Clinical trial NCT02423343
Conditions: Solid Tumor Non-Small Cell Lung Cancer Recurrent Hepatocellular Carcinoma Recurrent
Sponsor: Eli Lilly and Company
Start date: 2015-01-01; Completion date: 2020-07-08
Enrollment: 41 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main purpose of this study is to evaluate the safety, tolerability, and efficacy of the study drug known as galunisertib in combination with nivolumab in participants with advanced refractory solid tumors and in recurrent or refractory non-small cell lung cancer (NSCLC) or hepatocellular carcinoma (HCC).

Detailed description:

Arms: arm 1: 50 milligrams (mg) Galunisertib administered orally once daily (QD) on Day 1 through Day 14 of each 4-week cycle in combination with 3 milligrams per kilogram (3 mg/kg) nivolumab given intravenously (IV), every 2 weeks (Q2W), (Day 1 and Day 15). Participants may continue to receive study drug until discontinuation criteria are met. arm 2: 50 mg Galunisertib administered orally twice daily (BID) on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W,(Day 1 and Day 15). Participants may continue to receive study drug until discontinuation criteria are met. arm 3: 80 mg Galunisertib administered orally BID on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W, (Day 1 and Day 15). Participants may continue to receive study drug until discontinuation criteria are met. arm 4: 150 mg Galunisertib administered orally BID on Day 1 through Day 14 of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W,(Day 1 and Day 15). Participants may continue to receive study drug until discontinuation criteria are met. arm 5: 150 mg Galunisertib administered orally BID for the first 14 days of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W, (Day 1 and Day 15) of each 4-week cycle. Participants may continue to receive study drug until discontinuation criteria are met. arm 6: 150 mg Galunisertib administered orally BID for the first 14 days of each 4-week cycle in combination with 3 mg/kg nivolumab given IV, Q2W, (Day 1 and Day 15) of each 4-week cycle. Participants may continue to receive study drug until discontinuation criteria are met.
Interventions: intervention 1: Galunisertib intervention 2: Nivolumab
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered IV

Protocol documents:
Prot_000.pdf: 
Protocol H9H-MC-JBEF (c) 
A Phase 1b/2 Dose Escalation and Cohort Expansion Study of the Safety, Tolerability and 
Efficacy of a Novel Transforming Growth Factor–β Receptor I Kinase Inhibitor (Galunisertib) 
Administered in Combination with Anti–PD-1 (Nivolumab) in Advanced Refractory Solid 
Tumours (Phase 1b) and in Recurrent or Refractory Non–Small Cell Lung Cancer or 
Hepatocellular Carcinoma (Phase 2) 
NCT02423343 
Approval Date: 31-Jan-2017 


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
1.
Pr ot o c ol H 9 H -M C -J B E F ( c)
A P h a s e 1 b / 2 D o s e E s c al ati o n a n d C o h ort E x p a n si o n St u d y  
of t h e S af et y , T ol er a bilit y a n d Effi c a c y of a N o v el 
Tr a n sf or mi n g Gr o wt h F a ct or – R e c e pt or I Ki n a s e I n hi bit or 
( G al u ni s erti b) Ad mi ni st er e d i n C o m bi n ati o n wit h A nti – P D -1 
( Ni v ol u m a b) i n Ad v a n c e d R efr a ct or y  S oli d T u m ou r s
( P h a s e 1 b ) a n d i n R e c urr e nt or R efr a ct or y 
N o n – S m all C ell L u n g C a n c er or H e p at o c ell ul ar C ar ci n o m a
( P h a s e 2)
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s pr ot o c ol i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
g al u ni s erti b ( L Y2 1 5 7 2 9 9 ) c o m bi n e d wit h ni v ol u m a b ( B M S -9 3 6 5 5 8) , u nl e s s s u c h p er s o n s 
ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.   
N ot e t o R e g ul at or y A ut h oriti e s :  t hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e .  Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e .  I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s su bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .  
G al u ni s erti b ( L Y2 1 5 7 2 9 9 ) a n d ni v ol u m a b ( B M S -9 3 6 5 5 8)
T hi s i s a m ulti c e nt r e, n o nr a n d o mis e d, o p e n -l a b el, d o s e-e s c al ati o n P h a s e 1 b st u d y of  
g al u ni s erti b c o m bi n e d wit h ni v ol u m a b i n p ati e nt s wit h a d v a n c e d r efr a ct or y s oli d t u m ou r s
f oll o w e d b y a 3- c o h ort e x p a n si o n P h a s e 2 s t u d y in p ati e nt s wit h r efr a ct or y or r e c urr e nt
n o n – s m all c ell l u n g c a n c er or h e p at o c ell ul ar c ar ci n o m a .  
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y: 1 7 A pr il 2 0 1 5
A m e n d m e nt ( a) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y : 2 4 J ul y 2 0 1 5 
A m e n d m e nt ( b ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y :  3 0 A u g u st 2 0 1 6
A m e n d m e nt ( c ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n a p pr o v al d at e pr o vi d e d 
b el o w
A p pr o v al D at e: 3 1- J a n- 2 0 1 7 G M T


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
2.
Synopsis
Transforming growth factor–(TGF-β) is an important protein with tumour-promoting activity.  
Mechanisms to explain this activity include tumour neovascularisation (neoangiogenesis), 
immunosuppression, and loss of tumour-immune surveillance both through production of 
immunosuppressive cytokines and induction of immune suppressive cells and inhibition of 
antitumour immunity, and increased migration, invasion, and metastases (Akhurst and Derynck 
2001; Derynck et al. 2001; Wick et al. 2001a, 2001b; Siegel and Massagué 2003).  These 
combined effects on the tumour microenvironment by TGF-β promote tumour progression; 
inhibition of this cytokine by a TGF-β receptor type I kinase inhibitor is expected to arrest 
tumour growth and metastasis and improve immune function.
Programmed Cell Death–1 (PD-1) is expressed on activated T cells and can act to dampen the
immune response. Tumour cells overexpress programmed cell death–1 ligand (PD-L1), which 
potentially leads to inhibition of local immune response. PD-1 is a hallmark of exhausted T cells 
in the tumour microenvironment. Targeting PD-1 provides the opportunity to restore T-cell 
immunity via blocking both its inhibitory interactions with PD-L1 and B7-1. Thus, blockade of 
both TGF-β and PD-1 could be expected to reverse the immune escape associated with these 
molecules and the combination to potentially provide immune restoration to improve tumour 
response. Indeed the combination of galunisertib and nivolumab may act synergistically via 
suppression of the immune suppressive function of TGF-β at the maximum tolerated dose or 
pharmacologically active dose.  
This study is a Phase 1b/2 open-label study that will be conducted in 2 parts.  The Phase 1b part
of this study will consist of an open-label, dose-escalation assessment of the safety and 
tolerability of galunisertib administered at 50 mg daily (QD), 50 mg twice daily (BID), 80 mg 
BID, or 150 mg BID in combination with nivolumab 3 mg/kg in patients with advanced 
refractory solid tumours.  The Phase 2 part of this study will be disease restricted and include 
2 expansion cohorts of patients in tumours with documented monotherapy activity with 
nivolumab (non–small cell lung cancer; n = approximately 25 patients) or galunisertib 
(hepatocellular carcinoma [n = approximately 25 patients]).  Patients in the 2 cohorts will be 
enrolled independently and will be assigned to treatment concurrently; enrolment for each cohort 
will be complete when that cohort has reached the prespecified enrolment target. Galunisertib 
will be used to attempt to augment nivolumab activity via suppression of the immune 
suppressive function of TGF-β at the maximum tolerated dose or pharmacologically active dose.  
Additional cohorts of patients with specific alternative tumour histologies may be added and will 
require an amendment.


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
3.
Table of Contents
A Phase 1b/2 Dose Escalation and Cohort Expansion Study of the 
Safety, Tolerability, and Efficacy of a Novel Transforming Growth 
Factor–Receptor I Kinase Inhibitor (Galunisertib) Administered in 
Combination with Anti–PD-1 (Nivolumab) in Advanced Refractory 
Solid Tumours (Phase 1b) and in Recurrent or Refractory Non–Small 
Cell Lung Cancer or Hepatocellular Carcinoma (Phase 2)
Section
Page
1.
Protocol H9H-MC-JBEF(c) A Phase 1b/2 Dose Escalation and 
Cohort Expansion Study of the Safety, Tolerability and Efficacy of a 
Novel Transforming Growth Factor–Receptor I Kinase Inhibitor 
(Galunisertib) Administered in Combination with Anti–PD-1 
(Nivolumab) in Advanced Refractory Solid Tumours (Phase 1b) and 
in Recurrent or Refractory  Non–Small Cell Lung Cancer or 
Hepatocellular Carcinoma (Phase 2)....................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................3
4.
Abbreviations and Definitions...........................................................................................10
5.
Introduction ......................................................................................................................15
5.1.
Cancer Immunotherapy................................................................................................15
5.2.
Transforming Growth Factor–....................................................................................15
5.3.
Programmed Cell Death–1 ...........................................................................................16
5.4.
Rationale for H9H-MC-JBEF Protocol Amendment (a)................................................17
5.5.
Rationale for H9H-MC-JBEF Protocol Amendment (b) ...............................................19
5.6.
Rationale for H9H-MC-JBEF Protocol Amendment (c)................................................20
5.7.
Galunisertib..................................................................................................................20
5.8.
Nivolumab ...................................................................................................................21
5.9.
Objectives ....................................................................................................................24
5.9.1.
Primary Objective ................................................................................................24
5.9.2.
Secondary Objectives...........................................................................................24
5.9.3.
Exploratory Objectives.........................................................................................24
5.10. General Introduction to Galunisertib and Nivolumab....................................................25
5.10.1.
Mechanism of Action and In Vitro/In Vivo Activity of 
Galunisertib .........................................................................................................25
5.10.2.
Mechanism of Action and In Vitro/In Vivo Activity of 
Nivolumab ...........................................................................................................26
5.10.3.
Nonclinical Pharmacokinetics/Pharmacodynamics of 
Galunisertib .........................................................................................................26


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Galunisertib (LY2157299)/nivolumab
5.10.4.
Nonclinical Toxicology........................................................................................27
5.10.5.
Clinical Pharmacokinetics of Galunisertib............................................................27
5.10.6.
Clinical Pharmacokinetics of Nivolumab..............................................................29
5.11. Rationale for Selection of Dose....................................................................................29
6.
Investigational Plan...........................................................................................................32
6.1.
Study Population..........................................................................................................32
6.1.1.
Inclusion Criteria .................................................................................................32
6.1.2.
Exclusion Criteria ................................................................................................36
6.2.
Summary of Study Design............................................................................................40
6.2.1.
Phase 1b Dose Escalation.....................................................................................42
6.2.2.
Phase 2 Cohort Expansion....................................................................................42
6.2.3.
Study Completion and End of Trial......................................................................43
6.2.4.
Definitions of Study Periods.................................................................................43
6.3.
Discontinuations ..........................................................................................................44
6.3.1.
Discontinuation of Patients Inadvertently Enrolled...............................................44
6.3.2.
Discontinuation of Patients...................................................................................44
6.3.3.
Patients Lost to Follow-Up...................................................................................45
6.3.4.
Discontinuation of Study Sites .............................................................................45
6.3.5.
Discontinuation of the Study................................................................................45
7.
Treatment..........................................................................................................................46
7.1.
Materials and Supplies .................................................................................................46
7.1.1.
Galunisertib .........................................................................................................46
7.1.2.
Nivolumab ...........................................................................................................46
7.2.
Study Drug Administration ..........................................................................................46
7.2.1.
Dosing Schedule ..................................................................................................47
7.2.2.
Phase 1b Dose Escalation.....................................................................................48
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum 
Tolerated Dose Definition...............................................................................49
7.2.2.2.
Dose-Escalation Method.................................................................................50
7.2.2.3.
Pharmacologically Active Dose......................................................................51
7.2.3.
Phase 2 Cohort Expansion....................................................................................51
7.2.4.
Dose Adjustments, Delays, or Discontinuation from Study 
Drug.....................................................................................................................52
7.2.4.1.
Galunisertib Dose Adjustments and Delays, Criteria for 
Resumption of Galunisertib Treatment, and 
Discontinuation for Phase 1b and 2.................................................................52
7.2.4.1.1.
Galunisertib Dose Adjustments and Delays...............................................52
7.2.4.1.2.
Criteria to Resume Treatment with Galunisertib........................................52
7.2.4.1.3.
Discontinuation from Galunisertib ............................................................53


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
7.2.4.2.
Nivolumab Dose Adjustments and Delays, Criteria for 
Resumption of Nivolumab Treatment, and 
Discontinuation in Phase 1b and 2 ..................................................................54
7.2.4.2.1.
Nivolumab Dose Adjustments and Delays ................................................54
7.2.4.2.2.
Criteria for Resumption of Nivolumab Treatment .....................................55
7.2.4.2.3.
Discontinuation from Nivolumab..............................................................55
7.2.5.
Study Treatment beyond Disease Progression by RECIST 
Version 1.1...........................................................................................................57
7.2.6.
Management Algorithms for Immuno-Oncology Agents ......................................59
7.2.7.
Treatment of Nivolumab-Related Infusion Reactions ...........................................59
7.3.
Method of Assignment to Treatment ............................................................................61
7.4.
Blinding .......................................................................................................................61
7.5.
Concomitant Therapy...................................................................................................61
7.6.
Treatment Compliance .................................................................................................62
7.6.1.
Galunisertib Compliance......................................................................................62
7.6.2.
Nivolumab Compliance........................................................................................63
7.6.3.
Evaluable Phase 1b Patients .................................................................................63
8.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data 
Collection .........................................................................................................................65
8.1.
Safety Evaluations........................................................................................................65
8.1.1.
Safety Data Collection and Review ......................................................................65
8.1.2.
Adverse Events ....................................................................................................66
8.1.2.1.
Serious Adverse Events ..................................................................................67
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting .....................................68
8.1.2.2.1.
Prior to Administration of Study Drugs.....................................................68
8.1.2.2.2.
On Therapy...............................................................................................68
8.1.2.2.3.
Follow-Up Visits ......................................................................................69
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions..........................................69
8.1.2.4.
Summary of AE/SAE Reporting Guidelines ...................................................69
8.1.3.
Other Safety Measures .........................................................................................70
8.1.3.1.
Detection of Aneurysm Formation of the Ascending 
Aorta and Aortic Arch (Thoracic View)..........................................................70
8.1.3.2.
Electrocardiograms.........................................................................................70
8.1.3.3.
Echocardiography/Doppler.............................................................................71
8.1.3.4.
Cardiotoxicity Serum Markers as Determined by Central 
Laboratory......................................................................................................72
8.1.3.5.
Pulse Oximetry...............................................................................................72
8.1.4.
Safety Monitoring ................................................................................................72
8.1.5.
Complaint Handling.............................................................................................73


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
8.2.
Sample Collection and Testing.....................................................................................73
8.2.1.
Samples for Study Qualification and Health Monitoring.......................................73
8.2.2.
Samples for Drug Concentration Measurements 
Pharmacokinetics/Pharmacodynamics..................................................................74
8.2.2.1.
Pharmacokinetic Samples...............................................................................74
8.2.3.
Samples for Biomarker Research..........................................................................74
8.2.3.1.
Blood Samples................................................................................................75
8.2.3.2.
Tumour Tissue................................................................................................75
8.2.4.
Whole Blood for Pharmacogenetics .....................................................................76
8.2.5.
Samples for Immunogenicity Research.................................................................77
8.3.
Efficacy Evaluations ....................................................................................................77
8.4.
Procedure/Sampling Compliance..................................................................................78
9.
Data Management Methods...............................................................................................79
9.1.
Data Quality Assurance................................................................................................79
9.2.
Data Capture Systems ..................................................................................................79
9.2.1.
Case Report Form ................................................................................................79
9.2.2.
Ancillary Data......................................................................................................80
10.
Data Analyses...................................................................................................................81
10.1. General Considerations ................................................................................................81
10.1.1.
Sample Size .........................................................................................................81
10.2. Patient Disposition .......................................................................................................82
10.3. Patient Characteristics ..................................................................................................82
10.4. Safety Analyses............................................................................................................82
10.5. Pharmacokinetic Analyses............................................................................................83
10.6. Biomarker Analyses.....................................................................................................84
10.6.1.
Immunogenicity...................................................................................................84
10.7. Efficacy........................................................................................................................84
10.8. Interim Analyses ..........................................................................................................85
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................87
11.1. Informed Consent.........................................................................................................87
11.2. Ethical Review.............................................................................................................87
11.3. Regulatory Considerations ...........................................................................................87
11.3.1.
Investigator Information.......................................................................................88
11.3.2.
Protocol Signatures ..............................................................................................88
11.3.3.
Final Report Signature .........................................................................................88
12.
References ........................................................................................................................89


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
List of Tables
Table
Page
Table JBEF.6.1. Phase 1b Dose Levels ....................................................................................42
Table JBEF.7.1. Dose Adjustments for Galunisertib ................................................................52
Table JBEF.8.1. Adverse Event and Serious Adverse Reporting Guidelines for Study 
H9H-MC-JBEF .............................................................................................70
Table JBEF.10.1.Summary of Statistical Power for Response Rates .........................................81


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
List of Figures
Figure
Page
Figure JBEF.6.1. Study H9H-MC-JBEF design.........................................................................41


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
List of Attachments
List of Protocol Attachments
Attachment
Page
Attachment 1.
Protocol JBEF Study Schedule ......................................................................95
Attachment 2.
Protocol JBEF Clinical Laboratory Tests .....................................................106
Attachment 3.
Protocol JBEF Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ................................................................................................108
Attachment 4.
Protocol JBEF Pharmacokinetic, Biomarker, PK Time-Matched ECG, 
and Immunogenicity Sampling Schedule .....................................................109
Attachment 5.
Protocol JBEF Recommendations for Reporting 
Serious Adverse Events ...............................................................................111
Attachment 6.
Protocol JBEF ECOG Performance Status...................................................112
Attachment 7.
Protocol JBEF Creatinine Clearance Formula ..............................................113
Attachment 8.
Protocol JBEF RECIST Version 1.1 ............................................................114
Attachment 9.
Protocol JBEF Response Assessment in Neuro-Oncology (RANO) .............121
Attachment 10.
Protocol JBEF Echocardiographic Guidelines..............................................130
Attachment 11.
Protocol JBEF Management Algorithms for Immuno-Oncology Agents ......135
Attachment 12.
Protocol JBEF CYP3A4 Modulators............................................................143
Attachment 13.
Protocol JBEF Protocol Amendment H9H-MC-JBEF(c) Summary 
A Phase 1b/2 Dose Escalation and Cohort Expansion Study of the 
Safety, Tolerability and Efficacy of a Novel Transforming Growth 
Factor–β Receptor I Kinase Inhibitor (Galunisertib) Administered in 
Combination with Anti–PD-1 (Nivolumab) in Advanced Refractory 
Solid Tumours (Phase 1b) and in Recurrent or Refractory Non–Small 
Cell Lung Cancer or Hepatocellular Carcinoma (Phase 2)............................144


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
4.
Abbreviations and Definitions
Term
Definition
ADA
antidrug antibody 
AE
Adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event (AE) can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product.
AFP
-foetoprotein 
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve 
AUC
area under the concentration-time curve during 1 dosing interval
BID
twice daily
BNP
brain natriuretic peptide
CI
confidence interval
Cmax
maximum observed drug concentration
Cmax,ss
maximum observed drug concentration at steady state 
Cmin
minimum observed plasma concentration (trough)
CNS
central nervous system
complaint
Any written, electronic, or oral communication that alleges deficiencies related to the 
identity, quality, purity, durability, reliability, safety, effectiveness, or performance of a 
drug or drug delivery system.
compliance
Adherence to all the study-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.


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 11
Galunisertib (LY2157299)/nivolumab
CR
complete response
CrCl
creatinine clearance 
CRF/eCRF
case report form/electronic case report form:  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.
CRP
clinical research physician
CRS
clinical research scientist
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450 
DC
dendritic cell
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECHO
echocardiography 
ECOG
Eastern Cooperative Oncology Group
EMT
epithelial-mesenchymal transition
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.
enrol
Patients who are enrolled in the trial are those who have been assigned to a treatment and 
have received at least 1 dose of study treatment.  
enter
Patients who are entered in the trial are those who have signed the informed consent form 
directly or through their legally acceptable representatives.
ERB/IRB
ethical review board/institutional review board:  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 study are protected.
GCP
good clinical practice
GI
gastrointestinal
HBV
hepatitis B virus 
HCC
hepatocellular carcinoma 
HCV
hepatitis C virus 
HIV
human immunodeficiency virus


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 12
Galunisertib (LY2157299)/nivolumab
IB
Investigator’s Brochure
ICD-O
International Classification of Diseases for Oncology
ICF
informed consent form
IFN-
interferon-
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate in a 
particular trial, after having been informed of all aspects of the trial that are relevant to the 
patient’s decision to participate.  Informed consent is documented by means of a written, 
signed and dated informed consent form.
INR
international normalised ratio 
interim analysis
an analysis of clinical study data that is conducted before the final reporting database is 
authorised for database lock
investigational 
product
a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical trial
investigator
a person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
IV
intravenous
IWRS
interactive web-response system 
legal 
representative
An individual, judicial, or other body authorised under applicable law to consent on behalf 
of a prospective patient, to the patient’s participation in the clinical study.
Lilly Safety System
global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system
LLT
lower-level term 
LV
left ventricular
MedDRA
Medical Dictionary for Regulatory Activities 
MGMT
O6-methylguanine-DNA methyltransferase
monitor
a person responsible for ensuring the investigator site complies with the monitoring plan, 
applicable local standard operating procedures (SOPs) (if any), and global Medical SOPs.  
Monitors are trained on the investigational product(s), the protocol, informed consent 
document, any other written information provided to patients, relevant SOPs, International 
Conference on Harmonisation Good Clinical Practice guidelines (ICH-GCP), and all 
applicable laws (for example, privacy and data protection) and regulations.  
MRI
magnetic resonance imaging
MTD
maximum tolerated dose


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Galunisertib (LY2157299)/nivolumab
NK
natural killer
NCI
National Cancer Institute
NSCLC
non–small cell lung cancer 
open-label
a study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participants are aware of the drug therapy received during 
the study
ORR
objective response rate 
OS
overall survival 
PAD
pharmacologically active dose 
patient
a subject with a defined disease
PD
progressive disease
PD-1
programmed cell death–1
PD-L1
programmed cell death–ligand 1
PD-L2
programmed cell death–ligand 2
PET
positron emission tomography
PFS
progression-free survival 
PK
pharmacokinetic
PR
partial response
pSMAD
phosphorylated SMAD 
PT
preferred term
QD
daily
RANO
Response Assessment in Neuro-Oncology 
RECIST
Response Evaluation Criteria in Solid Tumours
rescreen
to screen a patient who was previously declared a screen failure for the same study
Q2W
every 2 weeks 
SAE
serious adverse event


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
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, 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.
screen failure
a patient who does not meet 1 or more criteria required for participation in a trial
SD
stable disease
sponsor
the party who takes responsibility for the initiation, management and/or financing of a 
clinical study
study completion
occurs (that is, the scientific evaluation will be complete) following the final evaluation of 
patients’ overall survival (OS).  The final evaluation may occur before all patients reach 
the OS endpoint if this earlier evaluation will not alter the statistical interpretation of OS.  
SUSAR
suspected unexpected serious adverse reactions
TGF-
transforming growth factor–
TPO
third-party organisation
TTP
time-to-progression 
ULN
upper limit of normal
WHO
World Health Organization


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
A Phase 1b/2 Dose Escalation and Cohort Expansion Study 
of the Safety, Tolerability and Efficacy of a Novel 
Transforming Growth Factor–Receptor I Kinase Inhibitor 
(Galunisertib) Administered in Combination with Anti–PD-1 
(Nivolumab) in Advanced Refractory Solid Tumours 
(Phase 1b) and in Recurrent or Refractory Non–Small Cell 
Lung Cancer or Hepatocellular Carcinoma (Phase 2)
5.
Introduction
5.1.
Cancer Immunotherapy
Cancer immunotherapy rests on the premise that tumours can be recognised as foreign rather 
than as self and can be effectively attacked by an activated immune system. Tumour progression 
may depend upon acquisition of traits that allow cancer cells to evade immunosurveillance and 
escape effective, innate, and adaptive immune responses (Dunn et al. 2002; Pardoll 2003; 
Zitvogel et al. 2006; Jemal et al. 2011).  An effective response in this setting is thought to rely on 
immune surveillance of tumour antigens expressed on cancer cells that ultimately results in an 
adaptive immune response and cancer cell death. Current immunotherapy efforts attempt to 
reverse the immunosuppression to tumour cells and antigens by either introducing cancer 
antigens by therapeutic vaccination or by modulating regulatory checkpoints of the immune 
system.
T-cell stimulation is a complex process involving the integration of numerous positive, as well as 
negative, costimulatory signals in addition to antigen recognition by the T-cell receptor 
(Greenwald et al. 2004). Collectively, these signals govern the balance between T-cell activation 
and tolerance. Programmed Cell Death–1 (PD-1) is a member of the CD28 family of T-cell 
costimulatory receptors that also includes CD28, CTLA-4, ICOS, and BTLA (Nishimura and 
Honjo 2001). PD-1 signalling has been shown to inhibit CD-28–mediated upregulation of IL-2, 
IL-10, IL-13, interferon-(IFN-) and Bcl-xL. PD-1 expression has also been noted to inhibit 
T-cell activation and expansion of previously activated cells. Evidence for a negative regulatory 
role of PD-1 comes from studies of PD-1 deficient mice, which develop a variety of autoimmune 
phenotypes (Sharpe et al. 2007). These results suggest that PD-1 blockade has the potential to 
activate anti-self T-cell responses, but these responses are variable and dependent upon various 
host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss 
of tolerance to self-antigens.
5.2.
Transforming Growth Factor–
Transforming growth factor–(TGF-) has been shown to be a tumour 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; Bierie and Moses 2010). TGF-also modulates immune function by influencing 
T-cell, neutrophil, monocyte, macrophage, natural killer (NK)–cell, carcinoma-associated 


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
fibroblast, and carcinoma-cell–autonomous signalling in the tumour microenvironment (Bierie 
and Moses 2006; Nagaraj and Datta 2010). Due to this regulation and the elevated TGF-levels 
present in many tumour types, an environment favourable for immune escape and tumour 
progression is created.  TGF-inhibition is then a reasonable hypothetical treatment option in 
patients with advanced cancer (Yingling et al. 2004). Inhibiting TGF-is a novel approach that 
should simultaneously inhibit tumour spread, neoangiogenesis and improve the host’s antitumour 
immune response. 
TGF-β also participates in down-regulation of the adaptive immune response (Ignotz and 
Massagué 1987; Bhowmick et al. 2004; Bierie and Moses 2006; Grady and Markowitz 2008;
Padua and Massagué 2009) by inhibiting activity of antigen-presenting cells including dendritic 
cells (DCs) (Rotzer et al. 2001; Grady and Markowitz 2008), B cells and cytotoxic T cells. For 
example, by suppressing IFN-γ secretion from activated T cells, decreased proliferation of these 
T cells occurs and TGF-β, thereby, further compromises immune function.
TGF-β upregulates the expression and signalling of the immunoregulatory enzyme indoleamine 
2,3-dioxygenase by plasmacytoid DCs. Other Treg-dependent mechanisms that impair the 
generation of host immunity also appear to be regulated by TGF-β, including CCL22 chemokine 
immunosuppression due to the ability of TGF-β to activate the CCL22 promoter.  The cytokines 
regulated by CCL22 induce chemotaxis for monocytes, DCs, NK cells, and chronically activated 
T cells.  These mechanisms suggest that inhibition of the TGF-β pathway will improve immune 
function by inhibiting production of immunosuppressive cytokines and restoring T-cell and other 
immune cell function (Hanks et al. 2013).
TGF-β promotes T-cell exhaustion, a state of T-cell dysfunction, which is identified by 
expression of markers including PD-1, LAG-3, TIM-3 and CTLA-4 (Wherry 2011).
5.3.
Programmed Cell Death–1
PD-1 (cluster of differentiation 279) is a cell surface signalling molecule that delivers inhibitory 
signals that regulate the balance between T-cell activation and tolerance by interacting with its 
ligands, PD-L1 and PD-L2.  It is a 55-kD type I transmembrane protein that is a member of the 
CD28 family of T-cell costimulatory receptors, which also includes CTLA-4, ICOS, and BTLA
(Freeman et al. 2000).  PD-1 contains an intracellular membrane proximal immunoreceptor 
tyrosine inhibitory motif and a membrane distal immunoreceptor tyrosine-based switch motif. 
PD-1 is primarily expressed on activated T, B, and myeloid cells (Nishimura and Honjo 2001).  
Its ligands, PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273), have been shown to down-
regulate T-cell activation upon binding to PD-1 in both murine and human systems (Latchman 
et al. 2001; Carter et al. 2002).  PD-1 delivers a negative signal by the recruitment of SHP-2 to 
the phosphorylated tyrosine residue in the immunoreceptor tyrosine-based switch motif in its 
cytoplasmic region (Chemnitz et al. 2004; Shepherd et al. 2000).  
In humans, PD-L1 is constitutively expressed on macrophage-lineage cells, activated T cells, 
lung, vascular endothelial cells, and placental syncytiotrophoblasts (Keir et al. 2008).  Aberrant 
expression of PD-L1 by tumour cells has been reported in a number of human malignancies
(Dong and Chen 2003; Konishi et al. 2004; Thompson et al. 2004; Ohigashi et al. 2005; 


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
Thompson et al. 2005a, 2005b; Tsushima et al. 2006).  PD-L1 expressed by tumour cells has 
been shown to enhance apoptosis of activated tumour-specific T cells in vitro (Chemnitz et al. 
2004).  Moreover, the expression of PD-L1 may protect the tumour cells from the induction of 
apoptosis by effector T cells (Azuma et al. 2008).  Retrospective analyses of several human 
tumour types suggest that tumour overexpression (as measured by immunohistochemistry) of 
PD-L1 may permit immune evasion by tumours. In renal cell carcinoma, high surface 
expression levels of PD-L1 on tumour cells are related to tumour aggressiveness. Patients with 
high tumour and/or lymphocyte PD-L1 levels are 4.5 times more likely to die from their cancer 
than patients exhibiting low levels of PD-L1 expression (Thompson et al. 2004).  In multivariate 
analysis, high expression of PD-L1 in melanoma is an independent predictor of vertical growth 
of primary melanomas and of worse outcome (Hino et al. 2010).  
Following most viral infections, the host is capable of eliciting an effective innate and adaptive 
immune response to eliminate the virus and prevent reinfection. In some cases, chronic viral 
infection is established. In the setting of chronic viral infection, antigen specific CD8 T cells 
may demonstrate increased expression of PD-1 (Barber et al. 2006).  These T cells have been 
termed “exhausted” due to their inability to control the infecting virus. Administration of an 
antibody that prevents PD-1 interaction with its ligands restores the ability of the cells to 
eliminate the virus infection and presumably restores immune function.
Thus blockage of both TGF-β and PD-1 could be expected to reverse the immunosuppression 
associated with these molecules; the combination of TGF-β and PD-1 blockade may be expected 
to act synergistically to induce immune restoration and to improve tumour control and response.  
5.4.
Rationale for H9H-MC-JBEF Protocol Amendment (a)
H9H-MC-JBEF protocol was amended to incorporate requests related to safety from the US 
Food and Drug Administration (FDA) submitted during review ending 26-Jun-2015.  These 
consisted of:

Addition of 2 cohorts to the Phase 1b part in order to lower the galunisertib 
starting dose.  At the request of FDA, these additional cohorts are added to 
decrease any potential risks to patients in the absence of combination data 
with galunisertib and nivolumab to decrease patient risk.  The revised 
galunisertib starting dose (in Cohort 1) will be 50 mg daily (QD) on a 14 day 
on/14 day off schedule; galunisertib dosing in the new Cohort 2 will be 50 mg 
twice daily (BID) on a 14 day on/14 day off schedule.  Nivolumab dosing will 
remain the same.

Addition of ≥CTCAE Grade 3 thrombocytopenia with clinically significant 
bleeding to the list of AEs considered as DLTs to ensure patient safety

Exclusion of concomitant use of strong cytochrome P450 (CYP)3A4 
inhibitors and inducers in order to minimise the influence of potential drug 
interactions on the galunisertib/nivolumab combination in Phase 1b

Clarification of galunisertib administration in regard to food intake


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
Other significant changes, modifications or clarifications made in this amendment but not 
requested by the FDA include:

Modification of “glioma” to “glioblastoma” and removal of “multiforme” 
from “glioblastoma multiforme” to conform to the most recent World Health 
Organization (WHO) guidelines

Addition of dosing information used in 2 Phase 2 studies (H9H-MC-JBAK 
[JBAK] and H9H-MC-JBAL [JBAL]) to galunisertib clinical background 
section

Revision of Inclusion Criterion 3 to remove eligibility for patients with 
gliosarcoma

Clarification added to Inclusion Criterion 3 to revise the documentation of the 
first recurrence of glioblastoma and to better define the requirement for 
patients with glioblastoma (International Classification of Diseases for 
Oncology [ICD-O] 9440/3, WHO grade IV)

Clarification of Inclusion Criterion 4 that for biopsies, fine-needle aspirates or 
other cytology samples are not acceptable  

Revision of Inclusion Criterion 6 to require that patients with MGMT 
(O6-methylguanine-DNA methyltransferase) unmethylated newly diagnosed 
glioblastoma may have received radiotherapy only and not radiotherapy and 
temozolomide

Clarification was added to Exclusion Criterion 45 to indicate that patients are 
to be excluded for a history of severe allergy to study drug components

Clarifications for dose adjustments for galunisertib were added to 
Table JBEF.7.1 and within Section 7 to align with the additions of the DLT of 
≥CTCAE Grade 3 thrombocytopenia with clinically significant bleeding and 
the 2 Phase 1b dose levels

Addition of on-study serum pregnancy tests to be conducted predose on Day 1 
of every cycle

Addition of the collection at baseline information on weight change for the 
previous 3 months and that weight and weight change from baseline would be 
assessed

Inclusion on Phase 1b patients in assessment of overall survival (OS)

Incorporation of additional information on different galunisertib formulations 
in consideration of the addition of the 50-mg galunisertib dose levels and 
corresponding 50-mg tablets

Addition of pharmacokinetic (PK) time-matched electrocardiograms (ECGs)

Modifications to the schedule of events (Attachment 1) and the PK and 
immunogenicity sampling schedule (Attachment 4) to improve consistency 
within the protocol and incorporate amendment changes


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
5.5.
Rationale for H9H-MC-JBEF Protocol Amendment (b)
H9H-MC-JBEF protocol (a) was amended for the following reasons:

To be consistent with other nivolumab clinical trials and to be able to assess toxicities 
between Study JBEF and other nivolumab clinical trials, this study was designed with 
a 56-day DLT period, consistent with 2 cycle lengths for galunisertib and 1 cycle
length for nivolumab.  
Many Phase 1 patients travel an above-average distance to participate in trials at Phase 1 
centres.  In addition, many Phase 1 patients are more ill than those enrolled in Phase 2 
clinical trials.  These 2 issues have resulted in patients withdrawing from this trial prior to the 
end of the DLT period, for reasons not due to DLTs or AEs. To minimise the impact of 
withdrawal, 1 additional patient will be enrolled in each dose level, for a total of 4 patients 
per dose level to allow for unforeseen discontinuation not due to a DLT before the DLT 
period is completed. If at least 3 patients in each cohort dose level complete the DLT period 
and the fourth patient discontinues for non-DLT reasons prior to completing the DLT period, 
the dose level will be considered successfully completed. Thus, depending on the number of 
DLTs observed, the minimum number of evaluable patients will be 3, 6, or 9 at each dose 
level.
Because of the progress of the study to date, this may affect Phase 1b Cohort 3 and will 
affect Cohort 4.  
The additional patient in each dose level will not impact the definition of the maximum 
tolerated dose (MTD), and it will assure adequate assessment of toxicity at each dose level
and will allow more rapid determination of the appropriate dose of galunisertib to use in 
combination with nivolumab.  Once this safety assessment is completed, the study can 
progress to the Phase 2 portion and allow patients with unmet medical needs, particularly 
those with hepatocellular carcinoma (HCC) and glioblastoma, to begin therapy with potential 
benefit.

In Section 7.3, the eligibility check between the site and Lilly was removed. This was 
an error because the site monitor performs this review.

The allowance of a 3-day window for ECG assessment before Day 1 of Cycles 2 
and 3 and within 3 days before Day 1 of every other odd-numbered cycle thereafter 
has been removed because patients must travel to sites to have ECGs performed on 
machines calibrated for QTc Fridericia, and patients will be at the sites on Day 1 of 
these cycles.

Collection and testing of high-sensitivity C-reactive protein was removed from this 
study because this is a nonspecific inflammatory marker that may reasonably be 
elevated in patients with malignancies and, if elevated, may not reflect abnormal 
cardiac status if this is the sole indicator of cardiac abnormality.  

Clarification has been added that pathology notes must accompany tissue biopsies.


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab

In Attachment 1, Study Schedules, a requirement was added for echocardiography
(ECHO) at the 30-day follow-up visit, and, for the Phase 2 portion, clarification was 
provided that imaging is to be collected centrally [see clarification in Section 5.5].  

In Attachment 2, Clinical Laboratory Tests, clarification was added that clinical 
chemistries and thyroid tests will be performed by a central laboratory (Lilly-
designated laboratory).
5.6.
Rationale for H9H-MC-JBEF Protocol Amendment (c)
H9H-MC-JBEF protocol (b) was amended for the following reasons:

Phase 2 portion of study:  to remove the glioblastoma cohort and update protocol text 
to reflect this change.  Results from 2 recently reported galunisertib trials,
Studies H9H-MC-JBAI and H9H-MC-JBAL, have indicated a lack of sufficient 
efficacy with galunisertib in glioblastoma.  

To clarify the rationale for the changes to the ECHOs in Attachment 1 made in 
protocol amendment (b) (see Section 5.5 bullet 6):  the requirement for ECHO 
(echocardiography) at the 30-day follow-up visit was restored into the protocol as this 
requirement had been inadvertently removed during Amendment A; for the Phase 2 
portion, clarification was provided that imaging is to be collected centrally.  

Attachment 2:  to add hepatitis B surface antigen testing to match what is already 
stated in Attachment 1, to add that hepatitis testing at baseline will be assayed by a 
local and a Lilly-designated laboratory and during the trial will be performed by a 
Lilly-designated laboratory; and to clarify in Attachment 2 the footnotes.  

Attachment 4:  to add a ±10-minute window to the blood biomarker collection on Cycle 1 
Day 1.
Minor editorial corrections or clarifications may have been made but not noted.  A detailed list of 
changes may be found in Attachment 13.
5.7.
Galunisertib
Galunisertib is an oral small molecule designed to selectively inhibit the serine/threonine kinase 
of the TGF-receptor type I (see Section 5.10). The highest selected Phase 2 study dose for the 
JBAK and JBAL studies discussed below was 150 mg BID on a 14 days on/14 days off schedule
(see the galunisertib Investigator’s Brochure [IB] Section 6.1.1).  
For detailed safety information, please refer to the galunisertib IB, Sections 3.2 and 6.2.
Non–Small Cell Lung Cancer 
No studies have been conducted evaluating galunisertib in non–small cell lung cancer (NSCLC).
Hepatocellular Carcinoma 
Study JBAK is a 4-part, Phase 2 study in HCC.  In this ongoing study, an interim analysis for 
Part A has reported response to galunisertib in 109 patients with advanced, unresectable HCC
who either failed or who were intolerant to sorafenib and had elevated α-fetoprotein (AFP) at 


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 2 1
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
baseli ne ( A F P ≥1. 5 ti mes (x) u p per li mit of n or mal [ U L N ]) (Fai vre et al. 2 0 1 4; Gi a n nelli et al. 
2 0 1 4).  Patie nts were als o e val uate d f or res p o nse base d u p o n T G F- β 1 ser u m  le vels at baseli ne 
( <, ≥3 4 1 1 p g/ m L).  

  
 
 
  
 
  
 
  
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
M ore i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits, ris ks a n d reas o na bl y a nt ici pate d 
a d verse e ve nts ( A Es) ma y be f o u n d i n t he I B.  I nf or mat i on o n A Es e x pecte d t o be relate d t o t he 
i n vesti gati onal pr o d uct ma y be f o u n d i n Sect i on 7 ( De vel o p me nt C ore Sa fety I nf or mat i on) of t he 
I B.  I nf or mati on o n seri o us a d verse e ve nts ( S A Es) e x pecte d i n t he st u d y  p o p ulat i on i n de pe n de nt 
of  dr u g e x p os ure a n d t hat will be assesse d b y t he s p o ns or i n a g gre gate, peri o dicall y d uri n g t he 
c o urse of t he st u d y, ma y be f o u n d i n Sec tio n 6 ( Effects i n H u ma ns) of t he I B.
5. 8.
Ni v ol u m a b
Ni v o l uma b (als o referre d t o as B M S -9 3 6 5 5 8) is a f ull y h u ma n m o n ocl o nal  a nti b o d y ( H u M A b; 
i m m u n o glo b uli n G 4 – S 2 2 8 P) t hat tar gets t he P D -1 cl uster of differe nt iati on 2 7 9 cell s urface 
me m bra ne rece pt or (see Secti o n 5. 1 0 ).  
C CI


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Galunisertib (LY2157299)/nivolumab
Safety
For detailed safety information, please refer to the nivolumab IB, Section 5.5.
The overall safety experience with nivolumab is based on experience in approximately 
4000 patients as either monotherapy or in combination with other therapeutics.  In general, for 
monotherapy, the safety profile is similar across tumour types.  
The most frequently reported treatment-related AE is fatigue, which is almost always of low 
grade.  Most related AEs are thought to be due to the effects of inflammatory cells on specific 
tissues.  A variety of preferred terms (PTs) have been used to describe similar kinds of 
organ-related AEs, with the result being that AE frequency tables organised by PTs can lead to 
underestimation of the frequency of similar kinds of organ-related AEs.  To address this issue, 
select AE categories were created.  Select AE categories group together the most common and
impactful PTs by organ category.  These categories include the following: pulmonary, 
gastrointestinal (GI), hepatic, skin, endocrine, hypersensitivity/infusion reaction, and renal AEs.  
It is also useful to consider the management of nivolumab-related AEs by organ category, as the 
diagnostic work-up often requires excluding other potential diagnoses and, when appropriate, 
instituting specific management principles as outlined in Attachment 11.
For suspected nivolumab-related AEs, based on the severity of the event, management with 
immunosuppressants may be necessary.  In general, dose delays and observation are adequate for 
low-grade AEs.  For moderate- and high-grade AEs, immunosuppression with corticosteroids 
should be used.  Once the AE has begun to improve, corticosteroids can be tapered over 
approximately 3 weeks to 6 weeks (depending on the severity of the AE).  The management of 
AEs considered related to any combination treatment is similar to the management of AEs 
caused by either agent alone and uses the same safety management algorithms.
NSCLC Efficacy
Nivolumab (OpdivoBristol-Myers Squibb, Inc. [BMS], New York, New York, USA) was 
approved to treat patients with metastatic squamous cell NSCLC with progression on or after 
platinum-based chemotherapy (BMS 2014).
Study 209017 was a 1:1 randomised, open-label study enrolling 272 patients with metastatic 
squamous NSCLC who had experienced disease progression during or after 1 prior platinum 
doublet-based chemotherapy regimen.  Patients received nivolumab (n=135) administered 
intravenously (IV) at 3 mg/kg every 2 weeks (Q2W) or docetaxel (n=137) administered IV at 
75 mg/m2 every 3 weeks.  The trial demonstrated a statistically significant improvement in OS
(p=.00025) for patients randomly assigned to nivolumab as compared with docetaxel at the 
prespecified interim analysis (9.2 [95% CI: 7.3-13.3] months compared to 6.0 [95% CI: 5.1-7.3] 
months, respectively) (BMS 2014).
Study 209063 was a monotherapy Phase 2 study involving 117 patients with refractory 
squamous NSCLC.  Based on an assessment by an independent review committee and with a 
minimum follow-up of at least 10 months for all patients, confirmed objective response rate 


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
(ORR) was 15% (95% CI:  9%, 22%), of which all were PRs.  The median time to onset of 
response was 3.3 months (range: 1.7 to 8.8 months) after the start of nivolumab treatment.  
Thirteen of the 17 patients (76%) with a confirmed response had ongoing responses with 
duration ranging from 1.9+ to 11.5+ months; 10 of these 17 (59%) patients had durable 
responses of 6 months or longer (BMS 2014).
Substantial monotherapy clinical activity has been observed in ≥ second-line NSCLC patients 
(n=129) treated in the completed Phase 1 multidose, dose-escalation study of nivolumab 
(CA209003). This study showed ORRs of 22% (squamous) to 26% (nonsquamous) at the 
3-mg/kg dose, greater than the historical ORR for second-line docetaxel (approximately 
8%-10%) (Fossella et al. 2000; Shepherd et al. 2000; Hanna et al. 2004) and similar to that for 
first-line platinum doublet chemotherapy (approximately 25%-30%) (Belani et al. 2008).  In 
addition, the 48-week PFS rate among NSCLC patients treated at the 3 mg/kg dose was 30% 
(both nonsquamous and squamous).  By comparison, the historical median PFS for second-line 
docetaxel is approximately 3 months (Fossella et al. 2000; Shepherd et al. 2000; Hanna et al. 
2004) and that for first-line platinum doublet chemotherapy is approximately 4 to 5.5 months 
(Scagliotti et al. 2008).  Among all CA209003 NSCLC patients with a response, the median 
duration of response was 17 months.  Furthermore, the AE profile for nivolumab appears 
favourable versus platinum doublet chemotherapy, as haematologic toxicities are currently rare 
and the majority of nonhaematologic toxicities are low grade and manageable.  
Hepatocellular Carcinoma 
There are no data published with nivolumab in HCC.  A Phase 1 dose-escalation study to 
investigate the safety, immunoregulatory activity, PK, and preliminary antitumour activity of 
nivolumab in advanced HCC in patients with or without chronic viral hepatitis (CA209040) is 
currently ongoing.  
In a study of tremelimumab (an anti–CTLA-4 antibody) in HCC (Sangro et al. 2013), 
investigators reported a good safety profile; no patients needed steroids because of severe 
immune-mediated AEs. Some patients had a transient intense elevation of transaminases after 
the first dose but not following subsequent cycles. PR rate was 17.6% and disease control rate 
was 76.4%. TTP was 6.48 months (95% CI: 3.95–9.14). A significant drop in viral load was 
observed while new emerging variants of the hypervariable region 1 of hepatitis C virus (HCV). 
HCV replaced the predominant variants present before therapy, particularly in those patients 
with a more prominent drop in viral load. This antiviral effect was associated with an enhanced 
specific anti-HCV immune response.
Additional information may be found in the nivolumab IB, Section 5.4.  


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 24
Galunisertib (LY2157299)/nivolumab
5.9.
Objectives
5.9.1. Primary Objective
Phase 1b
The primary objective of the Phase 1b part of this study is to assess the safety and tolerability of 
orally dosed galunisertib 14 days on/14 days off in combination with IV nivolumab 3 mg/kg 
Q2W by identifying dose-limiting toxicities (DLTs) and the MTD or pharmacologically active 
dose (PAD) of the combination in patients with advanced refractory solid tumours during the 
first 2 cycles.  
Phase 2
The primary objective of the Phase 2 part (expansion cohorts) of this study is to assess the safety 
of the combination of galunisertib and nivolumab in patients with refractory or recurrent NSCLC
or HCC who have failed 1 prior line of therapy.  
5.9.2. Secondary Objectives
The secondary objectives of this study are:

to characterise the PK of galunisertib and nivolumab when coadministered

to characterise the immunogenicity of nivolumab when administered in combination with 
galunisertib

to estimate the OS rate following the final analysis/evaluation of OS and the landmark 
OS at 6, 12, and 18 months following the start of therapy with the combination of 
galunisertib and nivolumab 

Phase 2 only:  To assess the preliminary antitumour activity including PFS, ORR, 
duration of response, and time to response of the combination of galunisertib and 
nivolumab in patients with NSCLC or HCC  
5.9.3. Exploratory Objectives
The exploratory objectives of this study are:  

to examine biomarkers, including pharmacodynamic markers, relevant to galunisertib, 
nivolumab, immune cells/immune functioning and the disease state, and to correlate these 
markers to clinical outcome

Phase 1b only:  To document the preliminary antitumour activity of the combination of 
galunisertib and nivolumab  


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 2 5
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
5. 1 0. G e n er al I ntr o d u cti o n t o G al u ni s erti b a n d Ni v ol u m a b
5. 1 0. 1. M e c h a ni s m of A cti o n a n d I n Vitr o/I n Vi v o A cti vit y
of 
G al u ni s erti b
T G F -has bee n s h o w n t o be a t u m o u r pr o m oter i n a d va nce d, metast atic ca ncer ( de Caestec ker 
et al. 2 0 0 0; Massa g ué et al . 2 0 0 0; Der y nc k et al. 2 0 0 1; Wa kefiel d a n d R o berts 2 0 0 2).  Se veral 
mec ha nis ms ha ve bee n pr o p ose d t o e x plai n t he t u m o ur- pr o m oti n g act i vity of  T G F-, s uc h as 
i ncrease d ne o vasc ularisatio n of  t he t u mo u r, i m m u n os u p pressi on lea di n g t o t he esca pe of t u m our-
i m m u ne s ur veilla nce, a n d i ncrease d mi grati o n a n d i n vasi o n res ulti n g i n metastasis ( A k h urst a n d 
Der y nc k 2 0 0 1; Der y nc k et al. 2 0 0 1; Sie gel a n d Massa g ué 2 0 0 3).  T hese c o m bi ne d effects of 
i m m u n os u p pressi on a n d t he t u m o u r micr oe n vir o n me nt c ha n ges i n d uce d b y TG F -pr o m ot e  
t u mo u r pr o gressi o n, a n d, t heref ore, a T G F-rece pt or t ype I ki nase i n hi bit or is e x pecte d t o ca use 
arrest of t u mo u r gr o wt h a n d metastasis i n patient s.  
T G F -β s hifts t he i m m u ne res p o nse fr o m a T h 1 (a nti-i nfla m mat or y) res p o nse t o a T h 2 
( pr oi nflam mat or y ) res p o nse, w hic h ca n be t u mo u r pr o moti n g.  I n vitr o a n d a ni mal st u dies ha ve 
s h o w n t hat in hi bit i on of t he T G F -β pat h wa y  ca n bl oc k acti vit y me diate d b y T re g ul at or y cells 
a n d e n ha nce N K a n d C D 8 T -cell act i vity ( Lill y, data o n file ; Z h o n g et al . 2 0 1 0). T h ese data
s u g gest t hat re versi o n of t he pr o -t u mo u rige nic T h 2 -li ke milie u t o a m o re T h 1-li ke 
micr o -e n vir o n me nt b y bl oc ka de of t he T G F -β pat h wa y  ma y res ult i n i m pr o ve d o utc o mes i n 
t u mo u rs t ypicall y u nres p o nsi ve t o sta n dar d c y t ot o xic t hera p y as well as tu m o u rs se nsiti ve t o 
sta n dar d c he m ot hera p y.  I n a d dit i on, t he re g ulat i on of e pit helial-mese nc h y mal tra nsit i on ( E M T)
a n d s u p pressi o n of ne oa n gi o ge nesis f urt her s u g gests t hat i n hi bit i on of T G F -β m a y re g ulate t he 
c o ntr ol of a n u m ber of t u m ou r t ypes.
  
 
 
 
 
 
 
 
 
 
G al u niserti b i n hi bits T G F-β – de pe n de nt cell si g nal li n g i n H C C cell li nes with eit her 
a nt i pr oliferati ve or a nti-i n vasi ve effects de pe n di n g o n t he m o del. I n t u mo u r sa mples fr o m 
pati e nts, i n hi bit i on of T G F -β si g nal li n g was ass ociate d wit h decrease d A F P le vels, i n hi biti on of 
pr oliferat i on a n d a p o pt osis i n d uc tio n ( Ser o va et al.  2 0 1 3). F urt her, r ece nt data fr o m a st u d y 
i n vesti gati n g t he t u m ou r effects of g al u niserti b ± s orafe ni b i n vari o us m o use m o dels of H C C a n d 
i n fres hl y gr o w n H C C s peci me ns fr om pat ient s de m o nstrate d t hat T G F -β si gnalli n g i n hi biti on 
usi n g g al u nisert i b ma y pre ve nt s orafe ni b -i n d uce d E M T, dela y t u mo u r gr o wt h, a n d i n d uce 
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 2 6
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
a p o pt osis i n vari o us H C C m o dels ( Ti jeras-Ra balla n d et al. 2 0 1 4 ).  
 
 
 
 
 
 
 
  
5. 1 0. 2. M e c h a ni s m of A cti o n a n d I n Vitr o/I n Vi v o A cti vit y of Ni v ol u m a b
Bl oc ka de of t he P D -1 pat h wa y  b y ni v ol u ma b has bee n st u die d i n a variety of  precli nical i n vitr o 
assa ys, a n d a ntit u m ou r activit y usi n g a m uri ne a nalo g ue of  ni v ol uma b has bee n s h o w n i n a 
n u m ber of i m m u n oc o m pete nt m o use ca ncer m o dels ( B M S N o ncli nical St u d y Re p orts f or St u dies 
M D X 1 1 0 6 -0 2 3- R [ B M S 2 0 0 6a] , M D X 1 1 0 6-0 3 2 - R [ B M S 2 0 0 6 b], M D X 1 1 0 6- 0 0 3- R [ B M S 
2 0 0 6c] , a n d M D X 1 1 0 6 - 0 0 6- R [ B M S 2 0 0 6 d]). Base d o n t hese a n d ot her precli nical data, P D -1 
bl oc ka de b y ni v o l u ma b has bee n p urs ue d as a pr o misi n g t hera pe utic strate g y t o re verse i m m u ne 
t olera nce a n d e n ha nce T -cell effect or f u nct i on i n se veral t u m ou r t ypes.
I n vitr o, ni v o l uma b bi n ds t o P D -1 wit h hi g h affi nit y (dr u g c o nce ntrati o n t hat pr o d uces 5 0 % of 
ma xi m u m effect = 0. 3 9 -2. 6 2 n M), a n d i n hi bits t he bi n di n g of P D -1 t o i ts li ga n ds P D-L 1 a n d 
P D -L 2 ( dr u g c o nce ntrati o n t hat re d uces t he ma xi m u m effect b y 5 0 % = 1 n M). Ni v o lu ma b
bi n ds s pecificall y t o P D -1 a n d n ot t o relate d me m bers of t he C D 2 8 fa mil y s uc h as C D 2 8, I C O S, 
C T L A -4 a n d B T L A. Bl oc ka de of t he P D -1 pat h wa y  b y ni v ol u ma b res ults i n a re pr o d uci ble 
e n ha nce me nt of b ot h pr oliferat i on a n d I F N -γ r elease i n t he mi xe d l y m p h oc yt e reacti o n. Usi n g a 
C M V re -sti m ulati on assa y  wit h h u ma n peri p heral  blo o d m o n o n uclear cells , t he effect of 
ni v o l u ma b o n a nti ge n s pecific recall res p o nse i n dicates t hat ni v ol uma b a u g me nte d I F N -
secreti o n fr om C M V s pecific me m or y  T cells i n a d ose -de pe n de nt  ma n ner vers us 
is ot ype- matc he d c o ntr ol. I n vi v o bl oc ka de of P D-1 b y  a m uri ne a nal o g of ni v ol uma b e n ha nces 
t he a nt itu m o u r i m m u ne res p o nse a n d res ult i n t u m ou r rejecti on i n se veral i m m u n oc o m pete nt 
m o use t u m o u r mo d el s ( M C 3 8 a n d S A 1/ N) ( W olch o k et al. 2 0 0 9) .
F or m ore i nf or m at i on, pl ease refer t o t he ni v o l uma b I B , Secti o n 4.
5. 1 0. 3. N o n cli ni c al P h ar m a c o ki n eti c s/ P h ar m a c o d y n a mi c s of 
G al u ni s erti b
As deter mi ne d b y meta b o lis m st u dies i n rats, m ost of g al u niserti b was e xcrete d i n faeces , wit h 
3 meta b o lites acc o u nt i n g f or 39 % of t he d ose e xcrete d i nt o uri ne a n d faeces . T he f u nct i on a n d 
acti vit y of  t hese meta b olites ha ve n ot bee n defi ne d at t his ti me.
Male a n d fe male Fisc her 3 4 4 rats were gi ve n dail y oral d oses of gal u niserti b at 0, 1 5, 5 0, or 
1 5 0 m g/ k g f or 1 m o nt h. Mal e a n d fe male bea gle d o gs were gi ve n dail y oral d oses of gal u nisert i b
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 2 7
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
at 0, 5 0, 2 5 0, or 5 0 0 m g/ k g f or 1 m o nt h. 
 
 
 
 
 
 
 
 
N o ncli nic al P h ar m ac o ki netic/ P h ar m ac o d y n a mic M o del
 
 
 
 
5. 1 0. 4. N o n cli ni c al T o xi c ol o g y 
 
  
 
5. 1 0. 5. Cli ni c al P h ar m a c o ki n eti c s of G al u ni s erti b
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 2 8
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
 
 
 
 
 
 
 
 
 
  
 
 
 
 
.  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
C CI
C CI
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 2 9
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
5. 1 0. 6. Cli ni c al P h ar m a c o ki n eti c s of Ni v ol u m a b
Si n gle -d ose P K of ni v o l u ma b was st u die d i n 3 9 p ati e nt s wit h ca ncer ( B M S Cli nical St u d y Re p ort 
f or St u d y M D X 1 1 0 6-0 1 [ B M S, 2 0 1 1]) . T he si n gle -d ose P K o f ni v o l u ma b was li near a n d 
d ose -pr o p orti o nal  in t he ra n ge of 0. 3 m g/ k g t o 1 0 m g/ k g ( B M S N o ncli nical St u d y Re p ort f or 
St u d y  M D X 1 1 0 6- 0 2 5-R [ B M S, 2 0 0 6e]) . T he mea n ter m i nal half -life of  ni v ol u ma b ra n ge d 
bet wee n 1 7 a n d 2 5 da y s acr oss t he d ose ra n ge of 0. 3 m g/ k g t o 1 0 m g/ k g. Ge o metric mea n t otal 
cleara nce varie d fr o m 0. 1 3 m L/ h/ k g t o 0. 1 9 m L/ h/ k g, w hile mea n v o l ume of distri b uti o n varie d 
bet wee n 8 3 m L/ k g a n d 1 1 3 m L/ k g acr o ss d oses. T he cleara nce a n d half -life of ni v o l u ma b are 
c o nsiste nt wit h t hat of i m m u n o gl o bul i n G 4. T he m ult i ple-d ose P K of ni v o l u ma b gi ve n Q 2 W 
was deter mi ne d b y t he M D X 1 1 0 6 -0 3 st u d y , as well as b y p op ul at i on P K usi n g data fr o m 
6 6 9 pati e nts acr oss ni v o l u ma b st u dies ( B M S C li nical St u d y Re p ort f or St u d y M D X 1 1 0 6 [ B M S, 
2 0 1 3]) . M ult i ple-d ose P K of ni v o l u ma b f oll owi n g Q 2 W d osi n g was li near wit h 
d ose -pr o p orti o nal  increase i n C m a x a n d area u n der t he c o nce ntrati o n-ti me c ur ve ( A U C) i n 
1 d osi n g i nter v al ( A U C ) i n t he st u die d ra n ge of 0. 1 m g/ k g t o 1 0 m g/ k g.  Ni v o l uma b 
acc u m ulat i on wi t h Q 2 W d osi n g fre q ue nc y was i n t he ra n ge of 2. 9 t o 3. 3 base d o n A U C , 2. 0 t o 
2. 4 base d o n C m a x , a n d 3. 1 t o 4. 8 base d o n mi ni m u m o bser ve d pl as ma c o nce ntratio n (tr o u g h) 
( Cmi n ). A p o p ul atio n P K  mo d el  was de vel o pe d b y n o nli near mi xe d effect m o delli n g usi n g data 
fr om 6 6 9 patie nts . Ni v o l uma b c o nce ntrati o n -ti me data were well descri be d b y a li near, 
2- c o mpart me nt, 0 -or der I V i nf usi o n m o d el  wit h first-or der eli mi nat i on. Ni v o l uma b P K  was 
f ou n d t o be li near, d ose i n de pe n de nt, a n d ti me i n varia nt. T he ge o metric mea n of ter mi nal 
half -life was 2 5. 6 da y s a n d t he t ypical cleara nce was 8. 8 m L/ h, w hic h are c o nsiste nt wit h t h ose 
of  full  hu ma n i m m u n o gl o b uli n a nti b o di es. Cl eara nce o f ni v o l u mab is i n de pe n de nt of d ose i n t he 
d ose ra n ge ( 0. 1 m g/ k g t o 1 0 m g/ k g) a n d t u m o u r t y pes st u die d. B o d y wei g ht n or mali se d d osi n g 
s h o we d a p pr o xi matel y c o nsta nt tr o u g h c o nce ntrati o ns o ver a wi de ra n ge of b o d y wei g hts.
5. 1 1. R ati o n al e f or S el e cti o n of D o s e
I n t he P hase 1 b part of t his st u d y , 4 d os a ge le vels of g alu niserti b (at 5 0 m g Q D, 5 0 m g BI D,
8 0 m g BI D , or 1 5 0 m g BI D , gi ve n o n a 1 4 da ys o n/ 1 4 d a y s off sc he d ule) will be a d mi nistere d 
orall y  wi t h ni v ol u ma b 3 m g/ k g I V i n patie nts wit h a d va nce d refract or y s oli d t u m ou rs ( 1 c ycle = 
2 8 da y s). 
 
  
 
 
 
 
 
 
 
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H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 3 0
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
 
 
 
 
 
 
 
 
 
I n t he ni v ol uma b cli nical de vel o p me nt pr o gra m me , t he rec o m me n de d ni v ol u ma b m o n ot hera p y 
d ose a n d sc he d ule of 3 m g/ k g Q 2 W is t he sa me acr oss t u m o ur t ypes.  
 
 
 
 
 
 
 
 
 
 
 
  
 
.  
T he safet y pr ofile of ni v o l u ma b c o m bi nati on t hera p y  o bser ve d i n ca ncer patient s treate d o n 
cli nical st u dies varies wit h t he a ge nt c o m bi ne d wit h ni v o l u ma b b ut is ge nerall y c o nsiste nt wit h 
t he safet y pr ofiles o bser ve d wit h eit her a ge nt al o ne a n d, i n s o me cases, t he fre q ue nc y o f A Es 
ma y be greater t ha n t hat o bser ve d wit h eit her a ge nt al o ne .  F or ni v o l uma b m o n ot hera p y  a n d 
c o m bi nat i on t hera p y , most hi g h -gra de e ve nts were ma na gea ble wit h use of l ow- d ose 
c ortic oster oids or h or m o ne re pl ace me nt t hera p y (e n d ocri n o pat hies) as i nstr ucte d i n t he 
ma na ge me nt g ui deli nes pr o vi de d i n Attac h me nt 1 1 .
C CI
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H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 31
Galunisertib (LY2157299)/nivolumab
Based on the nonclinical safety profile for galunisertib, treatment in rats for 6 months resulted in 
a continuum of changes in the GI tract. These changes included inflammation of the mucosa, 
simple mucosal hyperplasia, and adenocarcinoma.  These data suggest that there is potential for 
enhanced toxicity when nivolumab and galunisertib are administered in combination.
However, given the safety profile of nivolumab and galunisertib alone, the potential benefits of a 
combination study are expected to outweigh the potential risks.


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 32
Galunisertib (LY2157299)/nivolumab
6.
Investigational Plan
6.1.
Study Population
Patients who do not meet the criteria for participation within the 28-day screening period (screen 
failures) may be rescreened.  Note that repeating laboratory tests during the 28-day screening 
period does not constitute rescreening (any test that does not meet eligibility may be repeated 
within the 28-day period and not considered a rescreening).  Screening laboratory tests may not 
be repeated more than twice in order to meet eligibility during the 28-day screening period.  If a 
repeat laboratory value meets eligibility, that test must be repeated again to confirm eligibility.
Patients may be rescreened up to 2 times after the initial screening, if needed.  The interval 
between rescreenings should be at least 1 week.  If a patient does not meet eligibility within the 
first 28-day screening period, the patient may be rescreened beginning on Day 35.  Each time 
rescreening is performed, the patient must sign a new informed consent form (ICF) and be 
assigned a new identification number.  All required tests including laboratory tests, 
electrocardiograms (ECGs), echocardiograms (ECHOs), magnetic resonance imaging 
(MRI)/computed tomography (CT) scans with contrast must be repeated in patients who are 
rescreened in a new 28-day period (Attachment 1).
Prospective approval of protocol deviations to recruitment and enrolment criteria (also known as 
protocol waivers or exemptions) is not permitted.  Any missing laboratory or test results 
precludes patient from being enrolled on this study until those laboratory or test results are 
available.  Local laboratories will be used to assess eligibility.  
6.1.1. Inclusion Criteria
Patients may be included in the study if they meet all of the following criteria during screening 
prior to first dose of study drug.
[1] For Phase 1b, must have advanced refractory solid tumours in any line of 
therapy.  
[2] For Phase 2, must have 1 of the following tumour types:  recurrent or 
refractory NSCLC (any histology) or HCC with AFP ≥200 ng/mL.  
[3] For Phase 2, must have histological or cytological confirmation of recurrent 
disease based upon standard diagnostic criteria for the tumour type.  
[4] New (nonarchived) baseline tumour biopsies (defined as a biopsy specimen 
taken since completion of the first-line treatment regimen) are required for all 
cohorts (see Section 8.2.1).  In addition, in the Phase 2 part of the study, 
patients must agree to undergo an on-study biopsy; patients in the Phase 1b 
part of this study are strongly encouraged to agree to undergo an on-study 
biopsy.  See Section 8.2.3.2.  


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 33
Galunisertib (LY2157299)/nivolumab
For Phase 1b of the study, any glioblastoma patients must have either a new biopsy or 
archived tumour tissue available.  
Fine-needle aspirates or other cytology samples are not acceptable.
[5]
For NSCLC, HCC or other nonneuro-oncology tumours: have measurable 
disease as defined by RECIST version 1.1 (Eisenhauer et al. 2009; 
Attachment 8).  
For any glioblastoma patient in Phase 1b of the study:  have measurable disease as 
defined by RANO (Wen et al. 2010; Attachment 9). Patients with glioblastoma may 
have nonmeasurable disease if they have undergone resection and postresection 
radiation.  If measurable disease is present, at least 1 measurable glioblastoma lesion 
present prior to randomisation must meet the following criteria:

contrast-enhancing and clearly defined, bi-dimensionally measurable margins 
AND

at least 2 perpendicular diameters measuring 10 mm x 10 mm (Note:  
MRI measurements will not include surgical cavities, cysts, or necrotic area)
[6]
For Phase 2 only, have had disease progression or be refractory or intolerant
to 1 prior line of therapy (first-line therapy) for recurrent or refractory 
NSCLC or HCC and have refused currently approved second-line of therapy.  
First-line therapy is defined as therapy used to treat advanced disease. This 
may include multiple chemotherapeutic, targeted or immunotherapeutic agents 
with or without radiation therapy and/or surgery.  Each subsequent line of 
therapy is preceded by disease progression. A switch of an agent within the 
same drug class (eg, cisplatinum to carboplatinum) within a regimen in order 
to manage toxicity does not define the start of a new line of therapy.  
For NSCLC:  

Prior lines of therapy must include a platinum-based therapy.  Investigational 
agents used in combination with standard therapies are allowed.  Patients who 
received platinum-based neoadjuvant or adjuvant therapy and subsequently 
received platinum-based therapy as first-line of therapy are eligible.

Patients who have completed neoadjuvant or adjuvant therapy with a platinum 
doublet and have experienced disease recurrence within 6 months of completing 
the platinum doublet are eligible.

Tumours with driver mutations (epidermal growth factor receptor mutation 
positive or anaplastic lymphoma kinase fusion oncogene positive) treated with a 
tyrosine kinase inhibitor or crizotinib are eligible.  For patients who have 
progressed on a tyrosine kinase inhibitor or crizotinib or are intolerant to this 
targeted therapy, that patient must receive platinum-based therapy prior to 
enrolment in this study. Documentation of such mutations must be available and 
entered into the electronic case report form (eCRF).


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 34
Galunisertib (LY2157299)/nivolumab

Maintenance or switch maintenance therapy after first-line chemotherapy will be 
considered part of the first-line regimen and is acceptable.

Patients who completed and progressed on a platinum-containing regimen as 
adjuvant, neoadjuvant, or part of a course of chemoradiation therapy given from 
locally advanced disease and developed recurrent (local or metastatic) disease 
within the 6 months before screening would be counted as having received 1 prior 
platinum-containing regimen and therefore would not require retreatment with a 
platinum-containing regimen for Stage IIIB, IV, or recurrent disease and are 
eligible. However, patients must have received at least 2 cycles of platinum 
doublet-based chemotherapy before discontinuation for toxicity.  If patients 
received only 1 cycle of a platinum doublet and discontinue due to clear 
progression, that regimen should be counted as a prior line of therapy.
For HCC:

one prior line of therapy which must include sorafenib, or patient must have 
progressed or been intolerant to sorafenib for patients not eligible for transarterial 
chemoembolisation.  Patients who had sorafenib for locally advanced disease or 
are intolerant to sorafenib are eligible. Patients may have had clinical progression 
only following sorafenib or local therapy.  

must have Child-Pugh A only.  Patients may have any viral status (hepatitis B, 
hepatitis C, or none).

have a viral load <100 IU/mL

for hepatitis B patients, must be on a nucleoside analogue reverse transcriptase 
inhibitor (lamivudine, telbivudine, adefovir, tenofovir, or entecavir)
[7]
Are 18 years of age
[8]
Have given written informed consent prior to any study-specific procedures
[9]
Have adequate organ function, including:
For Phase 1b only:
Have sufficient haematological function, defined as a platelet count of 
100x109/L, haemoglobin concentration 9.0 g/dL or 5.6 mmol/L, and 
absolute neutrophil count (ANC) 1.5x109/L.  Patients may receive 
erythrocyte transfusions to achieve this haemoglobin level at the discretion of 
the investigator (at least 3 days before starting treatment with study drug).  
Initial treatment must not begin until 2 days after the erythrocyte transfusion 
and after the confirmation of haemoglobin level ≥9 g/dL.
Have sufficient hepatic function, defined as bilirubin 1.5xULN (except 
patients with Gilbert Syndrome who must have a total bilirubin level of 
<3.0xULN) and alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) levels 3.0xULN.  


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Galunisertib (LY2157299)/nivolumab
Serum creatinine 1.5 × institutional ULN OR measured or calculated CrCl 
(glomerular filtration rate can also be used in place of creatinine or CrCl; 
Attachment 7) ≥50 mL/min for patients with creatinine levels ≤1.5x 
institutional ULN.  
For Phase 2 only:
For all Phase 2 cohorts:

Renal:  Serum creatinine 1.5 × institutional ULN OR measured or calculated 
CrCl (glomerular filtration rate can also be used in place of creatinine or CrCl; 
Attachment 7) ≥50 mL/min for patients with creatinine levels ≤1.5x institutional 
ULN.  

Neurologic:  Patients with ≤ Grade 2 neuropathy are eligible and may enrol.
For NSCLC cohort only:

Haematologic:  platelets 100x109/L, and haemoglobin 9 g/dL or 5.6 mmol/L, 
ANC 1.5x109/L. Patients may receive erythrocyte transfusions to achieve this 
haemoglobin level at the discretion of the investigator (at least 3 days before 
starting treatment with study drug). Initial treatment must not begin until 2 days 
after the erythrocyte transfusion and after the confirmation of haemoglobin level 
≥9 g/dL.

Have sufficient hepatic function, defined as bilirubin 1.5xULN (except patients 
with Gilbert Syndrome who must have a total bilirubin level of <3.0xULN) and 
ALT and AST levels 3.0xULN.  
For HCC cohort only:

Haematologic:  platelets 50 x 109/L, haemoglobin 9 g/dL or 5.6 mmol/L, 
ANC 1.5x109/L. Patients may receive erythrocyte transfusions to achieve this 
haemoglobin level at the discretion of the investigator (at least 3 days before 
starting treatment with study drug). Initial treatment must not begin until 2 days 
after the erythrocyte transfusion and after the confirmation of haemoglobin level 
≥9 g/dL.

Hepatic:  bilirubin ≤2.5xULN (except patients with Gilbert Syndrome who must 
have a total bilirubin level of <3.0xULN), ALT, and AST ≤5.0xULN. 
Prothrombin time/international normalised ratio (INR) ≤2.3; or prothrombin time
6 seconds above control.
[10] Patients with recent major surgery must have recovered, in the opinion of the 
investigator, from the toxicity and/or complications from the intervention 
before starting therapy.
[11] Have an INR or prothrombin time ≤1.5xULN, except as noted for HCC 
patients in Inclusion Criterion 9, unless patient is receiving stable dose 
anticoagulant therapy.  These patients are eligible as long as prothrombin time
or INR is within therapeutic range of the intended use of the anticoagulant.


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
[12] Have a performance status of 0 or 1 on the Eastern Cooperative Oncology 
Group (ECOG) scale (refer to Attachment 6).
[13] Have discontinued previous treatments for cancer for at least 28 days and 
recovered from the acute effects of therapy and at least 42 days for 
mitomycin-C or nitrosoureas
[14] Are reliable and willing to be available for the duration of the study and are 
willing to follow study procedures
[15] Use an approved contraceptive method (for example, intrauterine device, birth 
control pills, or barrier device), if appropriate (male and female patients with 
reproductive potential) during the study and for 23 weeks for women of 
childbearing potential and 31 weeks for males sexually active with women of 
childbearing potential after discontinuation of study treatment.  If condoms 
are used as a barrier contraceptive, a spermicidal agent should be added to 
ensure that pregnancy does not occur. The selected contraceptive method 
should have a failure rate of <1%.
[16] Women of childbearing potential must have a negative -human chorionic 
gonadotropin pregnancy test documented within 7 days prior to treatment.  
Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should immediately discontinue study treatment 
and inform her treating physician immediately.  If pregnancy is confirmed,
patient will be discontinued from treatment.
[17] Have an estimated life expectancy of ≥12 weeks, in the judgement of the 
investigator
[18] Are able to swallow tablets
6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[19] Have received treatment within 28 days or 5 half-lives (whichever is longer) 
of the initial dose of study drug with an investigational product or 
nonapproved use of a drug or device (other than the study drug/device used in 
this study) for noncancer indications or are concurrently enrolled in any other 
type of medical research judged not to be scientifically or medically 
compatible with this study.
[20] For Phase 2 only, more than 1 prior line of therapy for their tumour type.
[21] Have moderate or severe cardiovascular disease:  

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


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab

have baseline elevated cardiac enzymes as follows: brain natriuretic peptide 
(BNP) or Cystatin C elevated more than 2xULN or Troponin I elevated above the 
ULN

have documented major ECG abnormalities (not responding to medical 
treatments)

have major abnormalities documented by ECHO with Doppler:
o
moderate or severe heart valve function defect including moderate or severe 
valve stenosis or regurgitation 
o
left ventricular (LV) ejection fraction <50%, evaluation based on the 
institutional lower limit of normal
o
have septal aneurysm or other heart aneurysm  
o
any aneurysm of the major vessels
For additional details, refer to the attached ECHO guidelines (Attachment 10).
[22] Have a serious concomitant systemic disorder including active infection with 
human immunodeficiency virus (HIV) (HIV 1/2 antibodies). 
[23] Active infection with hepatitis B virus (HBV) (positive hepatitis B surface 
antigen); HCV is allowed only in HCC patients. HCC patients at risk for 
HBV reactivation (as defined by anti–hepatitis B core antibody positive) are 
only eligible in the HCC cohort; see Inclusion Criterion 6.
[24] Are receiving immunosuppressive agents (eg, cyclosporine) for any reason 
except for corticosteroids for transfusions.  In the Phase 1b portion of the 
study, low-dose corticosteroids for glioblastoma are permitted (eg, prednisone
10 mg [approximately equivalent to 2 mg of dexamethasone] or less daily or 
equivalent dose of other corticosteroid).
[25] Have had prior monoclonal antibody therapy within 28 days before 
Study Day 1 or not recovered (≤ Grade 1 or at baseline) from AEs (except for 
fatigue or alopecia) due to agents administered more than 28 days earlier.
[26] Have had prior therapy with an anti–PD-1, anti–PD-L1, anti–PD-L2, 
anti-CD137, or anti–cytotoxic T lymphocyte-associated antigen-4 antibody 
(including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways) or a TGFβ R1 kinase inhibitor.  
[27] Have a second concurrent primary malignancy that, in the judgement of the 
investigator and Lilly, may affect the interpretation of results.
[28] Have prior malignancies.  Patients with carcinoma in situ of any origin and 
patients with prior malignancies who are in remission and whose likelihood of 
recurrence is very low (such as basal cell carcinoma), as judged by the Lilly 
clinical research physician (CRP), are eligible for this study. The Lilly CRP 
will approve enrolment of patients with prior malignancies in remission before 
these patients are enrolled.


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
[29] Receiving any concurrent antineoplastic therapy (ie, chemotherapy, hormonal 
therapy, immunotherapy, extensive, nonpalliative radiation therapy, or 
standard or investigational agents).  
[30] Have had prior radiotherapy within 2 weeks of therapy.  Patients must have 
recovered from all radiation-related toxicities, not require more than low-dose 
corticosteroids (except for low-dose corticosteroids for glioblastoma in the 
Phase 1b portion of the study, eg, prednisone 10 mg or less daily or equivalent 
dose of other corticosteroid), and not have had radiation pneumonitis.  A 
1-week washout is permitted for palliative radiation to non-CNS disease with 
Lilly physician approval.
[31] For glioblastoma patients in the Phase 1b portion of the study only, have 
diffuse leptomeningeal disease.
[32] Patients with known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Patients with stable, previously treated brain 
metastases may participate if neurologic symptoms have resolved, they have 
been off steroids for at least 7 days, and have no evidence of disease 
progression by imaging for at least 2 weeks before the first dose of study 
treatment.
[33] Have active known or suspected autoimmune disease or a documented history 
of autoimmune disease, or a syndrome that requires systemic steroids or 
immunosuppressive agents.  Patients with vitiligo, alopecia, type I diabetes 
mellitus, residual hypothyroidism due to autoimmune condition only requiring 
thyroid replacement therapy (must be on a stable dose started prior to study 
entry), and/or psoriasis not requiring chronic and systemic 
immunosuppressive treatment, are permitted to enrol if the above listed 
conditions are not expected to recur in the absence of an external trigger. 
[34] Patients requiring escalating or chronic supraphysiologic doses of 
corticosteroids for control of their disease at randomisation are excluded.  
However, patients with resolved childhood asthma/atopy, who require 
intermittent use of bronchodilators or local steroid injections, who have
hypothyroidism stable on thyroid replacement therapy at study entry, or who 
have Sjögren’s syndrome are eligible for the study.
[35] Patients with Crohn’s disease are not eligible.
[36] For glioblastoma patients in the Phase 1b portion of the study only, previous 
treatment with carmustine wafer except when administered as first-line 
treatment and at least 6 months prior to randomisation.  
[37] Concurrent treatment with Novo-Tumor Treating Fields® (Novocure; Haifa, 
Israel) is not permitted.  Prior whole brain or gamma knife radiosurgery is 
permitted for the treatment of glioblastoma or metastatic brain lesions.  


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
[38] Have evidence of interstitial lung disease that is symptomatic or may interfere 
with the detection or management of suspected drug-related pulmonary 
toxicity or active, noninfectious pneumonitis.
[39] Have an active infection requiring systemic therapy.
[40] Be a pregnant or nursing woman.
[41] Have received a live vaccine within 30 days before the first dose of study 
treatment.  Examples of live vaccines include, but are not limited to, the 
following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, 
Bacillus Calmette–Guérin, and typhoid vaccine.  Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed; however, 
intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and 
are not allowed.
[42] Have a GI condition that may affect drug absorption.
[43] Have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the study, interfere with the 
patient's participation for the full duration of the study, or is not in the best 
interest of the patient to participate, in the opinion of the treating investigator.
[44] Have known psychiatric or substance abuse disorders that in the opinion of the 
investigator would interfere with cooperation with the requirements of the 
study.
[45] Have a history of severe allergy or hypersensitivity to study drug components
(including monoclonal antibody therapy).
[46] For Phase 1b only: Concomitant use of strong CYP3A4 inhibitors and 
inducers is prohibited. See Attachment 12.
[47] For HCC patients only:

have known HCC with fibro-lamellar or mixed histology

have presence of clinically relevant ascites

have a history of hepatic encephalopathy

have had a liver transplant 

have experienced any Common Terminology Criteria for Adverse Events 
(CTCAE) Grade 3 or 4 GI bleeding or any variceal bleeding episode in the 
3 months prior to enrolment requiring transfusion or endoscopic or operative 
intervention.  (Patients with any bleeding episode considered life-threatening 
during the 3 months prior to enrolment are excluded, regardless of transfusion or 
intervention status.)

have oesophageal or gastric varices that require immediate intervention (eg, 
banding, sclerotherapy) or represent a high bleeding risk in the opinion of the 
investigator or consulting gastroenterologist or hepatologist


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Galunisertib (LY2157299)/nivolumab
6.2.
Summary of Study Design
This is a Phase 1b/2 study that will be conducted in 2 parts.  The first part (Phase 1b) of the study 
will consist of an open-label, dose-escalation assessment of the safety and tolerability of 
galunisertib administered at 50 mg QD (Cohort 1), 50 mg BID (Cohort 2), 80 mg BID
(Cohort 3), and 150 mg BID (Cohort 4) administered with nivolumab 3 mg/kg Q2W in patients 
with advanced refractory solid tumours (Figure JBEF.6.1).  The second part (Phase 2) of the 
study will be disease restricted to include 2 expansion cohorts in patients with recurrent or 
refractory NSCLC (n = approximately 25 patients) or HCC (n = approximately 25 patients) 
receiving nivolumab 3 mg/kg Q2W plus galunisertib at the dose determined from the Phase 1b 
part. Additional expansion of individual cohorts may occur depending upon activity based upon 
a 2-stage design after 3 cycles.  Details are found in Section 10.1.1.  NSCLC has a historically 
good activity under nivolumab monotherapy; HCC has documented activity with galunisertib
therapy.  
Additional cohorts of patients with specific alternative tumour histologies may be added, but this 
addition will require an amendment.
Safety assessments including laboratory assessments, PK blood draws, vital sign collection, 
medical history, weight and at baseline change in weight for previous 3 months, and physical 
examinations will be performed according to the schedule of events in Attachment 1.  AEs will 
be assessed continuously during the study and for 100 days after the last dose of combination 
treatment.  ECGs will be collected as described in Attachment 1 and Attachment 4.  ECHOs will 
be collected at baseline and every 8 weeks (end of every other cycle).  Additionally imaging 
examinations will be performed approximately every 8 weeks (end of every other cycle).  
Efficacy measures will be assessed following every other treatment cycle (end of Cycles 2, 4, 
etc). Disease assessment with CT and/or MRI, as appropriate, will be performed at baseline and 
approximately between Days 22 and 28 of every other cycle and completed before the first dose 
in the next cycle (or approximately every 8 weeks), until disease progression or patient
withdrawal from the study.  
Treatment decisions related to patient management and whether to treat a patient with advanced 
refractory solid tumours with additional cycles of study therapy will be based on RECIST
version 1.1 for all study patients except patients with glioblastoma, for whom treatment decisions 
will be based on RANO criteria.  
At the sponsor’s discretion, scans and measurements may be collected and reviewed by 
independent radiologists using RECIST version 1.1/RANO criteria at a later date, or at any time 
during the study.  
The planned duration of treatment is not fixed; patients will remain on study treatment until they 
fulfil 1 of the criteria for study discontinuation (Section 6.3). Patients demonstrating a benefit 
from treatment may continue on combination therapy if the patient and investigator feel that the 
patient is benefiting from treatment.  If a patient experiences an AE that requires the patient be 
discontinued from 1 of the 2 study drugs, the patient should continue on the other study drug 


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 4 1
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
( Sectio n 7. 2. 4 ).  La n d mar k a nal ysis of all st u d y  patie nts will occ ur at 6, 1 2, a n d 1 8 m o nt hs, a n d 
O S will be assesse d at t he e n d of trial .  
P ati e nts w h o ha ve disc o nt i n ue d fr o m c o m bi nat i on treat me nt will e nter t he Safet y F oll o w - Up 
p eri o d wi t h visits at a p pr o xi matel y 3 0 a n d 1 0 0 da ys.  If t he patie nt has o nl y disc o nti n ue d fr om 
1 of  t he 2 st u d y dr u gs , t he patie nt will c o nt i n ue o n treat me nt u ntil t he y disc o nti n ue fr om t he 
sec o n d dr u g, at w hic h ti me t he y will e nter t he Safet y F o ll ow- U p peri o d as n ote d a b o ve.  If 
pati e nts ha ve disc o nt i n ue d treat me nt f or reas o ns ot her t ha n disease pr o gressi o n, t u m ou r 
assess me nts s h o ul d c o nt i n ue e ver y 8 wee ks u ntil disease pr o gressi o n occ urs, i nitiati on of a ne w 
a nt ica ncer t hera p y, t he patie nt die s or is lost t o f ol l o w-u p.  P at ient s will be f oll owe d f or s ur vi val 
a p pr o xi matel y e v er y 1 2 wee ks ( ± 7 da ys) u ntil deat h or e n d of trial.  T his f ollo w -u p ma y  occ ur 
t hr o u g h a p h o ne call, e mail, or visit b y t he patie nt or t he patie nt's careta ker.
Refer t o Attac h me nt 1 f or t he st u d y sc he d ule.
A b bre viati o ns :  a p pr o x = a p pr o xi matel y; BI D = t wice dail y; I V = i ntra ve n o us; 
H C C = he pat ocell ular carci n o ma; n = n u m ber of patie nts; N S C L C = n o n – s mall cell 
l u n g ca ncer; Q 2 W = e ver y ot her wee k; Q D = dail y; T B D = t o be deter mi ne d.
Fi g ur e J B E F . 6. 1.
St u d y H 9 H -M C -J B E F d e si g n.
C
C
I
C CI
C CI


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Galunisertib (LY2157299)/nivolumab
6.2.1. Phase 1b Dose Escalation
A 3 + 3 + 3 design will be used to assess the safety of galunisertib given in combination with 
nivolumab 3 mg/kg. Beginning with Cohort 3 or 4, 1 additional patient will be enrolled in each 
dose level for a total of 4 patients per dose level to allow for unforeseen discontinuation not due 
to a DLT before the DLT period is completed (see Section 7.2.2.2). A cycle length for the 
combination of nivolumab and galunisertib is defined for the purpose of this study to be 28 days. 
The dosages during dose escalation are provided in Table JBEF.6.1.  The DLT observation 
period will last for 8 weeks or to the completion of Cycle 2, whichever is longer.  
After determining the MTD, PAD, or if dose escalation is completed without identifying the 
MTD and to further explore pharmacodynamic/biomarker objectives, 3 to 12 additional patients
may be enrolled in each dose level for a total of up to 15 patients at any dose level.
If at least 50 mg QD of galunisertib cannot be combined safely with nivolumab 3 mg/kg, then
following the review of available safety, PK, and pharmacodynamic data at the dose 
escalation/cohort review meetings, a lower dose of nivolumab may be considered and tested with 
galunisertib at 50 mg oral QD.  
Table JBEF.6.1.
Phase 1b Dose Levels
Cohort/Dose 
Level
Total Number of 
Evaluable Patients
Galunisertib
(PO)
Nivolumab
(IV)
1
n=3 to approx 15
50 mg QD 14 days 
on/14 days off
3 mg/kg Q2W
2
n=3 to approx 15
50 mg BID
14 days on/14 days off
3 mg/kg Q2W
3
n=3 to approx 15
80 mg BID
14 days on/14 days off
3 mg/kg Q2W
4
n=3 to approx 15
150 mg BID
14 days on/14 days off
3 mg/kg Q2W
Total
n=12 to approx 60 total
Abbreviations:  approx = approximately; BID = twice daily; IV = intravenous; PO = orally; Q2W = every 2 weeks; 
QD = daily.
6.2.2. Phase 2 Cohort Expansion
The purpose of the cohort expansions is to gather additional safety, PK, tolerability, preliminary 
efficacy and pharmacodynamic information regarding the combination of galunisertib and 
nivolumab 3 mg/kg.  Once the safety profile of all doses tested has been characterised and the 
MTD or PAD of combined administration of galunisertib and nivolumab has been defined in the 
Phase 1b part, the Phase 2 cohort expansions will be initiated at the MTD, or PAD.  Treatment 
doses in the cohort expansion groups will not exceed the MTD.  Two expansion cohorts will be 
tested in order to demonstrate efficacy of the combination in NSCLC and HCC. If
DLT-equivalent toxicities occur in 33% or more of patients within a tumour-specific cohort 
expansion in the first 2 cycles, then investigators and the Lilly CRP will assess the nature and 
severity of these toxicities.  No additional patients will be accrued until this safety review is 
completed and a decision is made either to continue at the current dose or to deescalate the dose 


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
and define a new dose for the expansion phase. The NSCLC cohort (NSCLC has demonstrated 
activity with nivolumab monotherapy) and the HCC cohort (HCC has documented monotherapy 
activity with galunisertib) will be used to assess activity of the combination.  Additional cohorts 
could be considered after reviewing the Phase 1b dose-escalation data to further explore activity 
of the combination. Any additions would require an amendment.
Approximately 25 patients will be initially enrolled in each cohort. These cohorts may be 
expanded depending upon activity observed in each individual cohort. These patients will be 
enrolled to allow for a more precise estimate of the ORR in these tumour types where 
preliminary data or Phase 3 data have suggested activity for monotherapy.  See Section 7.2.3 for 
dosing information.  For all tumour types, patients should receive a minimum of 6 cycles of 
therapy since responses may take up to 4 to 6 cycles unless they meet 1 of the discontinuation 
criteria.  Patients may continue on combination therapy past 6 cycles if in the opinion of the 
investigator and the Lilly physician the patient is deriving benefit.  
Continuous evaluation of toxicity in the cohort expansions will be performed throughout 
enrolment in the expansion cohorts.  If the rate of DLT-equivalent events exceeds 33% in the 
first 2 cycles, the findings will be discussed and further enrolment may be interrupted.  If an 
expansion cohort is discontinued due to toxicity, a new cohort may be initiated at a previously 
tested lower dose level.
6.2.3. Study Completion and End of Trial
Study completion occurs (that is, the scientific evaluation will be complete) following the final 
evaluation of patients’ OS.  The final evaluation may occur before all patients reach the OS 
endpoint if this earlier evaluation will not alter the statistical interpretation of OS. Investigators 
will continue to follow the study schedule for all patients until notified otherwise by Lilly.
“End of trial” refers to the date of the last visit or last scheduled procedure for the last patient.
6.2.4. Definitions of Study Periods 
Terms used to describe the periods during the study are defined below:

Baseline or screening (= patient entering the study):  begins when the ICF is signed 
and ends at the first study treatment (or at discontinuation, if no treatment is given).

Study Treatment Period:  begins at the first study treatment (= patient is enrolled in 
the study) and ends on the date the decision to discontinue the patient from combination 
treatment or if the patient has previously discontinued from 1 or the 2 study drug, ends on 
the date the decision to discontinue the patient from remaining study drug.  

Safety Follow-Up:  begins the day after the patient and the investigator agree that the 
patient will no longer continue combination treatment and includes 30-day and 100-day 
visits.
o
30-Day Follow-Up begins the day after the patient and the investigator agree that the 
patient will no longer continue study treatment and lasts approximately 30 days.  


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
o
100-Day Follow-Up begins the day after the 30-day follow-up visit and lasts 
approximately 70 days or approximately 100 days after the patient is no longer 
receiving study treatment.  
o
Long-Term Follow-Up begins the day after 100-day follow-up is completed and 
continues until the patient’s death or end of trial (approximately every 12 weeks
± 7 days the patient will be contacted).  

Study Completion: occurs (that is, the scientific evaluation will be complete) following 
the final analysis/evaluation of OS.  

End of Trial:  The term “end of trial” refers to the date of the last visit or last scheduled 
procedure for the last patient (includes follow-up periods).  The end of trial occurs after 
study completion, and after the last patient has discontinued study treatment and 
completed the 100-day follow-up (if applicable).
6.3.
Discontinuations
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorisation.
6.3.1. Discontinuation of Patients Inadvertently Enrolled
The criteria for enrolment must be followed explicitly. If the investigator site identifies a patient 
who did not meet enrolment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrolment criteria and who was 
inadvertently enrolled, the investigator site will be notified. A discussion must occur between 
the sponsor CRP and the investigator to determine whether the patient may continue in the study, 
with or without investigational product.  Inadvertently enrolled patients may be maintained in the 
study and on investigational product when the Lilly CRP agrees with the investigator that it is 
medically appropriate for that patient. The patient may not continue on study treatment if the 
Lilly CRP does not agree with the investigator’s determination that it is medically appropriate for 
the patient to continue. The investigator must obtain documented approval from the Lilly CRP 
to allow the inadvertently enrolled patient to continue in the study with or without investigational 
product.
6.3.2. Discontinuation of Patients 
Patients will be discontinued from the study drug and/or from the study in the following 
circumstances:

Enrolment in any other clinical trial involving an investigational product or enrolment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Investigator/physician decision
o
the investigator/physician decides that the patient should be discontinued from the 
study or study drug(s)


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Galunisertib (LY2157299)/nivolumab
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study drug(s) occurs prior to introduction of the other 
agent

Patient decision
o
the patient or the patient’s designee (for example, legal guardian) requests to be 
discontinued from the study or study drug.  

Sponsor decision
o
Sponsors stop 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)

The patient is noncompliant with study procedures and/or treatment (Section 7.6).

The patient experiences unacceptable toxicity.  If the patient discontinues from 1 study 
treatment due unacceptable toxicity (see Section 7.2.4.1.3 for galunisertib discontinuation 
and Section 7.2.4.2.3 for nivolumab discontinuation), the patient should continue on the 
other study treatment.  

The patient becomes pregnant.
The reason for and date of discontinuation from study treatment will be collected for all patients.  
The Date of Discontinuation (for any of the above reasons) from study treatment is to be reported 
on the case report form (CRF).  Patients who discontinue from study treatment will have 
follow-up procedures performed as shown in the study schedule (Attachment 1).
6.3.3. Patients Lost to Follow-Up
A patient would be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
6.3.4. 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 any scientific, medical, safety, regulatory, ethical, 
or other reasons consistent with applicable laws, regulations, and GCP.
6.3.5. Discontinuation of the Study
The study will be discontinued if Lilly, while considering the rights, safety, and well-being of the 
patient(s), judges it necessary for any scientific, medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP.


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Galunisertib (LY2157299)/nivolumab
7.
Treatment
7.1.
Materials and Supplies
7.1.1. Galunisertib
Galunisertib (50 mg) will be supplied in open-label blister packs or other appropriate packaging 
of uncoated, round white tablets.  Galunisertib (80 and 150 mg) will be supplied in open-label 
blister packs or other appropriate packaging of film-coated, paracapsule-shaped tablets that are 
light yellow/yellow in appearance.  No premedication is required for galunisertib.
All materials must be stored at room temperature within temperature range specified on the 
material label in the original container and to keep out of the reach of children.  Tablets should 
not be opened, crushed, or dissolved.  The material will be labelled according to regulatory 
requirements of the country.  Should the type of clinical trial material packaging change, it will 
adhere to country-specific regulations.  
The tablets should remain in the blister pack until just prior to administration.
Clinical study materials will be labelled according to the country’s regulatory requirements.  
7.1.2. Nivolumab
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) or 40 mg/4 mL (10 mg/mL), is a clear to 
opalescent, colourless to pale yellow liquid, which may contain light (few) particulates. The 
drug product is a sterile, nonpyrogenic, single-use, isotonic aqueous solution formulated at 
10 mg/mL in sodium citrate, sodium chloride, mannitol, diethylenetriaminepentaacetic acid 
(pentetic acid), and polysorbate 80 (TweenTM 80), pH 6.0 and includes a 0.7-mL overfill to 
account for vial, needle, and syringe holdup. It is supplied in 10-cc Type I flint glass vials, 
stoppered with butyl rubber stoppers and sealed with aluminium seals. The only difference 
between the 2 drug product presentations is the vial fill volume.
Clinical study materials will be labelled according to the country’s regulatory requirements.
7.2.
Study Drug Administration
The investigator or designee is responsible for:

explaining the correct use of the investigational agents and planned duration of 
each individual’s treatment to the site personnel or patient/legal representative

verifying that instructions are followed properly

maintaining accurate records of study drug dispensation, destruction, and 
collection, and returning or destroying all unused medication to Lilly or its 
designee at the end of the study

verifying completion of patient diary for galunisertib dosing during Cycles 1and 2 
of both Phase 1b and 2


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 4 7
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
Pat ient s will be i nstr ucte d t o c o ntact t he i n vesti gat or as s o o n as p ossi ble if t he y ha ve a c o m plai nt 
or pr o bl e m wit h t he st u d y dr u g(s) s o t hat t he sit uati on ca n be assesse d.
7. 2. 1.
D o si n g S c h e d ul e
T his st u d y  defi nes 1 c ycle as 4 wee ks or 2 8 da ys.  
T he pl a n ne d d urat i on of treat me nt is n ot fi xe d; pat ie nts will re mai n o n st u d y treat me nt u ntil t he y 
f ulfil 1 of t he crit eria for st u d y  disc o nti n uati on ( Secti o n 6. 3 ).  Patie nts de m o nstrati n g a be nefit 
fr om treat me nt ma y c o nti n ue o n t he c o m bi nat i on t hera p y.
G al u niserti b
Eac h patie nt will ta ke g alu niserti b orall y 1 4 da ys o n ( Da ys 1 t o 1 4) / 1 4 da ys off ( Da ys 1 5 t o 2 8) . 
I n t he P hase 1b p art of  t he st u d y, g alu nisert i b will be gi ve n i n a d ose -escalati o n sc he ma ; i n t he 
P hase 2 , galu niserti b will be gi ve n at t he P hase 1 b selecte d d ose.  
 
 
 
 
 
  
 
 
 
 
 
 
Ni v ol u m a b
P ati e nts s h o uld recei ve ni v o l u ma b at a d ose of 3 m g/ k g as a 3 0 -mi n ute I V i nf usi o n, o n Da ys 1 
a n d 1 5 of eac h treat me nt c ycle.  
D o si n g calc ulati ons s h o ul d be base d o n t he b o d y  w eig ht assesse d at baseli ne.  It is n ot necessar y  
t o recalc ulate s u bse q ue nt d oses if t he patie nt’s wei g ht is wit hi n 1 0 % of t he wei g ht use d t o 
calc ulate t he pre vio us d ose .  All d oses s h o ul d be r o u n de d t o t he nea rest milli gra m.  
C CI
C CI


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
Nivolumab may be dosed with no fewer than 12 days between doses and no more than 3 days 
after the scheduled dosing date.  Dose given after the 3-day window is considered a dose delay.  
A maximum delay of 42 days between doses is allowed. 
There are no premedications recommended for nivolumab on the first cycle.  
Patients should be carefully monitored for infusion reactions during nivolumab administration.  
If an acute infusion reaction is noted, patients should be managed according to Section 7.2.7.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
patient tolerates the treatment.  
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) and 40 mg/mL (10 mg/mL)
Nivolumab injection is to be administered at a dose of 3 mg/kg as a 30-minute IV infusion 
through a 0.2-micron to 1.2-micron pore size, low-protein binding polyethersulfone membrane 
in-line filter.  It is not to be administered as an IV push or bolus injection.  Nivolumab injection 
can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP or 
5% Dextrose Injection, USP to protein concentrations as low as 0.35 mg/mL.  Instructions for 
dilution and infusion of nivolumab injection may be provided in the clinical protocol, pharmacy 
binder, or pharmacy reference sheet.  Care must be taken to assure sterility of the prepared 
solution as the product does not contain any antimicrobial preservative or bacteriostatic agent.  
No incompatibilities between nivolumab and polyvinyl chloride, non-PVC/
non-(di(2-ethylhexyl)phthalate) IV components, or glass bottles have been observed.
Clinical study materials will be labelled according to the country’s regulatory requirements.  
7.2.2. Phase 1b Dose Escalation
The MTD (or PAD) of galunisertib defined during Phase 1b will be used for Phase 2.  
Four dose levels will be investigated (Table JBEF.6.1).  Dose escalation is described in 
Section 7.2.2.2.
Because this is a dose-escalation part of the study, data will be evaluated on an ongoing basis 
until the MTD, or PAD, is determined.  
Safety data, in particular AEs, will be the primary criteria for the dose escalation.  In addition, if 
available at the time of dose-escalation decision, PK will be used as secondary/supporting data 
for dose escalation.  No dose escalation can occur without prior discussion and agreement 
between the investigator and the Lilly study teams; the decision will be documented in writing.  
Based on the ongoing safety reviews, modifications to the dose-escalation strategy or other 
design elements may be made via protocol amendment to ensure patient safety.
No intrapatient dose escalation is allowed during Phase 1b within Cycles 1 or 2.  Intrapatient 
dose reduction is permitted for a DLT if a lower dose of galunisertib has been established to be 
safe in combination with nivolumab and the patient, in the opinion of the investigator and the 


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
Lilly physician, is deriving benefit.  Subsequent cycles may be dose adjusted as outlined in 
Sections 7.2.4.1.1, 7.2.4.1.2, 7.2.4.2.1, and 7.2.4.2.2.
Dose escalation will be based on the number of DLTs experienced during Cycles 1 and 2.
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum Tolerated Dose 
Definition
DLT is defined as an AE during Cycles 1 or 2 (8 weeks) that is possibly related to either study 
drug and fulfils any 1 of the following criteria using the National Cancer Institute’s (NCI’s) 
CTCAE version 4.03:

CTCAE Grade 3 nonhaematologic toxicity.  Exceptions that will not be 
considered a DLT are:
o
nausea, vomiting, diarrhoea, and constipation that can be controlled with 
treatment
o
fatigue relieved by rest, limiting self-care and/or activities of daily living
o
anorexia not associated with significant weight loss (weight loss of 
>10% baseline) or malnutrition (eg, inadequate oral caloric and/or fluid 
intake); tube feeding or total parenteral nutrition indicated
o
Grade 3 elevations of ALT and/or AST, without evidence of other hepatic 
injury, in the setting of preexisting hepatic metastasis and baseline elevation 
of these values may not be considered a DLT if agreed by the study 
investigator and Lilly CRP

CTCAE Grade 4 haematological toxicity of >5 days duration

any febrile neutropenia

≥CTCAE Grade 3 thrombocytopenia with clinically significant bleeding

for nivolumab, any toxicity occurring during Cycles 1 or 2 managed by 
discontinuation as described in Section 7.2.4.2.

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 study medication that requires the withdrawal of the patient 
from the study during Cycles 1 or 2) or results in the patient getting <75% of the 
total doses or leads to holding galunisertib for >2 weeks
Although no intrapatient dose escalation or reduction is allowed, for the purposes of patient
management, DLTs will lead to dose interruption regardless of the cycle in which a DLT occurs 
(see Section 7.2.2.2 for specific guidelines).
For the purpose of this study, the MTD is defined as the highest tested dose that has less than 
33% probability of causing a DLT.


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Galunisertib (LY2157299)/nivolumab
7.2.2.2.
Dose-Escalation Method
Cohorts 1 and 2
A 3 + 3 +3 design will be used to assess the safety of galunisertib given in combination with 
nivolumab 3 mg/kg.  The dosages during dose escalation are provided in Table JBEF.6.1.  The 
DLT observation period will last for 8 weeks or to the completion of Cycle 2.  Three patients 
will be treated initially at each dose level.  If no DLTs occur in a cohort of 3 patients at the lower 
dose level, a new cohort of 3 patients will be treated at the higher dose level.  If 1 of 3 patients 
experiences a DLT in either cohort, that cohort will be expanded to 6 patients.  If 1 of 6 patients 
experiences a DLT in the lower cohort, a new cohort of 3 patients will be treated at the higher 
dose level.  If 2 of 6 patients experience a DLT, that cohort will be expanded to 9 patients.  If 
2 of 3, 3 of 6, or 3 of 9 patients experience DLTs within a cohort, then that dose level will be 
determined to have exceeded the MTD or the intended maximum dose of galunisertib.
Additional patients will be enrolled in a cohort to achieve the minimum of 3 evaluable patients if 
dropouts or dose interruptions or reductions occur that result in a patient being nonevaluable for 
DLTs.  Patients who withdraw from the study during the DLT period for reasons other than a 
DLT should be replaced within the same dose level.  For the purpose of making decisions on 
dose escalation from a safety perspective, patients will be considered evaluable if they have 
received at least 3 out of the 4 scheduled nivolumab doses through the 8-week observation 
period and if at least 75% of the cohort-specified doses of galunisertib were taken (see 
Section 7.6.3).  Patients who receive fewer than 3 out of 4 nivolumab doses or less than 75% of 
galunisertib doses for reasons other than AEs or DLTs should be replaced.
Cohorts 3 and 4
A 3 + 3 + 3 design will be used to assess the safety of galunisertib given in combination with 
nivolumab 3 mg/kg. The dosages during dose escalation are provided in Table JBEF.6.1.  The 
DLT observation period will last for 8 weeks or to the completion of Cycle 2.  One additional 
patient will be enrolled in each dose level for a total of 4 patients per dose level to allow for 
unforeseen discontinuation not due to a DLT before the DLT period is completed.  If at least 
3 patients in each dose level complete the DLT period and the fourth patient discontinues for 
non-DLT reasons prior to completing the DLT period, the dose level will be considered 
successfully completed.  Thus, depending on the number of DLTs observed, the minimum 
number of evaluable patients will be 3, 6, or 9.  For the cohort expansions, up to 4 patients will 
be enrolled to ensure the minimum number of evaluable patients is achieved (6 or 9 patients).
For the purpose of making decisions on dose escalation from a safety perspective, patients will 
be considered evaluable if they have received at least 3 of the 4 scheduled nivolumab doses 
through the 8-week observation period and if at least 75% of the cohort-specified doses of 
galunisertib were taken (see Section 7.6.3).  Patients who receive fewer than 3 of 4 nivolumab 
doses or <75% of galunisertib doses for reasons other than AEs or DLTs should be replaced if 
the minimum number of evaluable patients has not been reached.


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Galunisertib (LY2157299)/nivolumab

If no DLTs occur in a cohort of 3 or 4 evaluable patients at the lower dose level, a new 
cohort of 4 patients will be treated at the higher dose level.

If 1 of 3 or 4 evaluable patients experiences a DLT, up to 4 additional patients (dose level 
expansion) will be enrolled into the cohort so that a minimum of 6 patients will be evaluable.  
The dose escalation can proceed if the DLT rate is <33%. If the DLT rate is 33%, up to 
4 additional patients (dose level expansion) will be enrolled into the cohort so that a 
minimum of 9 patients will be evaluable. The dose escalation can proceed if the DLT rate is 
<33%. If the DLT rate is ≥33%, then that dose level will be determined to have exceeded the 
MTD or the intended maximum dose of galunisertib.

If the DLT rate is >33% (for example, 2 of 3 or 4 evaluable patients experiences a DLT), that 
dose level will be determined to have exceeded the MTD or the intended maximum dose of 
galunisertib.
7.2.2.3.
Pharmacologically Active Dose 
The PAD of a targeted agent is not necessarily the same as the MTD.  The PAD of galunisertib
will be assessed using an appropriate pharmacodynamic marker.  
7.2.3. Phase 2 Cohort Expansion
Once the safety profile of all doses tested has been characterised and the MTD or PAD of 
combined administration of galunisertib and nivolumab has been defined in the Phase 1b part, 
the cohort expansions will be initiated.  
The Phase 2 part of the study will initially include 2 expansion cohorts (NSCLC and HCC [n = 
approximately 25 patients per cohort]). Additional cohorts of patients with specific alternative 
tumour histologies may be added and would require a protocol amendment.  If DLT-equivalent 
toxicities occur in 33% or more of patients within a tumour-specific cohort expansion, then 
investigators and the Lilly CRP will assess the nature and severity of these toxicities. No 
additional patients will be accrued until this safety review is completed and a decision is made 
either to continue at the current dose or to deescalate the dose and define a new dose for the 
expansion phase.  Treatment in all 3 cohorts will consist of 3 mg/kg nivolumab IV on Days 1 and 
15 and galunisertib given orally at the dose determined during the Phase 1b part on a schedule of 
14 days on/14 days off (taken on Days 1-14).  A cycle is 28 days.  
Continuous evaluation of toxicity in the cohort expansions will be performed throughout 
enrolment in the expansion cohorts.  If the rate of DLT-equivalent events exceeds 33% in the 
first 2 cycles, the findings will be discussed and further enrolment may be interrupted.  If an 
expansion cohort is discontinued due to toxicity, a new cohort may be initiated at a previously 
tested lower dose level.


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Galunisertib (LY2157299)/nivolumab
7.2.4. Dose Adjustments, Delays, or Discontinuation from Study Drug
7.2.4.1.
Galunisertib Dose Adjustments and Delays, Criteria for Resumption of 
Galunisertib Treatment, and Discontinuation for Phase 1b and 2
7.2.4.1.1. Galunisertib Dose Adjustments and Delays
During Phase 1b Cycles 1 and 2, no intrapatient dose escalation or reduction of galunisertib is 
allowed.  Subsequent cycles may be dose adjusted as outlined in Sections 7.2.4.1.2 and 7.2.4.2.
Table JBEF.7.1 summarizes dose adjustment for patients experiencing the following events that 
are considered possibly related to galunisertib during Phase 1b Cycle 3 and beyond and during 
Phase 2.  Galunisertib will be omitted until the event resolves.
Table JBEF.7.1.
Dose Adjustments for Galunisertib
Events Possibly Related to Galunisertib
Adjustment
ANC <0.5x109/L for longer than 7 days, or 
ANC <1.0x109/L with a single temperature of 
>101F/38.3C or a sustained temperature of 
>100.4F/38C for >1 hour
Galunisertib will be omitted until the event resolves.  
In Phase 1b, no dose reduction is permitted; in Phase 2, 
galunisertib should be reduced by 1 (Phase 1b) cohort 
dose level (see Table JBEF.6.1).  If the event has not 
recovered by Day 1 of the subsequent cycle, then 
galunisertib should be permanently discontinued.
Platelet count <25x109/L or platelet count <50 x 109/L 
with bleeding
Galunisertib will be omitted until the event resolves.  
In Phase 1b, no dose reduction is permitted; in Phase 2, 
galunisertib should be reduced by 1 (Phase 1b) cohort 
dose level (see Table JBEF.6.1).  If the event has not 
recovered by Day 1 of the subsequent cycle, then 
galunisertib should be permanently discontinued.
CTCAE Grade 3 or 4 nonhaematologic toxicity
Galunisertib will be omitted until the event resolves.  
In Phase 1b, no dose reduction is permitted; in Phase 2, 
galunisertib should be reduced by 1 (Phase 1b) cohort 
dose level (see Table JBEF.6.1).  If the event has not 
recovered by Day 1 of the subsequent cycle, then 
galunisertib should be permanently discontinued.  
Abbreviations:  ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for Adverse Events.
7.2.4.1.2. Criteria to Resume Treatment with Galunisertib
Patients may resume treatment with galunisertib when the drug-related AE(s) resolve(s) to 
Grade ≤1 or baseline, with the following exceptions:

Nonhaematologic toxicity must resolve to CTCAE Grade 0, 1, or baseline level before 
resuming treatment (with the exception of alopecia, fatigue, skin rash, nausea, vomiting, 
constipation, or diarrhoea that can be controlled with treatment).  

Haematologic toxicity must resolve to a level that, in the opinion of the investigator, is 
reasonable to allow for continuation of treatment.

Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in 
the presence of Grade 2 AST/ALT OR total bilirubin.


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Galunisertib (LY2157299)/nivolumab
If dosing is delayed for galunisertib-related AEs such that the patient cannot resume galunisertib 
treatment by Day 1 of the next cycle, the patient should be withdrawn from galunisertib.  At 
Cycle 3 and beyond in the Phase 1b part of the study, intrapatient dose reduction is permitted for 
a DLT if a lower dose of galunisertib has been established to be safe in combination with 
nivolumab, the patient has recovered by Day 1 of the next cycle, and the patient, in the opinion 
of the investigator and the Lilly physician, is deriving benefit.  In the Phase 2 part only, patients 
who do recover by Day 1 of the next cycle may have the dosage reduced to the next lower 
(Phase 1b) dose level (see Table JBEF.6.1).  If the Phase 2 galunisertib dose is 50 mg QD, no 
dose reduction will be allowed.  
If galunisertib dosing is omitted during the 14-day dosing period, dosing with galunisertib may 
resume within that same 14-day dosing period, to conclude as originally scheduled, if the patient 
has adequately recovered from the toxicity that required the galunisertib to be held. If the 
galunisertib cannot resume during that 14-day dosing period, it should continue to be held until 
Day 1 of the next cycle.  
If both galunisertib (see directions above) and nivolumab (see directions in Section 7.2.4.2.1) are 
held, each drug may be resumed per the directions for each individual drug.  
In case of a dose delay of galunisertib, patients can continue nivolumab treatment (at investigator 
discretion).
No patient will have his/her galunisertib dose reduced more than once.  Reescalation to the 
previous galunisertib dose is acceptable in the absence of continuing toxicities.  If subsequent 
galunisertib dose reduction is required after reescalation, the patient must be maintained at the 
reduced dose level for all remaining cycles.  
7.2.4.1.3. Discontinuation from Galunisertib
If dosing is delayed for galunisertib-related AEs such that the patient cannot resume galunisertib 
treatment by Day 1 of the next cycle, the patient should be withdrawn from galunisertib.  In the 
Phase 1b part, intrapatient dose reduction is permitted for a DLT if a lower dose of galunisertib 
has been established to be safe in combination with nivolumab, the patient has recovered by 
Day 1 of the next cycle, and the patient, in the opinion of the investigator and the Lilly physician, 
is deriving benefit.  In the Phase 2 part only, patients who do recover by Day 1 of the next cycle 
may have the dosage reduced to the next lower (Phase 1b) dose level (see Table JBEF.6.1).  If 
the Phase 2 galunisertib dose is 50 mg QD, no dose reduction will be allowed. If in the 
investigator’s opinion the toxicity is related to both study drugs, both drugs should be withheld.  
If moderate or severe heart valve toxicities are observed or a patient develops an aneurysm, the 
patient must immediately be discontinued from galunisertib treatment (for definitions see 
Attachment 10, including references on the ECHO assessment based on the Guidelines of the 
American and European Societies of Cardiac Echocardiography).  These events will be 
considered serious AEs (SAEs) and should be reported to Lilly per standard SAE reporting 
requirements (Table JBEF.8.1).  Exceptions to this rule must be approved by the ERBs and Lilly.  


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Galunisertib (LY2157299)/nivolumab
Patients with combined Grade 2 AST/ALT AND total bilirubin values meeting discontinuation 
parameters should have treatment permanently discontinued.
If a patient experiences an AE that requires the patient be discontinued from galunisertib, the 
patient should continue on nivolumab (if the patient has not previously met discontinuation 
criteria for nivolumab).  If in the investigator’s opinion the toxicity is related to both study drugs, 
both drugs should be held.
7.2.4.2.
Nivolumab Dose Adjustments and Delays, Criteria for Resumption of 
Nivolumab Treatment, and Discontinuation in Phase 1b and 2
Intrapatient dose escalations or reductions of nivolumab are not allowed in either Phase 1b or 
Phase 2.  
7.2.4.2.1. Nivolumab Dose Adjustments and Delays
Dose delay criteria specified below apply for all nivolumab-related AEs. Nivolumab must be 
delayed until treatment can resume.  There will be no dose reductions for nivolumab.
Nivolumab administration should be delayed for the following:

Any Grade ≥2 nonskin, drug-related AE, with the following exceptions:
o
Grade 2 drug-related fatigue or laboratory abnormalities do not require a 
treatment delay

Any Grade 3 skin, drug-related AE

Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
asymptomatic amylase or lipase, AST, ALT, or total bilirubin:
o
Grade 3 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis do not require a dose delay. It is 
recommended to consult with the Lilly CRP for Grade 3 amylase or lipase 
abnormalities, and to assess clinically relevant laboratory tests at more frequent 
intervals which will be determined by the investigator.
o
If a patient has a baseline AST, ALT, or total bilirubin that is within normal 
limits, delay dosing for drug-related Grade ≥2 toxicity
o
If a patient has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥3 toxicity
o
For HCC patients only, if a patient has baseline AST, ALT, or total bilirubin 
within the Grade 2 toxicity range, delay dosing if these become 2x baseline levels 
during the study.  

Any AE, laboratory abnormality, or intercurrent illness which, in the judgement of the 
investigator, warrants delaying the dose of study medication
If nivolumab dosing is omitted on Days 1 or 15 of a cycle, dosing with nivolumab will be
resumed 14 days later (next scheduled dose) as per the original schedule if the patient has 


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Galunisertib (LY2157299)/nivolumab
adequately recovered from the toxicity that required the nivolumab to be held. If the nivolumab
cannot be resumed on the following Day 1 or 15, it should continue to be held until the next 
Day 1 or 15.  Galunisertib should continue as scheduled.
If both galunisertib (see directions in Section 7.2.4.1.1) and nivolumab (see directions above) are 
held, each drug may be resumed per the directions for each individual drug.  
7.2.4.2.2. Criteria for Resumption of Nivolumab Treatment
Patients may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to 
Grade ≤1 or baseline, with the following exceptions:

Patients may resume treatment in the presence of Grade 2 fatigue

Patients who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity 

Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in 
the presence of Grade 2 AST/ALT OR total bilirubin

Drug-related pulmonary toxicity, diarrhoea, or colitis must have resolved to baseline 
before treatment is resumed. Patients with persistent Grade 1 pneumonitis after 
completion of a steroid taper over at least 1 month may be eligible for retreatment if 
discussed with and approved by the Lilly CRP

Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the Lilly CRP
Dose delay of nivolumab which results in treatment interruption of >6 weeks require treatment 
discontinuation, with exceptions as noted above.  
7.2.4.2.3. Discontinuation from Nivolumab 
Nivolumab treatment should be permanently discontinued for the following:

any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the retreatment period 
OR requires systemic treatment 

any Grade 3 nonskin, drug-related AE lasting >7 days, with the following exceptions for 
laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reactions, infusion reactions, and endocrinopathies:
o
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, 
or infusion reaction of any duration requires discontinuation
o
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation
o
Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except:
o
Grade 3 drug-related thrombocytopenia >7 days or associated with bleeding requires 
discontinuation


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Galunisertib (LY2157299)/nivolumab

any drug-related liver function test abnormality that meets the following criteria require 
discontinuation:
o
AST or ALT >8xULN
o
total bilirubin >5xULN
o
concurrent AST or ALT >3xULN and total bilirubin >2xULN
o
for HCC patients only:
o
AST or ALT >10xULN for >2 weeks
o
AST or ALT >15xULN irrespective of duration
o
Total bilirubin >8xULN irrespective of duration for patients with elevated 
bilirubin at study entry or >5xULN for those with normal total bilirubin at entry
o
Concurrent AST or ALT >3xULN and total bilirubin >5xULN for patients 
entering treatment with a normal bilirubin and up to 8xULN for patients with 
elevated bilirubin

Patients with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued.

any Grade 4 drug-related AE or laboratory abnormality, except for the following events 
which do not require discontinuation:
o
Grade 4 neutropenia 7 days
o
Grade 4 lymphopenia or leukopenia
o
isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis. The Lilly CRP should be 
consulted for Grade 4 amylase or lipase abnormalities.
o
isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset
o
Grade 4 drug-related endocrinopathy AEs (such as adrenal insufficiency, 
adrenocorticotropic hormone deficiency, hyperthyroidism or hypothyroidism, or 
glucose intolerance) which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling 
agents, respectively, may not require discontinuation after discussion with and 
approval from the Lilly CRP

any event that leads to delay in dosing lasting >6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
o
Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. Prior to reinitiating treatment in a patient with a dosing delay lasting 
>6 weeks from the previous dose, the Lilly CRP must be consulted. Tumour 
assessments should continue as per protocol even if dosing is delayed. Periodic study 
visits to assess safety and laboratory studies should also continue every 6 weeks or 
more frequently if clinically indicated during such dosing delays.
o
Dosing delays lasting >6 weeks from the previous dose that occur for 
nondrug-related reasons may be allowed if approved by the Lilly CRP. Prior to 
reinitiating treatment in a patient with a dosing delay lasting >6 weeks, the Lilly CRP
must be consulted. Tumour assessments should continue as per protocol even if 


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dosing is delayed. Periodic study visits to assess safety and laboratory studies should 
also continue every 6 weeks or more frequently if clinically indicated during such 
dosing delays.

any AE, laboratory abnormality, or intercurrent illness which, in the judgement of the 
investigator, presents a substantial clinical risk to the patient with continued nivolumab 
dosing
If a patient experiences an AE that requires the patient be discontinued from nivolumab, the 
patient should continue on galunisertib (if the patient has not previously met discontinuation 
criteria for galunisertib). If in the investigator’s opinion the toxicity is related to both study 
drugs, both drugs should be held.  
7.2.5. Study Treatment beyond Disease Progression by RECIST 
Version 1.1
Accumulating evidence indicates a minority of patients treated with immunotherapy may derive 
clinical benefit despite initial evidence of progressive disease (PD).  
Nonglioblastoma Patients
Nonglioblastoma patients treated with nivolumab and galunisertib will be permitted to continue 
treatment beyond initial RECIST version 1.1–defined PD if they meet the following criteria:

investigator-assessed clinical benefit and do not have rapid disease progression

tolerance of study drugs

stable performance status

treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)

patient provides written informed consent prior to receiving additional nivolumab 
treatment, using an ICF describing any reasonably foreseeable risks or discomforts, or 
other alternative treatment options
The decision to continue treatment should be discussed with the Lilly CRP and documented in 
the study records.  A radiographic assessment/scan should be performed within 8 weeks of 
original PD to determine whether there has been a decrease in the tumour size or continued PD.  
The assessment of clinical benefit should be balanced by clinical judgement as to whether the 
patient is clinically deteriorating and unlikely to receive any benefit from continued treatment 
with nivolumab/galunisertib.  If the investigator feels that the nivolumab/galunisertib patient 
continues to achieve clinical benefit by continuing treatment, the patient should remain on the 
trial and continue to receive monitoring according to Attachment 1.  For the patients who 
continue nivolumab/galunisertib study therapy beyond progression, further progression is 
defined as an additional 10% increase in tumour burden volume from time of initial PD.  This 
includes an increase in the sum of all target lesions and/ or the development of new measurable 
lesions.  Treatment should be discontinued permanently upon documentation of further disease 
progression.  New lesions are considered measurable at the time of initial progression if the 
longest diameter is at least 10 mm (except for pathological lymph nodes which must have a short 


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axis of at least 15 mm).  Any new lesion considered nonmeasurable at the time of initial 
progression may become measurable and therefore included in the tumour burden volume if the 
longest diameter increases to at least 10 mm (except for pathological lymph nodes which must 
have a short axis of at least 15 mm).  
Global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.”  
Every effort should be made to document objective progression (ie, radiographic confirmation) 
even after discontinuation from treatment.
Glioblastoma Patients
Standard treatment for glioblastomas (including radiation therapy and temozolomide) may result 
in a transient increase in tumour enhancement (pseudoprogression) in a subset of patients that 
eventually subsides without any change in therapy.  Pseudoprogression may be difficult to 
differentiate from true tumour progression and may have important implications for patient 
management.  In order to minimise premature discontinuation of study medication and 
distinguish pseudoprogression from PD, patients initially meeting radiologic criteria for disease 
progression may continue receiving study medication until confirmation of progression with an 
MRI performed approximately 12 weeks later.  
In order to continue study treatment after assessment of initial radiological progression, the 
following criteria must be met:  
1) The patient is believed to demonstrate clinical benefit as determined by the 
investigator.  
2) The patient is tolerating study medication.  
Patients with confirmed progression (approximately 12 weeks after initially assessed 
progression) will discontinue study medication and enter the follow-up/survival phase of the 
study.  If progression is confirmed, then the date of disease progression will be the first date the 
patient met the criteria for progression. In those cases in which radiologic progression cannot be 
differentiated from pseudoprogression and it is the investigator’s opinion that a surgical resection 
to obtain tumour tissue for histopathology is in the patient’s best interests, a surgical resection 
may be performed following consultation with the Lilly CRP. Tumour biopsy samples (blocks 
or slides) must be submitted for central review by a neuropathologist to minimise any 
interobserver variation in the histopathologic assessment of progression versus treatment-related 
changes. If tumour pathology confirms progression, then the patient will be discontinued from 
study medication per protocol discontinuation criteria and the date of progression will be the day 
that it was first suspected. If tumour pathology reveals treatment-related changes and does not 
confirm disease progression, the patient may continue study medication. An MRI after the 
resection is required prior to treatment continuation. The patient will then continue all 
on-treatment tumour assessments as per the treatment schedule (Attachment 1).  


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Central Neuropathologic Review of Tumour Samples after Biopsy or Resection 
In those cases in which radiologic progression cannot be differentiated from pseudoprogression 
and the patient undergoes a biopsy or diagnostic surgical resection to obtain tumour tissue for 
histopathology analysis, representative tumour tissue samples will be reviewed locally and 
submitted for central review by a neuropathologist. If there is discordance between the central 
and local neuropathologic determination of progression versus treatment-associated changes 
(pseudoprogression), then a second central neuropathologic review will be performed and serve 
as the final adjudicator of the histopathologic determination. Central review of histopathology 
will be blinded to the patient treatment arm assignment. Specific instructions will be provided to 
the investigative sites regarding the requirements for submission of tumour tissue for central 
neuropathologic review. If tumour tissue is not available for central neuropathology review, the 
reasons for not submitting tissue for central review must be clearly documented by the principle 
investigator and approval obtained from the Lilly CRP.
7.2.6. Management Algorithms for Immuno-Oncology Agents
Immuno-oncology agents are associated with AEs that can differ in severity and duration than 
AEs caused by other therapeutic classes. Nivolumab is considered an immuno-oncology agent in 
this protocol. Early recognition and management of AEs associated with immuno-oncology 
agents may mitigate severe toxicity. Management algorithms have been developed to assist 
investigators in assessing and managing the following groups of AEs:

GI

renal

pulmonary

hepatic

endocrinopathy

skin

neurological
The above algorithms are found in Attachment 11.
7.2.7. Treatment of Nivolumab-Related Infusion Reactions
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction 
were to occur, it might manifest with fever, chills, rigours, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the Lilly CRP and reported as SAEs if 
any meet the criteria. Infusion reactions should be graded according to NCI CTCAE 
(version 4.03) guidelines.  No blood sample will be collected with any infusion reaction.  


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Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms:  (mild reaction; infusion interruption not indicated; intervention not 
indicated):

Remain at bedside and monitor patient until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions:  diphenhydramine 
50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 
30 minutes before additional nivolumab administrations.
For Grade 2 symptoms:  (moderate reaction required therapy or infusion interruption but 
responds promptly to symptomatic treatment (eg, antihistamines, nonsteroidal anti-inflammatory 
drugs, narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic medications indicated 
for 24 hours):

Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the patient
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 
325 to 1000 mg; remain at bedside and monitor patient until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If 
the infusion is interrupted, then restart the infusion at 50% of the original infusion rate 
when symptoms resolve; if no further complications ensue after 30 minutes, the rate may 
be increased to 100% of the original infusion rate. Monitor patient closely. If symptoms 
recur, then no further nivolumab will be administered at that visit.

For future infusions, the following prophylactic premedications are recommended:  
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg should be administered at least 30 minutes before nivolumab infusions. If 
necessary, corticosteroids (up to 25 mg of Solu-Cortef® or equivalent) may be used.
For Grade 3 or 4 symptoms:  (severe reaction, Grade 3:  prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalisation indicated for other clinical sequelae (eg, renal 
impairment, pulmonary infiltrates). Grade 4:  Life-threatening; pressor or ventilatory support 
indicated):

Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline 
and treat the patient as follows:  Recommend bronchodilators, epinephrine 0.2 to 1 mg of 
a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10 000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Patient should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for 
the treatment of anaphylaxis. Remain at bedside and monitor patient until recovery of the 
symptoms.


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In case of late-occurring hypersensitivity symptoms (eg, appearance of a localised or generalised 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.3.
Method of Assignment to Treatment
This study is open-label for Phase 1b and Phase 2. No dose escalations (that is, to the next 
cohort) can occur without prior discussion and agreement between the investigator and the 
responsible Lilly CRP or clinical research scientist (CRS); the decision will be documented in 
writing. All patients must begin study treatment within 7 days of enrolment by interactive web-
response system (IWRS).
For Phase 1b, if investigators have eligible patients who have consented concurrently, more than 
3 patients (Cohorts 1 and 2) or 4 patients (Cohorts 3 or 4) may be entered at a particular dose 
level provided that accrual has not ceased due to excessive toxicity.  This enrolment procedure is 
allowed because of the advanced disease state of this patient population and the screening 
involved in defining eligibility.  This event should be approved by the sponsor following 
discussions with the investigators.
All patients who enter Phase 2 will be assigned to nivolumab/galunisertib combination therapy
by IWRS.  
7.4.
Blinding
The entire study is open label.
7.5.
Concomitant Therapy
Growth factors and erythropoietin are allowed per American Society of Clinical Oncology or 
National Comprehensive Cancer Network guidelines.  Granulocyte colony-stimulating factors 
must be discontinued at least 24 hours prior to the start of the next cycle of treatment.  
Transfusions are permitted.  Patients may receive prophylactic corticosteroids (such as, 
prednisolone, methylprednisolone or dexamethasone) to prevent transfusion reactions.  No other 
therapy, including routine use of growth factors or experimental medications (for example, 
immunotherapy or other not approved medication) will be permitted while the patients are on the 
study.  
Immunosuppressive agents (eg, cyclosporine) will not be allowed, except for glioblastoma for 
which low-dose corticosteroids will be permitted (eg, prednisone 10 mg [approximately 
equivalent to 2 mg of dexamethasone] or less daily or equivalent dose of other corticosteroid).
Immunosuppressive doses of systemic steroids will not be allowed except as outlined in
Attachment 11.  
Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, nonpalliative radiation therapy, or standard or investigational agents for treatment of
NSCLC, HCC, or any other tumour type) will not be allowed.


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Patients are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses >10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of nonautoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
Patients should receive full supportive care during the trial.  Appropriate documentation for all 
forms of premedications, supportive care, and concomitant medications must be captured for 
each cycle in the CRF.  Concomitant palliative and supportive care for disease-related symptoms 
(including bisphosphonates and RANK-L inhibitors) is allowed if initiated prior to first dose of 
study therapy. Prior palliative radiotherapy must have been completed at least 2 weeks prior to 
enrolment.
Palliative radiotherapy will be allowed. No toxicities have been observed when radiotherapy has 
been added to galunisertib.  The potential for overlapping toxicities with radiotherapy and 
nivolumab currently is not known. Therefore, palliative radiotherapy is not recommended while 
receiving nivolumab. If palliative radiotherapy is required, then nivolumab should be withheld 
for at least 1 week before, during and 1 week after radiation. Patients should be closely 
monitored for any potential toxicity during and after receiving radiotherapy, and AEs should 
resolve to Grade ≤1 prior to resuming nivolumab. In the NSCLC cohort, nontarget brain lesions 
and nontarget bone lesions without lung tissue included in the planned radiation field may 
receive palliative radiotherapy. Details of palliative radiotherapy should be documented in the 
source records and eCRF. Details in the source records should include:  dates of treatment, 
anatomical site, dose administered and fractionation schedule, and AEs. If warranted, symptoms 
requiring palliative radiotherapy should be evaluated for objective evidence of disease 
progression.  
In addition, any disease progression requiring other forms of specific antitumour therapy will 
also necessitate early discontinuation from the study.  Appropriate documentation for all forms 
of premedications, supportive care, and concomitant medications must be captured on the CRF.  
Replacement hormonal therapy initiated before study entry will be allowed.
Concomitant use of strong CYP3A4 inhibitors and inducers is prohibited in Phase 1b to 
minimise the influence of potential drug interactions on the galunisertib/nivolumab combination.  
See Attachment 12 for guidance on restricted medications.
All concomitant medications should be recorded throughout the patient’s participation in the 
study.
7.6.
Treatment Compliance
7.6.1. Galunisertib Compliance
Patient compliance with galunisertib will be assessed at each visit.  Compliance will be assessed 
by direct questioning, review of diary (diary for Cycles 1 and 2 only), and counting returned 
tablets.  Deviations from the prescribed dosage regimen should be recorded on the CRF.  


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For patients who are significantly noncompliant (<75% of expected study drug taken in a visit 
interval), investigative site personnel 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.  If these patients are discontinued for reasons other than AEs or DLTs, they 
should be replaced. A Lilly representative should be contacted upon the second instance of 
treatment noncompliance.  
The following procedures will be employed to ensure appropriate drug accountability:

Drug accountability will be emphasised 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 for the first 2 cycles (56 days) to document that they are taking 
galunisertib as prescribed.
7.6.2. Nivolumab Compliance
Nivolumab will be administered IV at the investigational site, under the direction of the 
investigator.  As a result, a patient’s compliance with study drug administration is ensured.  
Patients should attend scheduled clinic visits and must comply with study criteria under their 
control.  Deviation(s) from the prescribed dosage regimen should be recorded on the CRF.  
7.6.3. Evaluable Phase 1b Patients
For Phase 1b, any patient who discontinues from the study before completing the first 2 cycles of 
study treatment (56 days) will be deemed nonevaluable for assessment of a dose level and may 
be replaced within the same dose level, unless they experience a DLT prior to withdrawal. If the 
patient is noncompliant during Cycle 1 due to reasons other than drug-related toxicity, he or she 
will be considered nonevaluable and may be replaced. Nonevaluable patients may be replaced to 
ensure that at least 3 patients complete 1 cycle of therapy at each dose level, unless accrual to 
that cohort has stopped due to a DLT.  Safety analyses will be conducted on all patients who 
have received at least 1 dose of study drug, regardless of whether they are deemed evaluable for 
the assessment of a dose level.
For the purpose of making decisions on dose escalation from a safety perspective, patients will 
be considered evaluable if:

they have received at least 3 of 4 scheduled nivolumab doses through first 2 cycles 
(56 days)

they took at least 75% of the cohort-specified dose of galunisertib
Patients who have received less than 3 out of 4 nivolumab doses or less than 75% of galunisertib 
doses for reasons other than AEs or DLTs should be replaced.  In addition, in Phase 1b, patients


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with dosing delays in Cycles 1 and 2 of ≥3 weeks for non-DLT events will be considered not 
evaluable for making decisions on dose escalation and should be replaced.
Patients who are not evaluable for PK, but who complete 2 cycles of therapy, may be replaced 
upon consultation with the investigator(s) and the Lilly CRP or CRS to ensure adequate PK data, 
unless accrual to that cohort has stopped due to a DLT.


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8. Safety, Pharmacokinetic, Pharmacodynamic, and 
Efficacy Data Collection
8.1.
Safety Evaluations
Safety is the primary endpoint of this Phase 1b/2 study as determined by the NCI CTCAE
version 4.03.  All patients who receive at least one dose of galunisertib or nivolumab will be 
evaluated for safety as measured by the occurrence of AEs, SAEs, deaths, laboratory 
abnormalities, and weight and weight change from baseline, assessed during treatment and for 
approximately 100 days in follow-up.
Patients will have regularly scheduled study visits at the clinical site as shown in the study 
schedule (Attachment 1).  Safety assessments including AE collection, laboratory assessments, 
vital sign collection, oxygen saturation by pulse oximetry at rest (also monitor amount of 
supplemental oxygen if applicable), weight, medical history (screening only) and physical 
examinations will be performed during the study. Additionally, peripheral blood will be 
assessed for HBV DNA, HCV RNA, and HCC antiviral activity.  
Imaging studies will be performed every 8 weeks or sooner if clinically indicated. Liver 
function, as part of the routine clinical chemistry panel, will be tested every other week.  
Standard laboratory tests, per the study schedule, will be performed.  A serum pregnancy test 
will be administered if applicable.  Other clinical laboratory tests will also be collected.  
Study procedures and their timing are described in the study schedule (Attachment 1).  
Attachment 2 lists the specific tests that will be performed for this study. 
8.1.1. Safety Data Collection and Review
Investigators are responsible for monitoring the safety of patients who have entered into this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patient.  
The investigator is responsible for the appropriate medical care of the patient during the study.
The investigator remains responsible for following, through an appropriate health care option,
AEs that are serious, considered related to study treatment or the study, or that caused the patient 
to discontinue before completing the study.  The patient should be followed until:  

the event is resolved, 

the event is no longer considered to be drug-related, 

the event becomes stable or returns to baseline, 

a new treatment is initiated for the patient, or

the patient dies or is lost to follow-up.  
Frequency of AE and SAE follow-up evaluation is left to the discretion of the investigator.


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The timing of all safety evaluations is shown in the study schedule (Attachment 1).  
Table JBEF.8.1 presents a summary of AE and SAE reporting guidelines.  Table JBEF.8.1 also 
shows which database or system is used to store AE and SAE data.
8.1.2. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical occurrence 
in a patient or clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  Any clinically significant findings from 
laboratory results, vital sign measurements, etc, that occur should also be reported to Lilly or its 
designee as an AE.  Lack of drug effect is not an AE in clinical studies because the purpose of 
the clinical study is to establish drug effect.
The investigator, monitor, and sponsor will review the collected data regularly for evidence of 
AEs.  All patients will be assessed routinely for AEs as outlined in the study schedule.  All AEs 
observed will be graded using CTCAE version 4.03.
The NCI CTCAE version 4.03 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms. All AEs observed 
will be graded using CTCAE version 4.0.  Any minor version of CTCAE version 4.0 (for 
example, version 4.03) may be used for this study.  Minor CTCAE version 4.0 updates from the 
NCI will not necessitate a protocol amendment.  For AEs without matching terminology within 
the NCI CTCAE version 4.03 criteria, the investigator will be responsible for selecting the 
appropriate system organ class and assessing severity grade based on the intensity of the event.  
Note that both CTCAE term (actual or coded) and severity grade must be selected by study site 
personnel and collected on the CRF.  This collection is in addition to verbatim text used to 
describe the AE.
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by the sponsor or designee to corresponding terminology 
within the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.
Cases of pregnancy that occur during maternal or paternal exposures to study drug should be 
reported.  Data on foetal outcome and breastfeeding should be collected, if feasible, for 
regulatory reporting and drug safety evaluation.
Upon documentation of pregnancy, the patient must be removed from the study and treatment 
with study drugs must be stopped immediately.
In addition to AEs and pregnancy events as noted above, the following safety information is 
collected, even in the absence of an AE: overdose, medication error, drug-drug interaction and 
cases of suspected transmission of infectious agents via study drug and drug-induced liver injury.


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For all enrolled patients, 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.  While the patient is on study, site personnel will record any 
change in these preexisting condition(s) and the occurrence and nature of any AEs.  In addition 
all AEs related to protocol procedures are reported to Lilly or designee.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via CRF the circumstances and data leading 
to any such dosage reduction or discontinuation of treatment.  
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, study drug via CRF.
The investigator decides whether he or she interprets the observed AEs as either related to 
disease, to the study medication, study procedure, or other concomitant treatment or pathologies.  
To assess the relationship of the AE to the study drug, the following terminologies are defined:

Related:  a direct cause and effect relationship between the study treatment and 
the AE is likely.

Possibly related:  a cause and effect relationship between the study treatment and 
the AE has not been demonstrated at this time and is not probable, but is also not 
impossible.

Unrelated:  without question, the AE is definitely not associated with the study 
treatment.
As per Lilly’s standard operating procedures all “related” and “possibly related” AEs and SAEs 
will be defined as related to study drug.
8.1.2.1.
Serious Adverse Events
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalisations or elective procedures for underlying preexisting conditions that are 
already recorded in the patient’s medical history at the time of study enrolment should not be 
considered SAEs.  Hospitalisation or prolongation of hospitalisation without a precipitating 
clinical AE (for example, for the administration of study therapy or other protocol-required 
procedure) should not be considered SAEs.
An SAE is any AE during this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalisation (except for study drug 
administration)

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity


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
congenital anomaly/birth defect

considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalisation may be considered SAEs when, based on appropriate medical judgement, they 
may jeopardise the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
SAEs due to disease progression, including death, should not be reported unless the investigator
deems them to be possibly related to the study drug.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  
If an investigator becomes aware of SAEs occurring after the patient’s participation in the trial 
has ended, and the investigator believes that the SAE is related to a protocol procedure or study 
drug, the investigator should report the SAEs to the sponsor, and the SAEs will be entered in the
Lilly Safety System.
Recommendations for reporting SAEs may be found in Attachment 5.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.  
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
8.1.2.2.1. Prior to Administration of Study Drugs
AE or SAE collection begins after the patient has signed informed consent and has received 
study drug.  If a patient experiences an AE or SAE after signing informed consent but prior to 
receiving study drug, only AEs and SAEs related to protocol procedures are required to be 
collected.
8.1.2.2.2. On Therapy
All AEs and SAEs, regardless of relatedness to study drugs or protocol procedures, occurring 
while the patient is receiving study drug must be reported to Lilly or its designee.  A patient is 
considered to be receiving study drug from the time he/she receives the first dose of study drug 
to when he/she receives the last dose of study drug.


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8.1.2.2.3. Follow-Up Visits
All AEs and SAEs, regardless of relatedness to study drug(s) or protocol procedures, occurring 
during the safety follow-up visits occurring at approximately 30 and 100 days after last dose of 
combination treatment must be reported to Lilly or its designee (Attachment 1).  
For the Phase 1b part only, following the safety assessments (which occur after the patient 
discontinues from study treatment) which mark the end of the follow-up visit, the patient will be 
discontinued from the study, unless there is an ongoing AE or SAE that is possibly related to 
study drug or protocol procedures.  In this instance, the patient should be followed in subsequent 
follow-up visits until the event is resolved, the event is no longer considered to be drug-related, 
the event becomes stable or returns to baseline, a new treatment is initiated for the patient, or the 
patient dies or is lost to follow-up.
For the Phase 2 part only, following the safety assessments (which occur after the patient 
discontinues from study treatment) which mark the end of the follow-up visit, the patient will be 
followed only for survival (overall and 6, 12, and 18 months), unless there is an ongoing AE or 
SAE that is possibly related to study drug or protocol procedures.  In this instance, the patient 
should be followed in subsequent follow-up visits until the event is resolved, the event is no 
longer considered to be drug-related, the event becomes stable or returns to baseline, a new 
treatment is initiated for the patient, or the patient dies or is lost to follow-up.
If it is deemed to be in the best interest of the patient to start a new anticancer treatment prior to 
the scheduled end of the follow-up visit, the follow-up visit duration may be shortened. In this 
case, the follow-up assessments should be completed prior to the initiation of the new therapy.
After the follow-up visits, AEs are not required to be reported unless the investigator feels the 
AEs were related to either study drug, drug delivery system, or a protocol procedure. If an 
investigator becomes aware of SAEs believed to be related to protocol procedures or study drug, 
the investigator should report the SAE to the sponsor, and the SAE will be entered in the Lilly 
Safety System.
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are not listed in the
Development Core Safety Information (galunisertib IB Section 7) or Reference Safety 
Information for Adverse Drug Reactions (nivolumab IB Section 5.6) and that the investigator 
identifies as related to study drug or procedure.  The United States 21 CFR 312.32, the European 
Union Clinical Trial Directive 2001/20/EC, and the associated detailed guidances or national 
regulatory requirements in participating countries require the reporting of SUSARs.  Lilly has 
procedures that will be followed for the recording and expedited reporting of SUSARs that are 
consistent with global regulatory regulations and the associated detailed guidances.
8.1.2.4.
Summary of AE/SAE Reporting Guidelines
The AE and SAE reporting guidelines are summarised in Table JBEF.8.1.


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Table JBEF.8.1.
Adverse Event and Serious Adverse Reporting Guidelines for 
Study H9H-MC-JBEF
Timing
Types of AEs/SAEs Reported
Collection 
Database
Lilly Safety 
System
Prestudy (baseline assessments)
(Starts at the signing of informed 
consent and ends just before the 
first dose of study drug)
Preexisting conditions
All AEs
All SAEs regardless of relatedness 
x
x
x
x
On therapy
(Starts at first dose of study 
drug[s] and ends at last dose of 
study drug[s])
All AEs
All SAEs regardless of relatedness
x
x
x
Follow-up visits
(Starts just after the last dose of 
combination treatment and ends 
when end of study safety 
assessments are completed 
[2 visits at approximately 30 and 
100 days after last dose of study 
drugs])
All AEs
All SAEs regardless of relatedness
x
x
x
Subsequent follow-up visits, if 
necessary for patient monitoring 
Ongoing AEs possibly related to 
study drug(s) or protocol procedures
All SAEs related to protocol 
procedures or study drug
x
x
x
Patient no longer on study
All SAEs related to protocol 
procedures or study drug that the 
investigator becomes aware of
x
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
8.1.3. Other Safety Measures
8.1.3.1.
Detection of Aneurysm Formation of the Ascending Aorta and Aortic 
Arch (Thoracic View)
MRI or CT scan with contrast of the chest will be performed and assessed locally at the site at
baseline screening and every 6 months.  For Germany, MRI of the chest is an acceptable 
alternative and may be used instead of CT scans.  Each of the imaging techniques are used to 
detect aneurysms of the ascending aorta or aortic arch and must follow institutional guidelines.  
Once the method of assessment is chosen for a given patient, it must be used throughout the 
study for that patient.  
8.1.3.2.
Electrocardiograms
For each patient, a 12-lead ECG will be collected as indicated in Attachment 1 and 
Attachment 4.  Please see Attachment 4 for specific ECG times matched with PK blood draws.
For each patient, 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 


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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 
enrolment, 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 will be 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.
It is recognised 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 hospitalisations, and AEs.  Patients will be assessed before each visit by using 
the CTCAE v4.0.
8.1.3.3.
Echocardiography/Doppler
Echocardiography with Doppler will be locally assessed for enrolment and safety decisions by 
physicians or a team of people who are qualified by experience or training.  Individuals so 
qualified must be identified at each site. The same person should be responsible for reading the 
ECHOs on any individual study patient.  ECHOs will be as indicated in Attachment 1. The 
ECHO will be electronically transmitted to a designated central laboratory for analysis.  Data 
will be interpreted by the vendor cardiologist for data analysis and study report writing purposes.  
Cardiotoxicity: ECHO/Doppler imaging will include the following assessments and other 
standard evaluations (see Attachment 10):  an increase of 1 or more grades in the 
semiquantitative valvular insufficiency, LV function, or right ventricular systolic pressure 
(normal, mild, moderate, severe based on local laboratory limits).  After a normal baseline 


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ECHO, if a subsequent ECHO demonstrates an abnormality, then a repeat ECHO should be 
performed after 14 days.  If results confirm the abnormality at repeat ECHO, then the patient will 
be discontinued from study treatment.  If findings are normal, then the patient will continue 
treatment per study protocol.  If patient has clinically significant cardiac findings at 30-day 
follow-up visit, ECHO will be repeated every 2 cycles (approximately every 2 months).  If no 
clinically significant cardiac findings at the last cardiac assessment conducted within the last 
30 days and patient has started another treatment, 30-day follow-up visit will not be performed.  
If no clinically significant cardiac findings at 30-day follow-up visit, 1 more ECHO will be 
performed after 2 months unless the patient is receiving another treatment.  If the patient is 
receiving another form of treatment, further cardiac assessments will not be performed.
8.1.3.4.
Cardiotoxicity Serum Markers as Determined by Central Laboratory
In addition to ECHO/Doppler, the following serum markers will be followed for increases:

BNP:  an increase in BNP above 3 times the baseline value and above the ULN which is 
sustained at 2 consecutive, scheduled blood draws

troponin I:  above the ULN (with testing confirmation at the central laboratory)

cystatin C
See Attachment 1 for timing.
8.1.3.5.
Pulse Oximetry
Patients will have assessments of oxygen saturation by pulse oximetry at rest (also monitor 
amount of supplemental oxygen if applicable) at screening and during the study (Attachment 1). 
If a patient shows changes on pulse oximetry or other pulmonary-related signs (hypoxia, fever) 
or symptoms (eg, dyspnoea, cough, fever) consistent with possible pulmonary-related signs 
(hypoxia, fever) or symptoms (eg, dyspnoea, cough, fever) consistent with possible pulmonary 
AEs, the patient should be immediately evaluated to rule out pulmonary toxicity, according to 
the suspected pulmonary toxicity management algorithm in Attachment 11.
8.1.4. Safety Monitoring
The Lilly CRP or CRS will monitor safety data throughout the course of the study.  
Representatives from Lilly Global Patient Safety will specifically monitor SAEs.  Lilly will 
review SAEs within time frames mandated by company standard operating procedures.  The 
Lilly CRP/CRS will, as is appropriate, consult with the functionally independent Global Patient 
Safety therapeutic area physician or CRS, and periodically review:

trends in safety data

laboratory analytes

AEs

If a study patient experiences ≥Grade 3 amylase or lipase, clinical and laboratory 
monitoring should be initiated by the investigator.  


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
Except for patients with liver metastases or HCC, for any patient who experiences 
elevated ALT >3xULN and elevated total bilirubin >2xULN, clinical and laboratory 
monitoring should be initiated by the investigator.  

For patients with liver metastases or HCC entering the study with ALT between ULN and 
5xULN, monitoring should be triggered at ALT >2x baseline.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP/CRS regarding collection of specific recommended 
clinical information and follow-up laboratory tests (see Attachment 3).
8.1.5. Complaint Handling
Lilly collects complaints on study drugs used in clinical studies in order to ensure the safety of 
study participants, monitor quality, and facilitate process and product improvements.
Complaints related to nivolumab or concomitant drugs are reported directly to the manufacturers 
of those drugs in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
complaint process in accordance with the instructions provided for this study:

recording a complete description of the complaint reported and any associated AEs using 
the study-specific complaint forms provided for this purpose

faxing the completed 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.
8.2.
Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study.  
Attachment 3 lists the hepatic monitoring tests for treatment-emergent abnormalities.  
Attachment 4 contains the PK, biomarker, and immunogenicity sampling schedules.
8.2.1. Samples for Study Qualification and Health Monitoring
Blood will be collected to determine whether patients meet inclusion/exclusion criteria and to 
monitor patient health.
New baseline tumour biopsies (defined as a biopsy specimen taken since completion of the prior 
systemic regimen [see Inclusion Criterion 4 in Section 6.1.1]) are required at screening for all 
patients other than glioblastoma patients.  For glioblastoma patients at screening, either new
biopsy or archived tumour tissue is required.  
Due diligence should be used to ensure that tumour specimen (not normal adjacent or tumour 
margins) is provided.  Pathology notes accompanying the tissue will also be requested.  


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Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
8.2.2. Samples for Drug Concentration Measurements 
Pharmacokinetics/Pharmacodynamics
PK and pharmacodynamic samples will be collected as specified in Attachment 4.
8.2.2.1.
Pharmacokinetic Samples
At the visits and times specified in the study schedule, blood samples will be collected to 
determine the plasma concentrations of galunisertib and serum concentrations of nivolumab.  
Serum nivolumab PK concentrations will be measured to derive the Cmin and at specified visits.  
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and Lilly. Instructions for the 
collection and handling of blood samples will be provided by the sponsor.  The actual date and 
time (24-hour clock time) of each sampling will be recorded.  A patient diary will collect the 
time of all galunisertib doses taken during the first 2 cycles. In addition, the diary will record 
emesis to verify successful digestion of galunisertib.  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 should be obtained from the patient at the visit for blood sampling.  
These samples will be analysed at a laboratory designated by the sponsor.  Concentrations of 
galunisertib and nivolumab will be assayed using validated methods.
The PK samples will be stored at a facility designated by the sponsor.
The residual samples collected for PK may be pooled and used for exploratory metabolism work 
as deemed appropriate.
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last patient visit for the study.
8.2.3.
Samples for Biomarker Research
To understand the relationship between cancer, genetics, and response to therapy, this study may 
analyse biomarkers relevant to galunisertib, nivolumab, immune cells/immune functioning, and 
the disease state.  


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The following samples are mandatory (required), except as indicated otherwise:

blood samples for biomarker research (see Section 8.2.3.1)

tumour tissue (newly biopsied or archived) (see Section 8.2.3.2)

whole blood for DNA collection (pharmacogenetic analysis) (see Section 8.2.4)
Sample collection including blood (serum, plasma, whole blood) and tumour tissue samples will 
occur at specified time points as indicated in Attachment 1 and Attachment 4.  
8.2.3.1.
Blood Samples
Blood (serum, plasma, peripheral blood mononuclear cells, and whole blood) will be used for the 
analyses of biomarkers related to galunisertib, nivolumab, immune cells/immune functioning 
within the disease state, and cancer-related conditions.  Potential pharmacodynamic and/or 
circulating markers may include, but are not limited to:  disease specific markers (eg, AFP in 
HCC), factors important in disease (eg, viruses in HCC), gene expression, exosome isolation and 
associated assays, and/or circulating tumour DNA isolation and associated assays.  
Samples may be stored for a maximum of 15 years following last patient visit for the trial.  
8.2.3.2.
Tumour Tissue
Collection of tumour tissue samples (either newly biopsied or archived) is mandatory (required) 
for participation in this study, as follows:
In addition to the screening requirement of collecting newly biopsied tumour tissue, other 
biopsies during the study are also required for patients with cancers other than glioblastoma and 
are optional for patients with glioblastoma.
For nonglioblastoma patients, 2 treatment biopsy groups will be randomly assigned by IWRS at 
the time of the patient is originally enrolled by IWRS.  For the Phase 1b part of the study, the 
2 treatment biopsy groups will be randomly assigned; for the Phase 2 part, the 2 treatment biopsy 
groups will be randomly assigned within each cohort.  These on-treatment biopsies are also 
mandatory:

Approximately 50% of patients will have their on-treatment biopsy on Cycle 1 Day 15 
+3 days (post second nivolumab treatment).  If a patient’s second nivolumab dose is 
delayed, the biopsy will still occur on Cycle 1 Day 15 +3 days.  

Approximately 50% of patients will have their on-treatment biopsy on Cycle 2 Day 1 
+3 days (post third nivolumab treatment).  If a patient’s third nivolumab dose is delayed, 
the biopsy will still occur on Cycle 2 Day 1 +3 days.
If a patient with glioblastoma undergoes a biopsy for medical reasons during the study, an 
optional biopsy should be collected at that time.
Formalin-fixed paraffin-embedded tumour tissue should be provided as a block or (minimum 
of 20) unstained slides.  Due diligence should be used to make sure that tumour specimen (not a 
normal adjacent or a tumour margin sample) is provided.  Pathology notes accompanying 
archival tissue will also be requested.  Archived tumour tissue blocks will be returned to the site.  


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 7 6
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
A n y bl oc k fr o m a n o n- st u d y bi ops y , or sli des s u b mitte d or c ut fr o m t he bl oc k at a ce ntral 
la b orat or y will not be ret ur ne d .  A n y ne w t u m o u r tiss ue ac q uire d f or a patie nt o n st u d y t hat is 
o btai ne d f or st u d y  p ur p oses is se nt t o ce ntral la b orat or y for pr ocessi n g (see la b or at or y ma n ual f or 
f urt her i nstr ucti o ns).  If t he l ocal pat h ol og y  la bor at or y pr ef ers t o pr ocess tiss ue, t he n a tiss ue 
bl oc k or mi ni m u m of 2 0 sli des s h o ul d be se nt t o t he ce ntral la bor at or y .
 
 
 
 
 
8. 2. 4.
W h ol e Bl o o d f or P h ar m a c o g e n eti c s
A bl o o d sa m ple will be c ollecte d f or p har mac o ge netic a nal ysis w here l ocal re g ulat i ons a n d 
E R Bs all o w.  T hese sa m ples are n ot bei n g c o llecte d t o create a bi o ba n k f or c o n d ucti n g 
u ns pecifie d disease or p o p ulat i on ge netic researc h eit her n o w or i n t he f ut ure.
S a m ples ma y  be use d t o i n vesti gate varia ble res p o nse t o st u d y treat me nt a n d t o i n vest i gate 
ge net ic varia nts t h o u g ht t o pla y a r ole i n ca ncer.  Assess me nt of varia ble res p o nse m a y incl u de 
e val uat i on of A Es or differe nces i n efficac y.  T hese st u dies ma y i ncl u de b ut are n ot li mite d t o t he 
T G F - β pat h wa y a n d i m m u n o m o d ul at or y mec ha nisms t o e valuate t hei r ass ociatio n wi t h o bser ve d 
res p o nse t o st u d y treat me nt.
W here l ocal re g ulat i ons a n d E R Bs all o w, t hese sa m ples will be c ollecte d f or p har mac o ge net ic 
researc h as disc usse d bel o w a n d s pecifie d i n t he sa m pli n g sc he d ule ( At tac h me nt 1).
S a m ples will  be retai ne d f or a ma xi m u m of 1 5 years after t he last patie nt visit, or as l ocal 
re g ulat i ons a n d E R Bs all o w, f or t he st u d y  at a facilit y selecte d b y t he s p o ns or.  T his rete nti o n 
p eri o d e na bles use of ne w tec h n o l ogi es, res p o nse t o re g ulat or y q uest i ons, a n d i n vest i gati on of 
varia ble res p o nse t hat ma y n ot be o bser ve d u nt il later i n dr u g de vel o p me nt or w he n t he dr u g is 
c o m merciall y a vaila ble.
M olec ular tec h n o l ogi es are e x pecte d t o i m pr o ve d uri n g t he 1 5 -ye ar st ora ge peri o d a n d t heref ore 
ca n n ot be s p ecificall y na me d.  H o we ver, e xist i n g a p pr oac hes i ncl u de w h ole ge n ome or e x o me 
se q ue nci n g, ge n ome wi de ass ociati o n st u dies, ca n di date ge ne st u dies, a n d e pi ge netic a nal yses.  
Re gar dless of t he tec h n o l og y  us e d, ge n ot ypi n g data ge nerate d will be use d o nl y f or t he s pecific 
researc h sc o pe descri be d i n t his secti on.
C CI
C CI


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8.2.5. Samples for Immunogenicity Research
Blood samples to determine the occurrence of specific antidrug antibodies (ADAs) to nivolumab 
will be collected as indicated in Attachment 1 and Attachment 4.
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of nivolumab.  
Samples may be stored for a maximum of 15 years following last patient visit for the trial at a 
facility selected by the sponsor to enable further analysis of immune responses to nivolumab.  
The duration allows the sponsor to respond to regulatory requests related to nivolumab.
8.3.
Efficacy Evaluations
The following efficacy measures will be determined:

ORR and best overall response, time to response, duration of response, and PFS
— using RECIST version 1.1 (Attachment 8) for patients with NSCLC, HCC, and 
tumours other than glioblastoma
— using RANO (see Attachment 9) for patients with glioblastoma

survival at 6, 12, and 18 months following the start of treatment

OS determined from the date of first treatment until death due to any cause

change in ECOG performance status
Efficacy measures will be assessed as noted in Attachment 1. Disease assessment with CT 
and/or MRI, as appropriate, will be performed at baseline and every 8 weeks until disease 
progression per RECIST version 1.1 or until patients withdraw from the study. For patients who 
are being treated beyond initial progression, these patients should remain on study treatment until 
the next assessment period.  Patients who are treated beyond progression will be evaluated on an 
8 (nonglioblastoma patients)- or 12 (glioblastoma patients)-week basis to determine whether they 
should continue on treatment.  The use of MRI is mandatory to determine tumour response when 
using RANO criteria.  Brain imaging should be performed as clinically indicated. At the 
sponsor’s discretion, scans and measurements may be collected and reviewed by independent 
radiologists using RECIST version 1.1/RANO criteria at a later date, or at any time during the 
study.  
To confirm objective responses, all lesions should be radiologically assessed, and the same 
radiologic method used for the initial response determination should be repeated at least 4 weeks 
following the initial observation of an objective response, using the sample method that was used 
at baseline.  If a patient is discontinued from the study, repeat radiology assessments may be 
omitted if clear clinical signs of PD are present.
To facilitate this effort the radiologist reading the baseline imaging study is asked to provide in 
the baseline report or in a supplemental report a comparison of the size of target lesions and 
nodes reported in the baseline study with the size of these same lesions and nodes, if present, in 
the reference study.  The report should also make note of the date of the preceding referenced 
study.  Reference study data provided in the radiologist’s report should be entered into the eCRF 
by the investigator’s staff.


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8.4.
Procedure/Sampling Compliance
Every attempt will be made to enrol patients who have the ability to understand and comply with 
instructions.  Noncompliant patients may be discontinued from the study.
The collection times of safety assessments, PK samples, pharmacodynamic samples, and efficacy 
measurements are given as targets, to be achieved within reasonable limits.  The scheduled time 
points may be subject to minor alterations; however, the actual collection time must be correctly 
recorded on the eCRF.  
The scheduled collection times may be modified by the sponsor based on analysis of the safety 
and PK information obtained during the study.  Any major modifications that might affect the 
conduct of the study, patient safety, and/or data integrity will be detailed in a protocol 
amendment.


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9.
Data Management Methods
9.1.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the CRFs, and study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by 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 the original source documents.
9.2.
Data Capture Systems
9.2.1. Case Report Form
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
CRF data collected by the third-party organisation (TPO) will be encoded by the TPO and stored 
electronically in the TPO’s database system.  Validated data will subsequently be transferred to 
Lilly data warehouse, using standard Lilly file transfer processes.  For any data handled by the 
sponsor internally, it will be managed by the sponsor and stored electronically in the sponsor’s 
data warehouse.
Data managed by a central vendor, such as laboratory test 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 laboratory 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 paper diary to collect 


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patient-reported outcome measures (for example, a rating scale), a daily dosing schedule, or an 
event diary.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
9.2.2. Ancillary Data
Data managed by a central vendor will be stored electronically in the central laboratory’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
generic labs system and TPO’s system.
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly generic labs 
system and TPO’s system.
ECG data will be stored electronically in the central database system of Lilly’s central review 
organisation.  Data will subsequently be transferred from the central review organisation system 
to the Lilly generic labs system and TPO’s system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 8 1
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
1 0. D at a A n al y s e s
1 0. 1. G e n er al C o n si d er ati o n s
Stati stical a nal ysis of t his st u d y will be t he res p o nsi bilit y of  Eli Lill y a n d C o mp a n y .  A d dit i onal 
details o f st atistical assess me nts be yo n d w hat is detaile d i n t his secti on will  be pr o vide d i n a 
statistical a nal ysis pla n.
T he i nter pretati o n of t he st u d y  res ults will be t he res p o nsi bility of  t he i n vesti gat or wit h t he Lill y
C R P, p har mac o ki neticist, a n d statist icia n.  T he C R P a n d statisticia n will also be res p o nsi ble f or 
t he a p pr o priate c o n d uct of a n i nter nal re vie w f or b ot h t he fi nal st u d y  re p ort a n d a n y st u d y-relate d 
materi al t o be a ut h orise d b y Lill y f or p u blicati on.
Descri pt i ve statistics (i ncl u di n g mea n, sta n dar d de viat i on, a n d ra n ge) will be deri ve d w here 
a p pr o priate.  
1 0. 1. 1. S a m pl e Si z e
F or t he P hase 1 b C o h orts 1 a n d 2 (a n d p ossi bl y  3) d ose escalat i on, a 3 + 3 + 3 desi g n will be 
use d t o assess t he safet y of  gal u niserti b i n c om bi nati o n wit h ni v o l uma b 3 m g/ k g.  Bet wee n 3 a n d 
1 2 a d di tio n al  patient s ma y be e nr o lle d i n a c o h ort t o ac hie ve t he mi ni m u m of 3 e val ua ble 
pati e nts if dr o p o uts or d ose i nterr u pti o ns or re d ucti o ns occ ur t hat res ult i n a pat ient  bei n g 
n o ne val ua ble f or D L Ts.
F or t he P hase 1 b C o h orts 3 a n d 4 d ose escal at i on, a 3 + 3 + 3 desi g n will be use d t o assess t he 
safety of  g alu niserti b i n c o m bi nat i on wi t h ni v ol uma b 3 m g/ k g.  Bet wee n 3 or 4 a n d 1 2 a d dit i onal 
pati e nts ma y be e nr o lle d i n a c o h ort t o ac hie ve t he mi ni m u m of 3 e val ua ble pat ient s if dr o p o uts 
or d ose i nterr u pti o ns or re d ucti o ns occ ur t hat res ult i n a pat ient  bei n g n o ne val ua ble f or D L Ts.
A lth o u g h t he pri mar y o bject i ve re mai ns safety of  t he c om bi nat i on f or t he P hase 2 c o h ort 
e x pa nsi o n part , t he sa m ple size a p pears t o be a de q uate t o e val uate preli mi nar y a ntitu m o u r 
acti vit y of  t he c o m bi nati on. 
  
 
 
  
C CI
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 8 2
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
W he n t he 2 5 t h pati e nt fr om eac h c o h ort has c o m p lete d at least 3 c y cles, a n i nteri m a nal ysis will 
be c o n d ucte d. T w o -sta ge desi g n criteria ( Si mo n 1 9 8 9) will  be use d t o e valuate w het her
a d ditio nal  patie nts f or t h at c o h ort will be e nr o lle d.  
 
 
 
1 0. 2. P ati e nt Di s p o siti o n
All patie nt disc o nt i n uati ons will be d oc u me nte d, a n d t he e xte nt of eac h pat ient ’s partici pati on i n 
t he st u d y will be re p orte d.  If k n o w n, a reas o n f or t heir disc o nti n uati o n will be gi ve n. See 
Secti o n 6. 3 .
P ati e nt e nr ol me nt a n d dis p osit i on will be s u m mari se d a n d/ or liste d b y c o h ort i n P hase 1 b a n d 
i n dicati on i n P hase 2 f or u p t o st u d y c o mplet i on ( Secti o n 6. 2. 4 ).  
1 0. 3. P ati e nt C h ar a ct eri sti c s
P ati e nt c haracterist ics will i ncl u de a s u m mar y a n d/ or listi n g b y c o h ort i n P h ase 1 b a n d i n dicat i on 
i n P hase 2 of  t he f oll owi n g:

P ati e nt de mo gra p hics i ncl u di n g (f or e xa m ple) a ge, se x, et h nicit y /race, wei g ht a n d c ha n ge 
i n wei g ht fr o m baseli ne, a n d scree ni n g hei g ht will be re p orte d.

b aseli ne disease c haracteristics a n d i n P hase 2 i ncl u di n g hist ol o g y  

p rior di sease-relate d t hera pies

co nc o mita nt me dicat i ons
Ot her patie nt c haracterist ics will be s u m marise d as dee me d a p pr o priate.
1 0. 4. S af et y A n al y s e s
All patie nts w h o recei ve at least 1 d ose of eit her gal u nisert i b or ni v ol uma b will  be e val uate d for 
safety a n d t o xicit y. C T C A E t er ms ( b y e nteri n g t he a p pr o priate C T C A E c o de) a n d se verit y 
gra des will be assi g ne d b y  t he i n vesti gat or usi n g C T C A E v 4. 0 3 ). Ver bati m A E t er ms will be 
ma p pe d t o c orres p o n di n g Me d D R A
l ower -level ter m ( L L T) ter mi n ol og y  wi t hi n t he Me d D R A 
di ct i onar y .
B ot h t he C T C A E ter ms a n d Me d D R A L L T will be ma p pe d usi n g t he Me d D R A dict i onar y 
hierarc h y  t o pr o vide P Ts a n d b o d y s yste m or ga n class ter ms f or eac h dicti onar y .  F or C T C A E 
t er ms w here “Ot her ” is i n dicate d, t he C T C A E P T s will be t he sa me as t he P T s of t he Me d D R A 
P Ts create d fr o m ma p pi n g t hr o u g h t he ver bat i ms.  All safety s u m maries will re p ort t he P T s 
create d fr o m ma p pi n g t he i n vest i gat or assi g ne d C T C A E ter m.
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Treatment-emergent AEs will be identified using the CTCAE terms by comparing which events 
are present at baseline and postbaseline and severity grades predose and postdose for preexisting 
conditions.  Where CTCAE term is “Other,” the matching MedDRA LLT will be used to 
determine treatment emergent.
Safety analyses may include, but are not limited to, summaries of the following:

AEs, treatment-emergent AEs, and SAEs, including severity and possible relationship to 
study drug

dose exposure and any adjustments

laboratory values

DLTs at each dose level for Phase 1b and DLT-equivalent AEs for Phase 2 for Cycles 1 
and 2

vital signs to include pulse oximetry readings and weight/change in weight from baseline

ECGs

ECHO readings and cardiotoxicity serum markers (BNP, troponin I, cystatin C)

MRI/CT scans performed for detection of aneurysm formation of the ascending aorta and 
aortic arch
All recorded AEs, treatment-emergent AEs, and SAEs will be listed and tabulated by system 
organ class and CTCAE PT by cohort in Phase 1b and indication in Phase 2.  Summaries of 
maximum grades of CTCAE PTs will be provided. The rate of DLTs will be summarised for 
each cohort in Phase 1b.  Dose exposure and intensity will be calculated for both galunisertib and 
nivolumab for all patients and summarised by cohort in Phase 1b and by indication in Phase 2. 
Vital signs and clinical laboratory test results will be listed and summarised by indication.  Any 
significant physical examination findings and results of clinical laboratory tests will be listed.  
ECGs, collected as indicated in Attachment 1 and Attachment 4, and baseline and 8-week ECHO 
results will be evaluated by the investigator; abnormalities, if present, will be listed. Changes 
from baseline in ECG and ECHO parameters will be calculated and summarised at each visit.
Safety data will be compared over time to assess change from baseline, during treatment, and 
follow-up.
10.5. Pharmacokinetic Analyses
PK analyses will be conducted on patients who have received at least 1 dose of the study drug 
and have had samples collected.  
For galunisertib, population apparent clearance, volume of distribution, and exposure are steady 
state for galunisertib will be calculated.  For nivolumab, Cmin concentrations will be reported.
Summary statistics will be tabulated for the PK parameters of galunisertib by dose and study 
day/week.  Dose proportionality of galunisertib when coadministered with nivolumab during
Phase 1b will be assessed based on a power model.  Nivolumab Cmin concentration in Phase 1b
will be tabulated by summary statistics.  In Phase 2, sparse PK data may also be pooled with 
other datasets for population PK analysis which will be part of a separate report. Exploratory 


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PK/pharmacodynamic analyses may be conducted to identify the exposure-response 
(biomarkers) relationship in this study.
Additional exploratory analyses will be performed if warranted by data and other validated PK 
software programs (for example, NONMEM) may be used if appropriate and approved by 
Global Pharmacokinetic management.  The version of any software used for the analysis will be 
documented and the program will meet the Lilly requirements of software validation.
Log-transformed Cmax and AUC estimates will be assessed to estimate ratios of geometric 
means and the corresponding 90% CIs.
10.6. Biomarker Analyses
For details on biomarkers, see Section 8.2.3.
Pharmacodynamic data from all patients undergoing pharmacodynamic assessments will be 
analysed with appropriate standard nonlinear analytic software. Pharmacodynamic effects will 
be assessed by summary statistics, and investigated graphically to explore patterns of change 
over time, and how the patterns differ among dose levels or exposure.  If there is a meaningful 
indication in the pattern over time, further analysis (eg, by linear mixed model) may be 
performed to characterise the relationship.  
To identify and assess biomarkers for potential tailoring purpose, associations between baseline 
biomarker measures and clinical outcomes will be analysed using appropriate single-marker or 
multi-marker analysis approaches.
10.6.1. Immunogenicity
A listing will be provided of all available immunogenicity data.  Additionally, a listing of 
immunogenicity data from those patients with at least 1 positive ADA at any time point will be 
provided. The frequency of patients with at least 1 positive ADA assessment, and frequency of 
patients who develop ADA after a negative baseline assessment will be provided.  To examine 
the potential relationship between immunogenicity and safety, the frequency and type of AEs of 
special interest may be examined by overall immunogenicity status by cohort in Phase 1b and by 
indication in Phase 2.
10.7. Efficacy
Disease response data will be compared over time to assess change from baseline, during 
treatment, and follow-up.
Individual best overall response, ORR, time to and duration of response, and PFS will be listed 
using RECIST version 1.1 or RANO criteria, as appropriate.  Best overall response outcomes 
will be tabulated by disease type and dose.  The ORR and PFS and the corresponding CI will be 
provided by tumour type, and by histology in the case of lung.  The duration of response and PFS 
will be estimated by Kaplan-Meier methodology by tumour type, depending on data availability.  
PFS will be similarly estimated, based on Kaplan-Meier methodology.  Presentations of efficacy 
will include patients in cohort expansion and patients in dose escalation matching those in cohort 


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Galunisertib (LY2157299)/nivolumab
expansion by tumour type and treatment.  Individual changes in the tumour burden over time will 
be presented graphically within a tumour type.  Landmark OS will also be assessed as part of the 
secondary efficacy analysis by Kaplan-Meier plots and medians for each tumour type.  
For the NSCLC cohort, efficacy endpoints may be evaluated by adjusting for PD-L1 expression
and serum TGFβ-1 levels.  
For the HCC cohort, efficacy endpoints may be evaluated by adjusting for serum AFP and 
TGFβ-1 levels and tumour PD-L1 expression.
10.8. Interim Analyses
Since the Phase 1b part is a dose-finding study, data will be reviewed on a cohort-by-cohort basis 
during the study, until the MTD (or PAD) is determined.  The purpose of these cohort-by-cohort 
reviews is to evaluate the safety data at each dose level and determine whether a DLT has been 
observed that would suggest MTD has been met or exceeded.  The investigators and the Lilly 
study team will make the determination regarding dose escalation based upon their review of the 
safety and tolerability data as described in this protocol.  
After all patients who are deemed evaluable for the assessment of dose levels complete a DLT 
evaluation period or when MTD is determined, an interim safety and PK analysis may be 
conducted for planning next studies.
For the Phase 2 part, if DLT-equivalent toxicities occur in 33% or more of patients within a 
tumour-specific cohort expansion, then investigators and the Lilly CRP will assess the nature and 
severity of these toxicities. No additional patients will be enrolled until this safety review is 
completed and a decision is made either to continue at the current dose or to deescalate the dose 
and define a new dose for the expansion phase. The safety review and decision will be 
documented in writing.  Trial-level safety reviews will be conducted approximately 3 months 
after the first patient begins study drug on Cycle 1 Day 1, approximately 6 months after the first 
patient begins study drug on Cycle 1 Day 1, and approximately every 6 months thereafter.  These 
evaluations will not be assessed by any formal statistical test; only listings and summaries will be 
carried out.  
After enrolment has completed in a cohort (n = approximately 25) and the last enrolled patient in 
that cohort has completed or had the opportunity to complete 3 cycles of treatment, an interim 
analysis will be conducted for that particular cohort (for a total of 2 separate interim analyses to 
be conducted when each cohort reaches 25 patients complete at least 3 cycles of treatment). The 
intent of the interim analysis is to evaluate preliminary antitumour activity of galunisertib in 
combination of nivolumab. These interim analyses may be combined with the ongoing trial-
level safety review.  Pending review of the interim data, approximately 16 additional patients 
may be enrolled in that particular cohort if there are more than 4 and fewer than 9 patients who 
demonstrate responses (determined by ORR for the NSCLC cohort and by ORR or survival for 
the HCC cohort).  Enrolment of the other cohort, if not completely enrolled, will not be stopped 
during the interim analysis. No independent data monitoring committee will be required for this 


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study.  The interim analysis will be conducted by an assessment committee consisting of at least 
1 physician and 1 statistician. 
The number of safety reviews in the Phase 2 part may be increased if data from the Phase 1b part
suggest that increased monitoring would be appropriate; this will not require a protocol 
amendment.


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11. Informed Consent, Ethical Review, and 
Regulatory Considerations
11.1. 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 study in a timely manner.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study and to document that the 
patient is satisfied with his or her understanding of the potential risks and benefits of 
participating in the study and desires to participate in the study.
The investigator is ultimately responsible for ensuring that informed consent is given by each 
patient or legal representative before the study is started.  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.  
11.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites(s).  
All ICFs must be compliant with the International Conference on Harmonisation guideline on 
GCP.  
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  The ERB(s) will review the protocol as required.
The study site’s ERB(s) should be provided with the following:

the current IB and Package Insert, and updates during the course of the study

ICF

relevant curricula vitae
11.3. 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 GCP Guideline [E6]
3) applicable laws and regulations
The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of the sponsor will be assigned to a TPO.


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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 study-related 
data.
11.3.1. Investigator Information
Site-specific contact information may be provided in a separate document.
11.3.2. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
11.3.3. Final Report Signature
The final report coordinating investigator or designee will sign the 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 greatest technical knowledge will serve as the final report coordinating 
investigator.  If this investigator is unable to fulfil this function, another investigator will be 
chosen by Lilly to serve as the final report coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.


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Grady WM, Markowitz SD. TGF-β signaling pathway and tumor suppression. In: Derynck R, 
Miyazono K, editors. The TGF-β Family. New York: Cold Spring Harbor Laboratory Press; 
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H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
Attachment 1.Protocol JBEF Study Schedule


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 96
Galunisertib (LY2157299)/nivolumab
Phase 1b Dose Escalation—Baseline/Screening Assessments
Relative Day Prior to Day 1 of 
Cycle 1a
28
14
7
Comments
Informed consent 
X
Informed consent form signed (prior to performance of
any protocol-specific tests/procedures)
Radiological tumour assessment
X
These scans can be performed locally.  See Section 8.3 for 
details.  Radiologic assessment should include appropriate 
body scan for tumour type.  
Tumour biopsy
X
New tumour biopsy is required for patients with cancers 
other than glioblastoma.  Archived tissue or new tumour 
biopsy is required for patients with glioblastoma.  Biopsy 
should be taken only after study eligibility is confirmed.
Medical history
X
Including alcohol/tobacco use and other relevant habits
assessments
Physical examination
X
Vital signs 
X
Including height (baseline only), temperature, blood 
pressure, pulse rate, respiration rate, and pulse oximetry 
reading
Weight and change in weight for 
previous 3 months
X
ECOG performance status
X
ECG 
X
Single 12-lead ECGs.  Must be done prior to initiation of 
therapy on Cycle 1 Day 1.
ECHO/Doppler imaging
X
Can be done up to 3 days before Cycle 1 Day 1; must be 
done prior to initiation of therapy on Day 1 and must meet 
Exclusion Criterion 21.  
MRI/CT scan (of chest) with 
contrast
X
For safety:  baseline and then every 6 months.  NOTE:  at 
screening, if a MRI or CT scan with contrast has been 
done to assess the status of the primary tumour, this scan 
may be used for safety screening if the scan has properly 
assessed the great vessels and the heart.  Scans of other 
areas may be required for additional tumour assessment 
but not for safety.  
Cardiac serum markers
X
BNP, troponin I, cystatin C
Haematology 
X
See Attachment 2.
Serum chemistry 
X
See Attachment 2.
HBV DNA sample
X
All patients: peripheral blood
HCV RNA sample
X
All patients:  peripheral blood
HCC antiviral activity
X
HCC patients only:  peripheral blood collection for 
qHBsAg 
HBsAg, HCV, HIV serology
X
Required for all patients
PT/INR
X
Tumour measurement (palpable 
or visible)
X
If appropriate for the tumour
CTCAE v 4.03 grading 
(preexisting conditions)
X
To be reported only after study eligibility is confirmed.  
See Section 8.1.2.4 for reporting expectations


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
Phase 1b Dose Escalation—Baseline/Screening Assessments
Relative Day Prior to Day 1 of 
Cycle 1a
28
14
7
Comments
Concomitant meds
X
Blood biomarker samples
X
See Attachment 4.
Serum pregnancy test 
X
Whole blood for 
pharmacogenetics (DNA 
collection)
X
Must be collected prior to dosing on Cycle 1 Day 1
Abbreviations:  BNP = brain natriuretic peptide; CT = computed tomography; CTCAE = Common Terminology 
Criteria for Adverse Events; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECHO = 
echocardiograph; ECOG = Eastern Cooperative Oncology Group; HBV = hepatitis B virus; HBsAg = hepatitis B 
surface antigen; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HIV = 
human immunodeficiency virus; INR = international normalised ratio; meds = medications; MRI = magnetic 
resonance imaging; PT = prothrombin time; qHBsAg = quantitative hepatitis B surface antigen; 
RNA = ribonucleic acid; SAEs = serious adverse events; v = version.
a
With the exception of signing of the informed consent form (may be signed up to 3 days before initial visit), visit 
windows ±3 days.  


H9H-MC-JBEF(c) Phase 1 Oncology Protocol 
Page 98 
Galunisertib (LY2157299)/nivolumab 
During and Post-Study Assessments—Phase 1b Dose Escalation 
 
Cycle 1 
Cycle 2 
Cycle 3-n 
Follow-Up (days) 
Comments 
Relative Week 
Within a Cycle 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Relative Day 
Within a Cyclea 
1 
8 
15 
22 
1 
8 
1
5 
22 
1 
8 
15 
22 
Short-term 
Long-
termc 
30b 
100 
Galunisertib 
X 
 
 
X 
 
 
X 
 
 
 
 
 
14 days on/14 days off.  Orally once or twice daily, depending 
on cohort. 
Nivolumab 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Administered by IV at site 
Dispensing patient 
diary 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
First 2 cycles only for recording galunisertib dosing and any 
emesis episodes 
Collecting patient 
diary 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Weight 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
Vital signs  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Temperature, pulse rate, RR, BP, pulse oximetry 
Serum pregnancy 
test 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Predose 
Cardiotoxicity 
serum markers 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Troponin I, BNP, and cystatin C on Day 1 of every cycle 
12-lead ECG 
 
 
 
 
X 
D 
14 
only 
 
 
X* 
 
 
 
 
 
 
Collect predose (if applicable): 
 
See Attachment 4 for timing of PK time-matched ECGs 
* Starting at Cycle 3 Day 1, ECGs will be performed at 
every odd-numbered cycle thereafter (Cycles 5, 7, 9, etc)  
ECHO 
 
 
 
 
 
 
 
X 
 
 
 
* 
X 
 
 
Performed every other cycle within 5 days of when next cycle 
begins, beginning at the end of Cycle 2 (eg, Cycle 2 
Days 23-28=*).  Must be done predose.  After a normal 
baseline ECHO, if a subsequent ECHO demonstrates an 
abnormality, then a repeat ECHO should be performed after 
14 days.  If results confirm the abnormality at repeat ECHO, 
then the patient will be discontinued from study treatment.  If 
findings are normal, then the patient will continue treatment 
per study protocol. 
 
If patient has clinically significant cardiac findings at 30-day 
FUP Visit, ECHO will be repeated every 2 cycles 
(approximately every 2 months).  If no clinically significant 
cardiac findings at the last cardiac assessment conducted 
within the last 30 days and patient has started another 
treatment, 30-day FUP Visit will not be performed.  If no 
clinically significant cardiac findings at 30-day FUP Visit, 
1 more ECHO will be performed after 2 months unless the 
patient is receiving another treatment.  If the patient is 
receiving another form of treatment, further cardiac 
assessments will not be performed. 


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
During and Post-Study Assessments—Phase 1b Dose Escalation
Cycle 1
Cycle 2
Cycle 3-n
Follow-Up (days)
Comments
Relative Week 
Within a Cycle
1
2
3
4
1
2
3
4
1
2
3
4
Relative Day 
Within a Cyclea
1
8
15
22
1
8
1
5
22
1
8
15
22
Short-term
Long-
termc
30b
100
MRI/CT scan (of 
chest) with contrast
**
Every 6 months during treatment (eg, just prior to beginning 
Cycle 6=**). If there were no clinically significant findings 
at the last assessment conducted within the last 30 days and 
the patient has started another treatment, 30-Day FUP Visit 
MRI or CT scan with contrast will not be performed.
Haematology
X
X
X
X
X
X
X
X
See Attachment 2.
Serum chemistry
X
X*
X
X*
X
X*
X
X*
X
X
X
X
See Attachment 2.
*Only performed if the last assessment prior to this 
assessment had an elevated value for liver function compared 
to baseline. See Section 8.1.4.  
HBV DNA
X
X
X
X
X
All patients to be tested. Peripheral blood.  Predose.  
HCV RNA
X
X
X
X
X
All patients to be tested.  Peripheral blood.  Predose.
HCC antiviral 
activity
X
HCC patients only.  Peripheral blood collection for 
assessment of qHBsAg.  Predose Day 1 at every other cycle 
(Cycles, 3, 5, n).
CTCAE v 4.03 
Grading
X
X
X
X
X
X
X
X
X
Refer to Section 8.1.2.4 for reporting guidelines.
Concomitant meds
X
X
X
X
X
X
X
X
X
Throughout study as needed.
ECOG performance 
status
X
X
X
X
X
PK sampling 
X
D
14
X
X
D14
X
C4 
only
See Attachment 4 for timing.
Tumour 
measurement 
(palpable or visible)
X
X
X
To occur on or between Days 22 to 28 of every other cycle. 
At long-term FUP, every 12 weeks as appropriate.
Radiological tumour 
assessment
X
X
X
MRI/CT scan.  To occur on or between Days 22 to 28 of 
every other cycle. At short-term FUP, every 8 weeks as 
appropriate.
Radiological tumour 
assessment for 
pseudoprogression
For patients who are being treated beyond initial progression, 
these patients should remain on study treatment until the next 
assessment period.  Patients who are treated beyond 
progression will be evaluated on an 8- (nonglioblastoma) or 
12- (glioblastoma) week basis to determine whether they 
should continue on treatment.  
Survival
X
At FUP, at least every 12 weeks±7 days until death.  
Immunogenicity
X
D
14
X
X
*
X
Window of ±7 days for 100-day FUP.
*Collected at Week 13 and every 16 weeks thereafter 
(ie, Week 29, 45, etc.)


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 100
Galunisertib (LY2157299)/nivolumab
During and Post-Study Assessments—Phase 1b Dose Escalation
Cycle 1
Cycle 2
Cycle 3-n
Follow-Up (days)
Comments
Relative Week 
Within a Cycle
1
2
3
4
1
2
3
4
1
2
3
4
Relative Day 
Within a Cyclea
1
8
15
22
1
8
1
5
22
1
8
15
22
Short-term
Long-
termc
30b
100
Bio-
marker 
samples
Tumour 
biopsy
1/2
1/2
Required for patients with cancers other than glioblastoma, 
with half of patients randomly assign to biopsies on either 
Cycle 1 D15 or Cycle 2 D1 post nivolumab dosing.  If a 
patient with glioblastoma undergoes a biopsy during the study 
for other medical reasons, tissue should be collected at that 
time.  Note glioblastoma patients are in Phase 1b only.
For glioblastoma patients only (Phase 1b), if tumour biopsy is 
performed to distinguish between radiologic progression and 
pseudoprogression (not required), see Section 7.2.5 for 
instructions for proper handling of specimen.
Blood 
bio-
marker 
samples
D1 
and
D2
X
X
X
X
C4 
only
X
See Attachment 4 for sampling times.  
Abbreviations:  BNP = brain natriuretic peptide; BP = blood pressure; BSA = body surface area; C = cycle; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events; D = day; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECHO = echocardiography; ECOG = Eastern 
Cooperative Oncology Group; FUP = Follow-Up Period; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HR = heart 
rate; hrs = hours; IV = intravenous; MRI = magnetic resonance imaging; n = cycle number; PK = pharmacokinetic; qHBsAg = quantitative hepatitis B surface 
antigen; RNA = ribonucleic acid; RR= respiration rate; SAEs = serious adverse events; v = version.
a
Visit windows ±3 days.
b
Sometimes referred to as the end of treatment visit.  
c
Long-Term Follow-Up begins the day after 100-day follow-up is completed and continues until the patient’s death or end of trial (approximately every 
12 weeks ± 7 days the patient will be contacted).


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 101
Galunisertib (LY2157299)/nivolumab
Phase 2 Dose Expansion—Baseline/Screening Assessments
Relative Day Prior to Day 1 
of Cycle 1a
28
14
7
Comments
Informed consent 
X
Informed consent form signed (prior to performance of 
any protocol-specific tests/procedures)
Radiological tumour 
assessment
X
These scans can be performed locally and transmitted to a 
central imaging vendor.  See Section 8.3 for details.  
Radiologic assessment should include appropriate body 
scan for tumour type.
Tumour biopsy
X
New tumour biopsy is required.  Biopsy should be taken 
only after study eligibility is confirmed.
Medical history
X
Including alcohol/tobacco use and other relevant habits 
assessments
Physical exam
X
Vital signs 
X
Including height (baseline only), temperature, blood 
pressure, pulse rate, respiration rate, and pulse oximetry 
reading
Weight and change in weight 
for previous 3 months
X
ECOG performance status
X
ECG 
X
Single 12-lead ECG.  Must be done prior to initiation of 
therapy on Cycle 1 Day 1.
ECHO/Doppler imaging
X
Can be done up to 3 days before Cycle 1 Day 1; must be 
done prior to initiation of therapy on Day 1 and must meet 
Exclusion Criterion 21.
MRI/CT scan (of chest) with 
contrast
X
For safety:  baseline and then every 6 months.  NOTE:  At 
screening, if a MRI or CT scan with contrast has been 
done to assess the status of the primary tumour; this scan 
may be used for safety screening if the scan has properly 
assessed the great vessels and the heart.  Scans of other 
areas may be required for additional tumour assessment 
but not for safety.  
Cardiac serum markers
X
BNP, troponin I, cystatin c
Haematology 
X
See Attachment 2.
Serum chemistry 
X
See Attachment 2.
HBV DNA sample
X
All patients:  peripheral blood
HCV RNA sample
X
All patients:  peripheral blood
HCC antiviral activity
X
HCC patients only:  peripheral blood collection for 
qHBsAg 
HBsAg, HCV, HIV serology
X
Required for all patients
PT/INR
X
Tumour measurement 
(palpable or visible)
X
CTCAE v 4.03 grading 
(preexisting conditions)
X
To be reported only after study eligibility is confirmed.  
See Section 8.1.2.4 for reporting expectations.
Concomitant meds
X


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 102
Galunisertib (LY2157299)/nivolumab
Relative Day Prior to Day 1 
of Cycle 1a
28
14
7
Comments
Blood biomarker samples 
X
See Attachment 4.
Serum pregnancy test 
X
Whole blood for 
pharmacogenetics (DNA 
collection)
X
Must be collected prior to dosing on Cycle 1 Day 1
Abbreviations:  BNP = brain natriuretic peptide; CT = computed tomography; CTCAE = Common Terminology 
Criteria for Adverse Events; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
ECHO = echocardiograph; ECOG = Eastern Cooperative Oncology Group; HBsAg = hepatitis B surface antigen; 
HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; INR = international normalised ratio; meds = medications; MRI = magnetic resonance 
imaging; qHBsAg = quantitative hepatitis B surface antigen; PT = prothrombin time; RNA = ribonucleic acid; 
SAEs = serious adverse events; v = version.
a
With the exception of signing of the informed consent form (may be signed up to 3 days before initial visit), visit 
windows ±3 days.  


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
During and Post-Study Assessments—Phase 2 Dose Expansion
Cycle 1
Cycle 2
Cycle 3-n
Follow-Up (days)
Comments
Relative Week Within 
a Cycle
1
2
3
4
1
2
3
4
1
2
3
4
Relative Day Within a 
Cyclea
1
8
15
22
1
8
1
5
22
1
8
15
22
Short-term
Long-
termc
30b
100
Galunisertib
X
X
X
14 days on/14 days off.  Orally once or twice daily depending 
on dosing regimen from Phase 1b
Nivolumab
X
X
X
X
X
X
Administered by IV at site
Dispensing patient 
diary
X
X
First 2 cycles only for recording galunisertib dosing and any 
emesis episodes
Collecting patient diary
X
X
Physical examination
X
X
X
X
X
Weight
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
Temperature, pulse rate, RR, BP, pulse oximetry
Serum pregnancy test
X
X
X
Predose
Cardiotoxicity serum 
markers
X
X
X
X
X
X
Troponin I, BNP, and cystatin C on Day 1 of every cycle
12-lead ECG
X
D 
14
only
X*
Collect predose (if applicable):
See Attachment 4 for timing of PK time-matched ECGs.
* Starting at Cycle 3 Day 1, ECGs will be performed at every 
odd-numbered cycle thereafter (Cycles 5, 7, 9, etc)
ECHO
X
*
X
Performed every other cycle within 5 days of when next cycle 
begins, beginning at the end of Cycle 2 (eg, Cycle 2 
Days 23-28=*).  Must be done predose.  After a normal 
baseline ECHO, if a subsequent ECHO demonstrates an 
abnormality, then a repeat ECHO should be performed after 
14 days.  If results confirm the abnormality at repeat ECHO, 
then the patient will be discontinued from study treatment.  If 
findings are normal, then the patient will continue treatment 
per study protocol.
If patient has clinically significant cardiac findings at 30-day 
FUP Visit, ECHO will be repeated every 2 cycles 
(approximately every 2 months).  If no clinically significant 
cardiac findings at the last cardiac assessment conducted 
within the last 30 days and patient has started another 
treatment, 30-day FUP Visit will not be performed.  If no 
clinically significant cardiac findings at 30-day FUP Visit, 
1 more ECHO will be performed after 2 months unless the 
patient is receiving another treatment.  If the patient is 
receiving another form of treatment, further cardiac 
assessments will not be performed.


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
During and Post-Study Assessments—Phase 2 Dose Expansion
Cycle 1
Cycle 2
Cycle 3-n
Follow-Up (days)
Comments
Relative Week Within 
a Cycle
1
2
3
4
1
2
3
4
1
2
3
4
Relative Day Within a 
Cyclea
1
8
15
22
1
8
1
5
22
1
8
15
22
Short-term
Long-
termc
30b
100
MRI/CT scan with 
contrast
**
Every 6 months during treatment (eg, just prior to beginning 
Cycle 6=**).  If there were no clinically significant findings 
at the last assessment conducted within the last 30 days and 
the patient has started another treatment, 30-Day FUP Visit 
MRI or CT scan with contrast will not be performed.  
Haematology
X
X
X
X
X
X
X
X
See Attachment 2.
Serum chemistry
X
X
X
X
X
X
X
X
See Attachment 2.
HBV DNA
X
X
X
X
X
All patients to be tested. Peripheral blood.  Predose 
HCV RNA
X
X
X
X
X
All patients to be tested.  Peripheral blood.  Predose
HCC antiviral activity
X
HCC patients only:  peripheral blood collection for 
assessment of qHBsAg.  Predose Day 1 at every other cycle 
(Cycles, 3, 5, n)
CTCAE v 4.03 grading
X
X
X
X
X
X
X
X
X
Refer to Section 8.1.2.4 for reporting guidelines.
Concomitant meds
X
X
X
X
X
X
X
X
X
Throughout study as needed
ECOG performance 
Status
X
X
X
X
X
PK sampling 
X
D 
14
X
X
D 
14
X
C4 
only
See Attachment 4 for timing.  
Tumour measurement 
(palpable or visible)
X
X
X
To occur on or between Days 22 to 28 of every other cycle.  
At long-term FUP, every 12 weeks as appropriate.
Radiological tumour 
assessment
X
X
X
MRI/CT scan.  These scans can be performed locally and 
transmitted to a central imaging vendor.  To occur on or 
between Days 22 to 28 of every other cycle.  At short-term
FUP, every 8 weeks as appropriate.
Radiological tumour 
assessment for 
treatment past initial 
progression
MRI/CT scan.  These scans can be performed locally and 
transmitted to a central imaging vendor.  For patients who are 
being treated beyond initial progression, these patients should 
remain on study treatment until the next assessment period.  
Patients who are treated beyond progression will be evaluated 
on an 8-week basis to determine if they should continue on 
treatment.  
Survival
X
At FUP, at least every 12 weeks until death.  
Immunogenicity
X
D 
14
X
X
*
X
Window of ±7 days for 100-day FUP.
* Collected at Week 13 and every 16 weeks thereafter (ie, 
Week 29, 45, etc.)


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 105
Galunisertib (LY2157299)/nivolumab
During and Post-Study Assessments—Phase 2 Dose Expansion
Cycle 1
Cycle 2
Cycle 3-n
Follow-Up (days)
Comments
Relative Week Within 
a Cycle
1
2
3
4
1
2
3
4
1
2
3
4
Relative Day Within a 
Cyclea
1
8
15
22
1
8
1
5
22
1
8
15
22
Short-term
Long-
termc
30b
100
Bio-
marker 
samples
Tumour 
biopsy
1/2
1/2
Required, with half of patients randomly assign to biopsies on 
either Cycle 1 D15 or Cycle 2 Day 1 post nivolumab dosing.  
Blood 
Bio-
marker 
sample
D1 
& 
D2
X
X
X
X
C4 
only
X
See Attachment 4 for sampling times.
Abbreviations:  BNP = brain natriuretic peptide; BP = blood pressure; C = cycle; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events; D = day; ECG = electrocardiogram; ECHO = echocardiography; ECOG = Eastern Cooperative Oncology Group; FUP = Follow-Up Period; 
HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HR = heart rate; hrs = hours; n = cycle number; PK = pharmacokinetic; 
qHBsAg = quantitative hepatitis B surface antigen; RNA = ribonucleic acid; RR= respiration rate; SAEs = serious adverse events; v = version.
a
Visit windows ±3 days.
b
Sometimes referred to as the end of treatment visit.
c
Long-Term Follow-Up begins the day after 100-day follow-up is completed and continues until the patient’s death or end of trial (approximately every 
12 weeks ± 7 days the patient will be contacted).


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 106
Galunisertib (LY2157299)/nivolumab
Attachment 2.Protocol JBEF Clinical Laboratory Tests
Clinical Laboratory Tests
Haematologya
Clinical Chemistrya,b
Haemoglobin
Serum Concentrations of:
Haematocrit
Sodium
Magnesium
Erythrocyte count (RBC)
Potassium
Leukocytes (WBC)
Total bilirubin
Neutrophils
Alkaline phosphatase
Lymphocytes
Alanine aminotransferase
Monocytes
Aspartate aminotransferase
Gamma-glutamyl transpeptidase
Eosinophils
Blood urea nitrogen 
Basophils
Creatinine
Platelets
Uric acid
Calcium
Glucose, random
PT/INRa
Albumin
Total protein
Chloride
Bicarbonate
Amylase
Lipase
Thyroid-stimulating hormonea,b,c
Reflex to fT3/fT4a,b,c
Troponin Ib
BNPb
Cystatin Cb
HBsAga,b
qHBsAgd
HBV DNAd
Hep C Aba,b
HCV RNAd
HIVb
Serum Pregnancy Test (females only)a
Abbreviations:  aPTT = activated partial thromboplastin time, BNP = brain natriuretic peptide; DNA = 
deoxyribonucleic acid; fT3 = free triiodothyronine; fT4 = free thyroxine; HBsAg = hepatitis B surface antigen; 
HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; Hep C Ab = hepatitis C 
antibody; HIV = human immunodeficiency virus; PT/INR = international normalised ratio of prothrombin time; 
qHBsAg = quantitative hepatitis B surface antigen; RBC = red blood cells; RNA = ribonucleic acid; WBC = 
white blood cells.
a
Assayed by local laboratory.  
b
Assayed by Lilly-designated laboratory.  


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 107
Galunisertib (LY2157299)/nivolumab
Clinical Laboratory Tests
c
If thyroid-stimulating hormone test is abnormal, reflex to fT3/fT4 test must be performed.  
d
Baseline tests (screening) will be assayed by a local and a Lilly-designated laboratory.  Testing during the trial 
will be performed by a Lilly-designated laboratory.


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 108
Galunisertib (LY2157299)/nivolumab
Attachment 3.
Protocol JBEF Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly CRP.
Hepatic Monitoring Tests
Hepatic haematologya
Haptoglobina
Haemoglobin
Haematocrit
Hepatic coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils, segmented
Lymphocytes
Hepatic serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Antinuclear antibodya
AST
GGT
Anti–smooth muscle antibodya
CPK 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = international normalised ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated and local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 0 9
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
At t a c h m e nt 4. Pr ot o c ol J B E F P h ar m a c o ki n eti c , Bi o m ar k er ,
P K Ti m e -M at c h e d E C G, a n d I m m u n o g e ni cit y S a m pli n g 
S c h e d ul e
 
 
 
 
 
 
 
  
 
  
C CI


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 110
Galunisertib (LY2157299)/nivolumab
Blood Biomarker Sampling Schedule
Pharmacodynamic
Sample #
Cycle
Day
Sampling Windows for 
Blood Collection
1
1
1
Predose
2
1
1
2 hours postdose ± 10 
minutes
3
1
2
Predose
4
1
8
Predose
5
1
15
Predose
6
2
1
Predose
7
2
15
Predose
8
4
1
Predose
9
Follow-Up
Abbreviation: V = visit.


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 111
Galunisertib (LY2157299)/nivolumab
Attachment 5.Protocol JBEF Recommendations for 
Reporting Serious Adverse Events
Recommendations for Reporting Serious Adverse Events
When contacting Lilly to report an SAE, please have the following information available:
Patient Demographics

patient identification (number), sex, date of birth, origin, height, and weight
Study Identification

full trial protocol number, investigator's name, investigator’s number
Study Drug

drug code or drug name, unit dose, total daily dose, frequency, route, start dose, 
cycle details, start date and last dose date (if applicable)
Adverse Event

description, date of onset, severity, treatment (including hospitalisation), action 
taken with respect to study drug, clinical significance, test and procedure results 
(if applicable)
Relationship to Study Drug & Protocol Procedures
Concomitant Drug Therapy

indication, total daily dose, duration of treatment, start date, action taken
In Case of Death

cause, autopsy finding (if available), date, relationship to study drug and protocol 
procedures


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
Attachment 6.Protocol JBEF 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 
performance of a light or sedentary nature, for example, light housework, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair
5
Dead
Abbreviation:  ECOG = Eastern Cooperative Oncology Group.
Source:  Oken et al. 1982.


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 113
Galunisertib (LY2157299)/nivolumab
Attachment 7.Protocol JBEF Creatinine Clearance Formula
Note:  This formula is to be used for calculating CrCl from local laboratory results only.  
For serum creatinine 
concentration in mg/dL:
CrCl =
(140 – agea) (wt) 0.85 (if female), or 1.0 (if male)
(mL/min) 
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl =
(140 – agea) (wt) 0.85 (if female), or 1.0 (if male)
(mL/min)
0.81 serum creatinine 
(mol/L)
Abbreviation:  CrCl = creatinine clearance.
a Age in years, weight (wt) in kilograms.
Reference:  Cockcroft and Gault 1976.
-OR-
GFR(mL/min/1.73m2) = 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
PCr = plasma creatinine, mg/dL; SUN = serum urea nitrogen, mg/dL; Alb = serum albumin, 
g/dL.
Source:  Murray and Ratain 2003.


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 1 4
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
At t a c h m e nt 8. Pr ot o c ol J B E F
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
C CI
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 1 5
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 1 6
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
C CI
C CI
C CI
C CI
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 1 7
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
C CI
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 1 8
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
 
 
 
 
 
 
 
  
 
 
 
 
  
.
  
C CI
C CI
C CI
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 1 9
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 2 0
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
 
 
  
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 2 1
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
At t a c h m e nt 9. Pr ot o c ol J B E F
 
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 2 2
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 2 3
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 2 4
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b

 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
C CI
C CI
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 2 5
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
C CI
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 2 6
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
T a ble 1 :  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 2 7
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
T a ble 2 :  
 
  
 
  
 
  
  
 
 
 
  
  
  
 
 
  
  
 
  
 
 
 
  
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 2 8
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
  
 
 
 
 
 
 
 
 
T a ble 3:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
C CI
C CI


H 9 H -M C -J B E F ( c) P h a s e 1 O n c ol o g y Pr ot o c ol
P a g e 1 2 9
G al u ni s erti b ( L Y 2 1 5 7 2 9 9)/ ni v ol u m a b
R ef er e n c e
 
 
C CI


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 130
Galunisertib (LY2157299)/nivolumab
Attachment 10.
Protocol JBEF Echocardiographic 
Guidelines


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 131
Galunisertib (LY2157299)/nivolumab
Echocardiography
In this study, ECHO images will be acquired with the purpose of ascertaining that patients 
enrolled in the study have (and maintain during the study) baseline 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, or mild aortic 
regurgitation, and no more than mild mitral or aortic valvular stenosis).  Repeated ECHOs in 
each patient will be performed to establish the cardiac safety of galunisertib 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 ECHO examinations, in particular the use of standardised settings during the acquisitions 
of colour flow Doppler imaging.  Therefore, because quantitative ECHO 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 ECHO parameters to be serially quantified are:  LV cavity size (diameters, volumes), LV 
ejection fraction, 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 volume index, and extrapolation of pulmonary artery 
systolic pressure when obtainable.  
An ECHO with no clinically significant abnormalities is one defined specifically as:  the LV 
(Schiller et al. 1999) internal dimension in diastole should be 2.8 cm/m2, the left atrial (Tsang 
et al. 2002) end-systolic volume should be 36 mL/M2, the LV ejection fraction (Oh et al. 2006) 
should be 50% without regional wall motion abnormalities, 2-dimensional ECHO-derived LV 
mass index1 should be 115 g/M2 for males and 99 g/M2 for females, the pulmonary artery 
pressure should be normal (tricuspid regurgitation jet velocity 2.5 m/s and/or pulmonary valve 
flow acceleration time 120 ms), the LV diastolic function (Khouri et al. 2004) 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), 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 >2.0 cm2 and aortic 
valve area should be >1.5 cm2) and no evidence of more than mild mitral or aortic regurgitation 
(Singh et al. 1999; Zoghbi et al. 2003).  Patients enrolled in the 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; Zoghbi et al. 2003).


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
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(3):290-297.
Oh JK, Seward JB, Tajik AJ. The echo manual. 3rd ed. Philadelphia: Lippincott, Williams 
Wilkins; 2006.
Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, 
Reicheck N, Sahn D, Schnittger I, Silverman NH, Tajik AJ. Recommendations for quantitation 
of the left ventricle by two-dimensional echocardiography: American Society of 
Echocardiography Committee on Standards, Subcommittee on Quantitation of 
Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2(5):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(6):897-902.
Tsang TS, 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(12):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; American Society of Echocardiography. Recommendations for evaluation of 
the severity of native valvular regurgitation with two-dimensional and Doppler 
echocardiography. J Am Soc Echocardiogr. 2003;16(7):777-802.


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
Appendix:  Qualitative and Quantitative Parameters for Grading Valvular 
(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(6):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; American Society of Echocardiography. Recommendations for evaluation of 
the severity of native valvular regurgitation with two-dimensional and Doppler 
echocardiography. J Am Soc Echocardiogr. 2003;16(7):777-802.


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References
Henson J W, Ulmer S, et al. Brain tumor imaging in clinical trials. AJNR Am J Neuroradiol.
2008:29(3):419-424.
Kreisl TN, Kim L, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab 
plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol.
2009;27(5):740-745.
Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell.
2003;113(6):685-700.
Sorensen A, Patel S, et al. Comparison of diameter and perimeter methods for tumor volume 
calculation. J Clin Oncol. 2001;19(2):551-557.
Sorensen AG, Batchelor TT, et al. Response criteria for glioma. Nat Clin Pract Oncol. 2008.
Verhaak RG, Hoadley KA, et al. Integrated genomic analysis identifies clinically relevant 
subtypes of glioblastoma characterised by abnormalities in PDGFRA, IDH1, EGFR, and NF1. 
Cancer Cell. 2010;17(1):98-110.
Wick W, Puduvalli VK, et al. Phase III study of enzastaurin compared with lomustine in the 
treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010;28(7):1168-1174.
Wong ET, Gautam S, et al. Bevacizumab for recurrent glioblastoma multiforme:  a 
meta-analysis. J Natl Compr Canc Netw. 2011;9(4):403-407.


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Attachment 11.
Protocol JBEF Management Algorithms 
for Immuno-Oncology Agents
These general guidelines constitute guidance to the investigator and may be supplemented by 
discussions with the Lilly CRP.  The guidance applies to all immuno-oncology agents and 
regimens.  
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice.  Noninflammatory aetiologies should be considered and appropriately 
treated.  
Corticosteroids are a primary therapy for immuno-oncology drug-related AEs.  The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity.  The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.  
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.  
The frequency and severity of the related AEs covered by these algorithms will depend on the 
immuno-oncology agent or regimen being used.


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Attachment 12.
Protocol JBEF CYP3A4 Modulators
CYP3A4 Inducers
Strong
CYP3A4 Inhibitors
Moderate
CYP3A4 Inhibitors
aminoglutethimide
clarithromycin 
amiodarone
bosentan
chloramphenicol
amprenavir
carbamazepine
cobicistat 
aprepitant
efavirenz (in liver only)
conivaptan
atazanavir
fosphenytoin 
Cremophor EL
cimetidine
nafcillin
cyclosporine 
ciprofloxacin
nevirapine
delavirdine
clotrimazole
oxcarbazepine
diclofenac
darunavir
pentobarbital
diltiazem 
darunavir and ritonavir
phenobarbital
elvitegravir and ritonavir
desipramine
phenytoin
enoxacin
doxycycline
primidone
erythromycin 
dronedarone
rifabutin
fosamprenavir 
efavirenz
rifampin
grapefruit juice 
erythromycin
rifapentine
indinavir
FK1706
St. John's wort
indinavir and ritonavir
fluconazole 
itraconazole 
fluvoxamine
ketoconazole 
haloperidol
lopinavir and ritonavir
imatinib
mibefradil
metronidazole
miconazole
norfloxacin
nefazodone  
protease inhibitors
nelfinavir 
quinidine
nicardipine
Schisandra sphenanthera extract
posaconazole 
sertraline
quinidine
tetracycline
ritonavir 
tofisopam
saquinavir 
verapamil
telithromycin
theophylline 
troleandomycin 
voriconazole 


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Attachment 13.
Protocol JBEF Protocol Amendment 
H9H-MC-JBEF(c) Summary 
A Phase 1b/2 Dose Escalation and Cohort Expansion 
Study of the Safety, Tolerability and Efficacy of a Novel 
Transforming Growth Factor–β Receptor I Kinase Inhibitor 
(Galunisertib) Administered in Combination with Anti–PD-1 
(Nivolumab) in Advanced Refractory Solid Tumours 
(Phase 1b) and in Recurrent or Refractory Non–Small Cell 
Lung Cancer or Hepatocellular Carcinoma (Phase 2)
Overview
Protocol H9H-MC-JBEF(b) has been amended.  The new protocol is indicated by 
Amendment (c) and will be used to conduct the study in place of any preceding version of the 
protocol.
H9H-MC-JBEF protocol (b) was amended for the following reasons:

Phase 2 portion of study: to remove the glioblastoma cohort and update the protocol text 
to reflect this change.  Results from 2 recently reported galunisertib trials, 
Studies H9H-MC-JBAI and H9H-MC-JBAL, have indicated a lack of sufficient efficacy 
with galunisertib in glioblastoma.  

To clarify the rationale for the changes to the ECHOs in Attachment 1 made in protocol 
amendment (b) (see Section 5.5 bullet 6):  the requirement for ECHO (echocardiography) 
at the 30-day follow-up visit was restored into the protocol as this requirement had been 
inadvertently removed during Amendment A; for the Phase 2 portion, clarification was 
provided that imaging is to be collected centrally.  

Attachment 2:  to add hepatitis B surface antigen testing, which was inadvertently 
excluded previously; to clarify that all hepatitis testing at baseline will be assayed by a 
local and a Lilly-designated laboratory and during the trial will be performed by a Lilly-
designated laboratory; and to clarify footnotes.  

Attachment 4:  to add a ±10-minute window to the blood biomarker collection on Cycle 1 
Day 1.
Minor editing was made but not necessarily listed below.
A detailed list of text changes is below.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
Title page
A Phase 1b/2 Dose Escalation and Cohort Expansion Study of the Safety, Tolerability and 
Efficacy of a Novel Transforming Growth Factor–β Receptor I Kinase Inhibitor (Galunisertib) 
Administered in Combination with Anti–PD-1 (Nivolumab) in Advanced Refractory Solid 
Tumours (Phase 1b) and in Recurrent or Refractory Non–Small Cell Lung Cancer or 
Hepatocellular Carcinoma , or Glioblastoma (Phase 2)
…
This is a multicentre, nonrandomised, open-label, dose-escalation Phase 1b study of 
galunisertib combined with nivolumab in patients with advanced refractory solid tumours 
followed by a 3-cohort expansion Phase 2 study in patients with refractory or recurrent 
non–small cell lung cancer or hepatocellular carcinoma, or glioblastoma.  
…
Protocol Electronically Signed and Approved by Lilly:  17 April 2015
Amendment (a) Electronically Signed and Approved by Lilly:  24 July 2015 
Amendment (b) Electronically Signed and Approved by Lilly:  30 August 2016
Amendment (c) Electronically Signed and Approved by Lilly on approval date provided 
below
Approval Date:  30-Aug-2016 GMT
Synopsis
…
This study is a Phase 1b/2 open-label study that will be conducted in 2 parts.  The Phase 1b part 
of this study will consist of an open-label, dose-escalation assessment of the safety and 
tolerability of galunisertib administered at 50 mg daily (QD), 50 mg twice daily (BID), 80 mg 
BID, or 150 mg BID in combination with nivolumab 3 mg/kg in patients with advanced 
refractory solid tumours.  The Phase 2 part of this study will be disease restricted and include 
23 expansion cohorts of patients in tumours with documented monotherapy activity with 
nivolumab (non–small cell lung cancer; n = approximately 25 patients) or galunisertib 
(hepatocellular carcinoma [n = approximately 25 patients] and glioblastoma [n = approximately 
25 patients]).  Patients in the 23 cohorts will be enrolled independently and will be assigned to 
treatment concurrently;, and enrolment for each cohort will be complete when thatall cohort
hasve reached the prespecified enrolment target.  Galunisertib will be used to attempt to augment 
nivolumab activity via suppression of the immune suppressive function of TGF-β at the 


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maximum tolerated dose or pharmacologically active dose.  Additional cohorts of patients with 
specific alternative tumour histologies may be added and will require an amendment.
3.
Table of Contents
A Phase 1b/2 Dose Escalation and Cohort Expansion Study of the 
Safety, Tolerability, and Efficacy of a Novel Transforming Growth 
Factor–Receptor I Kinase Inhibitor (Galunisertib) Administered in 
Combination with Anti–PD-1 (Nivolumab) in Advanced Refractory 
Solid Tumours (Phase 1b) and in Recurrent or Refractory Non–Small 
Cell Lung Cancer or, Hepatocellular Carcinoma, or Glioblastoma
(Phase 2)
…
5.
Introduction
A Phase 1b/2 Dose Escalation and Cohort Expansion Study of the 
Safety, Tolerability, and Efficacy of a Novel Transforming Growth 
Factor–Receptor I Kinase Inhibitor (Galunisertib) Administered in 
Combination with Anti–PD-1 (Nivolumab) in Advanced Refractory 
Solid Tumours (Phase 1b) and in Recurrent or Refractory Non–Small 
Cell Lung Cancer or, Hepatocellular Carcinoma, or Glioblastoma
(Phase 2)
5.5.
Rationale for H9H-MC-JBEF Protocol Amendment (b)
…

In Attachment 1, Study Schedules, a requirement was added for echocardiography
(ECHO) at the 30-day follow-up visit, and, for the Phase 2 portion, clarification was 
provided that imaging is to be collected centrally [see clarification in Section 5.5].  
…
A detailed list of changes may be found in Attachment 13.
5.6.
Rationale for H9H-MC-JBEF Protocol Amendment (c)
H9H-MC-JBEF protocol (b) was amended for the following reasons:

Phase 2 portion of study: to remove the glioblastoma cohort and update the protocol text 
to reflect this change.  Results from 2 recently reported galunisertib trials,
Studies H9H-MC-JBAI and H9H-MC-JBAL, have indicated a lack of sufficient efficacy 
galunisertib in glioblastoma.  


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
To clarify the rationale for the changes to the ECHOs in Attachment 1 made in 
protocol amendment (b) (see Section 5.5 bullet 6):  the requirement for ECHO 
(echocardiography) at the 30-day follow-up visit was restored into the protocol as 
this requirement had been inadvertently removed during Amendment A; for the 
Phase 2 portion, clarification was provided that imaging is to be collected 
centrally.  

Attachment 2:  to add hepatitis B surface antigen testing, which was inadvertently 
excluded previously; to clarify that all hepatitis testing at baseline will be assayed by a 
local and a Lilly-designated laboratory and during the trial will be performed by a Lilly-
designated laboratory; and to clarify footnotes.  

Attachment 4:  to add a ±10-minute window to the blood biomarker collection on Cycle 1 
Day 1.
Minor editorial corrections or clarifications may have been made but not detailed above.  A 
detailed list of changes may be found in Attachment 13.
5.6.5.7.
Galunisertib
…
Glioblastoma
In glioblastoma (GB), anaplastic astrocytomas, anaplastic oligoastrocytoma, or anaplastic 
oligodendroglioma, galunisertib is expected to reduce neoangiogenesis; enhance antitumour 
cytotoxic T cells; and reduce fibrogenic remodelling associated with tumour necrosis, radiation, 
and surgery.  Of 32 patients with relapsed and recurrent GB who received galunisertib 
monotherapy and were assessed using either RECIST version 1.1 or MacDonald criteria in a 
recent first-in-human dose study (Study H9H-MC-JBAH [JBAH]), partial tumour responses 
were reported in 5 patients.  Based upon these data, second- and first-line studies are ongoing 
assessing the efficacy of blockade of the TGF-β signalling pathway in GB.
Based on preclinical data suggesting an additive antitumour effect of a TGF-β inhibitor and 
lomustine and the Study JBAH clinical data, a Phase 2 study, Study JBAL, was initiated to 
evaluate the activity of this combination in patients with GB after first progression.  In this study, 
158 patients were randomly assigned to 3 treatment arms:  galunisertib + lomustine (n=79), 
galunisertib alone (n=39), and placebo + lomustine (n=40) (Brandes et al. 2015).  

The median OS (95% CI) was 6.7 months (5.3, 8.5) for the galunisertib + lomustine arm, 
8.0 months (5.7, 11.7) for the galunisertib arm, and 7.5 months (5.6, 10.3) for the placebo 
+ lomustine arm.  Success criteria for superiority of the galunisertib + lomustine arm over 
the placebo + lomustine arm was not met (p [hazard ratio<1]<85%).

The median progression-free survival (PFS) (95% CI) was 1.8 months (1.7, 1.8) for the 
galunisertib + lomustine arm, 1.8 months (1.6, 3.0) for the galunisertib arm, and 
1.9 months (1.7, 1.9) for the placebo + lomustine arm.  


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
Best overall response as determined using Response Assessment in Neuro-Oncology 
(RANO) criteria included 1 CR in the galunisertib + lomustine arm and 2 PRs in the 
galunisertib arm.  

Thirty-four patients (24% patients in the galunisertib + lomustine arm; 13% in the 
galunisertib arm; 26% in the placebo + lomustine arm) had Grade 3/4 AEs related to 
study drug.  The most common drug-related Grade 3/4 AEs (galunisertib + lomustine, 
galunisertib, placebo + lomustine, respectively) were thrombocytopenia (8%, 0%, 13%), 
lymphopenia (9%, 3%, 0%), and neutropenia (8%, 0%, 5%).  
Study JBAL efficacy outcomes including OS and PFS were similar in all 3 treatment arms.  The 
treatment was safe and well tolerated.  Outcomes of an IDH-1–mutated subgroup is being 
analysed for clinical outcome to determine whether it is different from the general glioblastoma 
population.  In addition, in Study JBAL, higher baseline expression of MDC/CCL22 was a 
prognosticator of improved outcome, and patients whose CCL22 remained higher over the 
course of treatment had better outcomes (Hanks et al. 2013).  In addition, higher baseline levels 
of CD3, CD4, CD4CD25, CD8, and FoxP3 correlated with improved outcome, suggesting that a 
more intact immune function improves outcome.
Study H9H-MC-JBAI is an ongoing Phase 1b study evaluating galunisertib in the first-line 
setting in combination with temozolomide and radiation.  
…
5.7.5.8.
Nivolumab
…
Glioblastoma 
Recent improvements in OS achieved with immunotherapeutics in melanoma and prostate cancer 
suggest that immunotherapy approaches may offer promise in other difficult to treat cancers such 
as GB (Heimberger and Sampson 2011).  More specific immunologic data in support of this 
hypothesis include the longer survival observed in patients with elevated IgE levels compared to 
those with normal levels (Lin et al. 2011; Schlehofer et al. 2011; Schwartzbaum et al. 2012; 
Turner 2012) and upregulation of immune checkpoint receptors such as PD-L1 in glioblastomas 
(Parsa et al. 2007; Jacobs et al. 2009).  Studies have also suggested an association between 
malignancy grade of astrocytic tumours and tumour cell PD-L1 expression (Wilmotte et al. 2005; 
Yao et al. 2009).  Additionally, use of an inhibitor of PD-L1 in mouse glioblastoma models 
suggests benefit in combination with radiation therapy (Zeng et al. 2013).  
Although the efficacy of check point inhibitors such as nivolumab and ipilimumab have not 
previously been studied in GB, a multicentre, Phase 2 study to evaluate the response of brain 
tumour metastases to ipilimumab was previously performed (CA184042).  Patients (n=71) with 
advanced Stage IV melanoma and measurable active brain metastases were randomly assigned to 
ipilimumab monotherapy.  The study demonstrated that ipilimumab had clinical activity in 
patients with melanoma brain metastases with some patients showing prolonged clinical 


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responses, disease control, and prolonged survival.  Ipilimumab did not cause unexpected 
neurological toxicity in patients with brain metastases.
Nivolumab monotherapy is being evaluated in Study CA209143.  
…
5.9.1. Primary Objective
…
Phase 2
The primary objective of the Phase 2 part (expansion cohorts) of this study is to assess the safety 
of the combination of galunisertib and nivolumab in patients with refractory or recurrent NSCLC
or, HCC, or glioblastoma who have failed 1 prior line of therapy.  
5.9.2. Secondary Objectives
The secondary objectives of this study are:
…

Phase 2 only:  To assess the preliminary antitumour activity including PFS, ORR, 
duration of response, and time to response of the combination of galunisertib and 
nivolumab in patients with NSCLC or, HCC, or glioblastoma  
6.1.1. Inclusion Criteria
Patients may be included in the study if they meet all of the following criteria during screening 
prior to first dose of study drug.
…
[2] For Phase 2, must have 1 of the following tumour types:  recurrent or 
refractory NSCLC (any histology) or, HCC with AFP ≥200 ng/mL, or 
glioblastoma (primary).  
[3] For Phase 2, Mmust have histological or cytological confirmation of recurrent 
disease based upon standard diagnostic criteria for the tumour type.  
For glioblastoma, patients must have:
1)  previous or current histologically confirmed diagnosis of WHO glioblastoma 
(ICD-O 9440/3, WHO grade IV); and  
2)  first recurrence of glioblastoma as determined by RANO criteria (see
Attachment 9) following standard chemoradiation (Stupp protocol [Stupp et al. 
2009]).  If first recurrence of glioblastoma is documented by MRI, an interval of 
at least 12 weeks after the end of prior radiation therapy is required unless there 
is either:  i) histopathologic confirmation of recurrent tumour, or ii) new 


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enhancement on MRI outside of the radiotherapy treatment field (beyond the 
high-dose region or 80% isodose line) (Wen et al. 2010).  For glioblastoma 
patients, biopsy confirmation of recurrent disease is not required as long as new 
enhancement on MRI outside of the radiotherapy treatment field is documented.
[4] For patients other than glioblastoma patients, nNew (nonarchived) baseline 
tumour biopsies (defined as a biopsy specimen taken since completion of the 
first-line treatment regimen) are required for all cohorts (see Section 8.2.1).  
In addition, in the Phase 2 part of the study, patients must agree to undergo an 
on-study biopsy; patients in the Phase 1b part of this study are strongly 
encouraged to agree to undergo an on-study biopsy.  See Section 8.2.3.2.  
For Phase 1 of the study, any For glioblastoma patients must, have either a new 
biopsy or archived tumour tissue available.  
Fine-needle aspirates or other cytology samples are not acceptable.
[5]
For NSCLC, HCC or other nonneuro-oncology tumours:  have measurable 
disease as defined by RECIST version 1.1 (Eisenhauer et al. 2009; 
Attachment 8).  
For any For glioblastoma patient in Phase 1 of the study:  have measurable 
disease as defined by RANO (Wen et al. 2010; Attachment 9).  for the first 25 
patients.  If the cohort is expanded per the 2-stage design, then patients with 
either measurable or nonmeasurable disease as defined by RANO are eligible.  
Patients with glioblastoma may have nonmeasurable disease if they have 
undergone resection and postresection radiation. …
[6]
For Phase 2 only, have had disease progression or be refractory or intolerant 
to 1 prior line of therapy (first-line therapy) for recurrent or refractory for
NSCLC or , HCC, or glioblastoma and have refused currently approved 
second-line of therapy. …
For glioblastoma:

previous first-line of therapy with at least radiotherapy and temozolomide except 
for patients with MGMT unmethylated newly diagnosed GB (Stupp et al. 2009).  
Patients with MGMT unmethylated newly diagnosed GB may have received 
radiation therapy only (Hegi et al. 2005).
…
[9]
Have adequate organ function, including:
…
For Phase 2 only:
…


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For glioblastoma cohort only:

Haematologic:  platelets 100x109/L, and haemoglobin 9 g/dL or 5.6 mmol/L, 
ANC 1.5x109/L.  Patients may receive erythrocyte transfusions to achieve this 
haemoglobin level at the discretion of the investigator (at least 3 days before 
starting study drug).  Initial treatment must not begin until 2 days after the 
erythrocyte transfusion and after the confirmation of haemoglobin level ≥9 g/dL.

Hepatic:  total bilirubin ≤1.5xULN (except patients with Gilbert Syndrome who 
must have a total bilirubin level of <3.0xULN); alkaline phosphatase, AST, and 
ALT ≥3.0xULN.  
6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
…
[24] Are receiving immunosuppressive agents (eg, cyclosporine) for any reason 
except for corticosteroids for transfusions.  In the Phase 1b portion of the 
study, lLow-dose corticosteroids for glioblastoma are permitted (eg, 
prednisone 10 mg [approximately equivalent to 2 mg of dexamethasone] or 
less daily or equivalent dose of other corticosteroid).
…
[29] Receiving any concurrent antineoplastic therapy (ie, chemotherapy, hormonal 
therapy, immunotherapy, extensive, nonpalliative radiation therapy, or 
standard or investigational agents for treatment of NSCLC, HCC, or 
glioblastoma).  
[30] Have had prior radiotherapy within 2 weeks of therapy.  Patients must have 
recovered from all radiation-related toxicities, not require more than low-dose 
corticosteroids (except for low-dose corticosteroids for glioblastoma in the 
Phase 1b portion of the study, eg, prednisone 10 mg or less daily or equivalent 
dose of other corticosteroid), and not have had radiation pneumonitis.  A 
1-week washout is permitted for palliative radiation to non-CNS disease with 
Lilly physician approval.
[31] For glioblastoma patients in the Phase 1b portion of the study only, have 
diffuse leptomeningeal disease.
[32] For nonglioblastoma patients, pPatients with known active central nervous 
system (CNS) metastases and/or carcinomatous meningitis.  Patients with 
stable, previously treated brain metastases may participate if neurologic 
symptoms have resolved, they have been off steroids for at least 7 days, and 
have no evidence of disease progression by imaging for at least 2 weeks 
before the first dose of study treatment.
…


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[36] For glioblastoma patients in the Phase 1b portion of the study only, previous 
treatment with carmustine wafer except when administered as first-line 
treatment and at least 6 months prior to randomisation.  
6.2.
Summary of Study Design
. … The second part (Phase 2) of the study will be disease restricted to include 23 expansion 
cohorts in patients with recurrent or refractory NSCLC (n = approximately 25 patients) or HCC 
(n = approximately 25 patients) or glioblastoma (n = approximately 25 patients) all receiving 
nivolumab 3 mg/kg Q2W plus galunisertib at the dose determined from the Phase 1b part.  
Additional expansion of individual cohorts may occur depending upon activity based upon a 
2-stage design after 3 cycles.  Details are found in Section 10.1.1.  NSCLC has a historically 
good activity under nivolumab monotherapy; HCC and glioblastoma havehas documented 
activity with galunisertib therapy.
…
[[Updated design figure]]
Figure JBEF.6.1.
Study H9H-MC-JBEF design.
6.2.2. Phase 2 Cohort Expansion
… .  Three Two expansion cohorts will be tested in order to demonstrate efficacy of the 
combination in NSCLC and, HCC, and glioblastoma.  If DLT-equivalent toxicities occur in 33% 
or more of patients within a tumour-specific cohort expansion in the first 2 cycles, then 
investigators and the Lilly CRP will assess the nature and severity of these toxicities.  No 
additional patients will be accrued until this safety review is completed and a decision is made 
either to continue at the current dose or to deescalate the dose and define a new dose for the 
expansion phase.  The NSCLC cohort (NSCLC has demonstrated activity with nivolumab 
monotherapy), and the glioblastoma and HCC cohorts (HCC has documented monotherapy 
activity with galunisertib), will be used to assess activity of the combination. …
7.2.3. Phase 2 Cohort Expansion
…
The Phase 2 part of the study will initially include 23 expansion cohorts (NSCLC and , HCC,
and glioblastoma [n = approximately 25 patients per cohort]). …
7.5.
Concomitant Therapy
…


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Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, nonpalliative radiation therapy, or standard or investigational agents for treatment of 
NSCLC, HCC, or glioblastomaany other tumour type) will not be allowed.
…
8.1.4. Safety Monitoring
…
The Lilly CRP/CRS will, as is appropriate, consult with the functionally independent Global 
Patient Safety therapeutic area physician or CRS, and periodically review:
…

Except for patients with liver metastases or HCC, for any patient whoIf a study patient 
with NSCLC or glioblastoma experiences elevated ALT >3xULN and elevated total 
bilirubin >2xULN, clinical and laboratory monitoring should be initiated by the 
investigator.  
…
10.1.1. Sample Size
…
For HCC and glioblastoma, the response is defined based on ORR or survival at 10 months. …
10.7.
Efficacy
…
For the glioblastoma cohort, efficacy endpoints may be evaluated by adjusting for IDH 1/2 
expression, serum TGFβ-1 levels, and tumour PD-L1 expression.
10.8.
Interim Analyses
…
After enrolment has completed in a cohort (n = approximately 25) and the last enrolled patient in 
that cohort has completed or had the opportunity to complete 3 cycles of treatment, an interim 
analysis will be conducted for that particular cohort (for a total of 23 separate interim analyses to 
be conducted when each cohort reaches 25 patients complete at least 3 cycles of treatment).  The 
intent of the interim analysis is to evaluate preliminary antitumour activity of galunisertib in 
combination of nivolumab.  These interim analyses may be combined with the ongoing trial-
level safety review.  Pending review of the interim data, approximately 16 additional patients 
may be enrolled in that particular cohort if there are more than 4 and fewer than 9 patients who 
demonstrate responses (determined by ORR for the NSCLC cohort, and by ORR or survival for 
the HCC and glioblastoma cohorts).  Enrolment of the other cohort(s), if not completely enrolled, 
will not be stopped during the interim analysis. ...  


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
12.
References
…
Brandes AA, Carpentier A, Kesari, Sepulveda J, Wheeler H, Chinot O, Cher L, Steinbach J, 
Specenier P, Cleverly A, Smith C, Gueorguieva I, Guba SC, Desaiah D, Lahn MM, Wick W. 
A phase 2 randomized study of galunisertib monotherapy or galunisertib plus lomustine 
compared to lomustine monotherapy in patients with recurrent glioblastoma.  Abstract 144596 
to be presented at: Annual Meeting of the American Society for Clinical Oncology; 
29 May-2 June 2015; Chicago, Illinois, USA.  
…
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner 
JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, 
Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J 
Med. 2005;352(10):997-1003.
Heimberger AB, Sampson JH. Immunotherapy coming of age: what will it take to make it 
standard of care for glioblastoma? Neuro Oncol. 2011;13(1):3-13.
…
Jacobs JF, Idema AJ, Bol KF, Nierkens S, Grauer OM, Wesseling P, Grotenhuis JA, 
Hoogerbrugge PM, de Vries IJ, Adema GJ. Regulatory T cells and the PD-L1/PD-1 pathway 
mediate immune suppression in malignant human brain tumors. Neuro Oncol. 
2009;11(4):394-402.
…
Lin Y, Jin Q, Zhang GZ, Wang YJ, Jiang T, Wu AH, Wang JF, Qiu XG. Increase of plasma IgE 
during treatment correlates with better outcome of patients with glioblastoma. Chin Med J
(Engl). 2011;124(19):3042-3048.
…
Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan 
T, Jensen MC, Mischel PS, Stokoe D, Pieper RO. Loss of tumor suppressor PTEN function 
increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13(1):84-88.
…


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
Schlehofer B, Siegmund B, Linseisen J, Schüz J, Rohrmann S, Becker S, Michaud D, Melin B, 
Bas Bueno-de-Mesquita H, Peeters PH, Vineis P, Tjonneland A, Olsen A, Overvad K, Romieu 
I, Boeing H, Aleksandrova K, Trichopoulou A, Bamia C, Lagiou P, Sacerdote C, Palli D, 
Panico S, Sieri S, Tumino R, Sanchez MJ, Rodriguez L, Dorronsoro M, Duell EJ, Chirlaque 
MD, Barricarte A, Borgquist S, Manjer J, Gallo V, Allen NE, Key TJ, Riboli E, Kaaks R, 
Wahrendorf J. Primary brain tumours and specific serum immunoglobulin E: a case-control 
study nested in the European Prospectiv2e Investigation into Cancer and Nutrition cohort. 
Allergy. 2011;66(11):1434-1441.
Schwartzbaum J, Ding B, Johannesen TB, Osnes LT, Karavodin L, Ahlbom A, Feychting M, 
Grimsrud TK. Association between prediagnostic IgE levels and risk of glioma. J Natl Cancer 
Inst. 2012;104(16):1251-1259.
…
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, 
Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, 
Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross 
JG, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain 
Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials 
Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus 
radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis 
of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459-466.
…
Turner MC. Epidemiology: allergy history, IgE, and cancer. Cancer Immunol Immunother
2012;61(9):1493-1510.
…
Wilmotte R, Burkhardt K, Kindler V, Belkouch MC, Dussex G, Tribolet Nd, Walker PR, 
Dietrich PY. B7-homolog 1 expression by human glioma: a new mechanism of immune 
evasion. Neuroreport. 2005;16(10):1081-1085.
…
Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, Durham N, Meyer C, Harris TJ, 
Albesiano E, Pradilla G, Ford E, Wong J, Hammers HJ, Mathios D, Tyler B, Brem H, Tran 
PT, Pardoll D, Drake CG, Lim M. Anti-PD-1 blockade and stereotactic radiation produce 
long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys.
2013;86(2):343-349.
Attachment 1.
Protocol JBEF Study Schedule
…


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Galunisertib (LY2157299)/nivolumab
During and Post-Study Assessments—Phase 1b Dose Escalation
Cycle 1
Cycle 2
Cycle 3-n
Follow-Up (days)
Comments
Relative Week 
Within a Cycle
1
2
3
4
1
2
3
4
1
2
3
4
Relative Day 
Within a Cyclea
1
8
15
22
1
8
1
5
22
1
8
15
22
Short-term
Long-
termc
30b
100
…
12-lead ECG
X
D 
14 
only
X*
Collect predose (if applicable):
See Attachment 4 for timing of PK time-matched ECGs
* Starting at Cycle 53 Day 1, ECGs will be performed at 
every odd-numbered cycle thereafter (Cycles 5, 7, 9, etc) 
…
Bio-
marker 
samples
Tumour 
biopsy
1/2
1/2
Required for patients with cancers other than glioblastoma, 
with half of patients randomly assign to biopsies on either 
Cycle 1 D15 or Cycle 2 D1 post nivolumab dosing.  If a 
patient with glioblastoma undergoes a biopsy during the study 
for other medical reasons, tissue should be collected at that 
time.  
For glioblastoma patients only (Phase 1b), if tumour biopsy is 
performed to distinguish between radiologic progression and 
pseudoprogression (not required), see Section 7.2.5 for 
instructions for proper handling of specimen.
…


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 157
Galunisertib (LY2157299)/nivolumab
Phase 2 Dose Expansion—Baseline/Screening Assessments
Relative Day Prior to Day 1 
of Cycle 1a
28
14
7
Comments
…
Tumour biopsy
X
New tumour biopsy is required for patients with NSCLC 
and HCC.  Archived tumour tissue or new tumour biopsy 
is required for patients with glioblastoma.  Biopsy should 
be taken only after study eligibility is confirmed.
…
Tumour measurement 
(palpable or visible)
X
If appropriate for the tumour
…


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
Page 158
Galunisertib (LY2157299)/nivolumab
During and Post-Study Assessments—Phase 2 Dose Expansion
Cycle 1
Cycle 2
Cycle 3-n
Follow-Up (days)
Comments
Relative Week Within 
a Cycle
1
2
3
4
1
2
3
4
1
2
3
4
Relative Day Within a 
Cyclea
1
8
15
22
1
8
1
5
22
1
8
15
22
Short-term
Long-
termc
…
12-lead ECG
X
D 
14 
only
X*
Collect predose (if applicable):
See Attachment 4 for timing of PK time-matched ECGs.
* Starting at Cycle 35 Day 1, ECGs will be performed at 
every odd-numbered cycle thereafter (Cycles 5, 7, 9, etc)
…
Radiological tumour 
assessment for 
pseudoprogressiontreat
ment past initial 
progression
MRI/CT scan.  These scans can be performed locally and 
transmitted to a central imaging vendor.  For patients who are 
being treated beyond initial progression, these patients should 
remain on study treatment until the next assessment period.  
Patients who are treated beyond progression will be evaluated 
on an 8 (nonglioblastoma) or 12- (glioblastoma) -week basis 
to determine if they should continue on treatment.  
…
Bio-
marker 
samples
Tumour 
biopsy
1/2
1/2
Required for patients with cancers other than glioblastoma, 
with half of patients randomly assign to biopsies on either 
Cycle 1 D15 or Cycle 2 Day 1 post nivolumab dosing.  If a 
patient with glioblastoma undergoes a biopsy during the study 
for other medical reasons, tissue should be  collected at that 
time.  
For glioblastoma patients only, if tumour biopsy is performed 
to distinguish between radiologic progression and 
pseudoprogression (not required), see Section 7.2.5 for 
instructions for proper handling of specimen.
…


H9H-MC-JBEF(c) Phase 1 Oncology Protocol
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Galunisertib (LY2157299)/nivolumab
Attachment 2.
Protocol JBEF Clinical Laboratory Tests
Clinical Laboratory Tests
Haematologya
Clinical Chemistrya,b,c
Haemoglobin
Serum Concentrations of:
…
Thyroid-stimulating hormonea,b,c
Reflex to fT3/fT4a,b,cd
…
c
Assayed by local and investigator-designated laboratory.
d
If thyroid-stimulating hormone test is abnormal, reflex to fT3/fT4 test must be performed.  
d
Baseline tests (screening) will be assayed by a local and a Lilly-designated laboratory.  Testing during the trial 
will be performed by a Lilly-designated laboratory.
Attachment 4.
Protocol JBEF Pharmacokinetic, Biomarker, PK Time-Matched 
ECG, and Immunogenicity Sampling Schedule
…
Blood Biomarker Sampling Schedule
Pharmacodynamic 
Sample #
Cycle
Day
Sampling Windows for 
Blood Collection
1
1
1
Predose
2
1
1
2 hours postdose ± 10 
minutes
...


L e o  D o c u m e n t  I D  =  1 7 3 a 3 2 d f - 7 7 9 3 - 4 4 7 b - a 1 2 d - 6 8 5 2 0 0 4 e 2 6 5 3
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  3 1 - J a n - 2 0 1 7  1 3 : 4 0 : 4 7  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  3 1 - J a n - 2 0 1 7  1 5 : 4 0 : 1 8  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D

SAP_001.pdf: 
H9H-MC-JBEF Statistical Analysis Plan v2 
 
A Phase 1b/2 Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and 
Efficacy of a Novel Transforming Growth Factor-β Receptor I Kinase Inhibitor (Galunisertib) 
Administered in Combination with Anti-PD-1 (Nivolumab) in Advance Refractory Solid 
Tumours (Phase 1b) and in Recurrent or Refractory Non-Small Cell Lung Cancer or 
Hepatocellular Carcinoma (Phase 2) 
 
NCT02423343 
 
Approval Date: 26-Oct-2017 


H 9 H -M C -J B E F St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 1
L Y 2 1 5 7 2 9 9
1.
St ati sti c al A n al y si s Pl a n:
H 9 H -M C -J B E F ( c):  A P h a s e 1 b/ 2 D o s e E s c al ati o n a n d 
C o h ort E x p a n si o n St u d y  of t h e S af et y, T ol er a bilit y, a n d 
Effi c a c y  of a N o v el Tr a n sf or mi n g Gr o wt h F a ct or– 
R e c e pt or I Ki n a s e I n hi bit or ( G al u ni s erti b) A d mi ni st er e d i n 
C o m bi n ati o n wit h A nti – P D -1 ( Ni v ol u m a b) i n A d v a n c e d 
R efr a ct or y  S oli d T u m o ur s ( P h a s e 1 b) a n d i n R e c urr e nt or 
R efr a ct or y  N o n– S m all C ell L u n g C a n c er or H e p at o c ell ul ar 
C ar ci n o m a ( P h a s e 2)
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d t h e i nf or m ati o n c o nt ai n e d 
wit hi n it m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e a p pr o v al of Eli Lill y 
a n d C o m p a n y or it s s u b si di ari e s.
N ot e t o R e g ul at or y A ut h oriti e s :  T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e. I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
G al u ni s erti b ( L Y2 1 5 7 2 9 9 )
A P h a s e 1 b/ 2 D o s e E s c al ati o n a n d C o h ort E x p a n si o n St u d y of G al u ni s erti b A d mi ni st er e d i n 
C o m bi n ati o n wit h A nti – P D -1 ( Ni v ol u m a b) i n A d v a n c e d R efr a ct or y S oli d T u m o ur s ( P h a s e 
1 b) a n d i n R e c urr e nt or R efr a ct or y N o n – S m all C ell L u n g C a n c er or H e p at o c ell ul ar 
C a r ci n o m a ( P h a s e 2).
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol H 9 H -M C -J B E F ( c)
P h a s e 1 b/ 2
St ati sti c al A n al y si s Pl a n V er si o n 1 el e ctr o ni c all y si g n e d a n d a p pr o v e d b y Lill y o n 
5 O ct o b er 2 0 1 5 .
St ati sti c al A n al y si s Pl a n V er si o n 2 el e ctr o ni c all y si g n e d a n d a p pr o v e d b y Lill y o n d at e 
pr o vi d e d b el o w.
A p pr o v al D at e: 2 6- O ct- 2 0 1 7 G M T


H9H-MC-JBEF Statistical Analysis Plan Version 2
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LY2157299
2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan: H9H-MC-JBEF(c):  A Phase 1b/2 Dose 
Escalation and Cohort Expansion Study of the Safety, Tolerability, 
and Efficacy of a Novel Transforming Growth Factor–Receptor I 
Kinase Inhibitor (Galunisertib) Administered in Combination with 
Anti–PD-1 (Nivolumab) in Advanced Refractory Solid Tumours 
(Phase 1b) and in Recurrent or Refractory Non–Small Cell Lung 
Cancer or Hepatocellular Carcinoma (Phase 2)....................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................5
4.
Study Objectives.................................................................................................................6
4.1.
Primary Objective ..........................................................................................................6
4.2.
Secondary Objectives.....................................................................................................6
4.3.
Exploratory Objectives...................................................................................................6
5.
Study Design.......................................................................................................................7
5.1.
Summary of Study Design..............................................................................................7
5.2.
Determination of Sample Size ........................................................................................7
5.3.
Method of Assignment to Treatment ..............................................................................8
6.
A Priori Statistical Methods ................................................................................................9
6.1.
General Considerations ..................................................................................................9
6.1.1.
Analysis Populations............................................................................................10
6.1.2.
End of Study Definitions......................................................................................11
6.2.
Adjustments for Covariates ..........................................................................................11
6.3.
Handling of Dropouts or Missing Data.........................................................................11
6.4.
Patient Disposition .......................................................................................................12
6.5.
Patient Characteristics ..................................................................................................12
6.5.1.
Demographics......................................................................................................13
6.5.2.
Baseline Disease Characteristics ..........................................................................13
6.5.3.
Pre-existing Conditions and Medical History .......................................................13
6.5.4.
Prior Therapies.....................................................................................................13
6.6.
Concomitant Therapy...................................................................................................13
6.7.
Efficacy Analyses ........................................................................................................14
6.7.1.
Endpoint Definitions ............................................................................................14
6.7.2.
Analysis Methods.................................................................................................15
6.8.
Bioanalytical and Pharmacokinetic/Pharmacodynamics Methods.................................16
6.8.1.
Pharmacokinetics .................................................................................................16


H9H-MC-JBEF Statistical Analysis Plan Version 2
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6.8.2.
Pharmacodynamics and Tailoring Analyses..........................................................16
6.8.3.
Immunogenicity...................................................................................................17
6.9.
Safety Analyses............................................................................................................17
6.9.1.
Extent of Exposure...............................................................................................17
6.9.2.
Adverse Events ....................................................................................................17
6.9.2.1.
Dose Limiting Toxicities ................................................................................18
6.9.3.
Deaths, Serious Adverse events and Other Notable Events...................................18
6.9.4.
Clinical Laboratory Evaluation.............................................................................19
6.9.5.
Vital Signs and Other Physical Findings...............................................................19
6.9.6.
Electrocardiograms and Cardiac Assessment Data................................................19
6.10. Subgroup Analyses.......................................................................................................20
6.11. Protocol Violations.......................................................................................................20
6.12. Interim Analyses ..........................................................................................................20
6.13. Annual Report Analyses...............................................................................................21
6.14. Clinical Trial Registry Analyses...................................................................................21
7.
References ........................................................................................................................23


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Table of Contents
Table
Page
Table JBEF.5.1. Summary of Statistical Power for Response Rates ...........................................7
Table JBEF.6.1. Terms and Data Handling Conventions..........................................................10


H 9 H -M C -J B E F St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 5
L Y 2 1 5 7 2 9 9
3.
R e vi si o n Hi st or y
S A P Versi o n 1 was a p pr o ve d pri or t o t he first patie nt recei vi n g st u d y dr u g or a n y ot her pr ot oc ol 
i nter ve nt i on.   
S A P Versi o n 2 o verall c ha n ges a n d rat i onale f or t he c ha n ges are as f oll o ws : 
1.
Re m o ve d “ gli o blast o ma” fr o m P hase 2 of t he st u d y.
2.
Secti o n 5. 1. S u m mar y  of St u d y Desi g n, re vise d the sec o n d part ( P hase 2) of t he st u d y  
t o be disease restricte d t o i ncl u de 2 rat her t ha n 3 e x pa nsi o n c o h orts i n rec urre nt or 
refract or y N S C L C ( n = a p pr o xi matel y 2 5 p atie nts) or H C C ( n = a p pr o xi matel y 
2 5 pati e nts) b y re m o vi n g gli o blast o m a ( n = a p pr o xi matel y 2 5 p atie nts).
3.
Secti o n 5. 2. Deter mi nat i on of Sa m ple Size, re vise d t he st u d y desi g n t o be 3 + 3 + 3 
rat her 3 + 3 t o be c o nsiste nt wit h J B E F 0 5 Pr ot oc ol (c).
4.
Secti o n 5. 3. Met h o d of Assi g n me nt t o Treat me nt, P hase 1 b of t he st u d y was re vise d 
t o clarif y t hat 3 patie nts for C o h orts 1 a n d 2 or 4 patie nts f or C o h orts 3 a n d 4 ma y be 
e ntere d at a partic ular d ose le vel t o be c o nsiste nt with J B E F 0 5 Pr ot oc ol (c).  
5.
Secti o n 6. 7. 2. A nal ysis Met h o ds, t he a nal ysis o f i n di vi d ual c ha n ges i n t u m ou r values 
was re m o ve d f or pati e nts wit h glio blast o m a.  T he e val uat i on of efficac y  e n d p oi nts f or 
I D H, ½ e x pressi on, ser u m T G F β -1 l e vels, a n d t u m o u r P D-L 1 e x pressi o n was 
r e mo ve d.  T he use of  
 f or se nsit i vity e x pl orat or y  a nal ysis was re mo ve d.
C CI


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4.
Study Objectives
4.1.
Primary Objective
Phase 1b
The primary objective of the Phase 1b part of this study is to assess the safety and tolerability of 
orally dosed galunisertib 14 days on/14 days off in combination with IV nivolumab 3 mg/kg 
Q2W by identifying dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) or 
pharmacologically active dose (PAD) of the combination in patients with advanced refractory 
solid tumours during the first 2 cycles.  
Phase 2
The primary objective of the Phase 2 part (expansion cohorts) of this study is to assess the safety 
of the combination of galunisertib and nivolumab in patients with refractory or recurrent non–
small cell lung cancer (NSCLC) or hepatocellular carcinoma (HCC) who have failed 1 prior line 
of therapy.  
4.2.
Secondary Objectives
The secondary objectives of this study are:

to characterize the pharmacokinetics (PK) of galunisertib and nivolumab when 
coadministered

to characterize the immunogenicity of nivolumab when administered in combination with 
galunisertib

to estimate the overall survival (OS) rate following the final analysis/evaluation of OS 
and the landmark OS at 6, 12, and 18 months following the start of therapy with the 
combination of galunisertib and nivolumab 

Phase 2 only:  To assess the preliminary antitumour activity including progression-free 
survival (PFS), overall response rate (ORR), duration of response, and time to response 
of the combination of galunisertib and nivolumab in patients with NSCLC or HCC.
4.3.
Exploratory Objectives
The exploratory objectives of this study are:  

to examine biomarkers, including pharmacodynamic markers, relevant to galunisertib, 
nivolumab, immune cells/immune functioning and the disease state, and to correlate these 
markers to clinical outcome 

Phase 1b only:  To document the preliminary antitumour activity of the combination of 
galunisertib and nivolumab.


H 9 H -M C -J B E F St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 7
L Y 2 1 5 7 2 9 9
5.
St u d y  D e si g n
5. 1.
S u m m ar y of St u d y D e si g n
Pl ease refer t o t he pr ot oc ol  for a f ull descri pt i on of t he st u d y  d esig n. A br ief descri pt i on is 
pr o vi de d bel o w.
T his is a P hase 1 b / P hase 2 st u d y  t hat will be c o n d ucte d i n 2 parts.  T he first part ( P hase 1 b) of 
t he st u d y will c o nsist of a n o pe n-la bel, d ose-escalatio n assess me nt of t he safet y a n d t olera bilit y 
of  g alu niserti b a d mi nister e d at 5 0 m g Q D ( C o h ort 1), 5 0 m g BI D ( C o h ort 2), 8 0 m g BI D 
( C o h ort 3), a n d 1 5 0 m g BI D ( C o h ort 4) a d mi nistere d wit h ni v o l u ma b 3 mg/ k g Q 2 W i n pat ient s 
wi t h a d va nce d refract or y s oli d t u mo urs.  T he sec o n d part ( P hase 2) of t he st u d y  will b e disease 
restricte d t o i ncl u de 2 e x pa nsi o n c o h orts i n rec urre nt or refract or y  N S C L C ( n = a p pr o xi matel y 
2 5 pati e nts) or H C C ( n = a p pr o xi matel y 2 5 pati e nts), all recei vi n g ni v o l u ma b 3 m g/ k g Q 2 W pl us 
g al u niserti b at t he d ose deter mi ne d fr o m t he P hase 1 b part of  t he st u d y.  A d diti onal e x pa nsi o n of 
i n di vi d ual c o h orts ma y occ ur de pe n di n g u p o n acti vity base d u p o n a 2 -sta ge desi g n after 3 c ycles.  
5. 2.
D et er mi n ati o n of S a m pl e Si z e
F or t he P hase 1 b d ose escalat i on, a 3 + 3 + 3 desi g n will  be use d t o assess t he safet y of  gal u niserti b 
i n c o m bi natio n wi t h ni v ol u ma b 3 mg/ k g.  Bet wee n 3 a n d 1 2 a d dit i onal pat ient s ma y be e nr olle d 
i n a c o h ort t o ac hie ve t he mi ni m u m o f 3 e val ua ble patie nts if dr o p o uts or d ose i nterr u pti o ns or 
re d uctio ns occ ur t hat res ult i n a patie nt bei n g n o ne val ua ble f or D L Ts.
Alt h o u g h t he pri mar y o bject i ve re mai ns safety of  t he c om bi nat i on f or t he P hase 2 c o h ort 
e x pa nsi o n part, t he sa m ple size a p pears t o be a de q uate t o e val uate preli mi nar y a nt itu m o ur
acti vit y of  t he c o m bi nati on. 
 
 
  
 
 
  
W he n t he 2 5t h patie nt fr o m eac h c o h ort has c o m p lete d at least 3 c ycles, a n i nteri m a nal ysis will 
be c o n d ucte d.  T w o -sta ge desi g n criteria ( Si m o n 1 9 8 9) will be use d t o e val uate w het her 
a d ditio nal  patie nts f or t hat c o h ort will be e nr olle d.  T he n ull h y p ot hesis t hat t he n ull res p o nse 
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rate is 2 0 % will be teste d a gai nst a 1-si de d alter nati ve.  If t here are 4 or fe wer res p o nses i n t he 
i nitial 2 5 patient s w h o ha ve bee n e nr olle d a n d either disc o nt i n ue d fr o m t heir all ocate d treat me nt 
or c o m plete d at least 3 c y cles, n o a d ditio nal pat ients will be e nr o lle d.  If t here are ≥9 res p o nses, 
t he n n o a d dit i onal patie nts will be e nr olle d i nt o t his c o h ort i n P hase 2.  If t here are 5 t o 
8 res p o nses, t he n a p pr o xi matel y 1 6 a d diti onal pat ie nts ma y be accr ue d f or a t otal of 
a p pr o xi matel y 4 1 pat ient s f or t hat c o h ort.  
 
5. 3.
M et h o d of A s si g n m e nt t o Tr e at m e nt
T his st u d y  is o pe n-label f or P hase 1 b a n d P hase 2.  B efore eac h pati e nt’s e nr ol me nt i nt o t he 
st u d y, a n eli gi bilit y c hec k m ust be c o n d ucte d bet wee n t he i n vesti gati onal site a n d t he Lill y
cli nical researc h pers o n nel t o c o nfir m t hat eac h patie nt meets all e nr o l me nt criteria.  U p o n 
c o nfir mat i on of eli gi bilit y, t he s p o ns or will c o nf ir m t he d ose a n d i de ntificati o n n u m ber
assi g n me nt a n d c o h ort f or eac h patie nt.  N o d ose escalat i ons (t hat is, t o t he ne xt c o h ort) ca n 
occ ur wi t ho ut pri or disc ussi o n  a n d a gree me nt bet wee n t he i n vesti gat or a n d t he res p o nsi ble El i 
Lill y a n d C o m pa n y ( Lill y ) C R P or cli nical researc h scie nt ist ( C R S); t he deci sio n  will be 
d oc u m e nte d i n writin g.  All patie nts m ust be gi n st u d y  treat me nt wit hi n 7 da ys of e nr ol me nt b y 
i nteract i ve we b-res p o nse s yste m (I WR S).
F or P hase 1 b, if i n vesti gat ors ha ve eli gi ble patie nts w h o ha ve c o nse nte d c o nc urre ntl y, m ore t ha n 
3 pati e nts ( C o h orts 1 a n d 2) or 4 patie nts ( C o h orts 3 or 4) ma y be e ntere d at a partic ular d ose 
le vel pr o vi de d t hat accr ual has n ot cease d d ue t o e xcessi ve t o xicity.   T his e nr ol me nt pr oce d ure is 
all o we d beca use of t he a d va nce d disease state of t his pat ient  p o p ulati on a n d t he scree ni n g 
i n v ol ve d i n defi ni n g eli gi bility.  T his e ve nt s h o ul d be a p pr o ve d b y t he s p o ns or f o ll owi n g 
di sc ussi ons wi t h t he i n vesti gat ors.
All patie nts w h o e nter P hase 2 will be assi g ne d t o ni v o l u ma b/ gal u niserti b c o m bi nati on t hera p y  
b y I W R S.
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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Lilly.
The interpretation of the study results will be the responsibility of the investigator with the Lilly 
CRP, pharmacokineticist, and statistician.  The CRP and statistician will also be responsible for 
the appropriate conduct of an internal review for both the final study report and any study-related 
material to be authorized by Lilly for publication.
Additional exploratory analyses of the data not described in this plan will be conducted as 
deemed appropriate.  
By default, listings will include the study part (Phase 1b/2), the dose cohort for Phase 1b and the 
histology cohort for Phase 2. Summaries will generally be split by part and cohort as well.
For continuous measures, summary statistics will include sample size, means, standard
deviations and/or standard error, medians, minimums, and maximums. For categorical measures,
summary statistics will include frequency counts and percentages.  Any missing longitudinal
data will not be imputed; rather statistics will be estimated from an appropriate mixed effects 
model, unless otherwise specified. Transformations will be applied where assumptions behind 
any analysis are better satisfied by data being transformed onto an alternative scale. All results 
from any of these analyses will be back transformed to the original scale. Alternatively, 
nonparametric methods will be applied.
All confidence intervals for clinical parameters that are estimated will have a nominal confidence 
grade of 95%, unless otherwise stated.  
Statistical tests of treatment effects will be performed at a 2-sided significance level of 0.05, 
unless otherwise stated.
The following terms and data handling conventions (Table JBEF.6.1) will be used in the 
analysis.


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Table JBEF.6.1.
Terms and Data Handling Conventions
Term
Definitions or Rule
Study day
If assessment is on or after date of first study drug dose then (date of assessment) –
(date of first study treatment dose) + 1.
If assessment precedes first treatment dose then (date of assessment) – (date of first 
study treatment dose).
There is no study day 0. Study day 1 is the date of first dose and study day -1 is the 
day before the first dose.
Cycle day
If assessment is on or after date of first study drug dose then (date of assessment) –
(date of first study treatment dose in cycle) + 1.
If SOE planned pre-dose assessment precedes first treatment dose date in that cycle 
then (date of assessment) – (date of first study treatment dose in cycle).
There is no cycle day 0. Cycle day 1 is the date of first dose in the cycle and cycle 
day -1 is the day before the first dose.
Baseline
For change from baseline analysis, baseline value is defined as the last reported 
measure on or before the first dose date (or discontinuation, if no treatment is given). 
For change from baseline within a cycle, the measure prior to the first dose of that 
cycle is baseline.
Study treatment period
Time from treatment start to discontinuation from combination treatment or if the 
patient has previously discontinued from 1 of the 2 study drugs, ends on the date the 
decision to discontinue the patient from the remaining study drug.  
Post-discontinuation –
short-term follow-up (or 
safety follow-up)
Safety Follow-Up begins the day after the patient and the investigator agree that the 
patient will no longer continue combination treatment and includes 30-day and 100-
day visits.
o
30-Day Follow-Up begins the day after the patient and the investigator 
agree that the patient will no longer continue study treatment and lasts 
approximately 30 days.  
o
100-Day Follow-Up begins the day after the 30-day follow-up visit and 
lasts approximately 70 days or approximately 100 days after the patient 
is no longer receiving study treatment.  
Post-discontinuation –
long-term follow-up
Long-Term Follow-Up begins the day after 100-day follow-up is completed and 
continues until the patient’s death or end of trial (the patient will be contacted 
approximately every 12 weeks ±7 days). 
6.1.1. Analysis Populations
All safety and efficacy analyses will be conducted on the safety analysis set (ie, patients who
received at 1 dose of either galunisertib or nivolumab). 
All patients who have received at least 1 dose of either galunisertib or nivolumab and have 
evaluable PK samples will be included in the analysis of PK. 
Pharmacodynamics (PD) and/or tailoring biomarker analyses will be based on the subset of 
patients from the above populations from whom a valid assay result (according to laboratory 
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6.1.2. End of Study Definitions
Per protocol, the following definitions apply:

Study Completion corresponds to the final analysis/evaluation of OS. The final 
evaluation may occur before all patients reach the OS endpoint if this earlier evaluation 
will not alter the statistical interpretation of OS. Investigators will continue to follow the 
study schedule for all patients until notified otherwise by Lilly.

The term “end of trial” refers to the date of the last visit or last scheduled procedure for 
the last patient (includes follow-up periods). The end of trial occurs after study 
completion, and after the last patient has discontinued study treatment and completed the 
100-day follow-up (if applicable).
6.2.
Adjustments for Covariates
Additional exploratory analyses may be performed on safety or efficacy measures to adjust for 
factors that may affect outcomes.  
6.3.
Handling of Dropouts or Missing Data
Rules for handling dropouts or missing data are listed by type of analysis. Unless otherwise 
specified, observed data will be used and missing data will not be imputed or carried forward.
General rules for imputing dates related to adverse event (AE) or concomitant therapy
(pre-dose):

Onset date of an AE or start date of a concomitant therapy:
o
If only the day is missing, the date will be set to:

First day of the month that the event occurred, if the onset yyyy-mm is 
after the yyyy-mm of first study treatment.

The day of the first study treatment, if the onset yyyy-mm is the same as 
yyyy-mm of the first study treatment.
o
If both the day and month are missing, the complete date will be set to:

January 1 of the year of onset, if the onset year is after the year of the first 
study treatment.

The date of the first dose, if the onset year is the same as the year of the 
first study treatment.

Resolution date of an AE or end date of a concomitant therapy:
o
If only the day is missing, the date will be set to the last day of the month of the
occurrence, or to the date of death if the patient died in the same month.
o
If both the day and month are missing, the date will be set to 31 December of the
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If a date is completely missing, then the AE will be considered treatment emergent. In case of
additional therapies, the therapy will be considered concomitant.
General rule for imputing other dates: If a date variable is needed for an analysis, use the 
following general rule to impute incomplete date:

If the date has no missing year and month but the day is missing, then assign 1 to the day

If the date has no missing year, but has missing month, then assign January to the month.
However, after imputation, check if the imputed date is logically consistent with other relevant 
date variable(s) and make appropriate correction if necessary. For example, if a visit start date
was 10 May 2015 and a tumour assessment date was xx May 2015 (missing day) but it was 
known that it occurred after that visit, then after imputation, the tumour assessment date became 
01 May 2015. In this case, the imputed tumour assessment date should be compared to the visit 
start date and then corrected to be the visit start date, 10 May 2015.
Safety analysis: The following rule for missing data processing will apply for safety analysis:

Missing classifications concerning study medication relationship will be considered as 
related to study medication (both components).

If the AE onset date is missing or partial, the date will be compared as far as possible 
with the date of first dose of study medication when determining whether or not the AE is 
present at baseline. In this case, the AE will be assumed to be treatment emergent, unless 
there is clear evidence (through comparison of partial dates) to suggest that the AE 
started prior to the first dose of study medication.
Time-to-event analysis: All censored data will be accounted for using appropriate statistical
methods as described in the efficacy section.
6.4.
Patient Disposition
All patient discontinuation data collected on the eCRF will be listed, including the extent of the 
patient participation in the study. If known, a reason for their discontinuation from treatment and 
from study will be listed and summarized. All patients entered in the study will be included in 
the summary and listing.
All significant protocol violations will be listed by pre-determined categories (eg, 
inclusion/exclusion criteria, errors/missing data in the informed consent process, noncompliance 
with protocol procedures, patients continuing after meeting withdrawal criteria, or other 
violations as recorded on eCRFs or monitoring reports).
6.5.
Patient Characteristics
Patient characteristics will include a summary and/or listing by cohort in Phase 1b and histology 
cohort in Phase 2 of the following:

Patient demographics including (for example) age, sex, ethnicity/race, weight and change 
in weight from baseline, and screening height will be reported.


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
baseline disease characteristics and in Phase 2, including histology 

prior disease-related therapies

concomitant medications
6.5.1. Demographics
Patient demographics including age, sex, ethnicity, race, height at baseline, weight at baseline, 
body mass index (BMI) at baseline will be summarized for all treated patients using descriptive 
statistics and listed in a data listing.
6.5.2. Baseline Disease Characteristics
Eastern Cooperative Oncology Group (ECOG) performance status, initial pathological diagnosis, 
basis for initial diagnosis and disease stage will be summarized for all treated patients using 
descriptive statistics and listed in a data listing. 
6.5.3. Pre-existing Conditions and Medical History
Medical history (MH) conditions are historical illnesses, pre-existing conditions and relevant 
surgeries or other procedures that started prior to signing the informed consent document.  All 
MH conditions will be coded using the MedDRA dictionary and by using the Common 
Terminology Criteria for Adverse Events (CTCAE).
A historical condition is a MH condition that has ended prior to the date of informed consent.  
A preexisting condition is a MH condition that is either ongoing or has ended on or after the
date of informed consent.
Historical and preexisting conditions will be summarized and listed for all treated patients.  
Summaries will be presented by System Organ Class (SOC) and by decreasing frequency of
MedDRA Preferred Term (PT) within SOC.
The MH verbatim and MedDRA PT will be listed along with start and end dates.  Additionally, 
CTCAE severity grade will be listed for preexisting conditions.
6.5.4. Prior Therapies
Prior therapies, including systemic therapy, radiotherapies, and surgeries will be listed for all 
treated patients.  
The number of patients with prior therapies will be reported by category of prior therapy, as well 
as by reasons for regimen.  Additionally, the number of prior regimens for prior systemic therapy 
will be reported.
6.6.
Concomitant Therapy
All medications entered on the CRF will be coded according to the current WHO drug 
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C o nc o mita nt me dicat i ons will be liste d a n d s u m marize d f or all treate d patie nts. T he W H O 
classificat i on , start a n d e n d dates, a n d i n dicati on f or w hic h t he me d icati on was ta ke n will be 
i ncl u de d i n t he listi n g.
Palliat i ve ra di ot hera p y treat me nt d uri n g tr e at me nt will als o be s u m marize d. 
P os t disc o nti n uati on t hera p y  will be liste d a n d s u m marize d.
6. 7.
Effi c a c y A n al y s e s
F or t he P hase 1 b p orti o n of  t he trial, o ne o f t he e x pl orat or y o bject i ves is t o d oc u me nt t he 
preli mi nar y a nt itu m o ur acti vit y of  t he c o m bi nati on of  gal u niserti b a n d ni v ol u ma b.
F or t he P hase 2 p orti o n of t he trial, o ne of t he sec o n dar y o bjecti ves is t o e val uate preli mi nar y 
a nt itu m o ur acti vit y of  t he c o m bi nati on i ncl u di n g P F S, O R R, d urati o n of res p o nse, a n d ti me t o 
res p o nse of t he c o m bi nati on of gal u nisert i b a n d ni v ol uma b i n pat ient s wit h N S C L C or H C C .
6. 7. 1.
E n d p oi nt D efi niti o n s
T he f o ll owi n g efficac y e n d p o i nts will be deter mi ne d:
O ver all re s p o nse r ate ( O R R) is t he pr o p orti o n of patie nts w h o ac hie ve d a c o m plete res p o nse 
( C R) or partial res p o nse ( P R) as t heir best o verall res p o nse o ut of all patient s treate d set. 
T u m o u r res p o nses will be assesse d usi n g t he 
 g ui deli nes f or patie nts w ith N S C L C, 
H C C, a n d t u mo urs ot her t ha n gli o blast o m a.
T u m or res p o nses will be assesse d usi n g t he 
g ui deli nes f or patie nts wit h glio bl ast o m a. 
Best res p o nse is deter mi ne d fr o m a se q ue nce of res p o nses assesse d f or eac h pat ient per t he 
res pecti ve g ui deli nes. 
Dise ase C o ntr ol R ate ( D C R) is defi ne d as t he pr o p orti o n of treate d patie nts ac hie vi n g a best
o verall res p o nse of c o m p lete res p o nse ( C R), partial res p o nse ( P R), or sta ble disease ( S D) as t heir 
best o verall res p o nse o ut of al l patient s treate d set.
C h a n ge i n t u m o u r size ( C T S) will be assesse d i n eac h patie nt usi n g ra di o gra p hic i ma gi n g. T his 
e n d p o i nt will be base d o n t u m ou r meas ure me nts c ollecte d b y t he ce nters acc or di n g t o t he 
a p plica ble g ui deli nes. 

F or pati e nts wit h N S C L C, H C C, a n d t u m o u rs ot her t ha n gli o blast o m a, tu m o u r siz e is 
defi ne d as t he s u m of t he lar gest dia meter f or eac h tar get lesi ons at eac h t u m o u r 
e val uat i on f or 

F or pati e nts wit h glio blast o ma, t u mor si ze is defi ne d as t he s u m of t he lar gest dia meter 
f or eac h meas ura ble lesio n at eac h t u mor e val uat i on f or 
. C ha n ge i n t u m o u r siz e is 
defi ne d as t he perce nt c ha n ge i n t u m o u r size fr o m t he baseli ne e val uati on t o t he 
e val uat i on at t he eac h t u mo ur e val uat i on , o nl y incl u di n g t he t u mors prese nt at baseli ne .
T he c ha n ge i n t u m o u r size c orres p o n di n g t o t he best res p o nse f or eac h patie nt will be 
re prese nte d i n waterfall pl ots.
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Time to Response is defined only for responders.  It is measured from the date of first study 
treatment to the first documented response. 
Duration of Response will be calculated for ORR and is defined only for responders.  It is 
measured from the date of documented response to the date of first progression of disease or the 
date of death due to any cause, whichever is earlier. For each patient who is not known to have 
died or to have had a progression of disease at the cut-off date, duration of response will be 
censored at the date of last objective response assessment prior to the date of any subsequent 
systemic anticancer therapy.
Progression-free survival (PFS) is defined as the time from the date of first study treatment to 
the first date of documented progression or death due to any cause, whichever occurs first. For 
patients who are not known to have died or progressed as of the cut-off date, PFS time will be 
censored at the date of the last progression-free disease assessment prior to the date of any 
subsequent anticancer therapy.
Overall Survival (OS) is defined as the time from the date of first study treatment to the date of 
death from any cause.  For each patient who is not known to have died as of the cut-off date, OS 
will be censored for that analysis at the date of last contact prior to the data inclusion cutoff date 
(contacts considered in the determination of last contact date include AE date, lesion assessment 
date, visit date, and last known alive date).
The detailed algorithm for the censoring rules will be described in the analysis dataset 
requirements (Adam requirements).  
6.7.2. Analysis Methods
Individual best overall response, time to and duration of response, PFS, and OS will be listed and 
summarised by dose for the Phase 1b and by disease cohort for the Phase 2. Additional analyses 
may be performed as deemed appropriate depending on the final number of patients treated in 
each dose cohort.
For the Phase 2 portion of the study, the following analyses will be performed:

Rates including ORR and DCR will be computed for each cohort and the estimates will 
be reported with exact 95% confidence intervals.

Time to events variables including PFS, DOR, and OS will be analysed using the Kaplan-
Meier method (Kaplan and Meier 1958). Survival curves will be used to summarize the 
data and medians will be reported with the 95% confidence intervals for each cohort. In 
addition, for each time to event variable, survival rates at adequate time points may be 
reported (eg. 6, 12, 18 months).  

Time-to-response will be summarised using descriptive statistics by cohort.

Individual changes in the tumour size over time will be presented graphically by tumour 
type using spider plots. The change in tumour size corresponding to the best response


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base d o n tar get lesi o ns (f or  
 f or eac h patie nt will be re prese nte d i n waterfall 
pl ots b y  c o h ort.

E C O G perf or ma nce stat us o ver ti me will be p rese nte d gra p hicall y t o e x pl ore c ha n ges 
o ver ti me. 
T o u n dersta n d t he i m pact of baseli ne bi o mar kers o n efficac y, t he f o ll owi n g a nal yses ma y  b e 
c o nsi dere d:

F or t he N S C L C c o h ort, efficac y e n d p o i nts ma y be e val uate d b y a dj ust i n g f or baseli ne 
P D -L 1 e x pressi o n a n d ser u m T G F β -1 l e vels.  

F or t he H C C c o h ort, efficac y e n d p o i nts ma y be e valuate d b y  a djusti n g f or ser u m  AF P 
a n d T G F β -1 l e vels a n d t u mo ur P D -L 1 e x pressi o n.
I n a d diti on, se nsiti vity e x plor at or y  a nal yses ma y be c o n d ucte d usi n g arrests.
6. 8.
Bi o a n al yti c al a n d P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c s M et h o d s 
6. 8. 1.
P h ar m a c o ki n eti c s
Lill y P K will perf or m t he P K a nal yses per t he se parate P K/ P D a nal ysis pla n, e xce pt as i n dicate d 
bel o w.
P har mac o ki net ics a nal yses will be c o n d ucte d o n patie nts w h o ha ve recei ve d at least 1 d ose of t he 
st u d y dr ug a n d ha ve ha d sa m ples c o llecte d. F o r gal u niserti b, p o p ulati on a p pare nt cleara nce, 
v o l ume of distri b ut i on, a n d e x p os ure are stea d y  state f or gal u niserti b will be calc ulate d. F or 
ni v o l u ma b, Cmi n c o nce ntrati o ns will be re p orte d. If data warra nts , d ose pr o porti o nali t y of 
g al u niserti b w he n c oa d mi nistere d wit h ni v o l uma b d uri n g P hase 1 b ma y  be assesse d base d o n a 
p o wer m o del. Ni v o l uma b C mi n c o nce ntrati o n i n P hase 1 b will be ta b ulate d b y s u m mar y 
statistics. 
Pr o vi di n g t hat t he data all o w (ie , P K para meters are a vaila ble f or m ore t ha n 2 d ose l e vels), t he 
P K para meter esti mates f or g al u niserti b ma y  be e v aluate d statisticall y . T he de gree of d ose 
pr o p orti o nali t y will be assesse d b y fitti n g t he p o wer m o del t o t he l o g tra nsf or me d P K 
para m eters. Differe nt f o l d-ra n ges of  d oses will be c h ose n t o pr o vi de esti mates of rati os of d ose-
n or m alize d ge o metric mea ns, de pe n di n g o n t he act ual ra n ge of d oses teste d i n t he st u d y  ( S mit h 
et al. 2 0 0 0).
I n t he e ve nt t hat t he p o wer m o del is n ot a g o o d re prese ntati o n of t he data o ver t he e ntire d ose 
ra n ge teste d, alter nati ve m o dels ma y  be i n vest i gate d.
6. 8. 2.
P h ar m a c o d y n a mi c s a n d T ail ori n g A n al y s e s
Bi o m ar ker data fr o m all patient s u n der g oi n g bi omar ker assess me nts will be a nal yze d usi n g 
descri pt i ve statistics.  Bi o m ar kers will be e x pl ore d at baseli ne f or pr o g n ostic val ue i n efficac y  or 
safety o ut c o m es. 
F urt her e x pl orat or y  a nal yses of p har mac o d y na mic mar kers will be c o n d ucte d as warra nte d.
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6.8.3. Immunogenicity
A listing will be provided of all available immunogenicity data. Additionally, a listing of 
immunogenicity data from those patients with at least 1 positive ADA at any time point will be
provided. The frequency of patients with at least 1 positive ADA assessment, and frequency of
patients who develop ADA after a negative baseline assessment will be provided. To examine
the potential relationship between immunogenicity and safety, the frequency and type of AEs of 
special interest may be examined by overall immunogenicity status by cohort in Phase 1b and by
indication in Phase 2.
6.9.
Safety Analyses
All safety summaries and analyses will be based upon the safety population that includes patients 
that have received at least 1 dose of study drug. 
6.9.1. Extent of Exposure
All study drug information and dose level assignment will be listed for all patients on therapy. 
The total number of cycles received and duration of treatment for each patient will be 
summarised by cohort (for example, using a napoleon plot).
The following exposure-related variables will be summarised by cohort (using dose for the Phase 
1b portion and histology for the Phase 2) for each of the study drugs:

Duration of treatment

Number of cycles received

Number of patients with dose adjustments

Reasons for dose adjustments

Dose intensity as a percentage of dose received relative to the planned dose 

Dose compliance as a percentage of dose received relative to the prescribed dose (this 
takes into account dose adjustments)
The detailed algorithms for the exposure variables will be described in the analysis dataset 
requirements (ADaM requirements).
6.9.2. Adverse Events
All patients who receive at least 1 dose of either galunisertib or nivolumab will be evaluated for 
safety and toxicity. The CTCAE terms (by entering the appropriate CTCAE code) and severity 
grades will be assigned by the investigator using CTCAE). Verbatim adverse event terms will be 
mapped to corresponding MedDRA lower-level term (LLT) terminology within the MedDRA 
dictionary.
Both the CTCAE terms and MedDRA LLT will be mapped using the MedDRA dictionary 
hierarchy to provide PTs and body SOC terms for each dictionary. For CTCAE terms where 
“Other” is indicated, the CTCAE PTs will be the same as the PTs of the MedDRA PTs created 
from mapping through the verbatims. All safety summaries will report the PTs created from 
mapping the investigator assigned CTCAE term.


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Treatment-emergent AEs will be identified using the CTCAE terms by comparing which events 
are present at baseline and post baseline and severity grades pre-dose and post-dose for pre-
existing conditions. Where CTCAE term is “Other,” the matching MedDRA LLT will be used 
to determine treatment emergent. Details algorithm to identify TEAEs will be described in the 
analysis dataset requirements (ADaM requirements).
A listing of all AEs by patient will be presented. This listing will include patient number, AE, 
event start and end dates, CTCAE grade, relationship to study drug/procedure, seriousness, and 
outcome. A listing of serious adverse events (SAEs) will be produced using the similar format.
An overall summary will be provided for AEs. The number and percent of evaluable patients 
will be summarized for each category below. The summary will provide counts for all AEs, and 
AEs possibly related to study treatment.

Patients with at least 1 TEAE

Patients with at least 1 grade 3 or 4 TEAE

Patients with at least 1 SAE

Patients who discontinued due to AE

Patients who discontinued due to SAE

Patients who died due to AE on study treatment

Patients who died due to AE within 30 days of discontinuation from study treatment
The treatment-emergent adverse events (TEAEs) will be summarized by decreasing frequency of 
SOC by PT and by maximum CTCAE grade regardless of causality and related to any study drug
separately. The incidence of TEAE will also be summarized by dose cohort (Phase 1b) and by 
histology cohort (Phase 2). Additional analyses of TEAEs may be performed as deemed 
appropriate. 
6.9.2.1.
Dose Limiting Toxicities
A dose-limiting toxicity (DLT) is defined as an AE during Cycles 1 or 2 (8 weeks) that is 
possibly related to either study drug and fulfils the predefined criteria described in Section 
7.2.2.1 of the protocol.
All DLTs, as defined in the protocol, will be listed and summarized by dose level for all patients
on therapy in the Phase 1b portion of the study. Similarly, DLT-equivalent AEs occurring 
during Cycles 1 and 2 in the Phase 2 portion of the study will be listed and summarized.
6.9.3. Deaths, Serious Adverse events and Other Notable Events
All deaths in this study, including the reasons for death, will be listed by dose cohort (Phase 1b) 
and by histology cohort (Phase 2). The reasons for death will be also summarized separately for 
on-therapy, within 30 days of last dose of study drug, and during the long term follow-up 
periods. 
Serious adverse events will be summarized by PT and repeated for events deemed by the
investigator to be possibly related to study medication, with consolidated summary performed if


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needed. The SAEs will be summarized both up to 30 and 100 days after end of therapy. A 
listing of SAEs will be produced.
In addition, additional analyses may be performed for TEAEs of special interest.
6.9.4. Clinical Laboratory Evaluation
All laboratory results will be reviewed using Spotfire to assess changes over time and differences 
across cohorts. Key findings will be illustrated graphically using line plots over time or box 
plots for example.
Abnormal laboratory results will be listed for all patients on therapy. 
Calculated CTCAE grade using CTCAE v4.0 (or higher) will be summarised for laboratory 
parameters where CTCAE grades are available by dose cohort (phase 1b) and by histology 
cohort (Phase 2). 
6.9.5. Vital Signs and Other Physical Findings
All vital signs will be reviewed using Spotfire to assess changes over time and differences across 
cohorts. Key findings will be illustrated graphically using line plots over time or box plots for 
example.
Any significant physical examination findings and results of clinical laboratory tests will be 
listed.
6.9.6. Electrocardiograms and Cardiac Assessment Data
Electrocardiogram (ECG) and echocardiogram (ECHO) results will be evaluated by the
investigator and abnormalities, if present, will be listed.
Changes from baseline in ECG and ECHO parameters will be calculated and summarised at each 
visit. The ECG and ECHO parameters will be compared over time to assess change from 
baseline, during treatment, and during follow-up.
Myocardial information and quantitative results including PR, QRS, QTcB (Bazett’s correction), 
QTcF (Fridericia’s correction) and RR intervals will provided in patient listings for absolute and 
change from baseline. In addition, summaries of outlying corrected QT intervals (QTc, QTcB 
and QTcF) will be provided by treatment. Outlying intervals include absolute values >450, 
>480, and >500 msec and change from baseline >30 and >60 msec.
Cardiotoxicity serum markers (BNP, troponin I, high-sensitivity, C-reactive protein, cystatin C)
will be reviewed using Spotfire to assess changes over time and differences across cohorts. All 
parameters will be tabulated and summarized using tables and graphs. 
In addition, the results from MRI/CT scans performed for detection of aneurysm formation of the 
ascending aorta and aortic arch will be summarised.
Further exploratory analyses may be conducted as warranted.


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6.10. Subgroup Analyses
Exploratory subgroup analyses not described in this SAP will be performed as deemed 
appropriate to further our understanding of the clinical trial data.
6.11. Protocol Violations
Protocol violations will be identified based on information recorded on the investigator log. In 
addition, a list of data dependent protocol violations will be programmatically derived to ensure 
systematic check of key significant protocol violations in the following categories:

Inclusion/exclusion criteria not met 

Study drug administration non-compliance

Informed consent violations

Protocol violation leading to study discontinuation
Details of significant protocol violations to be checked programmatically will be detailed in the 
programming requirements. 
6.12. Interim Analyses
Since the Phase 1b part is a dose-finding study, data will be reviewed on a cohort-by-cohort basis 
during the study, until the MTD (or PAD) is determined. The purpose of these cohort-by-cohort
reviews is to evaluate the safety data at each dose level and determine whether a DLT has been
observed that would suggest MTD has been met or exceeded. The investigators and the Lilly
study team will make the determination regarding dose escalation based upon their review of the
safety and tolerability data as described in this protocol.
After all patients who are deemed evaluable for the assessment of dose levels complete a DLT 
evaluation period or when MTD is determined, an interim safety and PK analysis may be
conducted for planning next studies.
For the Phase 2 part, if DLT-equivalent toxicities occur in 33% or more of patients within a 
tumour-specific cohort expansion, then investigators and the Lilly CRP will assess the nature and
severity of these toxicities. No additional patients will be enrolled until this safety review is
completed and a decision is made either to continue at the current dose or to deescalate the dose
and define a new dose for the expansion phase. The safety review and decision will be
documented in writing. Trial-level safety reviews will be conducted approximately 3 months
after the first patient begins study drug on Cycle 1 Day 1, approximately 6 months after the first
patient begins study drug on Cycle 1 Day 1, and approximately every 6 months thereafter. These
evaluations will not be assessed by any formal statistical test; only listings and summaries will be
carried out.
After enrolment has completed in a cohort (n = approximately 25) and the last enrolled patient in
that cohort has completed or had the opportunity to complete 3 cycles of treatment, an interim
analysis will be conducted for that particular cohort (for a total of 3 separate interim analyses to
be conducted when each cohort reaches 25 patients complete at least 3 cycles of treatment). The
intent of the interim analysis is to evaluate preliminary antitumour activity of galunisertib in


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combination of nivolumab. These interims may be combined with the ongoing trial-level safety
review. Pending review of the interim data, approximately 16 additional patients may be
enrolled in that particular cohort if there are more than 4 and fewer than 9 patients who
demonstrate responses (determined by ORR for the NSCLC cohort and by ORR or survival for
the HCC cohort). Enrolment of the other cohort(s), if not completely enrolled, will not be 
stopped during the interim analysis. No independent data monitoring committee will be required 
for this study. The interim analysis will be conducted by an assessment committee consisting of 
at least 1 physician and 1 statistician.
6.13. Annual Report Analyses
The following reports are needed for the DSUR: 
1. Estimated cumulative subject exposure
2. Cumulative exposure to investigational drug, by demographic characteristics for ongoing 
unblinded clinical trials and completed clinical trials
3. Exposure information for ongoing clinical trials and clinical trials that completed during 
the reporting period
4. Listing of subjects who died during the DSUR period
5. Discontinuations due to AE during the DSUR Period. 
For guidance on creation of these reports, see the DSUR collaboration site 
(http://lillynetcollaboration.global.lilly.com/sites/GMRS_GPS/Surv/dsur/default.aspx?PageView
=Shared).
6.14. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements. 
Analyses provided for the CTR requirements include the following:
Summary of AEs, provided as a dataset which will be converted to an XML file. Both SAEs 
and ‘Other’ AEs are summarized: by treatment group, by MedDRA PT.

An AE is considered ‘Serious’ whether or not it is a TEAE.

An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each Serious AE and ‘Other’ AE, for each term and treatment group, the following are 
provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).


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
AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 
Analyses provided for the EudraCT requirements include the following:

Summary of AEs, provided as a dataset which will be converted to an XML file, in 
accordance with EudraCT requirements.

Categorical breakdown of age across the entire study, represented planned and actual 
number of patients for the following age groups: adults (18-64 years, 65-84 years, and 
85 years and over). 
For the purpose of CTR/ EudraCT reporting, patients who have died, or are still in the study but 
off treatment, at primary DBL will be considered a completer. Those that withdrew consent for 
all procedures, including follow-up, or were lost to follow up, will be considered as early 
discontinuers. Patients who remain on treatment will be counted as continuing treatment.


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7.
References
Kaplan EL, Meier P. Nonparametric Estimation from Incomplete Observations. J Am Stat Assoc.
1958;53(282):457-481.
Simon R. Optional two-stage designs for phase II clinical trials. Control Clin Trials. 
1989;10(1):1-10.
Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue ST. 
Confidence Interval Criteria for Assessment of Dose Proportionality. Pharm Res. 
2000;17(10):1278-1283.


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