implemented in all clinical trials of LY2157299, including Study JBAK, 
and has been ongoing until the time of this amendment.
Using a data cut-off date of 15 September 2015, Lilly has performed a cross-study 
cardiovascular (CV) safety analysis of 745 patients from 10 completed and ongoing unblinded 
studies of LY2157299, including patients assigned to standard of care control arms who did not 
receive LY2157299.  This analysis included a review of CV-related TEAEs and SAEs (with a 
focus on patients with increased valvular insufficiency and vascular-related 
hemorrhage/aneurysm, as well as patients with events of heart failure) and a correlation of 
TEAE/SAE data with central echocardiography findings, chest CT scan and/or MRI findings, 
cardiac laboratory markers (BNP, cystatin C, and troponin I) and central ECG findings.  The 
cumulative results of this cross-study analysis did not identify any concerning trends in AEs, in 
particular those related to valvulopathies or aneurysms.  
As described in Section 5.1.4, nonclinical toxicology data have determined a no-effect level for 
CV lesions that is higher than the observed and anticipated exposures in Study JBAK and other 
clinical trials.  There is also no evidence of accumulation in patients given multiple doses of 
LY2157299 at 150 mg BID, suggesting that daily exposures on a schedule with increased days of 
dosing will remain lower than the no-effect-level for CV lesions characterized in toxicology 
studies.
In view of  these clinical and nonclinical observations, Lilly has proposed and received 
endorsement from the United States (US) Food and Drug Administration to explore a new 
treatment schedule for LY2157299 in Part E of amended Study JBAK.  This schedule will dose 
LY215729 at 150 mg twice daily for 21 days, followed by 7 days off drug (cycle length= 28 
days).  The goal is to improve upon the efficacy that has been observed in patients receiving 
LY2157299 on a 14 days on/14 days off schedule by increasing time on target and thereby 
limiting chances for tumor regrowth and resistance.
Amendment (e) also includes the provision that Part D of Study JBAK will be conducted outside 
of the European Union (EU) and clarification on how Part D expansion will be conducted. 
Attachment 17 lists changes made in the protocol amendment. (e).
6.2. Secondary Objectives

To recommend which doses of LY2157299 as monotherapy and in 
combination with sorafenib or ramucirumab to use in future trials recruiting 
HCC patients 

To evaluate the safety and tolerability, pharmacokinetics and efficacy of 
LY2157299 as monotherapy administered according to a 21 days on/7 days 
off schedule

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LY2157299

To characterize other time-to-event distributions, such as progression-free 
survival (PFS, based on Response Evaluation Criteria in Solid Tumors
[RECIST] 1.1 and modified RECIST [mRECIST], for HCC) and OS
7.1. Summary of Study Design
Study JBAK is a multicenter, randomized trial characterizing the TTP distribution of 2 dose 
levels of LY2157299 in patients with Child-Pugh Class A or B HCC patients.
Approximately 205235 patients will be enrolled into the study:  107 109 have been enrolled into 
Part A, 40 into Part B, 4047 into Part C, and 15 inapproximately 18 into Part D and 
approximately 23 into Part E.
Starting with Amendment (de), there are 45 parts to this study:  Child-Pugh A and B7 patients 
are enrolled in Part A and Part B; 
Parts A and B are
Part A and Part B enrolled patients with Child-Pugh Class A and B7 status HCC, distinguished
based onby baseline AFP levels.  Parts A and B enrolled Child-Pugh A and B7 patients , who 
had either progressed on sorafenib or were ineligible to receive sorafenib, whereas Part C.  
Enrollment is enrolling  Child-Pugh A patients who have not received previous systemic therapy.
complete with 109 patients enrolled into Part D of the study will enroll Child-Pugh A patientsA 
and 40 into Part B.
In Part A, patients with AFP ≥1.5x ULN will bewere randomized to 2 cohorts based on initial 
dose of LY2157299 to be received (160 or 300 mg/day).  Eligible patients will bewere
randomized intoto 1 of these cohorts (the 2 cohorts being balanced as far as possible for AFP 
levels, etiology, and whether or not sorafenib -naïve or not at both planned interims) and the final 
analysis) and will receivereceived LY2157299 for 14 days followed by 14 days of rest (Figure 
JBAK.7.1).
At this point, Amendment (b) was implemented to continue enrolling into Cohort 2 of Part A and 
to initiate enrollment into Part B and included changes to the planned interim analyses.
In Part B, patients with AFP <1.5x ULN will receive LY2157299 300 mg/day for 14 days 
followed by 14 days of rest (Figure JBAK.7.1).  The third interim analysis will occur after 18 
patients have been The second planned interim analysis for Part A (based on N=106 patients, 
Cohorts 1 and 2) was completed after the last patient had enrolled into Cohort 2 (n=69) and 
started Cycle 1.  Detailed information is given in Section 12.2.14 (Interim Analyses).  
Enrollment continuescontinued during all data reviews and interim analyses.
In Part B, patients with AFP <1.5x ULN received LY2157299 300 mg/day for 14 days followed 
by 14 days of rest (Figure JBAK.1).  The third interim analysis occurred after 18 patients had 
been treated and completed 3 cycles or discontinued from study treatment.  Detailed information 
is given in Section 12.2.14 (Interim Analyses).

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LY2157299
Figure JBAK.7.1.1.
Illustration of study design for Protocol H9H-MC-JBAK Parts A and 
B.
Part C will evaluate
Part C evaluated LY2157299 in combination with sorafenib in patients with advanced HCC and 
Child-Pugh Class A status who havehad not received previous systemic treatment.  Up to 40 
patients maywere planned to be enrolled. Enrollment is complete and a total of 47 patients have 
been treated.  
Part C comprisescomprised a safety lead-in of 2 cohorts followed by an expansion phase with 
selected safe dose(s) (Figure JBAK.7.2).  Patients enrolled in Cohort 1 will bewere administered 
LY2157299 80 mg BID on Days 1 to 14 in combination with sorafenib at 400 mg BID on Days 1 
to 28 on a 28-day cycle.  Three patients will were planned to be enrolled onin Cohort 1; if no 
dose-limiting toxicities (DLTs) (related to LY2157299 or combination regimen) arewere
observed in Cycle 1, 3 patients willwere to be treated onin Cohort 2 at LY2157299 150 mg BID 
on Days 1 to 14 in combination with sorafenib at 400 mg BID on Days 1 to 28 on a 28-day cycle.  
If a DLT related to LY2157299 or combination regimen iswas observed in either cohort in the 
first 3 patients in Cycle 1, then that cohort willwas to be expanded to include an additional 3 
patients.  Six to 12 patients maywere planned to be enrolled in the safety lead-in, depending on 
the observed DLTs.  See Section 9.1.5 for more detailed dose escalation and expansion criteria.  
PK sampling will bewas conducted in Cycle 1 with the intent to assess drug-drug interactions 
between LY2157299 and sorafenib (Attachment 4).  
Depending on the results from the safety lead-in cohorts and analysis from Parts A and B, the 
expansion cohort willwas to consist of 1 of the following:

Single treatment group:  LY2157299 80 mg BID on Days 1 to 14 in combination with 
sorafenib at 400 mg BID on Days 1 to 28 on a 28-day cycle, or

Single treatment group:  LY2157299 150 mg BID on Days 1 to 14 in combination with 
sorafenib at 400 mg BID on Days 1 to 28 on a 28-day cycle, or

Two treatment groups:  LY2157299 80 mg BID on Days 1 to 14 in combination with 
sorafenib at 400 mg BID on Days 1 to 28 versus LY2157299 150 mg BID on Days 1 to 
14 in combination with sorafenib at 400 mg BID on Days 1 to 28.  Both cohorts willwere 
to be on a 28-day cycle.
Patients enrolled in the safety lead-in cohorts maywere to continue treatment as per that cohort.  

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Figure JBAK.7.2.2.
Illustration of study design for Protocol H9H-MC-JBAK Part C.
Part D
Part D will be conducted outside of the EU and will evaluate LY2157299 in combination with 
ramucirumab in patients with advanced HCC and Child-Pugh Class A status.  Up to 
approximately 15 patients may be enrolled.  
Part D comprises 2 cohorts (Figure JBAK.7.3).  Patients enrolled in Cohort 1 will be 
administered LY2157299 80 mg BID on Days 1 to 14 in combination with ramucirumab 
administered at 8 mg/kg as an intravenous (IV) infusion on Days 1 and 15 of every cycle.  
Approximately 18 patients may be enrolled to allow the selected dose to be expanded to 
approximately 15 patients in total.  
Three patients will be initially enrolled on Cohort 1; if no dose-limiting toxicities (DLTs) 
(related to LY2157299 or the combination regimen) are observed in Cycle 1, then 3 patients will 
be treated on Cohort 2 at LY2157299 150 mg BID on Days 1 to 14 in combination with 
ramucirumab 8 mg/kg administered as an IV infusion on Days 1 and 15 of every cycle.  If a DLT 
related to LY2157299 or combination regimen is observed in either cohort in the first 3 patients 
in Cycle 1, then that cohort will be expanded to include an additional 3 patients. the combination 
regimen is observed in the first 3 patients in Cycle 1 of Cohort 1, Cohort 1 will enroll an 
additional 3 patients.  If no further DLTs are observed, Cohort 2 will be opened.  If 1 or more 
additional DLTs are observed in Cohort 1, Part D will close.  If Cohort 2 is opened and no DLTs 
are observed in the first 3 patients, Cohort 2 will be expanded until approximately 15 patients 
have been enrolled.  If 1 DLT is observed in Cycle 1 in the first 3 patients in Cohort 2, another 3 
patients will be enrolled.  If 2 or more DLTs are observed in the first 3 patients or 1 or more 
DLTS are observed in the additional 3 patients in Cohort 2, a safety review by Lilly and the 
investigators will occur to decide whether to expand Cohort 1.  If no further DLTs are observed 
in Cohort 2, Cohort 2 will be expanded until a total of approximately 15 patients have been 
enrolled at this dose.  See Section 9.1.5 for more detailed dose escalation and expansion criteria.

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PK sampling will be conducted in Cycles 1 and 2 with the intent to assess changes in 
LY2157299 and ramucirumab exposure when coadministered with ramucirumab administered in 
combination (Attachment 4).  
Abbreviations:  BID = twice daily; IV = intravenous.
Figure JBAK.14.1.
Illustration of study design for Protocol H9H-MC-JBAK Part D.
Abbreviations:  BID = twice daily; IV = intravenous.
Figure JBAK.3.
Illustration of study design for Protocol H9H-MC-JBAK Part D.
Part E
Part E will evaluate the safety, tolerability, pharmacokinetics and efficacy of LY2157299 given 
according to a 21 days on/7 days off schedule in patients with Child-Pugh Class A HCC who 
have received at least one prior line of systemic treatment or who have not received prior 
Screening: 
Child-Pugh A
Part D
Cohort 1:  80mg LY2157299 BID Days 1-14 plus 
ramucirumab 8 mg/kg IV on Days 1 and 15 of each cycle
Cohort 2:  150mg LY2157299 BID Days 1-14 plus 
ramucirumab8 mg/kg IV on Days 1 and 15 of each cycle

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treatment and are ineligible for sorafenib treatment (at the investigator’s discretion).  Up to 
approximately 23 patients may be enrolled.  
Figure JBAK.4 shows the Part E study design.
It is planned that Part E will initially enroll up to 3 patients.  Enrollment will halt after the first 3 
patients have received their first dose of treatment.  If a patient discontinues study treatment 
within the first cycle of therapy for any reason other than a dose-limiting toxicity (DLT), that 
patient may be deemed unevaluable and replaced.  A safety evaluation will occur after the third 
evaluable patient has completed one cycle of therapy.  Dose -limiting toxicities will be as defined 
in Section 9.1.5.1.  If DLTs are observed in 2 of the first 3 patients dosed, Part E will close. If 
DLTs are observed in 1 of the 3 patients, a safety assessment will occur after the next 3 
evaluable patients have completed 1 cycle.  If the schedule is deemed to be tolerable (<33% 
DLTs in Cycle 1 as well as consideration of the overall safety profile from later cycles), 
additional patients will be enrolled so that data from approximately 20 patients will be available
to better characterize the safety of the schedule and allow comparison to safety, 
pharmacokinetics and efficacy results in other cohorts. 
Recognizing that potential CV effects may occur after the initial DLT period, patients will be 
regularly monitored according to a stringent schedule and as part of a trial level safety review.  
Trial level safety reviews will occur approximately every 3 months, beginning after the initial 
DLT evaluation period.
Abbreviation:  BID = twice daily.
Figure JBAK.4.
Illustration of study design for Protocol H9H-MC-JBAK Part E.
All Study Parts
One cycle is defined as 28 days (a minimum of 26 days and a maximum of 31 days:  the).  The
treatment period for LY2157299 must be a minimum of 10 days and a maximum of 14 days; (for 

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Parts A, B, C and D) and 21 days (for Part E); the “off-treatment” period can vary to ensure an 
overall cycle length of 26 to 31 days).  In extenuating circumstances, the “on study drug”
window for LY2157299 is allowable from Day 10 to Day 14. (In Part C and D safety lead-in 
Cycle 1 and Part D Cycle 1,, patients must have received 14 days of LY2157299 treatment). For 
Part E Cycle 1, all patients must receive 21 days of treatment, followed by 7 days off treatment.
If patients are not evaluable for safetyDLT assessment and/or PK in Cycle 1 of Part C or Part D
safety lead-in, or Cycle 1 of Part DE, the patients will be replaced.
Per patient, the screening period is no more than 4 weeks or 28 days before the first dose of 
LY2157299; the planned treatment duration is 6 cycles or approximately 24 weeks, but patients 
may continue to receive study drug if they are still benefiting from treatment in the opinion of 
the investigator and Lilly physician.  Follow-up visits consist of a visitwill occur approximately 
30 days after the last day of study treatment and any subsequent follow-upsubsequently 
approximately every 60 days (approximately 2 months) (± [±7 days).]).
In case of the occurrence of severe toxicities in later cycles in patients being treated with either 
LY2157299 monotherapy or with LY2157299 in combination with ramucirumab or sorafenib, 
the sponsor will review and choose a lower dose or discontinue the patient, if necessary.  
This PhaseThe final analysis for Parts A and B will be conducted after the study objectives for 
these 2 parts have been met.  This is likely to be after approximately 30 deaths have occurred in 
Part B in order to have a reasonable estimate of overall survival in this patient group (AFP <1.5x 
ULN).  study
Part C will be considered complete and the final analysis initiated once 85% of events for 
survival analysis in the expanded cohort in Part C have occurred and patients in .  
Part D havewill be considered complete and the final analysis initiated after the last patient has
discontinued from study treatment (includingand completed at least the 30-day follow-up visit 
([Visit 801).  Patients ].
Part E will be considered complete and the final analysis initiated after the last patient has 
discontinued from study treatment and completed at least the 30-day follow-up visit [Visit 801]. 
At the time all parts of the study are considered complete, the study will be considered complete 
and those patients still on treatment at the time that the study is considered complete may enter 
the treatment extension period and continue to receive the study treatment (see Section 7.1.1).
All patients will be followed for OS until study completion.
End of study (trial) is the date of the last visit or last scheduled procedure shown in the Study 
Schedule for the last active subject in the study. (this includes all patients who enter the 
extension period).  The European Union (EU) has additional reporting requirements associated 
with the end of study.  Consult regional standard operating procedures (SOPs) for further 
information.

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7.1.1. Extension Period
After study completion (ie,i.e., study objectives met, see Section 7.1), all patients who are on 
study treatment (LY2157299 alone or LY2157299 with sorafenib [in Part C] or, LY2157299 
with ramucirumab [in Part D]), or LY2157299 alone in Part E) and who are eligible for the 
extension period may continue to receive study treatment until one of the criteria for treatment 
discontinuation is met (Section 8.3.1).  Patients who are no longer on study treatment at the time 
of study completion and who have completed at least the 30-day follow-up visit (V801) will be 
discontinued from long-term follow-up and therefore reach the end of the study, unless they are 
being followed due to unresolved safety concerns.  Lilly will notify investigato rs when the 
extension period begins.  
AllDuring the extension period, all AEs and study drug exposure will be reported on the case 
report form (CRF).  SAEs will also be reported on the CRF and to Lilly Global Patient Safety 
(see Section 10.2.1.1).  In the event that an SAE occurs, Lilly may request additional information 
(such as local laboratory results, concomitant medications, and hospitalizations) in order to 
evaluate the reported SAE.
All patients in the extension period will be treated following the Study Schedule (see 
Attachment 1).  This will ensure that appropriate risk/benefit assessmentassessments are 
conducted for all patients.
The patient’s participation in the extension period will end after study drug(s) is discontinued.  
The date and reason for treatment discontinuation will be collected on the CRF.  Data will be 
collected until 30 days after the patient has been discontinued from study treatment and at this 
point, the patient will have ended the study.  If the patient dies within the 30-day follow-up 
period, the reason for study discontinuation will be “Death,””, and the cause and date of death 
recorded.  Otherwise, the reason for study discontinuation will be noted as “Completed.””.  
There will be no long-term postdiscontinuationpost-discontinuation follow-up period for these 
patients, unless any safety concerns have not resolved.  Requests for updates ofon survival may 
be requestedoccur.  
After the last of the patients in the extension period has completed their 30-day follow-up period, 
an addendum report will be written listing the details of data collected from patients entered onin
this phase.  The addendum report will not be delayed due to any patients beingcontinuing in 
long-term follow-up, but will note those patients who are still in long-term follow-up due to 
unresolved safety issues.  
7.2. Discussion of Design and Control
ThisPart A of this open-label, multicenter, multicountrymulti-country Phase 2 study began 
withof patients randomized ontoto receive 1 of 2 doses of LY2157299 is an appropriate design 
for assessing antitumor activity and tolerability in thisan HCC patient population, and who have
with no alternative therapy.  The options, including patients who the investigator may 
decidedecides not to give sorafenib (Parts A and B) based on its toxicity profile, the condition of 

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the patient, the institutional practice guidelines (see guidelines in Attachment 15), andor other 
reasons that justify not administering sorafenib.
TTP is recommended as the main time-to-event endpoint to capture possible antitumor benefits 
in Phase 2 trials testing molecular-targeted therapies in HCC because it is less vulnerable (only 
progression captured) than composite endpoints (Llovet et al. 2008; Thomas et al. 2010).  
The requirement of including patients in Part A with an elevated AFP (≥1.5 x ULN) in Part A is 
based on previous studies suggesting that patients with elevated AFP may also have increased 
levels of TGF-1 and thus have an activated TGF-pathway.  For Part B, it was decided to 
evaluate the effectsThe enrollment of LY2157299 in patients with AFP <1.5x5 x ULN to have an 
overallinto Part B, will allow a comprehensive assessment of LY2157299 efficacy in all HCC 
patients. Patients will be enrolled into Part A or B based on the local AFP assessment into Part 
A or Part B.  For the final study assessment, the centrally collected AFP values will be used.  At 
enrollment, the local AFP value may be higher or lower than the centrally -assessed AFP values,
and this will not constitute a protocol violation.  Part C will allow safety and efficacy assessment 
of LY2157299 combination with sorafenib in first-line patients.  Sorafenib is the approved agent 
in first-line HCC.  Part D will allow safety assessment of LY2157299 in combination with 
ramucirumab.
Part C will allow safety and efficacy assessment of LY2157299 combination with sorafenib as  
first-line treatment for HCC.  Sorafenib is the approved agent for first-line treatment of HCC.  
Part D will allow a safety assessment of LY2157299 in combination with ramucirumab.
Part E will allow assessment of the safety and tolerability, pharmacokinetics and efficacy of 
LY2157299 administered according to a 21 days on/7 days off schedule, as well as comparison 
of these endpoints to that observed in patients on the 14 days on/14 days off schedule.  At least 
approximately 20 patients must complete 21 days of therapy in order to have sufficient 
information to assess tolerability of the regimen.
8.1. Inclusion Criteria
[1]
Have histological evidence of a diagnosis of HCC not amenable to curative 
surgery.
[2]
HaveAre Child-Pugh Class:
- Parts A and B:
A or B7 (see Attachment 5)
- Parts C and D:  A
- Part E:  A
[5]
AgeAre age 18 years.
[6]
Have given written informed consent prior to any study-specific procedures.
[9]
Have either:
In Parts A and B:

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- received sorafenib and have progressed or were intolerant to sorafenib, or
- are ineligible for sorafenib treatment (at the investigator’s discretion).
In Part E: 
- received at least one prior line of systemic therapy, or
- not received prior treatment and are ineligible for sorafenib treatment (at the
  investigator’s discretion).
[10] In Parts A, B, and D and E:  have discontinued sorafenib for at least 2 weeks.
8.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion Criterion [15] eliminates drugs that cannot be mapped to a standard drug dictionary or 
for which little data are known to analyze the potential relationship of AEs or drug in teractions.
Exclusion Criterion [20] excludes patients with compromised cardiac function that could be at 
risk when receiving LY2157299.  Based on the nonclinical toxicology assessment, patients with 
cardiac insufficiency or damage to large vessels of the heart will be carefully screened.  All 
moderate and severe cases of cardiac insufficiency will be excluded.  Because of the average age 
of most patients eligible for this study, mild or minimal cardiac disease is commonly present, and 
therefore these patients will not be excluded (Singh et al. 1999).  If CT scan of the chest cannot 
be performed, MRI can also be used as an alternative imaging procedure.
9.1. Treatments Administered
Patients will keep a study diary to document that they are taking LY2157299 (Parts C, D and 
DE) and sorafenib (Part C only) correctly.
9.1.1. Parts A and B
Table JBAK.9.1.3.
Treatment Regimens for Parts A and B
LY2157299
Daily Dose
Schedule
Time of Day
Part A (Cohort 1) 
80 mg BID LY
Daily
14 days on/14 days off
Morning and evening for 
14 days and then paused for 
14 days.
Part A (Cohort 2) and Part B
150 mg BID LY
Daily
14 days on/14 days off
Morning and evening for 
14 days and then paused for 
14 days.
Abbreviations:  BID = twice daily; LY = LY2157299; PK = pharmacokinetic.
Note:  For patients who will have a Day 15 PK sample taken, the evening dose on Day 14 will be omitted to allow 
for a 24-hour time period between the Day 14 morning dose and the Day 15 PK sample.
In extenuating circumstances, the ‘on study drug’ window is allowable from Day 10 to Day 14.  
9.1.2. Part C
Part C comprises a safety lead-in of 2 dose-escalation cohorts followed by an expansion phase 
with selected dose(s).  This part involves characterization of LY2157299 administered at either 

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80 mg BID or 150 mg BID for 14 days followed by 14 days off and sorafenib 400 mg BID for 
28 days administered orally to Child-Pugh Class A HCC patients.  LY2157299 and sorafenib 
need to be taken at the same time, within a 15-minute window.  A cycle is defined as 28 days.  
Table JBAK.9.24 shows the proposed dose levels and schedule for Part C.  
Table JBAK.9.2..4.
Treatment Regimens for Part C
Daily Dose
Schedule
Time of Day
Safety lead-in Cohort 1 
80 mg BID LY
plus 
400 mg BID sorafenib 
Daily
14 days on/14 days off
Daily 
Morning and evening for 
14 days and then paused for 
14 days.
Take in the morning and 
evening with LY dose
Safety lead-in Cohort 2 
150 mg BID LY
plus 
400 mg BID sorafenib
Daily
14 days on/14 days off
Daily
Morning and evening for 
14 days and then paused for 
14 days.
Take in the morning and 
evening with LY dose 
Expansion cohort
Recommended LY 
dose(s) from safety 
lead-in
plus 
400 mg BID sorafenib
Daily
14 days on/14 days off
Daily
Morning and evening for 
14 days and then paused for 
14 days.
Take in the morning and 
evening with LY dose
Note:  For patients who will have a Day 15 PK sample taken, the evening dose on Day 14 will be omitted to allow 
for a 24-hour time period between the Day 14 morning dose and the Day 15 PK sample.
In extenuating circumstances, the “on study drug” window for LY2157299 is allowable from Day 10 to Day 14.
Abbreviations:  BID = twice daily; LY = LY2157299; PK = pharmacokinetic.
9.1.3. Part D
A cycle is defined as 28 days.  Table JBAK.9.35 shows the proposed dose levels and schedule 
for Part D.  
Table JBAK.9.3.5.
Treatment Regimens for Part D
Dose
Schedule
Time of Day
Cohort 1 
80 mg BID LY
plus 
8 mg/kg ramucirumab
Daily by oral administration
14 days on/14 days off
Days 1 and 15 each cycle by IV 
administration 
(given over 60 min)
Morning and evening for 
14 days and then paused for 14 days.
On Day 1 of each cycle, morning within 
30 min of LY2157299 administration; on 
Day 15 of each cycle, morning
Cohort 2 
150 mg BID LY
plus 
Daily by oral administration
14 days on/14 days off
Morning and evening for 
14 days and then paused for 14 days.

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8 mg/kg ramucirumab
Days 1 and 15 each cycle by IV 
administration 
(given over 60 min)
On Day 1 of each cycle, morning within 
30 min of LY2157299 administration; on 
Day 15 of each cycle, morning
Note:  For patients who will have a Day 15 PK sample taken, the evening dose on Day 14 will be omitted to allow 
for a 24-hour time period between the Day 14 morning dose and the Day 15 PK sample.
In extenuating circumstances, the on-study-drug window for LY2157299 is allowable from Day 10 to Day 14.
Abbreviations:  BID = twice daily; IV = intravenous; LY = LY2157299; min = minutes; PK = pharmacokinetic.
9.1.4. Part E
In Part E, LY2157299 will be administered orally at 150 mg BID for 21 days followed by 7 days 
off.  A cycle is defined as 28 days.  Section 9.1.5.1 details the DLT criteria that will be used.  
Table JBAK.6 shows the proposed dose level and schedule for Part E.  
Table JBAK.6.
Treatment Regimen for Part E
Dose
Schedule
Time of Day
LY2157299 150 mg BID Daily by oral administration
21 days on/7days off
Morning and evening for 
21 days and then paused for 7 days
Abbreviations:  BID = twice daily.
9.1.5. Criteria for Dose Escalation (Parts C and D)
By nature of being a dose-escalation safety assessment, data will be evaluated on an ongoing 
basis until the MTD is determined, as defined in Section 9.1.45.1.  The maximum dose of 
LY2157299 will be 150 mg BID.  Safety data, in particular AEs, will be the primary criteria for 
the dose escalation.  The dose will be escalated following assessment of toxicity using the 
standard scoring system, CTCAE version 4.0, established by the National Cancer Institute (NCI).  
Any AEs related to LY2157299 or sorafenib (Part C) or ramucirumab (Part D) will be 
considered as toxicities.
In this part, intrapatientIntrapatient 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 clinical research physician (CRP).  The decision will be documented in 
writing.
9.1.5.1. Dose-Limiting Toxicity Determination and Maximum Tolerated Dose Definition 
(Parts C, D and DE)
A DLT is defined as an AE during Cycle 1 in Cohorts 1 or 2 that is related to the LY2157299 
and sorafenib combination regimen orin Part C, to the LY2157299 and ramucirumab 
combination regimen in Part D, or to LY2157299 administered on a 21 days on / 7 days off 
schedule in Part E and fulfills any 1 of the following criterioncriteria using the NCI CTCAE v 
4.0:
For the purpose of this study, the MTD is defined as the highest tested dose in each part that has 
<33% probability of causing a DLT during Cycle 1.

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As patients receive more cycles of treatment, investigators, together with the Lilly CRP, can 
declare a DLT-equivalent toxicity if a patient is experiencing increasing toxicity during treatment 
in later cycles (ie, other than Cycle 1), and it becomes clear that it will not be possible to 
complete the treatment without exposing the patient to excessive risk.
Once the MTD has been defined, the expansion cohort(s) in Part Cthat dose level will be
openedexpanded in Parts C, D and E.  
If either toxicities are observed in the first cycle that would meet the DLT criteria defined above 
for Cohorts 1 and 2 or DLT-equivalent toxicities occur in 33% or more of patients within thisthe 
cohort expansionexpansions in Part C, D and E, then investigators and the Lilly CRP will assess 
the nature and severity of these toxicities.  The safety review and decision will be documented in 
writing.
9.2. Selection and Timing of Doses
For Part D and Part E, LY2157299 (for Part D) should be taken mornings and evening 
approximately 12 hours apart.  Patients should take the agent preferably 1 hour before a meal.  
In Part D, ramucirumab should be given in the mornings.  On Day 1 of each cycle, LY2157299 
should be taken within 30 minutes before the start of ramucirumab treatment.  
Tablets should be swallowed whole and not split, crushed, or dissolved for administration.  
9.3.1. LY2157299
The appearance of the tablet is white.LY2157299 will be provided as tablets in blister packs.  All 
materials must be stored at room temperature within temperature range specified on the material 
label.  The material will be labeled according to regulatory requirements of the country.  Should 
the type of clinical trial material packaging change, it will adhere to country -specific regulations.  
9.4. Method of Assignment to Treatment
In Part E, patients who have received at least one prior line of systemic therapy or who have not 
received prior treatment and are ineligible for sorafenib treatment (at the investigator’s 
discretion) and who meet all criteria for enrollment will be assigned by the IWRS to receive 
LY2157299 150 mg BID dosage after completing the screening visit.
9.5.1. LY2157299
If dosing is delayed for more than 2 weeks, the patient should be withdrawn from the study.  
Patients
For Parts A and B, patients who do recover within the 2-week time frame may have the dose 
reduced to 160 mg for 300-mg dose arm and to 100 mg for 160-mg dose arm.
For Parts C and D:  in case of a dose delay of LY2157299, patients can continue sorafenib or 
ramucirumab treatment (at investigator discretion).

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For Part E, patients who do recover within the 2-week time frame may have the dose reduced to 
160 mg or their schedule altered after discussion between the investigator and Lilly CRP. 
9.5.2. Sorafenib
Doses will be delayed or reduced for clinically significant hematologic and other toxicities 
(Table JBAK.9.47; see Table JBAK.9.58 for modifications due to skin toxicity) that are related 
to sorafenib.  In case of a dose delay of sorafenib, patient can continue LY2157299 treatment (at 
investigator discretion).  
Table JBAK.9.4..7.
Sorafenib Dose Modifications for Hematologic and 
Nonhematologic Toxicities
Grade
Dose Delay
Dose Modification
Hematologic toxicities
Grade 0-2
Treat on time
No change
Grade 3
Treat on time
Decrease 1 dose level
Grade 4
Delaya until Grade 2
Decrease 1 dose level
Nonhematologic toxicities (except skin toxicity)b
Grade 0-2
Treat on time
No change
Grade 3
Delaya until Grade 2
Decrease 1 dose levelc
Grade 4
Off protocol therapy
Off protocol therapy
Source:  Llovet et al. 2008 supplementary material.
a
If no recovery after 30-day delay, treatment will be discontinued unless patient is deriving clinical benefit.
b
Also excludes nausea/vomiting that has not been premedicated, and diarrhea.
c
If >2 dose reductions are required, treatment will be discontinued.
Table JBAK.9.5..8.
Suggested Sorafenib Dose Modifications for Skin Toxicity
Skin Toxicity Grade
Occurrence
Suggested Dose Modifications
Grade 1:  Numbness, dysesthesia, 
paresthesia, tingling, painless 
swelling, erythema or discomfort of 
the hands or feet that does not 
disrupt the patient’s normal 
activities
Any occurrence
Continue treatment with sorafenib and 
consider topical therapy for symptomatic 
relief
Grade 2:  Painful erythema and 
swelling of the hands or feet and/or 
discomfort affecting the patient’s 
normal activities
1st occurrence
Continue treatment with sorafenib and 
consider topical therapy for symptomatic 
relief.  If no improvement within 7 days, see 
below 
No improvement within 
7 days or 2nd or 3rd 
occurrence
Interrupt sorafenib treatment until toxicity 
resolves to Grade 0-1.  When resuming 
treatment, decrease sorafenib dose by 1 dose 
level (400 mg daily or 400 mg every other 
day)
4th occurrence
Discontinue sorafenib treatment
Grade 3:  Moist desquamation, 
ulceration, blistering or severe pain 
1st or 2nd occurrence
Interrupt sorafenib treatment until toxicity 
resolves to Grade 0-1.  When resuming 

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of the hands or feet, or severe 
discomfort that causes the patient to 
be unable to work or perform 
activities of daily living
treatment, decrease sorafenib dose by 1 dose 
level (400 mg daily or 400 mg every other 
day
3rd occurrence
Discontinue sorafenib treatment
Source:  FDA, 2011 (sorafenib prescribing information).  
9.5.3.3. Proteinuria
Monitor for the development or worsening of proteinuria during ramucirumab therapy.  If the 
urine protein level is ≥2+, perform a 24-hour urine collection.  Temporarily discontinue 
ramucirumab administration if the urine protein level is ≥2 g/24 hours.  Resume treatment at a 
reduced dose level (see Table JBAK.9.6) once the urine protein level returns to <2 g/24 hours.  A 
second dose reduction (see Table JBAK.9.6) is recommended if a urine protein level 
≥2 g/24 hours reoccurs.
Permanently discontinue ramucirumab therapy if the urine protein level is >3 g/24 hours or in the 
setting of nephrotic syndrome.
Table JBAK.9.6..9.
Ramucirumab Dose Reductions for Proteinuria
Initial Ramucirumab 
Dose
First Dose Reduction 
to:
Second Dose Reduction 
to:
8 mg/kg
6 mg/kg
5 mg/kg
10. Efficacy, Health Outcome/Quality of Life Measures, Safety Evaluations, Sample 
Collection and Testing (Standard Laboratory Testing, 
Pharmacokinetics, Biomarker Analysis), and Appropriateness of 
Measurements

Long-Term Follow-up Period:  All subsequent long-term follow-up visits will 
occur at 60-day intervals (7 days) (for example, Visit 802, Visit 803, etc.) until 
the patient meets the requirements to discontinue from the study.  These are the 
preferred windows for follow-up visits (Visit 802 and beyond); however, if some 
information cannot be obtained at all or not within the specified window for Visit 
802 and beyond, it will not result in a protocol violation if no cardiac toxicity was 
observed at V801 requiring further cardiac monitoring was observed at V801.
10.2.2. Summary of Adverse Event/Serious Adverse Event Reporting Guidelines
Table JBAK.10.1 presents the reporting schedule for AEs and SAEs.  

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LY2157299
Table JBAK.10.1.10.
Assessment Guide for Adverse Events and Serious Adverse 
Events
Timing
Types of AEs/SAEs Reported
Prestudy 
(Starts at the signing of informed consent 
and ends at the first dose of study drug)

Preexisting conditions

All AEs/SAEs (except for patients who do NOT enroll). For 
enrolled patients, only AEs/SAEs related to protocol 
procedures should be reported.
On therapy
(Starts at first dose of study drug[s] and 
ends at last dose of study drug[s])

All AEs and clinically significant lab values regardless of 
relatedness

All SAEs regardless of relatedness (except death due to 
progressive disease unless the investigator also deems there to 
be a possible contribution related to study drug)
Initial follow-up Visit (V801)
(Starts at discontinuation from study 
treatment and ends when end of study safety 
assessments are completed [30 days, ±3 
days, after discontinuation from study 
treatment]) 

All AEs and clinically significant lab values regardless of 
relatedness

All SAEs regardless of relatedness (except death due to 
progressive disease unless the investigator also deems there to 
be a possible relation with study drug)
Subsequent follow-up visits, if necessary

Ongoing or new AEs/SAEs possibly related to study drug(s) 
or protocol procedures
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
10.2.4. EchocardiographsEchocardiograms with Doppler and Chest CT Scans
Because of the cardiotoxicity monitoring in this study, echocardiographs with Doppler and chest 
CT scans are being performed (see Attachment 1,, Attachment 12, and Attachment 13).  
Echocardiography with Doppler will be locally assessed at screening for enrollment and 
throughout the study according to the Study Schedule (Attachment 1)) for safety decisions by a 
physician or a person who is qualified by experience or training.  The individual must be 
identified at each site.  A central reading will be performed for the data used in the study report.  
Chest CT scan with contrast of thorax and abdomen to evaluate the large vessels of the heart will 
be locally assessed at screening for enrollment and throughout the study according to the 
schedule of events (Attachment 1)) for safety decisions by a physician or a person who is 
qualified by experience or training.  Alternatively, chest and/or abdomen MRI are allowed.
10.3.2. Samples for Drug Concentration Measurements –
Pharmacokinetics/Pharmacodynamics
For Cycles 1 and 2 safety assessments during Part D, PK samples for LY2157299 andwill be 
collected on Days 1, 14 and 15, and samples for ramucirumab will be collected on Days 1, 14,
and 15.  One morning PK sample (Day 15 before ramucirumab dosing) will then be taken to 
evaluate the elimination-phase kinetics of LY2157299 during the nondosing phase of Cycles 1 
and 2 (see Attachment 4).and one ramucirumab PK sample at end of infusion will be taken.  
From Cycle 3 onwards, only predose Day 1 samples will be taken.  
For Part E, PK samples for LY2157299 will be collected on Days 1, 21 and 22 (Attachment 4).

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10.3.3.1. Pharmacogenomic Evaluations
Blood samples will be collected at the times specified in the Study Schedule (Attachment 1).  
Supplies required for the collection, handling, and shipment of the patients’ samples will be 
provided by the sponsor.  Samples will be stored at a facility selected by the sponsor in the 
United States (US)..  Collection of a blood sample for genetic testing is a mandatory part of this 
study where local regulations allow.  The blood sample for pharmacogenomics evaluation will be 
a 1-time collection unless the sample does not yield adequate DNA for use.  It is recommended 
that the blood sample be taken at the baseline visit but may be taken at any time while the patient 
is participating in the clinical study.  Genes related to safety, efficacy, PK, and/or the mechanism 
of action of LY2157299 may be tested.  Patients will not have the option to request test results 
and will not receive the genetic test results.
12.1. Determination of Sample Size
The first interim analysis was completed.  However, an additional data review was carried out 
prior to the planned second interim analysis, and this was when 64 patients had received at least 
1 dose of study drug and were reported in the clinical database.  Of these, 44 patients had 
completed at least 3 cycles of treatment or discontinued from study treatment.  The decision from 
this review was to stop enrollment into Cohort 1 (at 37 patients) and to complete enrollment of 
Cohort 2 (n=70 patients).  In addition, the protocol was amended (Amendment [b]) to have 2, 
and possibly 3, parts in this study.  The 2 cohorts planned in the original protocol and in the 
Amendment (a) will bewere designated as Part A.  Part B willwas to enroll 40 Child-Pugh Class 
A or B7 patients with HCC with AFP levels<1.5x ULN.  Part C willwas to enroll approximately 
40 Child-Pugh AB7 or B8 status patients who have not received any prior systemic therapy.
The 2 planned interim analyses described for Parts A and B in Amendment (b) have been 
completed (December 2012 and June 2013).  
With Amendment (c), the study planned to enroll approximately 190 patients:  109 patients have 
been enrolled in Part A (37 in Cohort 1, 72 in Cohort 2), and); 40 are planned for Part B, and 
40 for Part C.  With Amendment (d) and the addition of Part D, an additional 15 (amended to 
enroll Child Pugh A patients maywho had not received any prior systemic therapy and were to be 
enrolled.treated with LY2157299 plus sorafenib in a safety lead-in followed by an expansion at 
the selected dose).
With Amendment (d) and the addition of Part D, an additional 15 patients may be enrolled.  With 
Amendment (e) and the addition of Part E, approximately 23 additional patients may be enrolled.
The primary objective of the study now is to characterize the TTP distributions, the effect on 
TGF--associated serum biomarkers (for example, TGF-, AFP, E-cadherin) and the 
relationship between biomarker response and efficacy endpoints of:
1) Each of the 2 doses of LY2157299 in second-line patients or patients 
ineligible to receive sorafenib with HCC who have elevated AFP levels 
(Part A, Cohorts 1 and 2), 

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2) In second-line patients or patients ineligible to receive sorafenib with HCC 
who have AFP levels <1.5x ULN dosed at 300 mg/day (Part B),
3) In first-line patients with HCC treated with 2 doses of LY2157299 in 
combination with sorafenib.  If the decision in Part C is to use only 
1 treatment group in the expansion cohort, the results from patients at the 
other dose will simply be listed.
4) In second-line patients with HCC treated with LY2157299 given for 21 days on 
followed by 7 days off (Part E).
Data from patients from Part D and E will be summarized separately from the data in Parts A, B, 
and C.
12.2.1. General Considerations
Patients from all sites will be pooled for the purposes of analysis.  All confidence intervals of 
treatment effects will be provided at a 2-sided alpha level of 0.10, unless otherwise stated.  
Patients with Child-Pugh Class A and B7 will be considered as 1 group of patients, given the 
similarity of Class B7 patients to Class A patients.  If all patients in Part A and Part B are 
second-line, Part C patients will be analyzed as a separate group.  If there are some first-line 
patients in Part A or Part B, different subgroups may be required.  Part D will be conducted 
outside of the EU.  Data from patients from PartParts D and E will be analyzed separately from 
Parts A, B, and C.
12.2.8. Clinical Efficacy Analyses
Kaplan-Meier analysis will be performed on the observed distribution of TTP (Kaplan and Meier 
1958) for each dose in Part A, Part B, Part C, Part D and Part DE, with parameter estimates of 
the TTP median and quartiles being reported.  All parameter estimates will be quoted together 
with their 90% confidence limits.  The hazard ratio between the observed TTP distributions of 
each cohort in Part A will be estimated, recognizing that since 1 dose cohort did not enroll to its 
full complement, the precision of the HR will be lower than originally planned.  The hazard 
ratios between the 300 mg/day cohort in Part A and Part B cohort will also be estimated.  In 
addition, the hazard ratio between a subgroup of sorafenib-naive patients in Parts A and B and 
patients in Part C may be estimated.  The interpretation of any estimate will be considered in 
light of the size of this subgroup.
The overall response rate (ORR) for each cohort in Part A, Part B, Part C, Part D and Part DE
will be estimated by dividing the total number of confirmed responders by the number of patients 
who received at least 1 dose of study treatment.  The clinical benefit rate will be estimated for 
each treatment group by dividing the total number of patients experiencing benefit by the number 
of patients who received at least 1 dose of study treatment.  A patient is considered to have 
received benefit if they achieve a confirmed response, CR or PR, or SD per RECIST v1.1 or 
mRECIST.  Both mean and exact confidence limits will be provided for each group (Cohort 1 
and Cohort 2 in Part A, Part B, Part C, Part D and Part DE, as well as estimates of differences 
between 2 cohorts in Part A, between Parts A and B at 300 mg/day, and between sorafenib-naive 

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patients in Part A and Part B with those in Part C.  The interpretation of any estimate in the latter 
comparison will be considered in light of the size of this subgroup.
Additional exploratory analyses of efficacy endpoints will be performed to assess the effect of 
important prognostic factors on the outcome, including, but not exclusively, baseline AFP levels 
(either as a continuous factor and/or categorical factor), etiology, and whether sorafenib -naïve or 
not.  Analyses using subgroup identification methods, such as classification and regression tree
(CART) (classification and regression tool) may also be carried out.  The only difference 
between Part A and Part B patients is their baseline AFP levels, and therefore results from 
Cohort 2 in Part A and Part B will be combined in these analyses.  Similar analyses for patients 
in Parts C, D and DE may be carried out.
The original statistical analysis plan (SAP) was finalized prior to the first patient in the study 
being dosed.  The amended SAP was finalized prior to the first patient in Part B being dosed. 
The amended SAP (version 2) was finalized prior to the first patient in Part C being dosed.  The 
amended SAP (version 3) will be finalized prior to the first patient in Part D being dosed. An 
amended SAP (version 4) will be finalised prior to the first patient in Part E being dosed.
12.2.10. Pharmacokinetic/Pharmacodynamic Analyses
For the purposes of the JBAK study report, plasma-concentration data will be illustrated 
graphically and summarized descriptively.  If data isare sufficient, then data from patients in this 
study will be modeled using the population approach for characterizing LY2157299 PK.  In 
addition, if appropriate, data from patients in this study will be combined in a PK database with 
data from Study JBAH and other completed studies, for population PK analysis.  In Part C, 
Cycle 1 assessment on possible sorafenib exposure change during monotherapy and combination 
will be made.  In Part D, Cycle 1 and 2 assessment of the possible LY2157299 exposure and/or 
ramucirumab change when in administered in combination with ramucirumab will be evaluated.  
In Part E, Cycle 1 LY2157299 PK profile of patients dosed for 21 days on treatment and 7 days 
off treatment will be characterized.
12.2.13. Exploratory Analyses
Given the more limited number of patients to be enrolled in Part D and E, exploratory analyses 
will be carried out as appropriate.
12.2.14. Interim Analyses
For enrollment to continue in either dose level, there had to be no evidence of cardiotoxicity in 
any patient at that dose level and no drug-related CTCAE Grade 3/4 toxicity that was not 
manageable.  The PK of LY2157299 in HCC patients were compared to those of patients with 
glioblastoma observed in Study JBAH.  Since only sparse sampling is beingwas performed in 
this study,Study JBAK (Parts A and B), comparisons between the 2 populations were carried out 
by simulations (median and 20th and 80th percentiles) using the population PK model from 
Study JBAH.  
Enrollment after the first interim analysis continued in both dose cohorts, and a second interim 
analysis was planned when an additional 30 patients had been enrolled in each arm (ie,i.e., total 

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of 40 patients in each arm) and had been actively followed for 3 months or progressive disease or 
death had been observed.  This was to be after the second planned radiological assessment 
(planned every 6 weeks) and after the collection of biomarker (specifically AFP) samples for all 
patients.  Any patient who was lost to follow-up or started a new anticancer therapy before 
3 months had elapsed without an event being observed was not eligible for inclusion in the 
interim analysis.  
Analysis of the mean fold change from baseline of biomarker concentrations levels willwere to 
be estimated from a mixed-effects model with sampling time, dose and their interaction as fixed 
effects, baseline levels (either as a continuous variable or categorical [AFP:  ≤400 ng/mL or 
>400 ng/mL]) as a covariate and patient as a random effect.  The choice of variance-covariance 
structure will dependwas to have depended on the data.  Biomarker concentrations willwere to be 
log transformed prior to analysis.  Specific details of these analyses will be provided in the SAP.
However, the planned second interim analysis described in Amendment (a) was not carried out.  
The decision to carry out, but an additional data review is described in Section 5.1.5.1.was 
conducted.  Based on this review, the decision was to close Cohort 1 and continue enrollment 
until 70 patients have been enrolled ininto Cohort 2. At the time of the decision, 7464 patients 
had been treated.
As part of Amendment (b), the second interim analysis for Part A is now was changed and 
planned to be after the 70th patient has enrolled into Cohort 2 and started Cycle 1.  The purpose 
of this analysis iswas to help inform the decision to prepare for further development of the 
compound in patients with HCC with elevated AFP levels.  This analysis was completed in 
December 2012 (Faivre et al. 2013).
The purpose of the interim analyses in Part B (interim analysis 3) and Part C (interim analysis 4) 
iswas to prepare for further development of the compound and to inform the decision as to 
whether all second-line HCC patients, irrespective of baseline AFP levels, (Part B), and all first-
line Child-Pugh AB7 or B7B8 status (Part C) patients may benefit from treatment with 
LY2157299.  
The timing of the interim analyses for Parts B and C iswas based on assuming Parts B and C are 
designed as a Simon’s 2-stage design with the same characteristics as used in the original 
protocol:  where the assumption of a poor treatment is if the proportion free from disease 
progression is 50% at 3 months (assumes median TTP = 3 months) and a good treatment is if the 
proportion free from disease progression at 3 months is 63% (assumes median TTP = 
4.5 months).  The operating characteristics of this design are as follows:  The null hypothesis is 
that the true response rate is 50%.  In the first stage, 18 patients will be accrued and actively 
followed for at least 3 months or until they have discontinued.  If there are 8 or fewer patients 
free from disease progression in these 18 patients, this may be indicative that patients with 
normal AFP levels are not benefiting from the treatment.  The additional 22 patients will be 
accrued for a total of 40.  The null hypothesis will be ‘rejected’ at the end of Parts B and C if 
22 or more patients out of 40 patients in each part are observed to be free from disease the true 
response rate is 63%.

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From Amendment (c), the above calculations now only applyapplied to the third interim analysis 
(for Part B, completed June 2013).  Given the change in strategy for Part C, to enroll and treat 
first line Child Pugh A or B7 patients in amendment (c), only safety reviews are planned while 
the study is ongoing.  An additional analysis may be carried out if needed to help with clinical 
planning of the compound for treating first-line patients.
The final analysis for Parts A and B will be conducted after the study objectives for these 2 parts 
have been met.These analyses will be as described in the SAP and the results will help with the 
clinical planning of the compound for treating second-line patients.
Safety reviews for Part D are planned to determine the LY2157299 dose in combination with 
ramucirumab.  This will be after 3 patients have completed 1 cycle of treatment in Cohort 1 
(LY2157299 80 mg BID) prior to escalating to Cohort 2 (LY2157299 150 mg BID).  A further 
safety review will be carried out after 3 patients have completed 1 cycle in Cohort 2.
In Part E, safety data will be reviewed after 3 patients have completed one cycle.  If the schedule 
is deemed to be tolerable (<33% DLTs in Cycle 1 and consideration of the overall safety profile 
in later cycles), an additional 20 patients will be enrolled in order to better characterize the safety 
of the schedule and allow comparison to safety, pharmacokinetics and efficacy seen in other 
cohorts.  No additional interim analyses are planned for Part E.
The timing of the final analyses for each study parts’ clinical study reports and the final database 
lock is provided in Section 7.1.
14. References
Bruix J, Merle P, Granito A, Huang Y-H, Bodoky G, Yokosuka Q, Rosmorduc O, Breder V,  
Gerolami R, Masi G, Paul JR, Qin S, Song T, Bronowicki J-P, Ollivier-Hourmand L, Kudo M, 
LeBerre M-A, Baumhauer A, Meinhardt G, Han G on behalf of the RESORCE Investigators. 
Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma 
(HCC) progressing on sorafenib: results of the international, randomized phase 3 RESORCE 
trial. Annals of Oncol. 2016; 27(suppl 2): ii140-ii141.
Giannelli G,  Santoro A, Kelley RK, Gane E, Paradis V,  Cleverly A, Estrem S, Man M, Liu J, 
Desaiah D, Lahn MM, Raymond E, Benhadji KA, Faivre S. Final results of a phase 2 study of 
galunisertib, a transforming growth factor-beta (TGFβ) receptor I kinase inhibitor, in patients 
with advanced hepatocellular carcinoma (HCC) [abstract]. In: International Liver Cancer 
Association 10th annual meeting program; Sept 9-11, 2016; Vancouver, Canada. Abstract 
ABSSUB-380.
Zhu AX, Park JO, Ryoo B-Y, Yen C-J, Poon R, Pastorelli D, Blanc J-F, Chung HC, Baron AD, 
Pfiffer TEF, Okusaka T, Kubackova K, Trojan J, J Sastre J, Chau I, Chang S-C, Abada PB, 
Yang L, Schwartz JD, Kudo M for the REACH Trial Investigators. Ramucirumab versus 
placebo as second-line treatment in patients with advanced hepatocellular carcinoma following 
first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 
trial. Lancet Oncol. 2015; 16(7): 859-870.
Attachment 1. Protocol JBAK Study Schedule

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LY2157299
Part E
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, nl
Extension
Period
Visit 
801
Follow-
upf
Comments
Relative Day 
Within a Cycle
28
14
7
1i
8i
14i
21
22
1i
14i,
k
1i
14i,k
Procedures
Informed 
Consent 
X
Informed consent must be signed prior 
to performing any study procedures.
Medical History
X
Child-Pugh, 
Barcelona Clinic 
Liver Cancer 
(BCLC), and 
CLIP staging
Xh
Pregnancy Test
X
Physical Exam
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be performed 
once per cycle. Perform predose on 
Day 1 of each cycle in extension 
period. 
Vital Signs (heart 
rate, blood 
pressure)
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be performed 
once per cycle. Perform predose on 
Day 1 of each cycle in extension 
period.
CTCAE Grading
X
X
X
X
X
X
X
X
Xa
Starting in Cycle 3, to be performed 
once per cycle. Perform predose on 
Day 1 of each cycle in extension 
period.
DLT Assessment
X
Concomitant 
Medications 
X
X
X
X
X
X
X
Perform predose on Day 1 of each 
cycle in extension period.
Performance 
Status
X
X
X
X
X
X
X
X
Starting in Cycle 3, to be performed 
once per cycle. Perform predose on 
Day 1 of each cycle in extension 
period.

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Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension
Period
Visit 801
Follow-upf
Comments
Relative Day 
Within a Cycle
28
14
7
1i
8i
14i
21
22
1i
14
i,k
1i
14i,k
Tumor 
Assessment, 
Physical (Palpable 
or Visible)
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
Imaging 
Procedures 
Echocardiogram 
with Dopplerg
X
X
X
X
Xb
Xb
Cycle 2, 3, 4, and every other 
cycle (C6, C8, etc). Perform 
predose on Day 1 of each cycle 
in extension period
Chest CT Scan or 
Chest MRI
X
X
Xc
CT scan or MRI every 6 
months
Tumor 
Assessment, 
Radiological
X
X
X
Xd
Xd
Tumor assessment every 6 
weeks starting Cycle 2, Day 14. 
May be performed 3 days 
around the scheduled date. 
Optional during the extension 
period (including extension 
period V801)
ECG
X
X
X
X
Xb
Xb
Cycle 2, 3, 4, and every other 
cycle (C6, C8, etc). Perform 
predose on Day 1 of each cycle 
in extension period

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Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow-upf
Comments
Relative Day 
Within a Cycle
28
14
7
1i
8i
14i
21
22
1i
14i,
k
1i
14i,
k
Laboratory
/Diagnostic Tests
ECG chemistry
X
X
X
X
Xb
Xb
Cycle 2, 3, 4, and every other 
cycle (C6, C8, etc). Perform 
predose on Day 1 of each cycle 
in extension period.  Can be 
done at local labs during the 
extension period
Special chemistry
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period
Hematology
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period
Serum chemistry
X
X
X
X
X
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period
Urinalysis
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
Urine C-terminal 
telopeptides of 
Type 1 collagen
X
X
X
Optional during the extension 
period

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Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow-upf
Comments
Relative Day 
Within a Cycle
28
14
7
1i
8i
14i
21
22
1i
14i,
k
1i
14i,
k
PK samplinge
X
X
X
X
X
Timed with ECG.  See 
Attachment 4 for specific 
timepoints. 
Serum markers 
(AFP, AFP L3, E-
cadherin, PIVKA 
II)
X
X
X
X
X
AFP only
X
Perform predose on Day 1 of 
each cycle in extension period.  
Can be done at local labs 
during the extension period
Immuno-
phenotype
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
TGF-β+PF4
X
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
MAP panel
X
X
X
X
X
Optional during the extension 
period (including extension 
period V801)
Fibrotest
X
X
X
X
aPTT/PT/
INR
X
X
X
X
X
Perform predose on Day 1 of 
each cycle in extension period. 
Can be done at local labs 
during the extension period
Patient-Reported 
Outcomes
FACT-Hep
X
X
X
X
Optional during the extension 
period (including extension 
period V801)

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LY2157299
Cycle/Visitj
Prestudy
Cycle 1
Cycle 2
Cycle 3, 
nl
Extension 
Period
Visit 
801
Follow-upf
Comments
Relative Day 
Within a Cycle
28
14

7
1i
8i
14i
21 22
1i
14i,k 1i 14i,k
Translational 
Research
Whole blood for 
PGx
X
Obtained 
diagnostic tumor 
tissue, when 
available 
X
Optional tumor 
biopsy
X
X
+/- 3 days after end of treatment 
with LY2157299
Abbreviations:  AFP = alpha-fetoprotein; aPTT = activated partial prothrombin time; C = cycle; CLIP = Cancer of the Liver Italian Program; CT = computerized 
tomography; CTCAE = Common Terminology Criteria for Adverse Events; D = Day; ECG = electrocardiogram; FACT = Functional Assessment of Cancer 
Therapy; INR = international normalized ratio; MAP = multi-analyte panel; MRI = magnetic resonance imaging; PGx = pharmacogenomics; PIVKA II = 
prothrombin induced by vitamin K absence; PK = pharmacokinetic; PT = prothrombin time; TGF-β = transforming growth factor beta.
a
If drug-related toxicity is present 30 days after last cycle of study drug, patients must be followed up approximately every 30 days until toxicity resolution, 
stabilization, another therapy is initiated, or death.
b If the patient has clinically significant cardiac findings at discontinuation (V801), echocardiography with Doppler, ECG, and ECG chemistry will be repeated 
every 2 months for 6 months (V803, V804, and V805).  If there are no cardiac findings at discontinuation (V801), 1 more echocardiography with Doppler, 
ECG, and ECG chemistry will be performed after 2 months (V802) unless a patient is receiving another treatment (see Section 10.2.4).  
c
If there were no clinically significant findings at the last assessment conducted within the 30 days following discontinuation and the patient has started 
another treatment, Visit 801 CT scan or chest MRI with contrast will not be performed.
d Repeat radiological scans at study discontinuation may be omitted if a patient has objective disease progression or if imaging has been performed in the 
previous 3 to 6 weeks.
e
For details, see Attachment 4.  PK sampling will be performed on Cycle 1, with a predose sample on Day 1 of Cycle 2 and all subsequent cycles.
f
Follow-up consists of Visit 802 and all subsequent visits (60 days ±7 days).  All patients will be followed for OS until study completion. 
g Echocardiogram with Doppler can be performed up to 3 days prior to Day 1.
h Child-Pugh, BCLC, and CLIP assessment procedures can be found in Attachment 5, Attachment 6, and Attachment 7, respectively.  
i
To be performed predose LY2157299.
j
A delay at the start of a cycle (Day 1) of no more than 3 days, because of holidays, weekends, inclement weather, or other justifiable events, will be permitted 
and not counted as a protocol violation.

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k In extenuating circumstances, the ‘on study drug’ window is allowable from Day 10 to Day 14.  
l
Patients on study for more than 1 year (before entering extension phase) only need tests to be performed on Day 1 of each cycle.

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Attachment 2. Protocol JBAK Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Hemoglobin
Erythrocyte count (RBC)
Leukocytes (WBC)
Neutrophils, segmented + bands
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelets
Immunophenotypeb
Urinalysisa
Specific gravity
pH
Protein
Glucose
Ketones
Blood
Leukocyte esterase
ECG Chemistryb
Lipase
Thyroid Stimulating Hormone (TSH)
Tri-iodothyronine (T3)
Thyroxine (T4)
Calciumc
Glucose, random (nonfasting) c
Albuminc
Phosphorusc
Sodiumc
Potassiumc
Magnesiumc
Special Chemistryb
Cystatin C 
Troponin I
BNP
High-sensitivity C-reactive protein (hs-CRP)
Clinical Chemistryb
Total bilirubin
Direct bilirubin
Total Protein
Alkaline phosphatase
LDH
Creatinine kinase (CK)
ALT/SGPT
AST/SGOT
Blood urea nitrogen (BUN)
Creatinine
Uric acid
Calcium
Glucose, random (nonfasting)
Albumin
Cholesterol
Phosphorus
Sodium 
Potassium
Magnesium
AFPb
AFP L3b
PIVKA IIb
E-cadherinb
TGF-β+PF4b
aPPT/PT/INRb
Fibrotestb
Urine C-terminal telopeptides of Type 1 Collagenb
Serum Pregnancy Test (females only)a

H9H-MC-JBAK(e) Clinical Protocol
Page 206
LY2157299
Abbreviations:  AFP = alpha-fetoprotein; ALT = alanine aminotransaminase; aPTT = activated partial prothrombin 
time; AST = aspartate aminotransferase; BNP = brain natriuretic peptide; ECG = electrocardiogram; INR = 
international normalized ratio; LDH = Lactate Dehydrogenase; SGOT = serum glutamic oxaloacetic 
transaminase; SGPT = serum glutamic pyruvic transaminase; WBC = white blood cells; PIVKA II = prothrombin 
induced by vitamin K absence.
a
All samples will be discarded within 60 days of validated test results.  Validation will occur at the time of initial 
testing.  All these tests will be performed at a local or investigator-designated laboratory, with the exception of 
immunophenotype.
b
All samples will be discarded within 60 days of validated test results.  Validation will occur at the time of initial 
testing.  All these tests will be performed at a Lilly-designated laboratory.  Tests will be performed at a local 
laboratory if performed during the treatment extension period.
c
Test not performed if both chemistry and ECG chemistry are required.  See Attachment 1.
Attachment 4 Protocol JBAK Pharmacokinetic Sampling Instructions
Part D Sampling Schedule
Day
LY2157299 + RAM
Dosing Schedule
Pharmacokinetic
Sampling Times
(LY2157299) plasma
Pharmacokinetic
Sampling Times
(RAM) serum
Cycle 1 Day 1
(Day at which RAM and 
LY2157299 are combined)
Both drugs as per Section 9
Predosea
Predosea
1.5-3 h after 
LY2157299 dose 
End of RAM infusion 
Cycle 1 Day 14b
(last day of LY2157299 
dosing)
LY2157299 as per Section 9
Predosea
0.5 h after dose
2 h after dose
3 h after dose
6 h after dose
Cycle 1 Day 15b
RAM only as per Section 9
Morning (before RAM 
is taken)
Predose
Cycle 1 Day 15
RAM only as per Section 9
End of RAM infusion
Cycle 2 Day 1
Both drugs as per Section 9
Predosea
Predosea
1.5-3 hours after dose 
(LY)
End of RAM infusion
Cycle 2, Day 14b
LY2157299 as per Section 9
Predosea
0.5-2 hours
3-5 hours
Cycle 2, Day 15b
RAM only as per Section 9
Morning (before RAM 
is taken)
Predose
Cycle 2 Day 15
RAM only as per Section 9
End of RAM infusion
Cycle 3, Day 1
Both drugs as per Section 9
Predosea
Predosea
Cycle 4, n, Day 1
Both drugs as per Section 9
Predosea
Predosea
Abbreviations:  h = hour(s); LY = LY2157299; n = cycle number ≥Cycle 4; PK = pharmacokinetic; 
RAM = ramucirumab.
a
The predose sample has to be taken before receiving any LY2157299 or ramucirumab.
b
For patients who will have a Day 15 PK sample taken, their evening dose of LY2157299 on Day 14 should be 
omitted.

H9H-MC-JBAK(e) Clinical Protocol
Page 207
LY2157299
Part E Sampling Schedule for LY2157299
Sample Number
Cycle
Day
Sampling Windows for PK
1
1
1
Predosea
2
1
1
0.5-2 hours
3
1
21
Predosea
4
1
21
0.5-2 hours
5b
1
21
3-5 hours
6b
1
22
Morning
7
2
1
Predosea
8
3 - n
1
Predosea
Abbreviation:  PK = pharmacokinetic.
a
The predose sample should be taken before the patient receives any LY2157299.
b For patients who will have a Day 22 PK sample taken, the evening dose of LY2157299 on Day 21 should be 
omitted.

PPD
Leo Document ID = df27b9c3-c58a-4e4f-98ad-2fd23c31456a
Approver: 
Approval Date & Time: 17-Aug-2016 08:20:47 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 18-Aug-2016 20:19:15 GMT
Signature meaning: Approved
PPD