Clinical trial NCT02529553
Conditions: Advanced Cancer Metastatic Cancer
Keywords: bladder cancer
Sponsor: Eli Lilly and Company
Start date: 2015-09-01; Completion date: 2018-03-28
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to evaluate the safety of the study drug known as LY3076226 in participants with advanced or metastatic cancer.

Detailed description:

Arms: arm 1: Part A (dose escalation in advanced cancer): LY3076226 administered intravenously (IV) on day 1 of each 21 day cycle.

Part B (dose expansion in advanced urothelial carcinoma): LY3076226 administered IV on day 1 of each 21 day cycle.
Interventions: intervention 1: LY3076226
Intervention descriptions: intervention 1: Administered IV

Protocol documents:
Prot_000.pdf: 
Protocol  I7O-MC-JOBA(a) 
 
A Phase 1 Study of LY3076226, a Fibroblast Growth Factor Receptor 3 (FGFR3) Antibody-
Drug Conjugate, in Patients with Advanced or Metastatic Cancer 
 
NCT02529553 
 
Approval Date: 06-Aug-2015 


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1.
Protocol I7O-MC-JOBA(a)
A Phase 1 Study of LY3076226, a Fibroblast Growth 
Factor Receptor 3 (FGFR3) Antibody-Drug Conjugate,
in Patients with Advanced or Metastatic Cancer
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY3076226, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.  This document and its associated attachments are 
subject to United States Freedom of Information Act (FOIA) Exemption 4.
LY3076226
This Phase 1 study is a multicenter, nonrandomized, open-label, dose-escalation study of 
intravenous LY3076226 in patients with advanced or metastatic cancer.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly:  14 May 2015
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 06-Aug-2015 GMT


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2.
Synopsis
This Phase 1 study is a multicenter, outpatient, nonrandomized, open-label, dose-escalation study 
of intravenous (IV) LY3076226 in patients with advanced or metastatic cancer.


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3.
Table of Contents
A Phase 1 Study of LY3076226, a Fibroblast Growth Factor 
Receptor 3 (FGFR3) Antibody-Drug Conjugate,
in Patients with Advanced or Metastatic Cancer
Section
Page
1.
Protocol I7O-MC-JOBA(a)  A Phase 1 Study of LY3076226, a 
Fibroblast Growth Factor Receptor 3 (FGFR3) Antibody-Drug 
Conjugate, in Patients with Advanced or Metastatic Cancer ................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................3
4.
Abbreviations and Definitions.............................................................................................9
5.
Introduction ......................................................................................................................15
5.1.
Rationale and Justification for the Study ......................................................................15
5.2.
Objectives ....................................................................................................................17
5.2.1.
Primary Objective ................................................................................................17
5.2.2.
Secondary Objectives...........................................................................................17
5.2.3.
Exploratory Objectives.........................................................................................17
5.3.
General Introduction to LY3076226.............................................................................17
5.3.1.
Mechanism of Action and In Vitro/In Vivo Activity.............................................17
5.3.2.
Nonclinical Pharmacokinetics/Pharmacodynamics...............................................19
5.3.3.
Nonclinical Toxicology........................................................................................20
5.3.4.
Biomarkers...........................................................................................................23
5.4.
Rationale for Selection of Dose....................................................................................24
6.
Investigational Plan...........................................................................................................26
6.1.
Study Population..........................................................................................................26
6.1.1.
Inclusion Criteria .................................................................................................26
6.1.2.
Exclusion Criteria ................................................................................................28
6.2.
Summary of Study Design............................................................................................29
6.2.1.
Study Completion and End of Trial......................................................................31
6.2.2.
Continued Access Period......................................................................................31
6.3.
Discontinuations ..........................................................................................................31
6.3.1.
Discontinuation of Patients...................................................................................32
6.3.2.
Discontinuation of Study Sites .............................................................................33
6.3.3.
Discontinuation of the Study................................................................................33
7.
Treatment..........................................................................................................................34
7.1.
Materials and Supplies .................................................................................................34


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7.2.
Study Drug Administration ..........................................................................................34
7.2.1.
Dosing Schedule ..................................................................................................34
7.2.2.
Dose Escalation....................................................................................................35
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum 
Tolerated Dose Definition...............................................................................35
7.2.2.2.
DLT-Equivalent Toxicity................................................................................35
7.2.2.3.
Dose-Escalation Method.................................................................................36
7.2.3.
Dose Confirmation in Patients with Known Alterations of 
FGFR3 (Parts B and C)........................................................................................37
7.2.4.
Recommended Phase 2 Dose (RP2D)...................................................................37
7.2.5.
Infusion-Related Reactions ..................................................................................38
7.2.6.
Dose Adjustments and Delays..............................................................................39
7.2.6.1.
General Dose Adjustments and Delays ...........................................................39
7.3.
Method of Assignment to Treatment ............................................................................41
7.4.
Blinding .......................................................................................................................41
7.5.
Concomitant Therapy...................................................................................................41
7.6.
Treatment Compliance .................................................................................................43
7.6.1.
Evaluable Patients................................................................................................43
8.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data 
Collection .........................................................................................................................44
8.1.
Safety Evaluations........................................................................................................44
8.1.1.
Safety Data Collection and Review ......................................................................44
8.1.2.
Adverse Events ....................................................................................................45
8.1.2.1.
Serious Adverse Events ..................................................................................46
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting .....................................47
8.1.2.2.1.
Prior to Administration of Study Drug ......................................................47
8.1.2.2.2.
On-Study Treatment .................................................................................47
8.1.2.2.3.
Follow-Up Visit........................................................................................47
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions..........................................48
8.1.2.4.
Summary of AE/SAE Reporting Guidelines ...................................................49
8.1.3.
Other Safety Measures .........................................................................................50
8.1.3.1.
Electrocardiograms.........................................................................................50
8.1.4.
Safety Monitoring ................................................................................................51
8.1.5.
Complaint Handling.............................................................................................51
8.2.
Sample Collection and Testing.....................................................................................52
8.2.1.
Samples for Pharmacokinetics..............................................................................54
8.2.2.
Samples for Pharmacodynamics...........................................................................54
8.2.3.
Samples for Exploratory Biomarkers....................................................................55
8.2.4.
Samples for Pharmacogenetic Research ...............................................................55


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8.2.5.
Samples for Immunogenicity Research.................................................................56
8.3.
Efficacy Evaluations ....................................................................................................56
8.4.
Procedure/Sampling Compliance..................................................................................57
9.
Data Management Methods...............................................................................................58
9.1.
Data Quality Assurance................................................................................................58
9.2.
Data Capture Systems ..................................................................................................58
9.2.1.
Case Report Form ................................................................................................58
9.2.2.
Ancillary Data......................................................................................................59
10.
Data Analyses...................................................................................................................60
10.1. General Considerations ................................................................................................60
10.2. Patient Disposition .......................................................................................................60
10.3. Patient Characteristics ..................................................................................................61
10.4. Safety Analyses............................................................................................................61
10.5. Pharmacokinetic Analyses............................................................................................61
10.6. Pharmacodynamic Analyses.........................................................................................62
10.7. Immunogenicity Analyses ............................................................................................62
10.8. Efficacy........................................................................................................................62
10.9. Tailoring Biomarker.....................................................................................................62
10.10. Interim Analyses ..........................................................................................................63
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................64
11.1. Informed Consent.........................................................................................................64
11.2. Ethical Review.............................................................................................................64
11.3. Regulatory Considerations ...........................................................................................65
11.3.1.
Investigator Information.......................................................................................65
11.3.2.
Protocol Signatures ..............................................................................................65
11.3.3.
Final Report Signature .........................................................................................65
12.
References ........................................................................................................................66


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List of Tables
Table
Page
Table JOBA.1.
Exposure Multiples for Intravenous Administration of LY3076226 
Based on Administered Dose and Predicted Exposure in Humans..................23
Table JOBA.2.
Mean Predicted Plasma Exposure Levels at the Example LY3076226 
Dose Levels for Study I7O-MC-JOBA ..........................................................25
Table JOBA.3.
Example of LY3076226 Dose Levels for Part A ............................................37
Table JOBA.4.
LY3076226 Dosing Guidelines for Managing Adverse Events of 
Concern for Study I7O-MC-JOBA ................................................................40
Table JOBA.5.
Adverse Event and Serious Adverse Event Reporting Guidelines for 
Study I7O-MC-JOBA....................................................................................49


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List of Figures
Figure
Page
Figure JOBA.1. Illustration of I7O-MC-JOBA study design....................................................30


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List of Attachments
List of Protocol Attachments
Attachment
Page
Attachment 1.
Protocol JOBA Study Schedule .....................................................................71
Attachment 2.
Protocol JOBA Clinical Laboratory Tests ......................................................81
Attachment 3.
Protocol JOBA Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ..................................................................................................82
Attachment 4.
Protocol JOBA Pharmacokinetic, Pharmacodynamic, and 
Immunogenicity Sampling Schedule..............................................................83
Attachment 5.
Protocol JOBA Multiple Myeloma Tumor Assessment..................................86
Attachment 6.
Protocol JOBA Recommendations for Reporting 
Serious Adverse Events .................................................................................90
Attachment 7.
Protocol JOBA ECOG Performance Status....................................................91
Attachment 8.
Protocol JOBA Creatinine Clearance Formula ...............................................92
Attachment 9.
Protocol JOBA RECIST Criteria 1.1..............................................................93
Attachment 10.
Protocol JOBA Toxicity-Band Method for Phase 1 Dose Escalation............100
Attachment 11.
Protocol JOBA Alterations for FGFR3 ........................................................108
Attachment 12.
Protocol Amendment I7O-MC-JOBA(a) Summary
A Phase 1 Study of LY3076226, a Fibroblast Growth Factor Receptor 3 
(FGFR3) Antibody-Drug Conjugate,
in Patients with Advanced or Metastatic Cancer...........................................109


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4.
Abbreviations and Definitions
Note:  Terms used only once are not included in this table.
Term
Definition
ADA
anti-drug antibody(ies)
ADC
antibody-drug conjugate
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 unfavorable 
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.
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
audit
A systematic and independent examination of the study-related activities and documents 
to determine whether the evaluated study-related activities were conducted, and the data 
were recorded, analyzed, and accurately reported according to the protocol, applicable 
standard operating procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s).
C1D1
Cycle 1, Day 1
Cmax
maximum (observed) plasma concentration
Cmax,ss
maximum (observed) plasma concentration at steady state
CI
confidence interval
CL/F (or CL)
(apparent) systemic clearance
CNS
central nervous system
collection database
A computer database where clinical trial data are entered and validated.
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.


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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 either will 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.
continued access 
period
The period between study completion and end of trial during which patients on study 
treatment who continue to experience clinical benefit and no undue risks may continue to 
receive study treatment until one of the criteria for discontinuation is met.
CR
complete response
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.
CRM
continual reassessment method
CRP
clinical research physician
CRS
clinical research scientist
CSF
colony-stimulating factor
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCSI
Development Core Safety Information
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DM4
A maytansine derivative that is the cytotoxic payload (drug) of LY3076226.
DM4-Me
S-methyl-DM4
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ELISA
enzyme-linked immunosorbent assay
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.
enroll
Patients who are enrolled in the trial are those who have been assigned to a treatment and 
have received at least one dose of study treatment.
enter
Patients who are entered in the trial are those who have signed the informed consent form 
(ICF) directly or through their legally acceptable representatives.


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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.
FDA
Food and Drug Administration
FGFR
fibroblast growth factor receptor
FGFR3
fibroblast growth factor receptor 3
GCP
good clinical practice
G-CSF
granulocyte colony-stimulating factor
GI
gastrointestinal
GLS
(Lilly) generic laboratory system
HER2
human epidermal growth factor receptor 2
HNSTD
highest non-severely toxic dose
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation (International Conference on Harmonisation 
of Technical Requirements for Registration of Pharmaceuticals for Human Use)
Ig
immunoglobulin
IgG
immunoglobulin G
IgG1
immunoglobulin G, subclass 1
IHC
immunohistochemistry
IMC-D11
ImClone code name for an IgG1 monoclonal antibody against FGFR3 that is the antibody 
portion of LY3076226.
IMWG
International Myeloma Working Group
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 (ICF).
interim analysis
An analysis of clinical study data that is conducted before the final reporting database is 
authorized for data lock.
investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial.


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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.
IRR
infusion-related reaction
IV
intravenous(ly); also New York Heart Association classification
LC-MS
liquid chromatography-mass spectrometry
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous events 
occurring while using a drug/drug delivery system.
LY3076226
fibroblast growth factor receptor 3 (FGFR3) antibody-drug conjugate (ADC)
MED
minimally efficacious dose
menopausal women
Women with:
1)
spontaneous amenorrhea for at least 12 months, not induced by a medical 
condition such as anorexia nervosa and not taking medications during the 
amenorrhea that induced the amenorrhea (for example, oral contraceptives, 
hormones, gonadotropin releasing hormone, antiestrogens, selective estrogen 
receptor modulators [SERMs], or chemotherapy)
or
2)
spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone 
(FSH) level greater than 40 mIU/mL.
This language is relevant to the inclusion criteria.
MinTD
minimally toxic dose
monitor
A person responsible for ensuring the investigator site complies with the monitoring plan, 
applicable local 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 subjects, relevant SOPs, International Conference on 
Harmonisation Good Clinical Practice guideline (ICH GCP), and all applicable laws (for 
example, privacy and data protection) and regulations.
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MTD
maximum tolerated dose
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer


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open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participants are aware of the drug therapy received during 
the study.
ORR
overall response rate
patient
A subject with a defined disease.
PD
pharmacodynamic(s) (also progressive disease [in Attachments only])
PDX
patient-derived xenograft
PET
positron emission tomography
PK
pharmacokinetic(s)
PR
partial response; also an ECG interval
(Note:  “PR” is the abbreviation for pulse rate only in Attachment 1.)
prescreen
The act of determining if a patient meets the requirements for FGFR3 alteration status for 
Parts B and C in this study.
qd×1
single administration
q14d×2
2 administrations separated by a 14-day dosing interval
QT
an ECG interval
QTc
corrected QT interval
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
re-screen
To screen a patient who was previously declared a screen failure for the same study
RP2D
recommended Phase 2 dose
RR
an ECG interval
(Note:  “RR” is the abbreviation for respiration rate only in Attachment 1.)
SAE
serious adverse event
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, diagnostic, x-rays, 
and 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 one or more criteria required for participation in a trial.


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sponsor
The party who takes responsibility for the initiation, management and/or financing of a 
clinical study.
study completion
This study will be considered complete following the protocol-specified final analysis for 
the primary and secondary objectives.
SUSAR
suspected unexpected serious adverse reaction
t1/2
elimination half-life
TACC3
transforming acidic coiled-coil (fusion protein of FGFR3)
TCC
transitional cell carcinoma
TK
toxicokinetic(s)
TPO
third-party organization
ULN
upper limit of normal
V/F (or V)
(apparent) volume of distribution


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A Phase 1 Study of LY3076226, a Fibroblast Growth Factor 
Receptor 3 (FGFR3) Antibody-Drug Conjugate,
in Patients with Advanced or Metastatic Cancer
5.
Introduction
5.1.
Rationale and Justification for the Study
Fibroblast growth factor receptor (FGFR) is a receptor tyrosine kinase (RTK) involved in critical 
cellular activities such as angiogenesis, proliferation, survival, wound repair, and migration. 
Receptor dimerization initiates the tyrosine kinase cascade of diverse downstream signaling, 
such as SOS-GRB2-RAS-RAF-MAPK, GAB-1-PI3K-AKT, PLC-PIP3/DAG-PKC-RAF-
MAPK, p38MAPK, JNK, STAT, and ribosomal protein S6 kinase 2 (as reviewed by Turner and 
Grose 2010).  Activation of FGFR plays a pivotal role in cancer initiation and progression.
Fibroblast growth factor receptor 3 (FGFR3), 1 of 4 members of the FGFR family, is found to be 
constitutively active in bladder, multiple myeloma, non-small cell lung cancer (NSCLC), 
glioblastoma multiforme (GBM), and cervical cancer through overexpression, point mutations, 
and translocations (Singh et al. 2012; Parker et al. 2013; Williams et al. 2013; Wu et al. 2013).  
Aberrant activation of FGFR3 through overexpression has been shown to be sufficient to induce 
oncogenic transformation in fibroblasts, hematopoietic cells, and murine bone marrow 
transplantation models (Plowright et al. 2000; Chesi et al. 2001; Ronchetti et al. 2001; Chen et al. 
2005).
LY3076226 is an anti-FGFR3 antibody conjugated to a cytotoxic payload, DM4, a maytansine 
derivative that inhibits tubulin dynamics. The anti-FGFR3 antibody recognizes not only wild-
type (WT) receptor, but also constitutively active mutant receptors (S249C, Y373C, and others) 
and transforming acidic coiled-coil (TACC3) fusion proteins of FGFR3 (Stewart et al. 2004;
Kiemeney et al. 2010).  This allows LY3076226 to selectively internalize the FGFR3 receptor 
and deliver the cytotoxin into the target cancer cells that are aberrantly activated by the FGFR3 
receptor, regardless of mechanism.  DM4 is catabolized once the receptor—antibody-drug 
conjugate (ADC) complex is internalized, providing specific killing of the unwanted cancer cell 
along with bystander killing of neighboring cells within the tumor microenvironment.
Maytansine was developed in 1972 and tested in Phase 1 and 2 studies as a cytotoxic agent for 
treatment across multiple cancer types, including breast, melanoma, lung, colorectal, and ovarian 
in the late 1970s and early 1980s (Blum et al. 1978a; Blum et al. 1978b; Cabanillas et al. 1978; 
Chabner et al. 1978; Cabanillas et al. 1979; Neidhart et al. 1980; Ravry et al. 1985).  The adverse 
event (AE) profile was similar to other anti-tubulin agents, with gastrointestinal (GI) and central 
nervous system (CNS) toxicities being dose limiting.  The doses selected to avoid and mitigate 
higher-grade toxicity did not demonstrate sufficient activity and development was stopped. 
Selectively targeting aberrant cells using an antibody that recognizes cancer-specific cell surface 
receptors to deliver a maytansine derivative directly into the cell has the potential to decrease the 
systemic exposure, thereby potentially decreasing dose-limiting GI and CNS effects while 
potentially increasing the efficacy.  Another derivative of maytansine, DM1, has been 


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successfully conjugated to an anti-human epidermal growth factor receptor 2 (HER2) antibody 
for use in the treatment of HER2+ metastatic breast cancer (Kadcyla package insert, 2014). A 
number of other maytansine antibody-drug conjugates with either DM1 or DM4 payloads are 
currently in clinical trials (Trail 2013).
Urothelial carcinoma, a cancer involving the transitional epithelial lining of the urinary system,
is a type of cancer that typically occurs in the urinary bladder (90% of cases), renal pelvis (8%),
or ureters or urethra (remaining 2%, combined). For simplicity, the disease is often referred to as
bladder cancer. Transitional cell carcinoma (TCC) is the predominant histologic type of
urothelial carcinoma in North America and Europe, where it accounts for ≥90% of all bladder 
cancers (Billis et al. 2001; Chalasani et al. 2009). Other histologic subtypes are squamous cell,
adenocarcinoma, and small-cell tumors. Urothelial tumors with a mixture of histologic subtypes
and transitional cell predominance are generally treated similarly as urothelial (transitional cell)
carcinomas (NCCN 2014).
Almost half of patients with urothelial carcinoma have FGFR3 genetic mutations. In 2015 in the 
United States, there will be an estimated 74,000 newly diagnosed cases of bladder cancer with 
16,000 deaths (American Cancer Society 2015).  Point mutations (S249C in the extracellular 
domain, R248C in the transmembrane domain, and Y373C and Y375C in the kinase domain)
occur in 70% to 80% of patients with early stage TCC.  Despite multimodal therapy with bacillus 
Calmette-Guérin (BCG)/radiation/surgery, the recurrence rate is 50% to 70%, with 10% to 20% 
of patients progressing to muscle-invasive disease (Al-Ahmadie et al. 2011). In muscle-invasive 
disease, activating mutations of FGFR3 are reported in 11% to 20% of patients (TCGA 2014) 
and FGFR3 overexpression is seen in 35% to 50% of patients. Taken together, these data make 
FGFR3 a particularly relevant target for the treatment of urothelial carcinoma (Guancial et al. 
2014; Sung et al. 2014; Turo et al. 2015).
LY3076226 may overcome the dose-limiting toxicities (DLTs) of traditional cytotoxic therapy 
by selectively delivering the cytotoxic payload directly to the targeted cancer cells, resulting in 
greater tumor reduction/efficacy. This initial Phase 1 study with LY3076226, Study I70-MC-
JOBA (JOBA), will characterize the safety and determine the recommended Phase 2 dose 
(RP2D) of LY3076226 in patients with advanced or metastatic cancer.
The sponsor, monitor, and investigators will perform this study in compliance with the protocol, 
good clinical practice (GCP) and International Conference on Harmonisation (ICH) guidelines, 
and applicable regulatory requirements.


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5.2.
Objectives
5.2.1. Primary Objective
The primary objective of this study is to determine a recommended Phase 2 dose and schedule of 
LY3076226 that may safely be administered to patients with advanced or metastatic cancer.
5.2.2. Secondary Objectives
The secondary objectives of this study are:

to characterize the safety and toxicity profile of LY3076226

to characterize the pharmacokinetics (PK) of LY3076226

to document antitumor activity observed with LY3076226
5.2.3. Exploratory Objectives
The exploratory objectives of this study are:

to explore the effect of LY3076226 on pharmacodynamic (PD) markers

to explore the association between biomarkers and clinical outcome
5.3.
General Introduction to LY3076226
More information about the known and expected benefits, risks, and reasonably anticipated AEs 
may be found in the Investigator’s Brochure (IB).  Information on AEs expected to be related to 
the investigational product may be found in Section 7 (Development Core Safety Information
[DCSI]) of the IB.  Information on serious adverse events (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 study, may be found in Section 6 (Effects in Humans) of the 
IB.
5.3.1. Mechanism of Action and In Vitro/In Vivo Activity
LY3076226 is an antibody-drug conjugate (ADC) composed of IMC-D11, an immunoglobulin 
G, subclass 1 (IgG1) monoclonal antibody against FGFR3, attached with a cleavable linker, 
sulfo-SPDB (disulfide N-succinimidyl 4-[2-pyridyldithio]butyrate), to the maytansine derivative 
DM4, a tubulin inhibitor.  LY3076226 uses a selective, high-affinity, neutralizing, phage-
derived, fully human IgG1 monoclonal antibody against the human FGFR3b/c protein. This IgG 
1λ monoclonal antibody to FGFR3, IMC-D11, was generated for use in human cancer patients 
with FGFR3 amplifications, overexpression, and activating mutations. The antibody component 
of LY3076226, IMC-D11, blocks ligand-dependent as well as ligand-independent signaling in 
tumor-derived cell lines and in FGFR3 stably transfected cells.  The anti-FGFR3 IMC-D11 
epitope overlaps with heparin sulfate proteoglycan and FGFR3 ligand binding. IMC-D11 was 
selected for its ability to potently block primary FGFR3 ligand-dependent (ligands fibroblast 
growth factor [FGF]-1 and FGF-9 and all others) cancer cell proliferation and induce FGFR3 
receptor internalization and degradation with similar potency, which results in FGFR3-mediated 
cancer cell death. Importantly, IMC-D11 is fully cross-reactive with human, cynomolgus


I7O-MC-JOBA(a) Phase 1 Oncology Protocol
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LY3076226
monkey, rat, and mouse FGFR3b/3c receptors binding with similar affinities. IMC-D11 has 
comparable activity against wild type and mutant FGFR3 and has demonstrable tumor growth 
inhibition in vivo in several bladder cancer cell lines and multiple myeloma models, with marked 
decreases in receptor phosphorylation, as well as a significant decrease in phosphorylation of 
mitogen-activated protein kinase (MAPK).
IMC-D11 is conjugated to the maytansine derivative DM4 (a tubulin inhibitor) via a cleavable 
linker moiety (sulfo-SPDB).  LY3076226 binds specifically to the human FGFR3 protein with 
high affinity, and following internalization can deliver potent cytotoxic payload resulting in cell 
cycle arrest and cell death (Discovery, Eli Lilly and Company, preclinical in vitro study IMC37; 
LY3076226 Investigator’s Brochure, Eli Lilly and Company, 2015).  Sulfo-SPDB, the linker 
portion of LY3076226, was selected to balance the toxicity of the drug moiety by ensuring 
intracellular metabolism of the drug moiety (Discovery, Eli Lilly and Company, preclinical 
in vitro study IMC37; Discovery, Eli Lilly and Company, preclinical study 5404-12).  Sulfo-
SPDB conjugates, when metabolized intracellularly, generate 3 metabolic products (lysine-
N[epsilon]-SPDB-DM4, DM4, and S-methyl-DM4), 2 of which are capable of promoting 
bystander cell killing of neighboring cells through the delivery of free drug (DM4 and S-methyl-
DM4 [DM4-Me]), which can also increase toxicity through non-specific killing of proliferating, 
normal cells.  Sulfo-SPDB was selected over other cleavable linkers due to its high processing 
efficiency (Zhao et al. 2011), superior efficacy in some tumor models, as well as 
toxicity/tolerability considerations (Discovery, Eli Lilly and Company, preclinical study 5404-
12).  However, due to this bystander killing mechanism, sulfo-SPDB conjugates can also 
increase toxicity through non-specific killing of normal cells (Erickson et al. 2012).
LY3076226 was studied in 3 bladder patient-derived xenograft (PDX) models with unknown 
FGFR3 expression (receptor density not determined), 21 NSCLC models of varying antigen 
density (determined by FGFR3 messenger ribonucleic acid [mRNA]), and 7 in-house cell-line-
derived bladder xenograft models representative of FGFR3; wild type, S249C mutant, and 
TACC3 fusion-positive as defined by receptor density, mRNA expression, 
immunohistochemistry (IHC), and ModaPlex analysis.  Preclinical in vivo efficacy data 
demonstrate that treatment with LY3076226 inhibits tumor growth in a number of cell-line-
derived human bladder and multiple myeloma xenografts, as well as a squamous NSCLC PDX
model (LXFE 2227) that is TACC3 fusion-positive as defined by ModaPlex analysis. The 
in vivo responses observed (including complete response [CR], partial response [PR], and stable 
disease [SD]) are durable and LY3076226 was demonstrated to mechanistically induce tumor 
cell apoptosis.  Importantly, LY3076226 had no activity in xenograft models devoid of FGFR3 
cell surface expression, which further supports the FGFR3 specificity of the molecule.
Significant cytotoxic activity of LY3076226 was observed when the molecule was used to treat
each of the FGFR3-overexpressing bladder tumor cell lines. The compound was slightly more 
potent in the UMUC-14 tumor cell line, which overexpresses FGFR3 containing a mutation 
(S249C) in the extracellular domain that renders the receptor constitutively active. The negative 
control isotype-matched ADC showed no cytotoxicity in the concentration ranges seen with 
LY3076226 in any of the lines. A bladder tumor cell line, KU-19-19, that does not overexpress 


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FGFR3 was included in the experiment to assess nonspecific cytotoxicity. No cytotoxicity was 
observed with the KU-19-19 line, a cell line that is devoid of FGFR3 expression. It was 
concluded that specific in vitro cytotoxicity can be induced by LY3076226 in cell lines 
overexpressing FGFR3 wild type, FGFR3 S249C mutant, and FGFR3-TACC3 fusion.
In preclinical testing, LY3076226 has shown in vivo activity in bladder, squamous NSCLC, and 
multiple myeloma models containing wild type, mutated, and TACC3-fused FGFR3 that is 
overexpressed or constitutively active. LY3076226 may overcome the DLTs of traditional 
cytotoxic therapy by selectively delivering the cytotoxic payload directly to the targeted cancer 
cells, resulting in greater tumor reduction/efficacy.
5.3.2. Nonclinical Pharmacokinetics/Pharmacodynamics
Pharmacokinetics and/or toxicokinetics (TK) of LY3076226 have been studied in mice, rats, and 
cynomolgus monkeys following single intravenous (IV) administration of 3, 10, or 20 mg/kg or 
once-weekly repeat-dose administration of 1, 3, and 10 or 15 mg/kg.  Plasma PK of LY3076226, 
either conjugated LY3076226 (LY3076226 with at least one DM4 payload) or total LY3076226 
IgG, were characterized using enzyme-linked immunosorbent (ELISA) assays.  Plasma 
concentrations of free DM (total free immunoreactive maytansine species) were quantified by 
unvalidated ELISA assays in preliminary experiments.  In later studies, DM4 and DM4-Me were 
quantified with liquid chromatography-mass spectrometry (LC-MS) assays.
Following IV administration PK and TK studies, plasma concentration-versus-time profiles for 
conjugated LY3076226 and total LY3076226 IgG demonstrated similar maximum plasma 
concentration (Cmax) values and elimination profiles.  Plasma concentrations for both conjugated 
and total LY3076226 increased with increasing dose.  In both the rat and monkey, there was 
limited evidence of super-proportionality observed in Cmax and area under the plasma 
concentration-time curve (AUC) in some studies, but this was 2-fold or less across doses of 1 
through 20 mg/kg. There were no apparent sex differences in the PK/TK of LY3076226.  The 
mean elimination half-life (t1/2) for conjugated LY3076226 was approximately 20 hours in the 
mouse, 16 to 42 hours after a single dose in the rat, and 45 to 101 hours after single or multiple 
doses in the monkey.  The mean t1/2 for total LY3076226 IgG was approximately 23 hours in the 
mouse, 9 to 31 hours following single-dose administration in the rat, and 45 to 138 hours after 
single or multiple doses in the monkey.  In the rat, concentrations of conjugated and total 
LY3076226 IgG were variable (reduced or no longer quantifiable) in some animals after repeat 
administration, and no accumulation was apparent.  These observations in the rat were possibly 
affected by anti-drug antibodies (ADA).  In the monkey, once-weekly dosing at 1 or 3 mg/kg 
demonstrated little or no accumulation (2-fold or less).
Based on the validated LC-MS assay for DM4 and DM4-Me, plasma concentrations of these 
species in both rat and cynomolgus monkey increased with increasing dose and did not 
accumulate with repeated dosing.  There were insufficient data for t1/2 estimations for DM4 or 
DM4-Me in the monkey.  In the rat, mean DM4 and DM4-Me t1/2 estimates were 16 to 19 and 22 
to 29 hours, respectively.  DM4 and DM4-Me were a small fraction (generally less than 2.5% in 
the rat and 0.07% in the monkey on a molar basis) of conjugated LY3076226.


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Metabolism studies have not been conducted with LY3076226.  However, the metabolism of the 
molecule based on the construct and the PD activity of LY3076226 is expected to be ligand 
binding followed by receptor-mediated cellular uptake and degradation of the IgG portion of the 
molecule into component amino acids. The DM4 payload released by the proteolytic 
metabolism of the ADC is then available within the cell to bind to microtubules, inducing mitotic 
arrest and cytotoxicity (Erickson et al. 2010).  Both DM4 and DM4-Me have been identified in 
the ADC literature as active metabolites released both in vitro and in vivo (Erickson et al. 2006; 
Erickson et al. 2010).  Mouse studies suggest that active maytansine species are further 
detoxified by oxidation in the liver (Sun et al. 2011).
In vitro drug-drug interaction (DDI) studies have not been conducted with LY3076226.  The 
in vitro DDI potential of DM4 has been evaluated (Davis et al. 2012).  While the free sulfhydryl 
in DM4 has the potential to inactivate CYP3A4 in an NADPH-dependent manner, the low 
plasma concentrations observed clinically for free DM4 arising from ADCs suggest that this is of 
limited clinical concern.
5.3.3. Nonclinical Toxicology
To support clinical investigation of LY3076226, a package of nonclinical toxicology studies 
have been conducted with LY3076226.  These studies are supplemented with data from prior
nonclinical safety studies that investigated both the monoclonal antibody and drug conjugate 
parts of LY3076226.
The repeat-dose toxicology studies of LY3076226 consisted of 5-week studies in rats at dosages 
of 1, 3, or 10 mg/kg (equivalent to 6, 18, or 60 mg/m2, respectively) or in cynomolgus monkeys
at dosages of 1, 3, or 15 mg/kg (equivalent to 12, 36, or 180 mg/m2, respectively).  LY3076226 
was given by IV injection (slow bolus) once weekly for 5 occasions (Days 1, 8, 15, 22, and 29).  
The dosing schedule used in the toxicology studies represents a more intense schedule than is 
planned in this Phase 1 clinical trial.
The main toxicities associated with IV administration of LY3076226 comprised changes in the 
skin, and cornea.  In addition, there were effects on bone marrow, lymphoid tissue, GI tract,
liver, and reproductive systems consistent with the cytotoxic effects of the DM4 payload.  
Toxicities at the lower doses (1 or 3 mg/kg) were of lower severity and frequency than those 
observed at the high dose in either species.
Adverse skin reactions with subsequent generalized debilitation resulted in the premature 
euthanasia of rats and monkeys at the highest dose of LY3076226 tested in each species (10 or 
15 mg/kg, respectively).  Although adverse skin reactions were seen at lower dosages (1 or 
3 mg/kg) in both rat and monkey, these did not cause debilitation and premature euthanasia.
Dry, flaking, reddened, discolored and/or sloughing skin was seen in both rats (3 or 10 mg/kg) 
and monkeys (all dosages).  Skin changes were seen on the limbs (including injection sites), 
dorsal and ventral surfaces, face, eyelids and/or eyebrows.  In the monkey, microscopic changes 
in the skin comprised hyperkeratosis, dyskeratosis, necrosis, inflammation, and pigmentation at 
all dosages; in the rat, hyperplasia, ulceration, and inflammation were seen in the skin.  In both 


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species, increased mitoses and single-cell necrosis were seen in the skin (and in many other 
tissues).  After an 8-week reversibility period, skin lesions were still present in both rat and 
monkey, but the incidence and/or severity was reduced.
In the 5-week monkey study, haze at the corneal limbus was seen by slit-lamp examination after 
5 treatments in all animals treated at 3 mg/kg and was accompanied by corneal pigmentation in 
the majority of the affected animals.  Microscopically, increased mitoses and single-cell necrosis 
were present in the corneal epithelium at all dosages; dyskeratosis was seen in animals treated at 
3 mg/kg or more.  After the 8-week recovery period, the corneal hazing was not present, 
although pigmented corneas were still apparent – dyskeratosis and/or pigment were seen 
histologically.  Corneal pigmentation observed in recovery animals is a likely sequelae of the 
corneal injury noted in terminal and early death animals.  In the rat, although no corneal lesions 
were seen by ophthalmic examination, increased mitoses in the corneal epithelium were seen at 
all dosages after 5 weeks of treatment; this change was not apparent after the 8-week 
reversibility period.
Single-cell necrosis and increased mitoses were seen in the epithelium of some or all of the GI
tract in both rats and monkeys at the highest dose; these changes were completely reversible after 
8 weeks of recovery.
Effects on the bone marrow and lymphoid tissues, with concomitant effects on circulating red
and white blood cells, were consistent with the cytotoxic activity of the DM4 payload.  These 
changes were most severe at the high dose in rats and monkeys and comprised decreased 
erythroid and early myeloid progenitors and increased mitoses/single-cell necrosis in the bone 
marrow, increased mitoses and/or decreased cellularity of lymphoid tissue, decreased erythroid 
mass and decreased reticulocyte, neutrophil, lymphocyte, monocyte, and eosinophil counts; at 
the lower dosages, these effects were less severe and/or frequent in both species.  Effects on bone 
marrow, blood, and lymphoid tissue showed complete or almost complete recovery during the 
8-week reversibility period.
In male rats, tubular degeneration in the testis and hypospermia/inflammation in the 
epididymides were seen at the highest dose (10 mg/kg) and in 1 or 2 males at the 3-mg/kg dose; 
no similar changes were seen at 1 mg/kg.  The effects on testes and epididymides were only 
partially reversible.
Increased mitoses and/or single-cell necrosis was seen in a number of other tissues, including the 
liver, gallbladder, pancreas, salivary glands, kidneys, epididymides, prostate, seminal vesicles, 
ovaries, cervix, uterus, mammary gland, and/or vagina in monkeys or rats.  These changes were 
generally confined to the highest dose in either species and only rarely were these effects seen at 
the 3-mg/kg dose level.  The changes in the liver of rats were accompanied by mild increases in 
liver transaminase levels.
Increased heart rate and decreased RR, PR, and QT intervals were seen in monkeys following 
treatment at 3 or 15 mg/kg; no decrease in corrected QT (QTc) interval was apparent and there 
were no unusual or abnormal rhythms or waveforms.  Heart rates in monkeys treated at 3 or 
15 mg/kg were approximately 25% or 60% higher than either prestudy values or time-matched 


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control values. No effects on heart rate were seen at 1 mg/kg.  LY3076226 had no effect on 
body temperature, breathing rate, or neurological parameters.
Based on the nonclinical toxicology studies of LY3076226, the DLTs are expected to be skin 
lesions, corneal changes, myelosuppression, and/or GI toxicity.  These changes are considered 
manageable, and at least partial reversibility has been demonstrated.  Appropriate endpoints to 
monitor patient safety have been incorporated into this clinical protocol.
For Study JOBA, an initial clinical starting dose of 6 mg/m2 (equivalent to 0.18 mg/kg for a 
patient with a body surface area of 1.8 m2 and body weight of 60 kg) administered once every 
21 days was selected based on the highest non-severely toxic dose (HNSTD) in the most 
sensitive animal species and on PK projections that suggest the exposure at this dose is
comparable with the minimally efficacious exposure, while ensuring an adequate safety margin.  
The starting dose is one sixth of the HNSTD in the most sensitive species (based on a dose of 
3 mg/kg or 36 mg/m2 in cynomolgus monkeys).  Table JOBA.1 shows the calculated exposure 
multiples for the clinical starting dose and highest planned dose relative to the exposure at the 
HNSTD in monkeys.


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Table JOBA.1.
Exposure Multiples for Intravenous Administration of LY3076226 
Based on Administered Dose and Predicted Exposure in Humans
Dose
AUC(0-7 d)
Cmax
mg/m2
Multiplea
μg∙h/mL
Multipleb
μg/mL
Multiplec
Rat MinTD
18
-
1525
-
63.85
-
Monkey HNSTD
36
-
3473
-
63.85
-
Human:
Dose
AUC(0-21 d,ss)
Cmax,ss
mg/m2
Multiplea
μg∙h/mL
Multipleb
μg/mL
Multiplec
Starting dose 
(0.18 mg/kg)
6
rat:
3×
monkey:
6×
224
rat:
6.8×
monkey:
15.5×
4.7
rat:
13.6×
monkey:
13.6×
Highest dose
(5 mg/kg)
165
rat:
0.11×
monkey:
0.22×
15000
rat:
0.10×
monkey:
0.23×
110
rat:
0.58×
monkey:
0.58×
Abbreviations: AUC = area under the plasma concentration-time curve; Cmax = maximum observed plasma 
concentration; Cmax,ss = maximum observed plasma concentration at steady state; HNSTD = highest non-severely
toxic dose; MinTD = minimally toxic dose.
a
Dose multiple is the dose in animals/dose in humans based on body surface area (mg/m2).
b Exposure multiple is the mean AUC(0-7 d) on Day 1 in male and female animals/projected mean AUC(0-21 d,ss)
in humans.
c
Exposure multiple is the mean Cmax on Day 1 in male and female animals/projected mean Cmax,ss in humans.
MinTD based on 5-week repeat-dose toxicity study in the rat (Study No. 5000859).
HNSTD based on 5-week repeat-dose toxicity study in the cynomolgus monkey (Study No. 20056864).
5.3.4. Biomarkers
FGFR protein expression and patient genetic data identifying constitutively active or 
overexpressed FGFR on the cell surface of tumors have been linked to clinical outcomes to other 
pan-FGFR therapy (André et al. 2013a; André et al. 2013b; Nogova et al. 2014; Dienstmann et 
al. 2014). Analytes related to the FGFR pathway, the DM4 mechanism of action, and cancer 
pathobiology including, but not limited to, FGFR3 protein expression, along with somatic 
mutation status and/or copy number variations of FGFR3 pathway-related genes or genes related 
to cancer pathobiology may be assessed.
In addition, induction of cell cycle arrest will be examined by measuring Ki-67 and 
phosphohistone H3 (pHH3) in patients with known alterations of FGFR3. CK18, a circulating 
marker in blood, will be analyzed as an indirect measurement of apoptosis.


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5.4.
Rationale for Selection of Dose
A dose range of 0.2 (rounded up from 0.18 for ease of calculation) to 5 mg/kg of LY3076226 
administered IV on Day 1 of a 21-day cycle was selected based on nonclinical toxicology, 
efficacy, and PK data.
The starting dose for Study JOBA is a dose of 0.2 mg/kg (6 mg/m2) administered on Day 1 of a 
21-day cycle. As indicated in Table JOBA.1, when calculated on the basis of mg/m2 dosing, this 
dose is approximately 3-fold lower than the minimally toxic dose (MinTD) of 3 mg/kg 
(18 mg/m2) in rats and 6-fold lower than the HNSTD of 3 mg/kg (36 mg/m2) in cynomolgus 
monkeys.
Table JOBA.2 gives the mean predicted maximum (observed) plasma concentration at steady 
state (Cmax,ss) and AUC(0-21 d,ss) for the various anticipated dose levels to be tested in Study JOBA.  
Exposure levels (Cmax and AUC(0-7 d)) after multiple doses at the MinTD in rats and the HNSTD 
in cynomolgus monkeys are summarized in Section 5.3.3 (Nonclinical Toxicology).  Based on a 
human starting dose of 0.2 mg/kg given once every 21 days and the exposure observed after 
multiple doses at the MinTD of 3 mg/kg (18 mg/m2) in rats, the mean predicted exposure 
multiples are approximately 6.8 for AUC(0-21 d,ss) and 13.6 for Cmax,ss.  When calculated using 
exposures observed at the HNSTD of 3 mg/kg (36 mg/m2) in cynomolgus monkeys, the mean 
predicted exposure multiples are approximately 15.5 for AUC(0-21 d,ss) and 13.6 for Cmax,ss.
Preclinical efficacy associated with administration of LY3076226 was evaluated by investigating 
the exposure levels associated with xenograft tumor growth delay in mice.  In an RT112 
xenograft tumor model, the lowest dose associated with complete tumor regression in 4 out of 
5 mice per dose group was 10 mg/kg administered either as a single IV administration (qd×1) or 
as two 5-mg/kg IV administrations separated by a 14-day dosing interval (q14d×2).  A PK model 
developed for LY3076226 in mice indicates a mean AUC(0-28 d) and Cmax in plasma of 
approximately 3600 µg∙h/mL and 123 µg/mL, respectively, for the 10-mg/kg qd×1 dose group.  
AUC(0-28 d) and Cmax were estimated at 3030 µg∙h/mL and 61.2 µg/mL, respectively, after 
5 mg/kg administered q14d×2.
The minimally efficacious dose (MED) in humans was subsequently projected using a human 
PK model obtained by allometric scaling performed on cynomolgus monkey PK data.  This 
projected human PK model indicates that a dose of 1.6 to 1.8 mg/kg would be needed to achieve 
an AUC(0-21 d,ss) in patients similar to the AUC(0-28 d) observed in mouse.  Likewise, human Cmax
values similar to those obtained in mice would be obtained at a dose ranging from 3.0 to 
7.2 mg/kg.
Altogether, these results suggest a MED in humans ranging from 1.6 to 3.0 mg/kg.  Based on the 
LY3076226 plasma exposures observed at the MinTD in rats, the mean AUC exposure multiples 
predicted at steady state for this MED projection range from 0.5 to 0.2.  When using LY3076226 
plasma exposures observed at the MinTD in rats, the mean projected AUC exposure multiples at 
steady state range from 1.1 to 0.4.


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Based on data from the rat and nonhuman primate toxicology studies, the DLTs in humans are 
expected to be monitorable and reversible. The proposed dose-escalation strategy will thus be 
guided by safety assessments and the use of a human PK/PD model, which will be updated as 
human clinical PK data are available. The primary determinant, however, will be safety. The 
actual dose increment between cohorts and the example dose level of each cohort will be 
determined according to the constraints described in Section 7.2.2 (Dose Escalation).
Table JOBA.2.
Mean Predicted Plasma Exposure Levels at the Example
LY3076226 Dose Levels for Study I7O-MC-JOBA
LY3076226 Dose (mg/kg)
Cmax,ss (µg/mL)
AUC(0-21 d,ss) (µg∙h/mL)
0.2
4.7
224
0.4
8.16
521
0.8
16.4
1270
1.6
33.2
3220
2.4
50.5
5640
3.2
68.4
8430
4.0
86.9
11500
5.0
110
15500
Abbreviations: AUC = area under the plasma concentration-time curve; Cmax,ss = maximum plasma concentration at 
steady state.


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6.
Investigational Plan
6.1.
Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened.  Individuals may be re-screened one time.  Each time re-screening is performed, the 
individual must sign a new informed consent form (ICF) and will be assigned a new 
identification number.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
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]
Must be, in the judgment of the investigator, an appropriate candidate for 
experimental therapy after available standard therapies have failed to provide 
clinical benefit for their disease or if the patient refuses standard therapy.
Patients must be well informed about the benefit and risk of standard therapy 
prior to signing the informed consent.
Part A (dose escalation): Have histological or cytological evidence of a 
diagnosis of cancer (including multiple myeloma and lymphoma) that is 
advanced and/or metastatic.
Part B (dose expansion): Have histologically or cytologically confirmed, 
locally advanced, or unresectable or metastatic urothelial (transitional cell) 
carcinoma of the bladder, urethra, ureter, or renal pelvis, with locally 
determined overexpression or alterations of FGFR3 (refer to Attachment 11).
Part C (dose expansion): Have histological or cytological evidence of a 
diagnosis of cancer (including multiple myeloma and lymphoma) that is 
advanced and/or metastatic, with locally determined overexpression or 
alterations of FGFR3 (refer to Attachment 11).
[2]
Part A:  Have the presence of measurable and/or nonmeasurable disease as 
defined by the appropriate criteria: Response Evaluation Criteria in Solid 
Tumors, version 1.1 (RECIST 1.1 [refer to Attachment 9]; Eisenhauer et al. 
2009), multiple myeloma criteria (International Myeloma Working Group 
[IMWG; refer to Attachment 5]; Rajkumar et al. 2011), or lymphoma criteria
(Cheson et al. 2014).
Parts B and C:  Have the presence of measurable disease as defined by the 
appropriate criteria:  RECIST 1.1 (Eisenhauer et al. 2009), multiple myeloma 
criteria (IMWG; Rajkumar et al. 2011), or lymphoma criteria (Cheson et al.
2014).


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[3]
Parts B and C:  Are willing to provide a pretreatment tissue sample.  For 
patients who have disease recurrence/metastasis at body sites that are 
technically challenging for biopsy and who have available tissue from a 
previous regimen posttreatment biopsy and have not received intervening 
therapy, the investigator and sponsor may agree to omit the pretreatment 
biopsy.
[4]
Are 18 years of age.
[5]
Have given written informed consent prior to any study-specific procedures.
[6]
Have adequate organ function, including:

Hematologic:  Absolute neutrophil count (ANC) ≥1.5 × 109/L, platelets 
100 × 109/L, and hemoglobin 9 g/dL and have not received blood or 
blood components transfusion within 2 weeks (≤2 weeks) prior to the 
laboratory test.
In Part C only, patients with multiple myeloma are allowed the following: 
ANC ≥1.0 × 109/L, platelets 50 × 109/L, and hemoglobin 8 g/dL.

Hepatic:  Total bilirubin 1.5 × upper limit of normal (ULN) in the 
absence of Gilbert’s syndrome, direct bilirubin 1.5 × ULN in the 
presence of Gilbert’s syndrome, alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) 3 × ULN.

Renal:  Serum creatinine ≤1.5 × ULN or a calculated or measured 
creatinine clearance of ≥50 mL/min/1.73 m2 (refer to Attachment 8 for the 
Cockcroft and Gault formula to calculate creatinine clearance from local 
laboratory results).
[7]
Have a performance status of 0 or 1 on the Eastern Cooperative Oncology 
Group (ECOG) scale (refer to Attachment 7).
[8]
Have discontinued previous treatments for cancer and have resolution, except 
where otherwise stated in the inclusion criteria, of all clinically significant 
toxic effects of prior chemotherapy, surgery, or radiotherapy to Grade ≤1 by 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.0 (v 4.0) (CTEP 2009).


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[9a]
Male patients:
who are sterile (including vasectomy) or agree to use a reliable method of 
birth control and to not donate sperm during the study and for at least 
12 weeks following last dose of study drug or country requirements, 
whichever is longer.
[9b] Female patients:
are women not of childbearing potential due to surgical sterilization (at least 
6 weeks postsurgical bilateral oophorectomy with or without hysterectomy or 
tubal ligation) confirmed by medical history or due to menopause (refer to
Section 4 for the definition of menopausal women).
OR
are women of childbearing potential who test negative for pregnancy within 
7 days of enrollment based on a serum pregnancy test and agree to use a 
highly effective method of birth control* during the study and for 3 months 
following the last dose of the study drug and also must not be breastfeeding.
*A highly effective method of birth control is defined as one that results in a low 
failure rate (that is, <1% per year) when used consistently and correctly, such as 
implants, injectables, combined oral contraceptives, some intrauterine 
contraceptive devices (IUDs), sexual abstinence, or a vasectomized partner. For 
patients using a hormonal contraceptive method, information regarding the 
product under evaluation and its potential effect on the contraceptive should be 
addressed.
[10] Have an estimated life expectancy that, in the judgment of the investigator, 
will permit the patient to complete 3 cycles (9 weeks) of treatment.
6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[11] Have received treatment within 28 days of the initial dose of study drug with 
an investigational product or non-approved use of a drug or device (other than 
the study drug/device used in this study) or are concurrently enrolled in any 
other type of medical research judged not to be scientifically or medically 
compatible with this study.
[12] Have serious preexisting medical conditions (left to the discretion of the 
investigator).
[13] Have symptomatic CNS malignancy or metastasis (screening not required).
Patients with treated CNS metastases are eligible for this study if they are not 
currently receiving corticosteroids for this indication and/or anticonvulsants, 
and their disease is asymptomatic and radiographically stable for at least 28
days.


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[14] Have current acute or chronic leukemia.
[15] Have an active fungal, bacterial, and/or known viral infection including 
human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis 
(screening is not required).
[16] Have a second primary malignancy that, in the judgment of the investigator 
and sponsor, may affect the interpretation of results.
Curatively treated nonmelanoma skin cancer or in situ carcinoma of any 
origin is allowed.
[17] Have Fridericia-corrected QT interval (QTcF) >480 msec on screening 
electrocardiogram (ECG).
[18] Have a serious cardiac condition, such as congestive heart failure; New York 
Heart Association Class III/IV heart disease; unstable angina pectoris;
myocardial infarction within the last 3 months; valvulopathy that is severe, 
moderate, or deemed clinically significant; or arrhythmias that are 
symptomatic or require treatment (not including patients with rate-controlled
atrial fibrillation).
[19] Have preexisting corneal diseases that may interfere with assessment of 
potential toxicity in the eyes during the study. 
[20] Have skin disorders (for example, erythema, and dermatitis) of ≥Grade 2.
6.2.
Summary of Study Design
Study JOBA is a multicenter, nonrandomized, open-label, dose-escalation Phase 1 study of IV
LY3076226 in patients with advanced or metastatic cancer.  Eligible patients will receive 
LY3076226 as an IV infusion on Day 1 of a 21-day cycle.
Dose escalation for LY3076226 in Part A will be driven by an accelerated dose-escalation 
scheme. Initial cohorts will enroll at least one patient each until a dose level of 1.6 mg/kg is 
reached, unless toxicity observed requires enrolling additional patients to a dose level.  A
modified 3+3 dose-escalation scheme will be followed in subsequent cohorts, with incorporation 
of a Bayesian model-based dose-escalation method (Neuenschwander et al. 2008) to assist in 
estimation of the DLT rate at recommended dose levels.  Dose levels for Cohorts 2 and beyond 
will reflect a maximum increment of 100% from the prior dose level. The dose will be escalated 
until a maximum tolerated dose (MTD) has been identified. If the MTD has not yet been 
reached at the highest prespecified dose level, then additional dose levels may be investigated 
based on both safety and the available PK data.
Once MTD is identified in Part A, up to approximately 15 patients who have known alterations
of FGFR3 will be enrolled in each of Parts B (urothelial carcinoma) and C (other malignancies)
to further evaluate the safety profile of LY3076226, characterize the exploratory biomarker 
assays, and document any antitumor activity.


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Figure JOBA.1 is a representative illustration of the JOBA study design, showing the dose-
escalation design in advanced cancer (Part A) and MTD expansions focusing on selected patient 
populations with known alterations of FGFR3 in urothelial carcinoma (Part B) and other 
malignancies (Part C).
Abbreviations:  FGFR3 = fibroblast growth factor receptor 3; UC = urothelial 
carcinoma.
Figure JOBA.1.
Illustration of I7O-MC-JOBA study design.
To determine the recommended Phase 2 dose of LY3076226, an adequate sample size is 
required.  A sufficient sample size will allow for an accurate evaluation of the relationship 
between exposure and toxicity, as well as an evaluation of the relationship between exposure and 
pharmacological effects using descriptive statistics and appropriate modeling techniques, if data 
warrant.
The actual sample size of the dose escalation (Part A) will primarily be determined by the 
observed toxicity and the incidence of DLTs.  Under the modified 3+3 dose-escalation scheme, 
each cohort will include 3 to 6 patients. The anticipated sample size for Part A ranges from 
approximately 20 to 35 patients, depending on the observed toxicity. Each of Parts B and C 
expansion cohorts will enroll up to approximately 15 patients. The overall sample size is thus 
estimated to be approximately 65 patients.
The planned duration of treatment is not fixed.  Patients will have tumor assessments after 
receiving 3 cycles of treatment.  Patients without evidence of disease progression may continue 
treatment until they fulfill one of the criteria for study discontinuation (Section 6.3).
Refer to Attachment 1 for the Study Schedule.


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6.2.1. Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete [study 
completion]) following the protocol-specified final analysis for the primary and secondary 
objectives.
The end of trial occurs after study completion and after the last patient has discontinued study 
treatment and completed any applicable continued access follow-up.
6.2.2. Continued Access Period
All patients remaining on study treatment without disease progression following the final 
analysis for the primary and secondary objectives will be able to enter the continued access 
period of the study.  The continued access period begins after study completion and ends at the 
end of trial.  During the continued access period, patients on study treatment who continue to 
experience clinical benefit may continue to receive study treatment until disease progression, 
death, unacceptable toxicity, or start of new anticancer treatment.  The continued access period 
includes a follow-up visit.  The follow-up visit begins 1 day after the patient and the investigator 
agree that the patient will no longer continue treatment in the continued access period and lasts 
approximately 28 days.  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.
During the continued access period, all AEs, SAEs, study drug dosing, and dose reduction of 
treatment will be collected on the case report form (CRF).
Serious adverse events will also be reported to Lilly Global Patient Safety and collected in the 
pharmacovigilance system (Section 8.1.2.4).  In the event that an SAE occurs, additional 
information (such as local laboratory results, concomitant medications, and hospitalizations) may 
be requested by Lilly in order to evaluate the reported SAE.
Investigators may perform other standard procedures and tests needed to treat and evaluate 
patients; however, Lilly will not routinely collect the results of these assessments.
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 authorization.


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6.3.1. Discontinuation of Patients
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified. A discussion must occur between 
the sponsor clinical research physician (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 in the study with or without investigational product 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.
In addition, patients will be discontinued from the study drug and/or from the study in the 
following circumstances:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Investigator/Physician Decision
o
The investigator/physician decides that the patient should be discontinued from 
the study or study drug.
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 occurs prior to introduction of the other 
agent.

Patient Decision
o
The patient requests to be discontinued from the study or study drug.

Sponsor Decision
o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and GCP.

The patient has radiographic progressive disease or significant symptomatic disease
deterioration characterized as progression of disease, in the opinion of investigator, in the
absence of radiographic evidence of progressive disease.

The patient experiences unacceptable toxicity.

The patient is noncompliant with study procedures and/or treatment (Section 7.6).

The patient’s dosing is delayed for more than 2 weeks as the result of an AE that is at 
least possibly related to LY3076226. If this delay occurs for the start of Cycle 2, this will 
be considered a DLT.


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6.3.2. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges it necessary for any scientific, medical, safety, regulatory, ethical, 
or other reasons consistent with applicable laws, regulations, and GCP.
6.3.3. 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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7.
Treatment
7.1.
Materials and Supplies
LY3076226 drug product is supplied for clinical trial use as an aqueous solution (10mM acetate, 
9% sucrose, 0.01% polysorbate 20, pH 5.0) at a concentration of 5.0 mg/mL (in terms of 
antibody weight).  It is a clear to slightly opalescent, colorless to slightly brown or slightly 
yellow liquid.  The drug product is supplied as a single-use vial containing 100 mg LY3076226 
in 20 mL of solution (5.0 mg/mL).  LY3076226 will be administered as an IV infusion and 
sterile dextrose (5%) solution only must be used as a diluent.  Lilly instructions regarding 
dilution requirements should be followed.
Clinical study materials will be labeled 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 agent to the site personnel,

verifying that instructions are followed properly,

maintaining accurate records of study drug dispensation and collection, and

returning or destroying all unused medication to Lilly or its designee at the end of the 
study.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be assessed.
7.2.1. Dosing Schedule
For doses ≤250 mg, LY3076226 will be administered as an IV infusion over approximately 
60 minutes on Day 1 of each 21-day cycle.  The sponsor may instruct the sites to extend the 
infusion time for up to 2 hours for doses greater than 250 mg. The assigned dose and duration of 
infusion of LY3076226 will be provided by the sponsor on a patient registration form. 
Subsequent doses should be adjusted as described in Section 7.2.6.
Premedication is not permitted for the initial dose of LY3076226 for each patient so that any 
observed toxicities may be appropriately characterized.


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7.2.2. Dose Escalation
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum Tolerated Dose 
Definition
Dose-limiting toxicity (DLT) is defined as an AE occurring during Cycle 1 that is at least 
possibly related to LY3076226 and fulfills any one of the following criteria using the NCI-
CTCAE v 4.0:

CTCAE Grade ≥3 non-hematological toxicity.  Exceptions will be made for the 
following:
o
Nausea, vomiting, diarrhea, and constipation that can be controlled with treatment
(Grade 3 and Grade 4 nausea, vomiting, or diarrhea should be considered DLTs if 
persisting for more than 48 hours, despite supportive intervention.)
o
Anorexia
o
Grade 3 fatigue lasting ≤5 days

Grade 3 elevations of ALT and/or AST lasting >7 days.

Concurrent elevation of ALT >3 × ULN and total bilirubin >2 × ULN in the absence of 
biliary obstruction or other causes that could reasonably explain the elevation.

CTCAE Grade 4 neutropenia of >7 days’ duration

Any febrile neutropenia

CTCAE Grade 3 thrombocytopenia with bleeding

CTCAE Grade 4 thrombocytopenia with or without bleeding

Any other significant toxicity deemed by the primary investigator and Lilly clinical 
research personnel to be dose limiting (for example, any toxicity that is at least possibly 
related to the study medication and that requires the withdrawal of the patient from the 
study during Cycle 1 or delays the start of Cycle 2 by >14 days).
For the purpose of this study, the MTD is defined as the highest dose tested that has less than 
33% probability of causing a DLT.
7.2.2.2.
DLT-Equivalent Toxicity
A DLT-equivalent toxicity is defined as an AE occurring during Cycle 2 and beyond that would 
have met the criteria for a DLT if it had occurred during Cycle 1. For individual patients 
experiencing a DLT-equivalent toxicity, dose adjustments will be made as outlined in Section 
7.2.6. At each interim analysis (as defined in Section 10.10), the rate of DLT-equivalent 
toxicities will be assessed. If the rate of DLT-equivalent toxicities is unacceptable (for example, 
a DLT-equivalent toxicity is observed in >33% patients at a given dose level), the data will be 
reviewed by study investigators and the Lilly CRP/clinical research scientist (CRS) and a safety 
analysis may be triggered. If the findings indicate that a dose level does not have an acceptable 
safety profile for chronic (Cycle 2 or later) administration, then a lower dose level will be chosen 
for further investigation. This decision will be documented in writing.


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7.2.2.3.
Dose-Escalation Method
For Part A, the proposed starting dose level will be 0.2 mg/kg.  Dose escalation will proceed at a 
maximum dose increment of 100%.  An accelerated dose-escalation scheme will be used, as 
follows:  initial cohorts will enroll at least one patient each until a dose level of 1.6 mg/kg is 
reached, unless a ≥Grade 2 toxicity that is at least possibly related to LY3076226 is observed
requiring additional patients to be enrolled to a dose level. After which a modified 3+3 scheme,
with incorporation of a Bayesian model-based, toxicity-band method (Neuenschwander et al. 
2008), will be followed, wherein at least 3 patients will be enrolled in each of the subsequent 
cohorts. The Bayesian model-based, toxicity-band method incorporates the prior expectations of 
the dose-toxicity curve and the observed DLT data after each cohort and provides quantitative 
guidance on the determination of the dose level for the next cohort, with control of overdosing 
probability. This method will be applied to the observed data on an ongoing basis throughout the 
dose escalation. The toxicity-band method will stop if the prespecified maximum number of 
patients is reached or the recommended next dose level has been administered to at least 6 
patients.
During the dose-escalation period, the investigators and Lilly CRP/CRS will consider both the 
model recommendation and the observed DLT rate at each cohort to determine the next dose 
level and determine when to stop dose escalation. Safety data, in particular, AEs, will be the 
primary criteria for dose escalation. In addition, if available at the time of the dose-escalation 
decision, PK (Cmax, AUC, and systemic clearance [CL]) results will be used as 
secondary/supporting data for dose escalation. Additional patients may, therefore, be enrolled at 
a specific dose level to characterize PK/PD. No dose escalation can occur without prior 
discussion and agreement between the investigator and the Lilly CRP/CRS; the decision will be 
documented in writing.  Intrapatient dose escalations are not permitted.
The example dose levels for Part A are shown in Table JOBA.3.  Intermediate or higher dose 
levels may be explored, if deemed necessary, after discussion between the Lilly CRP/CRS and 
investigators. The toxicity-band method has the ability to accommodate additional dose levels 
naturally.
Details regarding the toxicity-band method for this study are provided in Attachment 10.
If, during dose escalation, a situation presents itself that is not described above, Lilly CRP/CRS 
and investigators will determine the best method to select the appropriate dose for the patient(s) 
involved, using all available information. The decision will be documented in writing. No dose 
escalation can occur without prior discussion and agreement between the site-specific 
investigator and the Lilly CRP/CRS. Written notification will be sent to the site specifying the 
dose to be used for each patient at each dose level.


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Table JOBA.3.
Example of LY3076226 Dose Levels for Part A
Cohort
LY3076226 Dose Level (mg/kg)
1
0.2
2
0.4
3
0.8
4
1.6
5
2.4
6
3.2
7
4.0
8
5.0
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.
7.2.3. Dose Confirmation in Patients with Known Alterations of 
FGFR3 (Parts B and C)
Once the MTD has been defined in Part A, Parts B (urothelial carcinoma) and C (other 
malignancies) will be activated and will enroll up to approximately 15 patients who have known 
alterations of FGFR3, to further define the safety and tolerability of LY3076226 and to 
characterize the exploratory biomarker assays. The dose of LY3076226 in Parts B and C will 
not exceed the MTD of LY3076226, as defined during dose escalation in Part A.  The exact 
sample size of this cohort will be dependent on the number of patients who have known FGFR3 
alterations treated at the MTD during dose escalation in Part A, and will be adjusted so that a 
total of approximately 15 patients will be treated.
If a DLT-equivalent toxicity occurs in one third or more of patients during Cycle 1 (with a 
minimum of 6 patients enrolled), the enrollment of new patients will cease until the Lilly 
CRP/CRS and investigators assess the severity and nature of the toxicities.  A data review will be 
performed to determine whether to continue at the current LY3076226 dose or whether the dose 
of LY3076226 should be reduced. The toxicity-band method used in the dose-escalation phase 
will be updated with the additional data observed in Parts B and C to confirm the MTD selection 
and/or to inform any need to further refine the MTD. This decision will be documented in 
writing.
7.2.4. Recommended Phase 2 Dose (RP2D)
The RP2D will be determined after the completion of Parts B and C.  The RP2D will be agreed 
upon following discussion between the investigators and the Lilly CRP or CRS and will include 
an assessment of safety, PK, and PD data. This will not exceed the MTD.


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7.2.5. Infusion-Related Reactions
Due to the risk of hypersensitivity reactions with any biological agents, all patients should 
continue to be closely monitored for signs and symptoms indicative of an infusion-related 
reaction (IRR) both in the acute period (immediately or within 24 hours after dosing) and up to 
several days to a few weeks after dosing for delayed reactions. Acute assessments should 
include an assessment of vital signs starting at the time of initiation of the infusion and 
continuing until at least 60 minutes after the end of the infusion. At a minimum, vital signs 
should be obtained prior to infusion, during infusion, and at 1 hour post-infusion. The exact 
frequency of the monitoring is left to the discretion of the investigator. Monitoring should be 
performed in an area where resuscitation equipment and other agents (for example, epinephrine, 
corticosteroids) are readily available.
Per the CTCAE v 4.0 definition of IRRs, symptoms occurring during or following infusion of 
investigational therapy may be defined according to AE categories such as allergic reaction, 
anaphylaxis, or cytokine release syndrome. In the setting of symptoms occurring during or 
following infusion of investigational therapy, investigators are encouraged to use the AE term 
“infusion-related reaction” and any additional terms, including those not listed here, that best 
describe the event.
Section 7.2.6 provides treatment recommendations for IRRs.
If, at any time, a patient experiences an IRR to LY3076226, all attempts will be made to obtain a 
blood sample for immunogenicity analysis as close to the onset of the event as possible, at the 
resolution of the event, and 30 days following the event.  A portion of the sample taken for 
immunogenicity testing may be used for PK analysis, in the setting of IRRs.
If IRRs are observed, premedication with diphenhydramine hydrochloride (or equivalent), 
dexamethasone (or equivalent), or other medications as medically indicated may be considered 
for future patients. The decision to implement premedication for drug administration in 
subsequent patients will be made following a discussion between the investigators and sponsor 
and will be documented in writing.


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7.2.6. Dose Adjustments and Delays
7.2.6.1.
General Dose Adjustments and Delays
Once a patient has had a dose reduction (has started a new cycle at the reduced dose), all 
subsequent infusions will be at the reduced dose level; there will be no resumption to prior dose 
level(s).  Any patient experiencing toxicity that would necessitate more than 2 dose reductions 
must discontinue treatment.
The following criteria should guide dosing:

Before the start of each cycle, the following parameters are required:
o
Hematologic: ANC ≥1.5 × 109/L, platelets ≥100 × 109/L, and hemoglobin
≥8 g/dL.  (In Part C only, patients with multiple myeloma are allowed the 
following:  ANC ≥1.0 × 109/L, platelets 50 × 109/L, and hemoglobin 8 g/dL.)
o
Non-hematologic: AEs must resolve to CTCAE v 4.0 Grade ≤1 or baseline.  
Exceptions will be made for: alopecia, fatigue, or other toxicities that can be
controlled with standard treatment; these toxicities must resolve to Grade ≤2.

If subsequent cycles are delayed by more than 14 days due to an AE that is at least 
possibly related to LY3076226, the patient should be removed from study drug treatment 
and should complete subsequent follow-up.

If the patient is in Cycle 3 or beyond and is continuing to receive benefit from therapy, 
delays of greater than 14 days may be acceptable if agreed upon by both the investigator 
and sponsor. For instance, if a patient has a non-drug-related AE such as prolonged flu, 
the patient may continue on therapy if, in the opinion of the investigator, he/she is 
showing benefit from therapy and has recovered sufficiently from the AE.

A delay of no more than 7 days because of holidays, weekends, inclement weather, or 
other justifiable events will be permitted and will not be counted as a protocol deviation.
Table JOBA.4 presents LY3076226 dosing guidelines for managing AEs of concern, which may 
or may not be associated with LY3076226 therapy.


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Table JOBA.4.
LY3076226 Dosing Guidelines for Managing Adverse Events of Concern for Study I7O-MC-JOBA
Event and Grade
Specifics
LY3076226 Dosing Guidelines, Including Dose Reductions and 
Delays
Infusion-Related Reactions
Grade 1
First occurrence
Decrease LY3076226 infusion rate by 50% and monitor closely for any 
worsening.
For subsequent infusions, premedicate with diphenhydramine 
hydrochloride; additional premedication may be administered at the 
investigator's discretion.
Grade 2
First occurrence
Stop LY3076226 infusion. Administer diphenhydramine hydrochloride 
and acetaminophen for fever.  Supply oxygen. Resume infusion at 50% 
of previous rate once the infusion-related reaction has resolved or 
decreased to Grade 1 in severity, and monitor closely for any worsening.
For subsequent infusions, premedicate with diphenhydramine 
hydrochloride; additional premedication may be administered at the 
investigator's discretion. The reduced rate should be used for all 
subsequent infusions.
Grade 1 or 2
Second occurrence
Administer dexamethasone.
Grade ≥3
Stop LY3076226 infusion and disconnect infusion tubing from the 
patient.  Administer diphenhydramine hydrochloride, dexamethasone, 
bronchodilators for bronchospasm, and other medications/treatment as 
medically indicated.
Patients must not receive any further LY3076226 treatment.
Other Toxicities
Grade ≥3
First occurrence
Delay LY3076226 treatment until Grade ≤1 or baseline following the 
rules in Section 7.2.6.1.  Based on the investigator's discretion, the full 
dose of LY3076226 may be administered or the dose may be reduced to 
the next lowest dose level.  If the event recurs at the same grade, then
dose reduce LY3076226 to the next lowest dose level.
Grade ≥3
Second occurrence
Delay LY3076226 treatment until Grade ≤1 or baseline following the 
rules in Section 7.2.6.1.  Dose reduce LY3076226 to the next lowest 
dose level.


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7.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive LY3076226.  Before 
each patient’s enrollment into the study, an eligibility check must be conducted between the 
investigational site and the Lilly clinical research personnel to confirm that each patient meets all 
enrollment criteria.  Upon confirmation of eligibility, the sponsor will confirm the dose and 
identification number assignment and cohort for each patient.  No dose escalations (that is, to the 
next cohort) can occur without prior discussion and agreement with the responsible Lilly
CRP/CRS.
If investigators have eligible patients who have consented concurrently, more than the minimum 
number of patients for a cohort (1 or 3) may be entered at a particular dose level if accrual has 
not ceased due to excessive toxicity.  This enrollment 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.
7.4.
Blinding
This is an open-label study.
7.5.
Concomitant Therapy
In the absence of clinical experience with LY3076226, patients should be closely evaluated to 
ensure identification of exacerbations of known side effects of concomitant medications.  These 
should be reported immediately to the sponsor.
No other chemotherapy, radiotherapy, immunotherapy, cancer-related hormone therapy, or 
experimental drugs will be permitted while the patients are on this study. The need for any form 
of radiotherapy (including palliative) will be cause for early discontinuation from the study. In 
addition, any disease progression requiring other forms of specific antitumor 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 will be allowed.  Patients on stable doses of bisphosphonates are 
allowed to continue.
Concomitant use of strong CYP3A4 inhibitors (for example, ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
and voriconazole) with LY3076226 should be avoided due to the potential for an increase in 
DM4 exposure and toxicity. Where possible, consider an alternate medication with no or 
minimal potential to inhibit CYP3A4. Concomitant use of strong CYP3A4 inducers (for 
example, avasimibe [not commercially available], carbamazepine, phenytoin, rifampin, and St. 
John’s wort) with LY3076226 should be avoided due to the potential for a decrease in DM4 
exposure and potentially efficacy. Where possible, consider an alternate medication with no or 
minimal potential to induce CYP3A4. Concomitant use of strong CYP2D6 inhibitors (for 
example, bupropion, fluoxetine, paroxetine, and quinidine) with LY3076226 should be avoided 


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due to the potential for an increase in DM4 exposure and toxicity. Where possible, consider an 
alternate medication with no or minimal potential to inhibit CYP2D6. Refer to the Food and 
Drug Administration (FDA) website for a complete list 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm).
Patients should receive full supportive care with the exception that the routine use of granulocyte 
colony-stimulating factor (G-CSF) is not permitted during this study. Patients should not receive 
G-CSF prophylactically in any cycle.  G-CSF may only be used for patients who have ANC
<0.5 109/L, neutropenic fever, or documented infections while neutropenic.  G-CSF must be 
discontinued at least 24 hours before the start of the next cycle of treatment.  Should the use of 
hematopoietic colony-stimulating factors (CSFs) be necessary, follow the American Society of 
Clinical Oncology (ASCO) recommendations for the use of CSFs (Smith et al. 2006).  If 
clinically indicated at any time during the study, erythropoietin and packed red blood cell 
transfusions may be used according to ASCO guidelines (Rizzo et al. 2010).
Premedication is not permitted for the initial dose of LY3076226 for each patient.  Appropriate 
treatment with topical/oral corticosteroids and/or antibiotics may be instituted at the discretion of 
the investigator if skin reaction occurs.
All concomitant medications, including premedications, should be recorded throughout the 
patient’s participation in the study.


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7.6.
Treatment Compliance
LY3076226 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.
7.6.1. Evaluable Patients
Patients who withdraw from the study before receiving study drug will be replaced and will not 
be included in the safety or efficacy assessments.  Safety analyses will be conducted on all 
patients who have received at least one dose of study drug, regardless of whether they are 
deemed evaluable for the assessment of a dose level.
Any patient who is discontinued from the study before completing one cycle of LY3076226
treatment may be deemed non-evaluable for assessment of a dose level, unless they experience a 
DLT prior to withdrawal.
Patients who receive LY3076226 on Cycle 1, Day 1 (C1D1) but discontinue from study 
treatment before the end of Cycle 1 will be considered evaluable for the assessment of a dose 
level provided it can be documented if the patient experienced a DLT within 21 days of C1D1.
Nonevaluable patients may be replaced to ensure that enough patients complete one cycle of 
therapy at each dose level, unless accrual to that cohort has stopped due to a DLT.
Patients who are not evaluable for PK, but who complete one cycle of therapy, may be replaced 
upon consultation with the investigator(s) and the Lilly CRP/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
The safety and tolerability of LY3076226 has been assessed in nonclinical toxicology studies 
and the results from these studies are detailed in the IB.  This Phase 1 study contains detailed 
safety monitoring that will permit initial characterization of the safety profile of LY3076226 in 
patients.  Study procedures and their timing, including collection of blood and urine samples, are 
described in the Study Schedule (Attachment 1).
Standard laboratory tests, including chemistry, hematology, coagulation and urinalysis panels, 
will be performed.  A serum pregnancy test will be administered if applicable.  Other clinical 
laboratory tests will also be collected.  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.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  Table 
JOBA.5 presents a summary of AE and SAE reporting guidelines.  Table JOBA.5 also shows 
which database or system is used to store AE and SAE data.


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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 
unfavorable 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 labs, 
vital sign measurements, and so on, 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 v 4.0.
The National Cancer Institute (NCI)-CTCAE v 4.0 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 v 4.0.  Any minor version of CTCAE v 4.0 (for 
example, version 4.0X) may be used for this study.  Minor CTCAE v 4.0 updates from the NCI 
will not necessitate a protocol amendment. For AEs without matching terminology within the 
NCI-CTCAE v 4.0 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 fetal 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 drug must be stopped immediately.
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 electronic data entry the circumstances 
and data leading to any such dosage reduction or discontinuation of treatment.


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Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure and/or study drug via electronic data entry.
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 hospitalizations or elective procedures for underlying preexisting conditions that are 
already recorded in the patient’s medical history at the time of study enrollment should not be 
considered SAEs.  Hospitalization or prolongation of hospitalization without a precipitating 
clinical AE (for example, for the administration of study treatment or other protocol-required 
procedure) should not be considered SAEs.
An SAE is any AE during this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization (except for study drug 
administration)

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.
Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study drug.


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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.
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.
Refer to Attachment 6 for recommendations for reporting SAEs.
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 Drug
During prescreening and screening, all AEs and SAEs (regardless of relatedness to protocol 
procedures) are collected after the patient has signed the ICF.  For patients who do not enroll in 
the trial (that is, have not received at least one dose of study treatment), only AEs and SAEs 
related to protocol procedures are required to be collected.
8.1.2.2.2.
On-Study Treatment
All AEs and SAEs, regardless of relatedness to study drug 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.
8.1.2.2.3.
Follow-Up Visit
All AEs and SAEs, regardless of relatedness to study drug or protocol procedures, occurring 
during the follow-up visit (Visit 801) must be reported to Lilly or its designee.  The follow-up 
visit begins the day after the patient and the investigator agree that the patient will no longer 
continue study treatment.  The duration of the follow-up visit is 28 ± 5 days.  At the end of the 
follow-up visit, the patient will be required to have specific safety assessments (Attachment 1).  
If it is deemed to be in the best interest of the patient to start a new anti-cancer 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.
Following the safety assessments, which mark the end of the follow-up visit (Visit 801), the 
patient will be discontinued from the study, unless there is an ongoing AE or SAE that is 
possibly related to study drug.  In this instance, the patient should be followed until the event is 


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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.
After the follow-up visit (Visit 801), 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 an SAE 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
DCSI in the IB and that the investigator identifies as related to study drug or procedure.  The 
United States 21 Code of Federal Regulations (CFR) 312.32, the European Union Clinical Trial 
Directive 2001/20/EC and the associated detailed guidance 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 guidance.


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8.1.2.4.
Summary of AE/SAE Reporting Guidelines
The AE and SAE reporting guidelines are summarized in Table JOBA.5.
Table JOBA.5.
Adverse Event and Serious Adverse Event Reporting Guidelines 
for Study I7O-MC-JOBA
Timing
Types of AEs/SAEs Reported
Collection 
Database
Lilly Safety 
System
Prestudy (baseline assessments)
(Starts at the signing of the ICF 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 
and ends at last dose of study drug)
All AEs
All SAEs regardless of relatedness
x
x
x
Follow-up visit (Visit 801)
(Begins the day after the patient and 
the investigator agree that the 
patient will no longer continue 
study treatment.  The duration of 
the follow-up visit is 28 ± 5 days.)
All AEs
All SAEs regardless of relatedness
x
x
x
Continued access period
All AEs
All SAEs regardless of relatedness
x
x
x
Continued access period follow-up
All AEs
All SAEs regardless of relatedness
x
x
x
Subsequent follow-up visits, if 
necessary for patient monitoring
Ongoing AEs at least possibly related 
to study drug, 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; ICF = informed consent form; SAEs = serious adverse events.


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8.1.3. Other Safety Measures
8.1.3.1.
Electrocardiograms
For each patient, a 12-lead digital ECG will be collected according to the Study Schedule 
(Attachment 1).  Patients must be supine or semi-recumbent for approximately 5 to 10 minutes 
before ECG collection and remain supine or semi-recumbent but awake during ECG collection.
During Cycle 1, triplicate ECGs (consecutive replicate ECGs at approximately 1-minute 
intervals) will be done as specified in the Study Schedule (Attachment 1). Beginning with 
Cycle 2 and beyond, only a single ECG will be required. Electrocardiograms may be obtained at 
additional times, when deemed clinically necessary. Collection of more ECGs (more replicates)
than expected at a particular time point is allowed to ensure high-quality records.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria at the relevant visit(s) 
and for immediate patient management, should any clinically relevant findings be identified.
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the patient can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in patient management is 
needed and must document his/her review of the ECG printed at the time of evaluation from at 
least one of the replicate ECGs from each time point.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (for example, 
demographics and study details) then store the ECGs in a database.  At a future time, the stored 
ECG data may be overread at the central ECG laboratory for further evaluation of machine-read 
measurements or to meet regulatory requirements.
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless an overread of the ECGs is conducted prior to completion of the final study 
report (in which case the overread data would be used).


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8.1.4. Safety Monitoring
The Lilly CRP/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.
Ophthalmologist may perform additional examinations when visual changes or other ocular 
symptoms occur, at their discretion as clinically indicated.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities. Potential for biliary obstruction should be assessed. 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).  If a study patient experiences concurrent elevated ALT >3 × ULN and 
elevated total bilirubin >2 × ULN, clinical and laboratory monitoring should be initiated by the 
investigator.  If this is determined to be in the absence of biliary obstruction or other causes than 
can reasonably explain the concurrent elevation, then the patient should be discontinued from 
LY3076226.
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 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 AE
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.


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8.2.
Sample Collection and Testing
Attachment 1 (Study Schedule) lists the schedule for sample collections in this study.
Attachment 2 lists the clinical laboratory tests that will be performed for this study.
Attachment 4 is the PK, PD, and immunogenicity sampling schedule for this study.
Required and optional sample collection for PD and patient tailoring (exploratory biomarkers) is
as follows:
REQUIRED
Required samples to be collected in this study include:

Parts A, B, and C
o
Whole blood (refer to Section 8.2.4)
o
Exploratory plasma sample (refer to Section 8.2.3)

Part B only
o
Urine (refer to Section 8.2.3)
o
CK18 sample (refer to Section 8.2.2)
o
Pretreatment tissue biopsy (refer to Sections 8.2.2 and 8.2.3)
However, for patients who have disease recurrence/metastasis at body sites that are technically 
challenging for biopsy or who have available tissue from a prior regimen posttreatment biopsy 
and have not received intervening therapy, the investigator and sponsor may agree to omit the 
pretreatment biopsy.

Part C only
o
CK18 sample (refer to Section 8.2.2)
o
Pretreatment tissue biopsy (refer to Sections 8.2.2 and 8.2.3)
However, for patients who have disease recurrence/metastasis at body sites that are technically 
challenging for biopsy or who have available tissue from a prior regimen posttreatment biopsy 
and have not received intervening therapy, the investigator and sponsor may agree to omit the 
pretreatment biopsy.
If the FGFR3 alteration status is not known for a patient who is a potential candidate for 
participating in Parts B or C and an archived tissue sample is not available, the patient may have 
a biopsy collected locally to determine the FGFR3 alteration status for eligibility. If the patient 
qualifies for the study, a portion of this biopsy sample may be used for the required centrally 
collected pretreatment biopsy for PD and exploratory biomarker evaluation.


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OPTIONAL
Optional samples for biomarker research that should be collected from patients in the study,
where possible, include:

Parts A, B, and C
o
Archived tumor tissue (refer to Section 8.2.3)
If a patient has archived tumor tissue previously taken to evaluate the patient’s disease, a small 
amount of this tissue will be requested, if available, for biomarker research.

Parts B and C only
o
Posttreatment tissue biopsy (refer to Section 8.2.2)
Blood, urine, and tissue samples will be collected to determine whether patients meet 
inclusion/exclusion criteria and to monitor patient health.
Standard laboratory tests, including hematology and urinalysis panels, will be performed and 
analyzed by a local laboratory. Chemistry panels will be performed and analyzed centrally. 
Enrollment or dose adjustment decisions may be based upon chemistry results performed at a 
local laboratory; however, a sample must be sent to the central laboratory. These central 
chemistry laboratory results will be used for subsequent safety analyses. In the event of minor 
discrepancies between local and central laboratory results, the investigator may use the local 
results for treatment decisions, and the central laboratory results will remain part of the safety 
database. Discrepancies between local and central results that may have an impact on treatment 
decisions will not be considered protocol violations.
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.


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8.2.1. Samples for Pharmacokinetics
At the visits and times specified in Attachment 4, venous blood samples of approximately 6 mL 
each will be collected to determine the plasma concentrations of conjugated LY3076226, total 
LY3076226 IgG, and the metabolites DM4 and DM4-Me.
A maximum of 5 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.
These samples will be analyzed at laboratories designated by the sponsor.  Plasma concentrations
of conjugated LY3076226 and total LY3076226 IgG will be assayed using validated ELISA 
methods.  Plasma concentrations of DM4 and DM4-Me will be assayed using a validated LC-MS 
assay.
The PK samples will be stored at a facility designated by the sponsor located in the 
United States.
The remaining plasma from the 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.
8.2.2. Samples for Pharmacodynamics
Samples will be taken to measure cell cycle arrest and apoptosis.  Tissue biopsy may be taken by 
core needle biopsy and/or surgical biopsy (pretreatment and posttreatment fresh tumor biopsies 
in Parts B and C).  Due diligence should be used to ensure that tumor specimen (not normal 
adjacent or tumor margins) is provided.  Pathology notes accompanying the tissue may also be 
requested.
Bioanalytical tissue samples collected to measure Ki-67, pHH3, and caspase 3 will be identified 
by the patient number (coded) and retained for a maximum of 15 years or until testing is 
complete following last patient visit for the study at a facility selected by the sponsor.
In Parts B and C, bioanalytical blood samples will also be collected at visits and times indicated 
in Attachment 1 in order to measure CK18 levels.  These blood samples will be identified by the
patient number (coded) and retained for a maximum of 5 years or until testing is complete
following last patient visit for the study at a facility selected by the sponsor.


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8.2.3. Samples for Exploratory Biomarkers
Exploratory analysis may be conducted using blood (including ethylenediaminetetraacetic acid 
[EDTA] plasma), urine, and tumor tissue to explore potential biomarkers related to LY3076226
mechanism of action, the FGFR3 pathway, DM4 mechanism of action, and the cancer 
pathobiology, to better understand relationship with clinical outcomes.  Tumor tissue samples 
may be analyzed to explore potential tumor gene signature(s) associated with response or 
resistance to LY3076226 therapy.  These studies may be analyzed at a laboratory designated by 
the sponsor and may include IHC of proteins, fluorescence in situ hybridization (FISH) for copy 
number amplifications, ribonucleic acid (RNA) gene-expression profiling, and/or genetic 
analyses of the tumor specimen deoxyribonucleic acid (DNA). Such analyses may employ 
targeted or high-throughput sequencing approaches.
8.2.4. Samples for Pharmacogenetic Research
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology, and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a blood sample will be collected for pharmacogenetic analysis.  In 
the event of an unexpected AE or the observation of unusual response, the pharmacogenetic 
biomarker samples may be genotyped and analysis may be performed to evaluate a genetic 
association with response to study drug.  These investigations may be limited to a focused 
candidate gene study or, if appropriate, genome-wide analysis may be performed to identify 
regions of the genome associated with the variability observed in drug response.  The 
pharmacogenetic biomarker samples will only be used for investigations related to disease and 
drug or class of drugs under study in the context of this clinical program.  They will not be used 
for broad exploratory unspecified disease or population genetic analysis.
The samples will be coded with the patient number and stored for up to a maximum 15 years 
after the last patient visit for the study at a facility selected by the sponsor.  The samples and any 
data generated from them can only be linked back to the patient by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the study drug.
Samples will be destroyed according to a process consistent with local regulation.


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8.2.5. Samples for Immunogenicity Research
At the visits and times specified in Attachment 1, blood samples for immunogenicity testing will 
be collected to determine antibody production against study drug.  Immunogenicity will be 
assessed by a validated assay designed to detect anti-drug antibodies (ADA) in the presence of 
study drug.  Antibodies may be further characterized and/or evaluated for their ability to 
neutralize the activity of study drug.
In addition to planned sampling for immunogenicity testing, if at any time a patient experiences 
an IRR to study drug, all attempts will be made to obtain a blood sample for immunogenicity 
analysis as close to the onset of the event as possible, at the resolution of the event, and 30 days 
following the event.  A portion of the sample taken for immunogenicity testing may be used for 
PK analysis, in the setting of IRRs.
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 study drug.  
The duration allows the sponsor to respond to regulatory requests related to study drug.
8.3.
Efficacy Evaluations
A secondary objective of the study is to document any antitumor activity.  Refer to Attachment 1
for details regarding the timing of specific efficacy measures.
Each patient will be assessed by one or more of the following radiologic tests for tumor 
measurement:

Computed tomography (CT) scan

Magnetic resonance imaging (MRI)

For lymphoma patients only, positron emission tomography (PET)/CT is permitted if 
appropriate for standard of care (Cheson et al. 2014)
Each patient’s full extent of disease will also be assessed with:

Tumor measurement by RECIST 1.1 (Eisenhauer et al. 2009), international 
uniform response criteria for multiple myeloma (Rajkumar et al. 2011), or 
response criteria for lymphomas (Cheson et al. 2014).

Evaluation of tumor markers, if indicated.

Evaluation of performance status (refer to the ECOG scale, Attachment 7).
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 progressive disease are present.


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8.4.
Procedure/Sampling Compliance
Every attempt will be made to enroll 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, PD samples, and efficacy measurements 
are given as targets, to be achieved within reasonable limits. Every attempt should be made to 
adhere to the sample collection times in the first 3 cycles. The scheduled time points may be 
subject to minor alterations; however, the actual collection time must be correctly recorded on 
the CRF or laboratory requisition form. However, delays of ±1 day due to holidays, inclement 
weather, or other justifiable events will be permitted and will not be counted as a protocol 
deviation.
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 institutional 
review boards (IRBs)/ERBs with direct access to the original source documents.
9.2.
Data Capture Systems
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.
9.2.1. Case Report Form
Case report form data will be encoded and stored in a clinical trial database.
For data handled by a data management third-party organization (TPO), CRF data and some or 
all data that are related will be managed and stored electronically in the TPO system.  
Subsequent to the final database lock, validated data will be transferred to the Lilly SAS for 
Drug Development (SDD) system, using Lilly Integration Broker file transfer processes.
For data handled by the sponsor internally, CRF data and some or all data that are related will be 
managed by the sponsor and stored electronically in the sponsor’s system.


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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 laboratory system (GLS).
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly GLS.
Electrocardiogram data will be stored electronically in the central database system of Lilly’s 
central review organization.  Data will subsequently be transferred from the central review 
organization system to the Lilly GLS.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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10. Data Analyses
10.1. General Considerations
Up to approximately 65 patients may be enrolled in this multicenter, nonrandomized, open-label 
Phase 1 dose-escalation study of LY3076226. Patients will be enrolled into cohorts sequentially 
without randomization to dose. The Bayesian model-based, toxicity-band method will be 
followed to assist dose escalation. The toxicity-band method will provide quantitative guidance 
on the determination of the dose level for the next cohort based on the observed DLT data.
Compared with the traditional 3+3 method, the toxicity-band method provides a lower 
underdosing rate and a higher MTD selection rate, with a well-controlled overdosing rate at a 
prespecified criterion. Refer to Attachment 10 for more details. The sample size for Part A will 
primarily be determined by the incidence of DLTs prior to establishing the MTD in Part A.  The 
anticipated sample size for Part A ranges from approximately 20 to 35 patients. In each of Parts 
B and C, up to approximately 15 patients who have known alterations of FGFR3 will be 
enrolled. The sample sizes of Parts B and C have been selected to allow adequate assessment of 
safety at the recommended dose and to characterize the biomarker assay.
Statistical analysis of this study will be the responsibility of Eli Lilly and Company.
The analyses for this study will be descriptive; no p-values will be calculated. Data analyses will 
be provided by cohorts and for all study patients combined whenever appropriate. For 
continuous variables, summary statistics will include number of patients, mean, median, standard 
deviation, standard error, minimum, and maximum. Categorical endpoints will be summarized 
using number of patients, frequency, percentages, and their standard errors. Missing data will 
not be imputed.
The interpretation of the study results will be the responsibility of the investigator with the Lilly
CRP/CRS, pharmacokineticist, and statistician.  The CRP/CRS 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.
Exploratory analyses of the data not described in Sections 10.2 through 10.9 will be conducted as 
deemed appropriate.
10.2. Patient Disposition
All patient discontinuations will be documented, and the extent of each patient’s participation in 
the study will be reported.  If known, a reason for their discontinuation will be given.
Patients are expected to have tumor assessments after receiving 3 cycles of treatment. Patients 
completing the study are defined as patients who received tumor assessments after 3 cycles. 
Patient disposition will be summarized for patients not completing 3 cycles.


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10.3. Patient Characteristics
Patient characteristics will include a summary and/or listing of the following:

Patient demographics including age, sex, screening height and weight, and screening 
body mass index (BMI)

Baseline disease characteristics

Prior disease-related therapies

Concomitant medications
Other patient characteristics will be summarized as deemed appropriate.
10.4. Safety Analyses
All patients who receive at least one dose of LY3076226 will be evaluated for safety and 
toxicity.  Adverse event terms and severity grades will be assigned by the investigator using 
CTCAE v 4.0.
Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drug

dose adjustments

laboratory values

vital signs

DLTs at each dose level

ECG readings
10.5. Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on patients who have received at least one dose of 
the study drug and have had samples collected.
Pharmacokinetic parameter estimates for conjugated LY3076226 and total LY3076226 IgG and 
metabolites DM4 and DM4-Me will be calculated by standard noncompartmental methods of 
analysis.  The primary parameters for analysis will be Cmax and AUC of conjugated LY3076226 
and total LY3076226 IgG and metabolites DM4 and DM4-Me.  Other noncompartmental 
parameters, such as t1/2, CL, and volume of distribution (V) may be reported.
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.
Pharmacokinetic parameter estimates will be evaluated to delineate effects of dose 
proportionality using methods described previously (Smith et al. 2000).  Log-transformed Cmax
and AUC estimates will be assessed to estimate ratios of geometric means and the corresponding 
90% confidence intervals (CIs).


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10.6. Pharmacodynamic Analyses
Pharmacodynamic data will be summarized by dose, drug concentrations, and time from dose. 
Potential PD markers-versus-time data will be presented graphically for each patient and 
summarized by dose. Absolute and/or percentage change from baseline may be evaluated. Data 
may be log-transformed prior to summarizing, if necessary. The interpatient and intrapatient 
variability of the PD markers may also be assessed where appropriate.
If the data allow, a PK/PD analysis may also be performed, wherein PD data from all patients 
would be analyzed using linear and/or nonlinear fixed and mixed effects models as appropriate.
10.7. Immunogenicity Analyses
Immunogenicity data will be summarized by dose, drug concentrations, and time from dose.
If the data allow, immunogenicity data from all patients may also be analyzed using linear and/or 
nonlinear fixed and mixed effects models as appropriate.
10.8. Efficacy
The study is not designed to make an efficacy assessment.  However, any tumor response data 
will be tabulated.  Particularly, the antitumor effect will be summarized by the overall response 
rate (ORR). A patient is considered to have a tumor response if they achieve a confirmed CR or 
PR according to RECIST 1.1 (Eisenhauer et al. 2009) or lymphoma criteria (Cheson et al. 2014);
or a confirmed stringent complete response (sCR), CR, very good partial response (VGPR), or
PR according to multiple myeloma (IMWG) criteria (Rajkumar et al. 2011). The ORR will be 
estimated by dividing the total number of confirmed complete and partial responders (CR+PR) 
by the total number of enrolled patients. A 90% exact CI will be constructed to determine the 
level of precision of the tumor response rate. Time-to-event variables will also be tabulated. For 
PFS and duration of response, the Kaplan-Meier method (Kaplan and Meier 1958) will be used 
to estimate the survival curves, medians, and survival rates if applicable.
10.9. Tailoring Biomarker
Biomarker assessments in this study will focus on identifying markers and/or marker signatures 
that may indicate the patients most likely to respond or be resistant to LY3076226. Exploratory 
analysis may be conducted using blood, urine, and tumor tissue to explore potential biomarkers 
related to LY3076226 mechanism of action, the FGFR3 pathway, DM4 mechanism of action, 
and the cancer pathobiology, to better understand relationship with clinical outcomes.  Tumor 
tissue samples may be analyzed to explore potential tumor gene signature(s) associated with 
response or resistance to LY3076226 therapy.
In all analyses, adjustments may be made to account for other baseline patient characteristics, 
safety, and PK/PD data. Unless otherwise stated, given the small sample sizes involved, 
statistical analyses results will be considered exploratory and will not consider multiple 
comparison adjustments.


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10.10.
Interim Analyses
Once the LY3076226 MTD is defined for Part A, an interim analysis will be performed prior to 
opening Parts B and C.
At the end of Parts B and C, an analysis may be conducted to review available safety, PK, and 
efficacy data once all evaluable patients have either completed 3 cycles of study treatment or 
discontinued from the study treatment.
Because this is a dose-finding study, data will be reviewed on a cohort-by-cohort basis during the 
study, until the MTD is determined for Part A.  The purpose of these cohort-by-cohort reviews is 
to evaluate the safety data and any available PK data at each dose level and determine if 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.
In Parts B and C, if a DLT-equivalent toxicity occurs in one third or more of patients during 
Cycle 1 (with a minimum of 6 patients enrolled), a data review will be performed to determine 
whether to continue at the current LY3076226 dose or whether the dose of LY3076226 should 
be reduced. Refer to Section 7.2.3 for more details.
If an unplanned interim analysis is deemed necessary, the sponsor will determine if it is 
necessary to amend the protocol.


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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.
There may be 2 ICFs used in this study:  a prescreening ICF and a study ICF.  The prescreening 
ICF will provide relevant information and document that the patient is satisfied with his or her 
understanding of the collection and testing of the tumor sample for FGFR3 alterations, for 
potential study candidates when FGFR3 alteration status is unknown.
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.
As used in this protocol, the term “informed consent” includes all consent given by patients or 
their legal representatives.
11.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative site(s).  All 
ICFs must be compliant with the ICH guideline on GCP.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  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 updates during the course of the study

ICF

relevant curricula vitae


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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
(CIOMS) International Ethical Guidelines
2) the ICH 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.
An identification code assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting AEs and/or other 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 most enrolled patients will serve as the final report coordinating 
investigator.  If this investigator is unable to fulfill 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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JG, Zagzag D, Mikkelsen T, Finocchiaro G, Lasorella A, Rabadan R, Iavarone A. 
Transforming fusions of FGFR and TACC genes in human glioblastoma. Science. 
2012;337(6099):1231-1235.
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.
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, Cantor 
SB, Crawford J, Cross SJ, Demetri G, Desch CE, Pizzo PA, Schiffer CA, Schwartzberg L, 
Somerfield MR, Somlo G, Wade JC, Wade JL, Winn RJ, Wozniak AJ, Wolff AC. 2006 update 
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Stewart JP, Thompson A, Santra M, Barlogie B, Lappin TR, Shaughnessy J Jr. Correlation of 
TACC3, FGFR3, MMSET and p21 expression with the t(4;14)(p16.3;q32) in multiple 
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antibody-maytansinoid conjugates allows for efficient detoxification via liver metabolism. 
Bioconjug Chem. 2011;22:728-735.
Sung JY, Sun JM, Chang Jeong B, Il Seo S, Soo Jeon S, Moo Lee H, Yong Choi H, Young Kang 
S, Choi YL, Young Kwon G. FGFR3 overexpression is prognostic of adverse outcome for 
muscle-invasive bladder carcinoma treated with adjuvant chemotherapy. Urol Oncol. 
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Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev 
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I7O-MC-JOBA(a) Phase 1 Oncology Protocol
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Attachment 1.
Protocol JOBA Study Schedule
Baseline Assessments
Relative day
to Cycle 1, Day 1
Pre-
screening
Screening
Comments
28
14
7
Informed consent
X
X
ICF signed (prior to performance of any protocol-
specific tests/procedures).  Prescreening consent 
for Parts B and C only, for patients with unknown 
FGFR3 alteration status.
Collection of tumor 
tissue sample for 
local FGFR3 
alteration testing for 
eligibility (Parts B 
and C only)
X
Archived tissue or biopsy if archived tissue is not 
available.  If prescreening biopsy is performed 
and results are positive and patient signs study 
ICF, a portion of this biopsy may be used for 
pretreatment biopsy for the study.
Radiological tumor 
assessment according 
to RECIST 1.1
X
Radiological assessments obtained previously 
(≤28 d prior to C1D1) as part of routine clinical 
care may be used as the baseline assessment.  
Appropriate tumor assessment criteria should be 
used for patients with multiple myeloma (IMWG 
[Rajkumar et al. 2011; refer to Attachment 5]) or 
lymphoma (Cheson et al. 2014).
Medical history
X
Including alcohol/tobacco use and other relevant 
habits assessments.
Physical examination
X
Including height and weight.
Standard ophthalmic 
examination
X
Performed by an ophthalmologist.
Vital signs
X
Including temperature, BP, PR, RR.
ECOG performance 
status
X
Central ECG
X
One set of triplicate ECGs.
Local hematology
X
Refer to Attachment 2.
Central serum 
chemistry 
X
Refer to Attachment 2.  Enrollment or dose 
adjustment decisions may be based upon 
chemistry results performed at a local laboratory; 
however, a sample must be sent to the central 
laboratory.
Coagulation (local)
X
Refer to Attachment 2.
Local urinalysis
X
Tumor measurement 
(palpable or visible)
X
CTCAE v 4.0 grading 
(preexisting 
conditions)
X
Refer to Section 8.1.2.


I7O-MC-JOBA(a) Phase 1 Oncology Protocol
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Baseline Assessments (continued)
Relative day
to Cycle 1, Day 1
Pre-
screening
Screening
Comments
28
14
7
Concomitant 
medications
X
Local tumor markers
X
If applicable.
Central archived 
tissue sample
X
Collected only if patient has met 
inclusion/exclusion criteria.
Local pregnancy test, 
serum
X
For women of childbearing potential.
Central pretreatment 
tumor tissue biopsy 
(Parts B and C only)
X
Collected only if patient has met 
inclusion/exclusion criteria.  If the patient had 
prescreening biopsy to assess FGFR3 alteration 
status, a portion of the prescreening biopsy may 
be used for pretreatment biopsy for the study.
Abbreviations:  BP = blood pressure; C = cycle; CTCAE = Common Terminology Criteria for Adverse Events; D = 
day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FGFR3 = fibroblast growth factor 
receptor 3; ICF = informed consent form; IMWG = International Myeloma Working Group; PR = pulse rate; 
RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1; RR = respiration rate.


I7O-MC-JOBA(a) Phase 1 Oncology Protocol
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During Study-Treatment Assessments
Cycle 1
Cycle 2
Cycle 3
Cycles
4-n
Comments
Relative day 
within a cycle
1
2
4
8
15
1
8
15
1
2
4
8
15
1
Cycle duration = 21 d
LY3076226
X
X
X
X
Physical 
examination
X
X
X
X
X
X
X
X
X
X
Performed on Day 1 of each cycle.  
Physical examination can be done 
≤24 h prior to Day 1 of each cycle
or ±24 h for other days.
Ophthalmic 
examination
X
Performed by an ophthalmologist 
anytime from Days 15-21.
Additional monitoring may occur 
if clinically indicated at the 
discretion of the ophthalmologist. 
Weight
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Temperature, BP, PR, RR.  At a 
minimum, vital signs should be 
obtained prior to infusion, during 
infusion, and at 1 h following end 
of infusion.  Refer to Section
7.2.5.
Central ECG
X
X
X
In Cycle 1, triplicate ECGs 
collected predose and at end of 
infusion.  In Cycles 2 and 3, single 
ECG collected predose and at end 
of infusion.  Refer to Attachment 
4.
Local 
hematology
X
X
X
X
X
X
X
X
X
X
Can be drawn ≤24 h prior to Day 
1 or ±24 h for other days.
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During Study-Treatment Assessments (continued)
Cycle 1
Cycle 2
Cycle 3
Cycles 
4-n
Comments
Relative day 
within a cycle
1
2
4
8
15
1
8
15
1
2
4
8
15
1
Cycle duration = 21 d
Central serum 
chemistry
X
X
X
X
X
X
X
X
X
X
Can be drawn ≤24 h prior to Day 
1 of a cycle or ±24 h for other 
days.  Enrollment or dose 
adjustment decisions may be 
based upon chemistry results 
performed at a local laboratory; 
however, a sample must be sent to 
the central laboratory.
Local urinalysis
X
X
X
X
Can be collected ≤24 h prior to 
Day 1 of a cycle.
CTCAE v 4.0 
grading
X
X
X
X
Throughout study as needed.  
Refer to Section 8.1.2 for 
reporting guidelines.
Data on SAEs that occur before 
the end of trial will be stored in 
the collection database and the 
Lilly Safety System.
Concomitant 
medications
X
X
X
X
Throughout study as needed.
ECOG 
performance 
status
X
X
X
X
Central PK 
sampling
X
X
X
X
X
X
X
X
X
X
X
X
Refer to Attachment 4 for exact 
timing.
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I7O-MC-JOBA(a) Phase 1 Oncology Protocol
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During Study-Treatment Assessments (continued)
Cycle 1
Cycle 2
Cycle 3
Cycles 
4-n
Comments
Relative day 
within a cycle
1
2
4
8
15
1
8
15
1
2
4
8
15
1
Cycle duration = 21 d
Tumor 
measurement 
(palpable or 
visible)
X
X
X
X
Radiological 
tumor 
assessment
X
X
Use RECIST 1.1 (Eisenhauer et 
al. 2009), multiple myeloma 
criteria (IMWG [Rajkumar et al. 
2011; refer to Attachment 5]), or 
lymphoma criteria (Cheson et al. 
2014).
The same method of imaging used 
at baseline should be used for 
each subsequent assessment.  
Imaging should be performed 
during the last wk of every third 
cycle; that is, Cycles 3, 6, 9, 12, 
and so on). May be omitted if 
patient has clear signs of
progressive disease. In addition, 
any patient whose disease has not 
progressed by 1 y after entering 
the trial may be assessed every 
18 wk.
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During Study-Treatment Assessments (continued)
Cycle 1
Cycle 2
Cycle 3
Cycles 
4-n
Comments
Relative day 
within a cycle
1
2
4
8
15
1
8
15
1
2
4
8
15
1
Cycle duration = 21 d
Local tumor 
markers
X
X
X
If applicable to patient’s tumor 
type.  May be drawn up to 3 d 
prior to the planned assessment.
Posttreatment
tumor biopsy 
(Parts B and C 
only)
X
Optional.  Posttreatment biopsy 
may be performed on C1D4 or 
C1D5 to allow flexibility for 
scheduling.
Central urine 
sample for 
biomarkers 
(Part B only)
X
X
Collect preinfusion on C1D1. 
Refer to Attachment 4 for exact 
timing.
Central CK18
X
X
X
X
X
X
X
X
X
X
X
X
Parts B and C only.  Refer to 
Attachment 4 for exact timing.
Whole blood for 
central DNA 
storage
X
Collect once. Sample can be 
collected at any time if not 
collected on C1D1.
Central
exploratory
plasma sample
X
X
X
X
X
X
X
X
X
X
X
X
Refer to Attachment 4 for exact 
timing.
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I7O-MC-JOBA(a) Phase 1 Oncology Protocol
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During Study-Treatment Assessments (continued)
Cycle 1
Cycle 2
Cycle 3
Cycles 
4-n
Comments
Relative day 
within a cycle
1
2
4
8
15
1
8
15
1
2
4
8
15
1
Cycle duration = 21 d
Central 
immunogenicity 
sample
X
X
X
X
Refer to Attachment 4 for exact 
timing. Note that after Cycle 3, 
sample will be collected every 
other cycle (for example, C5, C7, 
etc).
In addition to the scheduled 
samples, if a patient should have 
an IRR to LY3076226, all 
attempts should be made to obtain 
an immunogenicity sample as 
close to the onset of the event as 
possible, at the resolution of the 
event, and 30 d following the 
event. A portion of the sample 
taken for immunogenicity testing 
may be used for PK analysis.
Abbreviations:  BP = blood pressure; C = cycle (as in C#D#); CK18 = cytokeratin 18; CTCAE = Common Terminology Criteria for Adverse Events; D = day (as 
in C#D#); DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; IMWG = International Myeloma Working 
Group; IRR = infusion-related reaction; PK = pharmacokinetic(s); PR = pulse rate; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1;
RR= respiration rate; SAE = serious adverse event.


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Posttreatment Discontinuation Follow-Up Assessments
Study Period
Short-Term 
Follow-Up
Visit
801
The follow-up visit begins the day after the patient and the investigator agree that the patient will no longer continue study 
treatment.
Duration
28±5 d
Procedure
Comments
Weight
X
Vital signs
X
Including temperature, BP, PR, RR.
ECOG performance status
X
Tumor measurement (palpable or visible)
X
Performed if lesion is assessed as target or non-target.  Not required if progressive disease is documented while on treatment.
Radiologic imaging
X
Use RECIST 1.1 (Eisenhauer et al. 2009), multiple myeloma criteria (IMWG [Rajkumar et al. 2011; refer to Attachment 5]), or 
lymphoma criteria (Cheson et al. 2014).
The same method of imaging used at baseline should be used for each subsequent assessment.  Not required if progressive 
disease is documented while on treatment or if there are clear signs of clinical progression.
CTCAE v 4.0 grading
X
Refer to Section 8.1.2.  Report all AEs during the Short-Term Follow-Up period.  After Visit 801, only study protocol- or drug-
related events are reported.  If a patient has an ongoing AE or SAE at least possibly related to LY3076226, 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.
Concomitant medication notation
X
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I7O-MC-JOBA(a) Phase 1 Oncology Protocol
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Posttreatment Discontinuation Follow-Up Assessments (continued)
Cycle
Short-Term 
Follow-Up
Visit
801
The follow-up visit begins the day after the patient and the investigator agree that the patient will no longer continue study 
treatment.
Duration
28±5 d
Procedure
Comments
Local hematology
X
Central serum chemistry
X
Central ECG
X
Single ECG.
Local urinalysis
X
Local tumor markers
X
If applicable to tumor type of the patient.
Central immunogenicity sample
X
In addition to the scheduled sample, if a patient should have an IRR to LY3076226, all attempts should be made to obtain an 
immunogenicity sample as close to the onset of the event as possible, at the resolution of the event, and 30 d following the 
event.
If a patient requires subsequent follow-ups (eg, for an ongoing AE), an immunogenicity sample should be obtained, if possible.  
A portion of the sample taken for immunogenicity testing may be used for PK analysis.
Refer to Attachment 4 for exact timing.
Central PK sample
X
Refer to Attachment 4 for exact timing.
Central urine sample for biomarkers (Part B only)
X
Central exploratory plasma sample
X
Abbreviations:  AE = adverse event; BP = blood pressure; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = 
Eastern Cooperative Oncology Group; IMWG = International Myeloma Working Group; IRR = infusion-related reaction; PK = pharmacokinetic(s); PR = pulse 
rate; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1; RR = respiration rate; SAE = serious adverse event.
Note:  No follow-up procedures will be performed for patients who withdraw informed consent unless he or she has explicitly provided permission and consent.


I7O-MC-JOBA(a) Phase 1 Oncology Protocol
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Continued Access Schedule
Study Period
Continued Access 
Treatment Period
Continued Access 
Follow-Up
Visit
501-5XX
901
Relative day 
within a cycle
1
Procedure
Comments
Weight
X
LY3076226
X
CTCAE v 4.0 
grading
X
X
Refer to Section 8.1.2.  In the event that SAE occurs, additional information 
(such as local laboratory results, concomitant medications, and 
hospitalizations) may be requested by Lilly in order to evaluate the reported 
SAE.
Central 
immunogenicity 
sample
If applicable
During the continued access period, if a patient should have an IRR to 
LY3076226, all attempts should be made to obtain immunogenicity sample as 
close to the onset of the event as possible, at the resolution of the event, and 
30 d following the event.
If a patient requires subsequent follow-ups (for example, for an ongoing AE), 
an immunogenicity sample should be obtained, if possible. A portion of the 
sample taken for immunogenicity testing may be used for PK analysis.
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; IRR = infusion-related reaction; PK = pharmacokinetic(s); 
SAE = serious adverse event.


I7O-MC-JOBA(a) Phase 1 Oncology Protocol
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Attachment 2.
Protocol JOBA Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya:
Clinical Chemistryb:
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Magnesium
Leukocytes (WBC)
Potassium
Neutrophils
Total bilirubin
Lymphocytes
Direct bilirubin
Monocytes
Alkaline phosphatase
Eosinophils
Alanine aminotransferase
Basophils
Aspartate aminotransferase
Platelets
Blood urea nitrogen
Creatinine
Coagulationa:
Creatinine clearance, calculatedc
Prothrombin time (PT or INR)
Uric acid
Partial thromboplastin time (PTT or aPTT)
Calcium
Ionized calcium
Glucose, random
Urinalysisa:
Albumin
Specific gravity
Total protein
pH
Chloride
Protein
Glucose
Serum Pregnancy Test (females only)a
Ketones
Blood
Urine leukocyte esterase
Abbreviations:  aPTT = activated partial thromboplastin time; PT/INR = international normalized ratio of 
prothrombin time; RBC = red blood cells; WBC = white blood cells.
a
Local or investigator-designated laboratory.
b
Lilly-designated (central) laboratory.  Enrollment or dose adjustment decisions may be based upon chemistry 
results performed at a local laboratory; however, a sample must be sent to the central laboratory.
c
Cockcroft and Gault formula will be used for calculated creatinine clearance.  See Attachment 8.


I7O-MC-JOBA(a) Phase 1 Oncology Protocol
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Attachment 3.
Protocol JOBA 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 hematologya
Haptoglobina
Hemoglobin
Hematocrit
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
Anti-nuclear 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 normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Attachment 4.
Protocol JOBA Pharmacokinetic, 
Pharmacodynamic, and Immunogenicity Sampling 
Schedule


I7O-MC-JOBA(a) Phase 1 Oncology Protocol
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Pharmacokinetic, Pharmacodynamic, and Immunogenicity Sampling Schedule
Type of Sample or Assessment
Visit 
(Cycle)/Day
Sampling Time
(relative to LY3076226 dosing)
PK:
LY3076226 
and 
metabolites
PD:
CK18
(Parts B
and C)
Exploratory
plasma
PD:
Tumor tissue 
biopsy
(Parts B and C)
Urine for 
biomarkers
(Part B only)
ECG
IG
V0/≤28 d
≤28 d prior to the first dose
x
x
C1/Day 1
Prior to infusion
x
x
x
x
x
x
Within 5 min post infusion
x
xa
1 ± 0.1 h post infusion
x
3 ± 0.25 h post infusion
x
6 ± 0.25 h post infusion
x
C1/Day 2
24 ± 1 h post infusion
x
x
x
C1/Day 4
72 ± 1 h post infusion
x
x
x
xb
C1/Day 8
Anytime
x
x
x
C1/Day 15
Anytime
x
x
x
C2/Day 1
Within 15 min prior to infusion
x
x
x
xc
x
Within 5 min post infusion
x
xa
C3/Day 1
Within 15 min prior to infusion
x
x
x
xd
xc
x
Within 5 min post infusion
x
xa
1 ± 0.1 h post infusion
x
3 ± 0.25 h post infusion
x
6 ± 0.25 h post infusion
x
C3/Day 2
24 ± 1 h post infusion
x
x
x
C3/Day 4
72 ± 1 h post infusion
x
x
x
C3/Day 8
Anytime
x
x
x
C3/Day 15
Anytime
x
x
x
C4/Day 1
Within 15 min prior to infusion
x
x
x
Within 5 min post infusion
x
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I7O-MC-JOBA(a) Phase 1 Oncology Protocol
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Pharmacokinetic, Pharmacodynamic, and Immunogenicity Sampling Schedule (continued)
Type of Sample or Assessment
Visit 
(Cycle)/Day
Sampling Time
(relative to LY3076226 dosing)
PK:
LY3076226 
and 
metabolites
PD:
CK18
(Parts B 
and C)
Exploratory 
plasma
PD:
Tumor tissue 
biopsy
(Parts B and C)
Urine for 
biomarkers
(Part B only)
ECG
IG
C5 and then 
every other 
cycle/Day 1
Within 15 min prior to infusion
x
x
Within 5 min post infusion
x
Short-Term 
Follow-Up 
(V801)
28 ± 5 d after treatment discontinuation 
decision
x
x
x
x
Abbreviations:  C = cycle (as in C#D#); CK18 = cytokeratin 18; D = day (as in C#D#); ECG = electrocardiogram; IG = immunogenicity; PD = 
pharmacodynamic(s); PK = pharmacokinetic(s); V = visit.
a
Post-infusion ECG can be done within 15 minutes after end of infusion.
b
Posttreatment biopsy may be performed on C1D4 or C1D5 to allow flexibility for scheduling.
c
Predose ECG can be obtained prior to predose blood samples.
d
Predose urine biomarker sample (Part B only) can be obtained prior to predose blood samples.


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Attachment 5.
Protocol JOBA Multiple Myeloma Tumor 
Assessment
For patients with multiple myeloma enrolled to this trial, the International Myeloma Working 
Group (IMWG) uniform response criteria (Rajkumar et al. 2011) will be used for tumor 
assessment.  Each patient with multiple myeloma will be assessed at baseline via serum and 
urine protein electrophoresis (SPEP or UPEP, respectively), serum and urine immunofixation 
electrophoresis (SIFE or UIFE, respectively), and serum free light chains (SFLC).  Patients will 
have baseline imaging of plasmacytomas and, after eligibility criteria have been met, patients 
should have a skeletal survey and a bone marrow examination.  Refer to the following tables for 
assessments and timing and a summary of IMWG response criteria.


I7O-MC-JOBA(a) Phase 1 Oncology Protocol
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Assessments and Timing for Patients with Multiple Myeloma
Myeloma 
Assessment
Baseline
C1 - CX
Short-Term
Follow-Up
(Visit 801)
Comments
Local 
quantitative 
immunoglobulins
X
X
X
Baseline performed ≤28 d prior to C1D1.  On study:  Performed on D1 of each cycle, prior to 
treatment.  Short-term follow-up (Visit 801):  May be omitted if progressive disease is previously 
documented or if there are clear signs of clinical progression.
Local SPEP/IFE
X
X
X
Baseline performed ≤28 d prior to C1D1.  On study:  Performed on D1 of each cycle, prior to 
treatment.  Short-term follow-up (Visit 801):  May be omitted if progressive disease is previously 
documented or if there are clear signs of clinical progression.
Local 24-h urine 
for UPEP/IFE
X
X
X
Baseline performed ≤28 d prior to C1D1.  On study:  Performed prior to D1 of each cycle.  The 
urine collection should be completed as close to the visit as possible.  Short-term follow-up (Visit 
801):  May be omitted if progressive disease is previously documented or if there are clear signs of 
clinical progression.
Local serum free 
light chains
X
X
X
Baseline performed ≤28 d prior to C1D1.  On study:  Performed on D1 of each cycle, prior to 
treatment.  Short-term follow-up (Visit 801):  May be omitted if progressive disease is previously 
documented or if there are clear signs of clinical progression.
Local bone 
marrow aspirate
X
A bone marrow aspirate is required prior to start of study therapy and to confirm CR, sCR, 
immunophenotypic CR, or molecular CR.
Skeletal survey
X
A skeletal survey should include skull, spine, pelvis, bilateral femur, and bilateral humerus.  Skeletal 
survey should be repeated as clinically indicated or at least every 12 mo.
Plasmacytoma 
measurement
X
X
If a plasmacytoma is present, CT or MRI should be used to obtain bi-dimensional measurements at 
baseline, and the test used at baseline should be repeated to assess response.  If a measureable 
plasmacytoma is present at baseline, plasmacytoma needs to be evaluated (perform a CT scan or 
MRI) every time that response is assessed.
Abbreviations:  C# = cycle; CR = complete response; CT = computed tomography; D# = day; IFE = immunofixation electrophoresis (serum/urine); MRI = 
magnetic resonance imaging; sCR = stringent complete response; SPEP = serum protein electrophoresis; UPEP = urine protein electrophoresis.


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International Myeloma Working Group Uniform Response Criteria
Response
Criteria
CRa,b,c,d
Negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND <5% plasma cells in 
bone marrow
Clarification:  In patients in whom the only measurable disease is by serum FLC levels, normal FLC ratio of 0.26-1.65 is 
required, in addition to CR criteria.
sCRa,b,c,d
CR (as defined above) PLUS normal FLC ratio AND absence of clonal plasma cells by immunohistochemistry or 2- to 4-color 
flow cytometry
Immunophenotypic CR
sCR (as defined above) PLUS absence of phenotypically aberrant plasma cells (clonal) in bone marrow with a minimum of 1 
million total bone marrow cells analyzed by multiparametric flow cytometry (with >4 colors)
Molecular CR
CR (as defined above) PLUS negative ASO-PCR, sensitivity 10−5
VGPRa,b,c,d
Serum and urine M-component detectable by immunofixation but not on electrophoresis OR ≥90% reduction in serum M-
component plus urine M-component <100 mg/24 h
Clarification:  In patients in whom the only measurable disease is by serum FLC levels, a >90% decrease in the difference 
between involved and uninvolved FLC levels is required, in addition to VGPR criteria.
PRa,b,c
≥50% reduction of serum M-protein AND reduction in 24-h urinary M-protein by ≥90% or to <200 mg/24 h
If serum and urine M-protein are not measurable, a decrease ≥50% in the difference between involved and uninvolved FLC levels 
is required in place of the M-protein criteria.
If serum and urine M-protein and serum FLC assay are not measurable, ≥50% reduction in bone marrow plasma cells is required 
in place of M-protein, provided baseline percentage was ≥30%.
In addition to the above criteria, if present at baseline, ≥50% reduction in size of soft tissue plasmacytomas is also required.
MR for relapsed refractory 
myeloma onlye
≥25% but ≤49% reduction of serum M-protein AND reduction in 24-h urine M-protein by 50%-89%
In addition to the above criteria, if present at baseline, 25%-49% reduction in size of soft tissue plasmacytomas is also required.
No increase in size or number of lytic bone lesions (development of compression fracture does not exclude response).
SDb,c,d
Not meeting criteria for CR, VGPR, PR, or PD
- Table is continued on the next page. -


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International Myeloma Working Group Uniform Response Criteria (continued)
Response
Criteria
PDa,d
Increase of 25% from lowest response value in any of following:

serum M-component (absolute increase must be ≥0.5 g/dL; serum M-component increases ≥1 g/dL are sufficient to 
define relapse if starting M component ≥5 g/dL)

urine M-component (absolute increase must be ≥200 mg/24 h)

only in patients without measurable serum and urine M-protein levels:  the difference between involved and uninvolved 
FLC levels (absolute increase must be >10 mg/dL)

only in patients without measurable serum and urine M-protein levels and without measurable disease by FLC level: 
bone marrow plasma cell percentage (absolute percentage must be ≥10%)
Definite development of new bone lesions or soft tissue plasmacytomas, or definite increase in the size of existing bone lesions or 
soft tissue plasmacytomas
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to the plasma cell 
proliferative disorder
Clarification:  Bone marrow criteria for PD are to be used only in patients without measurable disease by M-protein and by FLC 
levels; “25% increase” refers to M-protein, FLC, and bone marrow results and does not refer to bone lesions, soft tissue 
plasmacytomas, or hypercalcemia, and the “lowest response value” does not need to be a confirmed value.
Abbreviations:  ASO-PCR = allele-specific oligonucleotide polymerase chain reaction; CR = complete response; EBMT = European Group for Blood and 
Marrow Transplantation; FLC = free light chain; M= monoclonal; MR = minimal response; PD = progressive disease; PR = partial response; sCR = stringent 
complete response; SD = stable disease; VGPR = very good partial response.
a
All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before the institution of any new therapy.
b
CR, sCR, VGPR, PR, and SD also require no known evidence of progressive or new bone lesions if radiographic studies were performed.
c
VGPR and CR categories require serum and urine studies regardless of whether disease at baseline was measurable on serum, urine, both, or neither.  CR, 
sCR, VGPR, PR, and SD also require no known evidence of progressive or new bone lesions if radiographic studies were performed.
d
Radiographic studies are not required to satisfy these response requirements.  Bone marrow assessments need not be confirmed.
e
Adopted from the EBMT criteria (Bladé et al. 1998).
Source:  Rajkumar et al. 2011


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Attachment 6.
Protocol JOBA 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 hospitalization), 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, investigator assessment of relationship 
to study drug and protocol procedures.


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Attachment 7.
Protocol JOBA ECOG Performance Status
Eastern Cooperative Oncology Group (ECOG) Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction.
1
Restricted in physically strenuous activity but ambulatory and able 
to carry out 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.
Source:  Oken et al. 1982.


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Attachment 8.
Protocol JOBA Creatinine Clearance 
Formula
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)
a age in years, weight (wt) in kilograms.
Reference:  Cockcroft and Gault 1976.


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Attachment 9.
Protocol JOBA RECIST Criteria 1.1
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumors (RECIST): Revised RECIST 
Guideline (version 1.1; Eisenhauer et al. 2009).
Measurability of Tumor at Baseline
Tumor lesions/lymph nodes will be categorized at baseline as measurable or nonmeasurable.  
Measurable disease is defined by the presence of at least 1 measurable lesion.
Measurable 
Tumor lesions:  Measured in at least 1 dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of:

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (slice thickness 5 mm)

10 mm caliper measurement by clinical exam (non-measurable lesions if cannot 
be accurately measured with calipers)

20 mm by chest X-ray
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan thickness recommended 
to be 5 mm).
Nonmeasurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis) as well as truly nonmeasurable lesions.  Lesions considered truly 
non-measurable include:  leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitis involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measureable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone lesions:

Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.

Blastic bone lesions are non-measurable.


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


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should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessed by clinical exam.
An adequate volume of a suitable contrast agent should be given so that the metastases are 
demonstrated to best effect and a consistent method is used on subsequent examinations for any 
given patient.  If prior to enrollment it is known a patient is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or 
MRI (with or without IV contrast) should be used to evaluate the patient at baseline and follow-
up should be guided by the tumor type under investigation and the anatomic location of the 
disease.
Clinical Lesions:  Clinical lesions will only be considered measurable when they are superficial 
and 10 mm diameter as assessed using calipers (for example, skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size of the 
lesion is recommended.  When lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may be reviewed at the 
end of the study.
Chest X-ray:  Chest CT is preferred over chest X-ray when progression is an important endpoint.  
Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded 
by aerated lung.
CT and MRI:  CT scan is the best currently available and reproducible method to measure lesions 
selected for response assessment.  Measurability of lesions on CT scan is based on the
assumption that CT slice thickness is 5 mm.  When CT scan have slice thickness >5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (for example, for body scans).  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances.
Ultrasound:  Ultrasound should not be used to measure lesion size.  Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a later date and, because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in the course 
of the study, confirmation by CT or MRI is advised.
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques can be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint.
Tumor Markers:  Tumor markers alone cannot be used to assess tumor response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete response (CR).  Specific guidelines for both prostate-specific antigen (PSA) response 
(in recurrent prostate cancer) and CA-125 response (in recurrent ovarian cancer) have been 
published.


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


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Non-CR/ non-PD:  Persistence of 1 or more non-target lesions and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease:  Unequivocal progression of existing non-target lesions.  The appearance 
of 1 or more new lesions is also considered progression.
Not Evaluable: When a change in method of measurement from baseline occurs and impacts the 
ability to make a reliable evaluation of response.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
the earliest of objective progression or start of new anticancer therapy, taking into account any 
requirement for confirmation.  The patient’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions.  The Best Overall Response will be calculated via an algorithm using 
the assessment responses provided by the investigator over the course of the trial.
Time Point Response
It is assumed that at each protocol-specified time point, a response assessment occurs.  (When no 
imaging/measurement is done at all at a particular time point, the patient is not evaluable [NE] at 
that time point.)  Table 1 of this attachment provides a summary of the overall response status 
calculation at each time point for patients who have measurable disease at baseline.
Table 1.
Time Point Response: Patients with Target (non-target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations:  CR = complete response; PR = partial response; SD = stable disease.; PD = progressive disease; NE 
= not evaluable.
Table 2 of this attachment is to be used when patients have nonmeasurable disease only.


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


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


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Attachment 10. Protocol JOBA Toxicity-Band Method for 
Phase 1 Dose Escalation
The need to minimize the number of patients treated below the biological active dose and the 
understanding of LY3076226 from earlier nonclinical and clinical studies supports a more 
efficient dose-escalation design for Study JOBA.  Therefore, the Bayesian model-based method 
is used in this trial to determine the next dose level, based on the predicted probabilities of DLT 
rates.  The exact dose-escalation increment will be determined by the investigators and Lilly 
CRP/CRS and may be different from the model recommendation.  This section introduces the 
background of a model-based dose-escalation method and toxicity-band design 
(Neuenschwander et al. 2008) and describes the key elements for this trial.  Simulation results 
from the toxicity-band design are presented.  These results are also compared with that from the 
simulation of traditional 3+3 design to demonstrate the benefit of implementing a toxicity-band 
design in this trial.  Fixed and Adaptive Clinical Trial Simulator (FACTS) software version 3.5 is 
used for all the simulations.
Introduction to Continual Reassessment Method (CRM) Approaches
The continual reassessment method (CRM; O’Quigley et al. 1990) is the first Bayesian model-
based approach developed for dose-escalation studies.  Compared to the traditional 3+3 design 
that only used current dose-level DLT data to estimate the MTD, CRM utilizes prior dose 
toxicity information and all available DLT data to effectively estimate the MTD.  To improve the 
operating characteristics of CRM, Goodman et al. (1995), among others, have proposed modified
CRM (MCRM) procedures to make the model-based designs more acceptable in practice.  The 
major modifications include:

Always start at the lowest dose level.

Limit the escalation increment.

Escalate by cohorts rather than single patients.
Babb et al. (1998) proposed the escalation-with-overdose-control method (EWOC) that directly 
controls the probability of overdosing during dose escalation.  EWOC is also a CRM-type 
method.  During the escalation, EWOC selects the next dose such that the predicted probability 
that the new dose exceeds the MTD is equal to a prespecified feasibility bound α=0.25.  The 
connection between CRM and EWOC is that CRM typically uses the middle (mean or median) 
of the MTD’s posterior distribution as the next recommended dose, whereas EWOC uses the 
25th percentile.  Therefore, EWOC is a more conservative method than the original CRM 
method.


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Toxicity-Band Design 
Neuenschwander et al. (2008) extended the concept of EWOC (Babb et al. 1998) and proposed 
considering the uncertainty of the posterior distributions and using interval estimates to make the 
dose recommendation, herein referred to as the toxicity-band design. 
The Model 
A 2-parameter logistic model is used to model the relationship between dose and probability of a 
DLT: 
logit	
 =  +  log  	
	∗ ,     > 0.  1.1
  
In the model, 	 is the true dose and 	
 is the probability of a DLT at dose 	.  	∗ is the 
reference dose, such that  is interpreted as the log-odds of a DLT at  	∗. 
Toxicity Band 
The probability of a DLT is categorized to 4 bands: 
• Underdosing:  	
 in (0, 0.20] 
• Targeted toxicity:  	
 in (0.20, 0.33] 
• Excessive toxicity:  	
 in (0.33, 0.60] 
• Unacceptable toxicity:  	
 in (0.60, 1.00] 
Overdosing is defined as 	
 > 0.33. 
Dose Recommendation 
During the escalation, after each cohort of patients, the following will be done: 
1. Calculate the posterior probabilities of  the 4 toxicity bands for each dose. 
2. Exclude the doses such that the posterior probabilities of overdosing are larger than 0.25 
(overdosing control criteria).  The remaining doses are the ones that satisfy the overdose 
control criteria. 
3. Among the remaining doses, the dose with the highest posterior probability in the 
targeted toxicity band will be the model recommendation of the next dose. 
The data will be evaluated on an ongoing basis until the MTD is determined.  Once the MTD has 
been identified, a discussion between the sponsor and investigators may occur in order to treat 
additional patients at intermediate doses below the MTD. 
Dose Range and Reference Dose 
It is assumed that the starting dose level for the toxicity-band method is 1.6 kg/mg.  Based on the 
preclinical data, the highest dose level that will be explored in this study is 5 mg/kg and the 
reference dose in model (1.1) is chosen as d∗= 5 mg/kg. 


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The Prior Distribution on Model Parameters 
A quantile-based uninformative prior (Neuenschwander et al. 2008) is used to derive a bivariate-
normal prior on (α, logβ).  Based on preclinical experience of LY3076226, the median 
probability of DLT for the dose levels from 1.6 mg/kg to 5 mg/kg was determined as in Table 1
of this attachment. Any intermediate dose level within the starting doses to 5 mg/kg can be 
explored.
Table 1.  Prior Median Probability of DLT at Each Dose Level
Dose (mg/kg)
Median Probability of DLT
1.6
0.075
2.4
0.125
3.2
0.175
4
0.225
5
0.35
Abbreviation:  DLT = dose-limiting toxicity.
For each dose, the minimally informative unimodal Beta distribution (a,b) is derived as the prior 
distribution for the probability of DLT, so that the operating characteristics of the model are 
robust to the selected prior distribution of DLT:

For median probability of DLT <0.5, b=1 and a(<1) are tuned to match the median.

For median probability of DLT >0.5, a=1 and b(<1) are tuned to match the median.
Figure 1 shows the median and the 95% CI of the prior distribution of the DLT rate at each dose
level.
Abbreviations:  CI = confidence interval; DLT = dose-limiting toxicity.
Figure 1.  The prior distribution of DLT rate at each dose level.


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A bivariate normal distribution was derived on (α, logβ) that stochastically gives the best fit to 
the 2.5%, 50%, and 97.5% quantiles of the prior probability of DLT at each dose.  The 
parameters (α, logβ) have a bivariate normal distribution with mean=(-0.69,0.39), 
SD=(1.95,1.05), and ρ=-0.25.
Simulation Studies
Simulations were performed under different scenarios of possible dose-toxicity relationships to 
investigate the operational characteristics of the toxicity-band versus traditional 3+3 design:

3-patient cohorts starting from the lowest dose.

Maximum number of patients: 24 for toxicity-band method and 30 for traditional 3+3 
method.

Stopping rules for toxicity-band method:  maximum sample size reached or at least 6 
patients have been treated at the recommended next dose level.
Assuming that the starting dose level is 1.6 mg/kg, 4 scenarios were considered to represent a 
wide range of possible dose-toxicity relationships as shown in Figure 2 and Table 2 of this 
attachment. DLT rates for the starting dose level are chosen to take into account single-patient 
cohorts before. The true DLT rate of the MTD is set at 20% to 33% across scenarios.  Scenarios 
1 and 2 have MTD at 5 mg/kg, and Scenarios 3 and 4 have MTD at 4 mg/kg. When the dose-
toxicity curve is steep around MTD, the concern is the risk of overdosing; when the dose-toxicity 
curve is flat around MTD, the concern is underdosing. The simulation studies will access the 
performance of the toxicity-band method and compare it to the traditional 3+3 focusing on these 
concerns.
Figure 2.  The dose-toxicity relationships under each scenario.
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
1.6
2.4
3.2
4
5
Scenario 1
Scenario 2
Scenario 3
Scenario 4


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Table 2.  The Dose-Toxicity Relationships under Each Scenario Starting from 1.6 mg/kg
Dose 
(mg/kg)
Scenarios
1
2
3
4
1.6
0.05
0.075
0.1
0.13
2.4
0.08
0.135
0.15
0.19
3.2
0.12
0.185
0.2
0.245
4
0.18
0.235
0.3
0.3
5
0.28
0.28
0.42
0.38
One thousand (1000) simulations were conducted under each scenario to investigate the 
operational characteristics of toxicity-band and traditional 3+3 methods.  The results are 
summarized in Table 3 of this attachment.
Table 3. Comparison of Toxicity-Band and Traditional 3+3 Methods
Rate of Selected as 
MTD for Each Dose 
(mg/kg)
Scenarios
1
2
3
4
TB
3+3
TB
3+3
TB
3+3
TB
3+3
1.6
0.079
0.08
0.185
0.192
0.25
0.258
0.392
0.394
2.4
0.078
0.119
0.155
0.199
0.209
0.208
0.195
0.233
3.2
0.134
0.183
0.122
0.214
0.257
0.242
0.196
0.177
4
0.305
0.285
0.198
0.177
0.22
0.209
0.143
0.135
5
0.404
0.333
0.34
0.218
0.064
0.083
0.074
0.071
Rate of selecting Ph2 
dose below true MTD
0.596
0.667
0.66
0.782
0.611
0.671
0.783
0.818
Rate of selecting Ph2 
dose above true MTD
0
0
0
0
0.064
0.083
0.074
0.071
Rate of DLT events 
during the trial
0.16
0.14
0.20
0.19
0.22
0.22
0.26
0.25
Mean # subjects
17.5
16.4
16.0
14.9
14.2
14.0
12.8
12.4
Abbreviations:  TB = toxicity-band method; DLT = dose-limiting toxicity; MTD = maximum tolerated dose.
Results based on 1000 simulations.
The traditional 3+3 design is generally conservative and has a higher rate of selecting a dose 
level below the true MTD to be recommended for future Phase 2 studies, increasing the risk of 
under-dosing and failure rate of Phase 2 studies. The toxicity-band method is slightly more 
aggressive in general and has a lower rate of MTD selection below the true level, and a higher 
rate of MTD selection at the true level. The mean percentages of a DLT event in each scenario 
are in general higher in the toxicity-band method, but strictly kept below the prespecified 
overdosing control criterion at 0.25.


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Examples
Examples from Scenario 1 and Scenario 4 are provided here to illustrate how the toxicity-band 
method operates under certain circumstances.
Example 1
Scenario 1 has a true MTD at 5 mg/kg with a DLT rate of 0.28 in Table 2. With a slowly
increasing relationship between the dose level and the DLT rate, patients could be assigned to 
dose levels under MTD and cause underdosing when DLT occurs in the first few cohorts.
With the toxicity-band method, the next recommended dose level is 5 mg/kg after the 15th
patient is treated (Figure 3a), although 2 DLTs are observed at 4 mg/kg, and 4 mg/kg will be 
declared as MTD after 21 patients are treated. However, using the traditional 3+3 method, dose 
de-escalation will be conducted after the 12th patient, since 2 DLTs have already been seen at 
the current dose level. The toxicity-band method has also allocated more patients at the MTD 
dose level.
Abbreviation:  MTD = maximum tolerated dose.
Figure 3a.  A case study for Scenario 1.


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Example 2
Scenario 3 has a true MTD at 4 mg/kg with a DLT rate of 0.3 in Table 2. With a relatively steep 
increasing relationship between the dose level and the DLT rate, patients could be assigned to 
dose levels above MTD and cause overdosing when few DLT occurs in the first few cohorts.
With the toxicity-band method, the next recommended dose level is still 4 mg/kg after the 18th
patient is treated (Figure 3b), although 1 DLT is observed at 4 mg/kg. As 6 patients have already 
been treated at the next recommended dose level, the dose escalation is ceased and 4 mg/kg will 
be declared as MTD. However, using the traditional 3+3 method, the lower do se, 3.2 mg/kg, 
will be selected as MTD. Therefore, the selected MTD from the toxicity-band method is closer 
to the true MTD comparing to the traditional 3+3 method.
Abbreviation:  MTD = maximum tolerated dose.
Figure 3b.  A case study for Scenario 3.


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Summary
As a conclusion, based on the simulation studies on a variety of scenarios and the illustrative 
examples, the toxicity-band method is slightly more aggressive than the traditional 3+3 design, 
and therefore provides a lower underdosing rate and a higher MTD selection rate, with a well-
controlled overdosing rate at a prespecified criterion. Therefore, the modified 3+3 method that 
incorporates the principles of the toxicity-band method will be used in this study rather than the 
traditional 3+ 3 escalation paradigm.


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Attachment 11. Protocol JOBA Alterations for FGFR3
Such as the following FGFR3 alterations:
R248C
S249C
G372C
Y375C
K650E
K652E
FGFR3-TACC3 fusion
t(4;14)(p16.3;q32.3)


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Attachment 12.
Protocol Amendment I7O-MC-JOBA(a) 
Summary
A Phase 1 Study of LY3076226, a Fibroblast Growth Factor 
Receptor 3 (FGFR3) Antibody-Drug Conjugate,
in Patients with Advanced or Metastatic Cancer
Overview
Protocol I7O-MC-JOBA, A Phase 1 Study of LY3076226, a Fibroblast Growth Factor 
Receptor 3 (FGFR3) Antibody-Drug Conjugate, in Patients with Advanced or Metastatic Cancer,
has been amended.  The new protocol is indicated by Amendment (a) and will be used to conduct 
the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

As requested by the Food and Drug Administration (FDA), patients with 
preexisting corneal diseases that may interfere with assessment of potential 
toxicity in the eyes during the study have been excluded in Section 6.1.2.

As requested by the FDA, patients with skin disorders (for example, erythema, 
dermatitis) of ≥Grade 2 have been excluded in Section 6.1.2.

As requested by the FDA, in reference to patients who may have refused standard 
therapy, wording has been added to Section 6.1.1 to state that these patients must 
be well informed about the benefit and risk of the standard therapy before signing 
the informed consent.

As requested by the FDA, dose-limiting toxicity criteria (DLT) in Section 7.2.2.1
have been revised to indicate that the following events considered at least possibly 
related to LY3076226 will be DLTs:  Grade 3 fatigue lasting >5 days, Grade 3 
elevations in AST or ALT lasting >7 days, and concurrent elevation of ALT >3 × 
ULN and total bilirubin >2 × ULN in the absence of biliary obstruction or other 
causes that could reasonably explain the elevation. In addition, wording was 
added to Section 7.2.2.1 and Section 6.3.1 to indicate that significant related 
toxicity resulting in a >14-day delay in starting Cycle 2 would be considered a 
DLT.

As requested by the FDA, infusion duration information was added to Section 
7.2.1.

As requested by the FDA, clarification that premedication is not permitted for the 
initial dose of LY3076226 for each patient was added to Section 7.2.1.

As requested by the FDA, clarification on expanding one-patient cohorts when 
Grade 2 or greater events considered at least possibly related to study drug are 
observed has been added to Section 7.2.2.3.


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
As requested by the FDA, Section 8.1.4 has been modified to indicate that 
patients who have a concurrent elevation of ALT >3 × ULN and total bilirubin >2 
× ULN and who, following assessment by the investigator, have no evidence of 
biliary obstruction or other causes that can reasonably explain the concurrent 
elevation, will be discontinued from the study.  Additionally, Section 7.2.2.1 was 
revised as noted above for consistency with Section 8.1.4.

As requested by the FDA, additional ophthalmic examinations as clinically 
indicated at the ophthalmologist’s discretion were added to Section 8.1.4 and 
Attachment 1.

As requested by the FDA, information about FGFR3 alteration types has been 
added in Attachment 11 and is referenced in Section 6.1.1 Inclusion Criteria.

As requested by the FDA, a section has been added to specifically address the 
RP2D determination, Section 7.2.4.

As requested by the FDA, wording regarding avoidance of strong inducers and 
inhibitors of CYP3A and strong inhibitors of CYP2D6A has been added to 
Section 7.5.

Additional minor changes were made to increase the clarity and consistency of the 
document and to correct typographical errors.


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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.
4.  Abbreviations and Definitions
Term
Definition
C1D1
Cycle 1, Day 1
FDA
Food and Drug Administration
RP2D
recommended Phase 2 dose
6.1.1.  Inclusion Criteria
[1]
Must be, in the judgment of the investigator, an appropriate candidate for 
experimental therapy after available standard therapies have failed to provide 
clinical benefit for their disease or if the patient refuses standard therapy.  
Patients must be well informed about the benefit and risk of standard therapy 
prior to signing the informed consent.
Part A (dose escalation):  Have histological or cytological evidence of a 
diagnosis of cancer (including multiple myeloma and lymphoma) that is 
advanced and/or metastatic.
Part B (dose expansion):  Have histologically or cytologically confirmed, 
locally advanced, or unresectable or metastatic urothelial (transitional cell) 
carcinoma of the bladder, urethra, ureter, or renal pelvis, with locally 
determined overexpression or alterations of FGFR3 (refer to Attachment 11).
Part C (dose expansion):  Have histological or cytological evidence of a 
diagnosis of cancer (including multiple myeloma and lymphoma) that is 
advanced and/or metastatic, with locally determined overexpression or 
alterations of FGFR3 (refer to Attachment 11).
[2]
Part A:  Have the presence of measurable and/or nonmeasurable disease as 
defined by the appropriate criteria:  Response Evaluation Criteria in Solid 
Tumors, version 1.1 (RECIST 1.1 [refer to Attachment 9]; Eisenhauer et al. 
2009), multiple myeloma criteria (International Myelo ma Working Group 
[IMWG; refer to Attachment 5]; Rajkumar et al. 2011), or lymphoma criteria 
(Cheson et al. 200714).
Parts B and C:  Have the presence of measurable disease as defined by the 
appropriate criteria:  RECIST 1.1 (Eisenhauer et al. 2009), multiple myeloma 
criteria (IMWG; Rajkumar et al. 2011), or lymphoma criteria (Cheson et al. 
200714).


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6.1.2.  Exclusion Criteria
[13] Have symptomatic CNS malignancy or metastasis (screening not required).
Patients with treated CNS metastases are eligible for this study if they are not 
currently receiving corticosteroids for this indication and/or anticonvulsants, 
and their disease is asymptomatic and radiographically stable for at least 28 
days.
[19] Have preexisting corneal diseases that may interfere with assessment of 
potential toxicity in the eyes during the study. 
[20] Have skin disorders (for example, erythema, and dermatitis) of Grade ≥2.
6.3.1.  Discontinuation of Patients
In addition, patients will be discontinued from the study drug and/or from the study in the 
following circumstances:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Investigator/Physician Decision
o
The investigator/physician decides that the patient should be discontinued from 
the study or study drug.
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 occurs prior to introduction of the other 
agent.

Patient Decision
o
The patient requests to be discontinued from the study or study drug.

Sponsor Decision
o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and GCP.

The patient has radiographic progressive disease or significant symptomatic disease 
deterioration characterized as progression of disease, in the opinion of investigator, in the 
absence of radiographic evidence of progressive disease.

The patient experiences unacceptable toxicity.

The patient is noncompliant with study procedures and/or treatment (Section 7.6).

The patient’s dosing is delayed for more than 2 weeks as the result of an AE that is at 
least possibly related to LY3076226.  If this delay occurs for the start of Cycle 2, this will 
be considered a DLT.


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7.2.1.  Dosing Schedule
For doses ≤250 mg, LY3076226 will be administered as an IV infusion over approximately 60 
minutes on Day 1 of each 21-day cycle.  The sponsor may instruct the sites to extend the infusion 
time for up to 2 hours for doses greater than 250 mg. The assigned dose and duration of infusion 
of LY3076226 will be provided by the sponsor on a patient registration form.  Subsequent doses 
should be adjusted as described in Section 7.2.6.
Premedication is not permitted for the initial dose of LY3076226 for each patient so that any 
observed toxicities may be appropriately characterized.
7.2.2.1.  Dose-Limiting Toxicity Determination and Maximum Tolerated Dose Definition
Dose-limiting toxicity (DLT) is defined as an AE occurring during Cycle 1 that is at least 
possibly related to LY3076226 and fulfills any one of the following criteria using the NCI-
CTCAE v 4.0:

CTCAE Grade ≥3 non-hematological toxicity.  Exceptions will be made for the 
following:
o
Nausea, vomiting, diarrhea, and constipation that can be controlled with treatment 
(Grade 3 and Grade 4 nausea, vomiting, or diarrhea should be considered DLTs if 
persisting for more than 48 hours, despite supportive intervention.)
o
Fatigue and aAnorexia
o
Grade 3 fatigue lasting ≤5 days

Grade 3 elevations of ALT and/or AST lasting >7 days, 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 or 
clinical research scientist (CRS).

Concurrent elevation of ALT >3 × ULN and total bilirubin >2 × ULN in the absence of 
biliary obstruction or other causes that could reasonably explain the elevation.

CTCAE Grade 4 neutropenia of >7 days’ duration

Any febrile neutropenia

CTCAE Grade 3 thrombocytopenia with bleeding

CTCAE Grade 4 thrombocytopenia with or without bleeding

Any other significant toxicity deemed by the primary investigator and Lilly clinical 
research personnel to be dose limiting (for example, any toxicity that is at least possibly 
related to the study medication and that requires the withdrawal of the patient from the 
study during Cycle 1 or delays the start of Cycle 2 by >14 days).
7.2.2.2.  DLT-Equivalent Toxicity
If the rate of DLT-equivalent toxicities is unacceptable (for example, a DLT-equivalent toxicity 
is observed in >33% patients at a given dose level), the data will be reviewed by study 
investigators and the Lilly CRP/clinical research scientist (CRS) and a safety analysis may be 
triggered.


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7.2.2.3. Dose-Escalation Method
For Part A, the proposed starting dose level will be 0.2 mg/kg.  Dose escalation will proceed at a 
maximum dose increment of 100%.  An accelerated dose-escalation scheme will be used, as 
follows:  initial cohorts will enroll at least one patient each until a dose level of 1.6 mg/kg is 
reached, unless a ≥Grade 2 toxicity that is at least possibly related to LY3076226 is observed 
requires requiring enrolling additional patients to be enrolled to a dose level.  After which a 
modified 3+3 scheme, with incorporation of a Bayesian model-based, toxicity-band method 
(Neuenschwander et al. 2008), will be followed, wherein at least 3 patients will be enrolled in 
each of the subsequent cohorts.  The Bayesian model-based, toxicity-band method incorporates 
the prior expectations of the dose-toxicity curve and the observed DLT data after each cohort and 
provides quantitative guidance on the determination of the dose level for the next cohort, with 
control of overdosing probability.  This method will be applied to the observed data on an 
ongoing basis throughout the dose escalation.  The toxicity-band method will stop if the 
prespecified maximum number of patients is reached or the recommended next dose level has 
been administered to at least 6 patients.
7.2.4.  Recommended Phase 2 Dose (RP2D)
The RP2D will be determined after the completion of Parts B and C.  The RP2D will be agreed 
upon following discussion between the investigators and the Lilly CRP or CRS and will include 
an assessment of safety, PK, and PD data.  This will not exceed the MTD.
7.2.6.1.  General Dose Adjustments and Delays

Before the start of each cycle, the following parameters are required:
o
Hematologic:  ANC ≥1.5 × 109/L, platelets ≥100 × 109/L, and hemoglobin 
≥8 g/dL.  (In Part C only, patients with multiple myeloma are allowed the 
following:  ANC ≥1.0 × 109/L, platelets 50 × 109/L, and hemoglobin 8 g/dL.)
o
Non-hematologic:  AEs must resolve to CTCAE v 4.0 Grade ≤1 or baseline.  
Exceptions will be made for:  alopecia, fatigue, or other toxicities that can be 
controlled with standard treatment; these toxicities must resolve to Grade ≤2.

If subsequent cycles are delayed by more than 14 days due to an AE that is at least 
possibly related to LY3076226, the patient should be removed from study drug treatment 
and should complete subsequent follow-up.


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7.5.  Concomitant Therapy
Concomitant use of strong CYP3A4 inhibitors (for example, ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
and voriconazole) with LY3076226 should be avoided due to the potential for an increase in 
DM4 exposure and toxicity. Where possible, consider an alternate medication with no or 
minimal potential to inhibit CYP3A4. Concomitant use of strong CYP3A4 inducers (for 
example, avasimibe [not commercially available], carbamazepine, phenytoin, rifampin, and St. 
John’s wort) with LY3076226 should be avoided due to the potential for a decrease in DM4 
exposure and potentially efficacy. Where possible, consider an alternate medication with no or 
minimal potential to induce CYP3A4. Concomitant use of strong CYP2D6 inhibitors (for 
example, bupropion, fluoxetine, paroxetine, and quinidine) with LY3076226 should be avoided 
due to the potential for an increase in DM4 exposure and toxicity. Where possible, consider an 
alternate medication with no or minimal potential to inhibit CYP2D6. Refer to the Food and 
Drug Administration (FDA) website for a complete list 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm).
Premedication is not permitted for the initial dose of LY3076226 for each patient.  Appropriate 
treatment with topical/oral corticosteroids and/or antibiotics may be instituted at the discretion of 
the investigator if skin reaction occurs.
7.6.1.  Evaluable Patients
Any patient who is discontinued from the study before completing one cycle of LY3076226 
treatment will may be deemed non-evaluable for assessment of a dose level, unless they 
experience a DLT prior to withdrawal.
Patients who receive LY3076226 on Cycle 1, Day 1 (C1D1) but discontinue from study 
treatment before the end of Cycle 1 will be considered evaluable for the assessment of a dose 
level provided it can be documented if the patient experienced a DLT within 21 days of C1D1.
8.1.2.2.3.  Follow-Up Visit
Following the safety assessments, which mark the end of the follow-up visit (Visit 801), the 
patient will be discontinued from the study, unless there is an ongoing AE or SAE that is 
possibly related to study drug.  In this instance, the patient should be followed in subsequent 
follow-up visits (Visits 802 through 8XX), 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.


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8.1.2.4.  Summary of AE/SAE Reporting Guidelines
Table JOBA.5.  Adverse Event and Serious Adverse Event Reporting Guidelines for 
Study I7O-MC-JOBA
Timing
Types of AEs/SAEs Reported
Collection 
Database
Lilly Safety 
System
Prestudy (baseline assessments)
(Starts at the signing of the ICF 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 
and ends at last dose of study drug)
All AEs
All SAEs regardless of relatedness
x
x
x
Follow-up visit (Visit 801)
(Begins the day after the patient and 
the investigator agree that the 
patient will no longer continue 
study treatment.  The duration of 
the follow-up visit is 28 ± 5 days.)
All AEs
All SAEs regardless of relatedness
x
x
x
Continued access period
All AEs
All SAEs regardless of relatedness
x
x
x
Continued access period follow-up
All AEs
All SAEs regardless of relatedness
x
x
x
Subsequent follow-up visits, if 
necessary for patient monitoring
Ongoing AEs at least possibly related 
to study drug, 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; ICF = informed consent form; SAEs = serious adverse events.


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8.1.4.  Safety Monitoring
The Lilly CRP/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.
Ophthalmologist may perform additional examin ations when visual changes or other ocular 
symptoms occur, at their discretion as clinically indicated.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities. Potential for biliary obstruction should be assessed. 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).  If a study patient experiences concurrent elevated ALT ≥>5 3 × ULN and 
elevated total bilirubin ≥>2 × ULN, clinical and laboratory monitoring should be initiated by the 
investigator.  If this is determined to be in the absence of biliary obstruction or other causes than 
can reasonably explain the concurrent elevation, then the patient should be discontinued from 
LY3076226.
For patients entering the study with ALT ≥3 × ULN, monitoring should be triggered at 
ALT ≥2 × baseline.
8.3.  Efficacy Evaluations
Each patient will be assessed by one or more of the following radiologic tests for tumor 
measurement:

Computed tomography (CT) scan

Magnetic resonance imaging (MRI)

For lymphoma patients only, positron emission tomography (PET)/CT is permitted if 
appropriate for standard of care (Cheson et al. 200714)
Each patient’s full extent of disease will also be assessed with:

Tumor measurement by RECIST 1.1 (Eisenhauer et al. 2009), international 
uniform response criteria for multiple myeloma (Rajkumar et al. 2011), or 
response criteria for lymphomas (Cheson et al. 200714).
10.8.  Efficacy
The study is not designed to make an efficacy assessment.  However, any tumor response data
will be tabulated.  Particularly, the antitumor effect will be summarized by the overall response 
rate (ORR).  A patient is considered to have a tumor response if they achieve a confirmed CR or 
PR according to RECIST 1.1 (Eisenhauer et al. 2009) or lymphoma criteria (Cheson et al. 
200714); or a confirmed stringent complete response (sCR), CR, very good partial response 
(VGPR), or PR according to multiple myeloma (IMWG) criteria (Rajkumar et al. 2011).  The 
ORR will be estimated by dividing the total number of confirmed complete and partial 


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responders (CR+PR) by the total number of enrolled patients.  A 90% exact CI will be 
constructed to determine the level of precision of the tumor response rate.  Time-to-event 
variables will also be tabulated.  For PFS and duration of response, the Kaplan-Meier method 
(Kaplan and Meier 1958) will be used to estimate the survival curves, medians, and survival 
rates if applicable.
12.  References
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, 
Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai 
K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on 
Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-
586.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, 
Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; 
European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European 
Organisation for Research and Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo 
Español de Linformas y Trasplantes de Médula Ósea; German High-Grade Lymphoma Study 
Group; German Hodgkin's Study Group; Japanese Lymphoma Study Group; Lymphoma Study 
Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest 
Oncology Group; United Kingdom National Cancer Research Institute. Recommendations fo r 
initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: 
the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
Attachment 1.  Protocol JOBA Study Schedule
Baseline Assessments
Relative day
to Cycle 1, Day 1
Pre-
screening
Screening
Comments
28
14
7
Radiological tumor 
assessment according 
to RECIST 1.1
X
Radiological assessments obtained previously 
(≤28 d prior to C1D1) as part of routine clinical 
care may be used as the baseline assessment.  
Appropriate tumor assessment criteria should be 
used for patients with multiple myeloma (IMWG 
[Rajkumar et al. 2011; refer to Attachment 5]) or 
lymphoma (Cheson et al. 200714).
Central Ppretreatment 
tumor tissue biopsy 
(Parts B and C only)
X
Collected only if patient has met 
inclusion/exclusion criteria.  If the patient had 
prescreening biopsy to assess FGFR3 alteration 
status, a portion of the prescreening biopsy may 
be used for pretreatment biopsy for the study.


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During Study-Treatment Assessments
Cycle 1
Cycle 2
Cycle 3
Cycles 
4-n
Comments
Relative day 
within a cycle
1
2
4
8
15
1
8
15
1
2
4
8
15
1
Cycle duration = 21 d
Ophthalmic 
examination
X
Performed by an ophthalmologist 
anytime from Days 15-21.
Additional monitoring may occur 
if clinically indicated at the 
discretion of the ophthalmologist. 
Local urinalysis
X
X
X
X
Can be collected ≤24 h prior to 
Day 1 of a cycle.
Radiological 
tumor 
assessment
X
X
Use RECIST 1.1 (Eisenhauer et 
al. 2009), multiple myeloma 
criteria (IMWG [Rajkumar et al. 
2011; refer to Attachment 5]), or 
lymphoma criteria (Cheson et al. 
200714).
The same method of imaging used 
at baseline should be used for 
each subsequent assessment.  
Imaging should be performed 
during the last wk of every third 
cycle; that is, Cycles 3, 6, 9, 12, 
and so on).  May be omitted if 
patient has clear signs of 
progressive disease.  In addition, 
any patient whose disease has not 
progressed by 1 y after entering 
the trial may be assessed every 
18 wk.


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Cycle 1
Cycle 2
Cycle 3
Cycles 
4-n
Comments
Relative day 
within a cycle
1
2
4
8
15
1
8
15
1
2
4
8
15
1
Cycle duration = 21 d
Central urine 
sample for 
biomarkers 
(Part B only)
X
X
Collect preinfusion on C1D1.  
Refer to Attachment 4 for exact 
timing.
Posttreatment Discontinuation Follow-Up Assessments
Study Period
Short-Term 
Follow-Up
Visit
801
The follow-up visit begins the day after the patient and the investigator agree that the patient will no longer continue study 
treatment.
Duration
28±5 d
Procedure
Comments
Radiologic imaging
X
Use RECIST 1.1 (Eisenhauer et al. 2009), multiple myeloma criteria (IMWG [Rajkumar et al. 2011; refer to Attachment 5]), or 
lymphoma criteria (Cheson et al. 200714).
The same method of imaging used at baseline should be used for each subsequent assessment.  Not required if progressive 
disease is documented while on treatment or if there are clear signs of clinical progression.
CTCAE v 4.0 grading
X
Refer to Section 8.1.2.  Report all AEs during the Short-Term Follow-Up period.  After Visit 801, only study protocol- or drug-
related events are reported.  If a patient has an ongoing AE or SAE at least possibly related to LY3076226, 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.  Any subsequent follow-up(s) 
for AEs (Visits 802-8XX) will be no more than 28 d ± 5 d in duration.


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Attachment 2.  Protocol JOBA Clinical Laboratory Tests
Clinical Laboratory Tests
Creatinine clearance, calculatedc
c
Cockcroft and Gault formula will be used for calculated creatinine clearance.  See Attachment 8.
Attachment 4.  Protocol JOBA Pharmacokinetic, Pharmacodynamic, and Immunogenicity 
Sampling Schedule
a
Post-infusion ECG can be done within 15 minutes after end of infusion.
b
Posttreatment biopsy may be performed on C1D4 or C1D5 to allow flexibility for scheduling.
c
Predose ECG can be obtained prior to predose blood samples.
d
Predose Uurine biomarker sample (Part B only) can be obtained prior to predose blood samples.


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Attachment 5.  Protocol JOBA Multiple Myeloma Tumor Assessment
Assessments and Timing for Patients with Multiple Myeloma
Myeloma 
Assessment
Baseline
C1 - CX
Short-Term
Follow-Up 
(Visit 801)
Comments
CentralLocal 
quantitative IgG, 
IgA, 
IgMimmunoglobulins
X
X
X
Baseline performed ≤28 d prior to C1D1.  On study:  Performed on D1 of each cycle, prior to 
treatment.  Short-term follow-up (Visit 801):  May be omitted if progressive disease is 
previously documented or if there are clear signs of clinical progression.
Abbreviations: C# = cycle; CR = complete response; CT = computed tomography; D# = day; IFE = immunofixation electrophoresis (serum/urine); Ig =
immunoglobulin; MRI = magnetic resonance imaging; sCR = stringent complete response; SPEP = serum protein electrophoresis; UPEP = urine protein
electrophoresis.


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Attachment 8.  Protocol JOBA Creatinine Clearance Formula
Note:  This formula is to be used for calculating CrCl from local laboratory results only.
Attachment 11.  Protocol JOBA Alterations for FGFR3
Such as the following FGFR3 alterations:
R248C
S249C
G372C
Y375C
K650E
K652E
FGFR3-TACC3 fusion
t(4;14)(p16.3;q32.3)

SAP_001.pdf: 
Statistical Analysis Plan  I7O-MC-JOBA 
 
A Phase 1 Study of LY3076226, a Fibroblast Growth Factor Receptor 3 (FGFR3) Antibody-
Drug Conjugate, in Patients with Advanced or Metastatic Cancer 
 
NCT02529553 
 
Approval Date: 24-Jun-2015 


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1.
Statistical Analysis Plan:  
I7O-MC-JOBA:  A Phase 1 Study of LY3076226, a 
Fibroblast Growth Factor Receptor 3 (FGFR3) Antibody-
Drug Conjugate, in Patients with Advanced or Metastatic 
Cancer
Confidential Information
The information contained in this Statistical Analysis Plan (SAP) is confidential and the 
information contained within it may not be reproduced or otherwise disseminated without 
the approval of Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachments or appendices are subject to United States Freedom of Information Act 
Exemption 4.
FGFR3 Antibody-Drug Conjugate (LY3076226)
This Phase 1 study is a multicenter, nonrandomized, open-label, dose-escalation study of 
intravenous LY3076226 in patients with advanced or metastatic cancer.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I7O-MC-JOBA
Phase 1
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 24-Jun-2015 GMT


I7O-MC-JOBA Statistical Analysis Plan
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I7O-MC-JOBA:  A Phase 1 Study of 
LY3076226, a Fibroblast Growth Factor Receptor 3 (FGFR3) 
Antibody-Drug Conjugate, in Patients with Advanced or Metastatic 
Cancer ................................................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................7
4.1.
Primary Objective ..........................................................................................................7
4.2.
Secondary Objectives.....................................................................................................7
4.3.
Exploratory Objectives...................................................................................................7
5.
Study Design.......................................................................................................................8
5.1.
Summary of Study Design..............................................................................................8
5.2.
Determination of Sample Size ........................................................................................8
5.3.
Method of Assignment to Treatment ..............................................................................9
6.
A Priori Statistical Methods ..............................................................................................10
6.1.
General Considerations ................................................................................................10
6.2.
Handling of Dropouts or Missing Data.........................................................................11
6.3.
Population for Analysis ................................................................................................11
6.4.
Patient Disposition .......................................................................................................11
6.5.
Patient Characteristics ..................................................................................................11
6.6.
Treatment Compliance .................................................................................................12
6.7.
Concomitant Therapy...................................................................................................12
6.8.
Safety Analyses............................................................................................................12
6.8.1.
Extend of Exposure..............................................................................................12
6.8.2.
Dose Limiting Toxicity ........................................................................................12
6.8.3.
Adverse Events ....................................................................................................13
6.8.4.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................13
6.8.5.
Clinical Laboratory Evaluation.............................................................................14
6.8.6.
Vital Signs and Other Physical Findings...............................................................14
6.8.7.
Electrocardiograms ..............................................................................................14
6.9.
Pharmacokinetic Analyses............................................................................................14
6.10. Pharmacodynamic Analyses.........................................................................................15
6.11. Immunogenicity Analyses ............................................................................................15
6.12. Efficacy Analyses ........................................................................................................15


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6.13. Tailoring Biomarker Analyses......................................................................................16
6.14. Protocol Violations.......................................................................................................16
6.15. Interim Analyses and Data Monitoring.........................................................................16
6.16. Annual Report Analyses...............................................................................................17
6.17. Clinical Trial Registry Analyses...................................................................................17
7.
References ........................................................................................................................19


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Table of Contents
Table
Page
Table JOBA.6.1.
Data Handling Conventions ......................................................................10


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Table of Contents
Figure
Page
Figure JOBA.5.1.
Illustration of Study JOBA study design. ....................................................9


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3.
Revision History
SAP Version 1 was approved prior to the first patient visit.  


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4.
Study Objectives
4.1.
Primary Objective
The primary objective of this study is to determine a recommended Phase 2 dose and schedule of
LY3076226 that may safely be administered to patients with advanced or metastatic cancer. 
4.2.
Secondary Objectives
The secondary objectives of this study are:

to characterize the safety and toxicity profile of LY3076226

to characterize the pharmacokinetics (PK) of  LY3076226

to document antitumor activity observed with LY3076226
4.3.
Exploratory Objectives 
The exploratory objectives of this study are:

to explore the effect of LY3076226 on pharmacodynamics (PD) markers

to explore the association between biomarkers and clinical outcome


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5.
Study Design
5.1.
Summary of Study Design
Study JOBA is a multicenter, outpatient, nonrandomized, open-label, dose-escalation Phase 1 
study of intravenous (IV) LY3076226 in patients with advanced or metastatic cancer.  Eligible 
patients will receive LY3076226 as an IV infusion on Day 1 of a 21-day cycle.
Dose escalation for LY3076226 in Part A will be driven by an accelerated dose-escalation 
scheme.  The initial dose levels will enroll one patient per cohort.  A modified 3+3 dose-
escalation scheme will be followed in subsequent cohorts, with incorporation of a Bayesian 
model-based dose-escalation method (Neuenschwander et al. 2008).  For more details, please 
refer to Protocol Section 6.2 and 7.2.2.
Once MTD is identified in Part A, up to approximately 15 patients who have known alterations 
of FGFR3 will be enrolled in each of Parts B (urothelial carcinoma) and C (other malignancies) 
to further evaluate the safety profile of LY3076226, characterize the exploratory biomarker 
assays, and document any antitumor activity.
Figure JOBA.5.1 is a representative illustration of Study JOBA study design, showing the dose 
escalation design in advanced cancer (Part A) and MTD expansions Parts B and C.
5.2.
Determination of Sample Size
To determine the recommended Phase 2 dose of LY3076226, an adequate sample size is 
required.  A sufficient sample size will allow for an accurate evaluation of the relationship 
between exposure and toxicity, as well as an evaluation of the relationship between exposure and 
pharmacological effects using descriptive statistics and appropriate modeling techniques, if data 
warrant.
The actual sample size of Part A will primarily be determined by the observed toxicity and the 
incidence of DLTs.  Under the modified 3+3 dose-escalation scheme, each cohort will include 3 
to 6 patients.  The anticipated sample size for Part A ranges from approximately 20 to 35 
patients, depending on the observed toxicity.  Each of Parts B and C expansion cohorts will 
enroll up to approximately 15 patients.  The overall sample size is thus estimated to be 
approximately 65 patients.


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Figure JOBA.5.1.
Illustration of Study JOBA study design.
5.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive LY3076226.  Before 
each patient’s enrollment into the study, an eligibility check must be conducted between the 
investigational site and the Eli Lilly and Company (Lilly) clinical research personnel to confirm 
that each patient meets all enrollment criteria.  Upon confirmation of eligibility, the sponsor will 
confirm the dose, identification number, and cohort assignment for each patient.  No dose 
escalations (that is, to the next cohort) can occur without prior discussion and agreement with the 
responsible Lilly Clinical Research Physician/Clinical Research Scientist (CRP/CRS).
If investigators have eligible patients who have consented concurrently, more than 1 or 3 patients 
may be entered at a particular dose level (or 6 if the cohort has been expanded due to a DLT) 
provided that accrual has not ceased due to excessive toxicity.  This enrollment 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.


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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company.  The 
interpretation of the study results will be the responsibility of the investigator with the Lilly 
CRP/CRS, pharmacokineticist, and statistician.  The CRP/CRS 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.
The analyses for this study will be descriptive; no p-values will be calculated.  Data analyses will 
be provided by cohort and overall whenever appropriate.  For continuous variables, summary 
statistics will include number of patients, mean, median, standard deviation, standard error, 
minimum, and maximum.  Categorical endpoints will be summarized using number of patients, 
frequency, percentages, and their standard errors.  Exploratory analyses of the data that are not 
described in the protocol will be conducted as deemed appropriate.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feather of the protocol.  Any other change to the data analysis 
methods described in the protocol and the justification for making the change will be described 
in the clinical study report (CSR).
The following data handling conventions will be used in the analysis (see Table JOBA.6.1).
Table JOBA.6.1.
Data Handling Conventions
Term
Definition or Rule
Relative Study Day
If assessment is on or after date of first dose then
(date of assessment)-(date of first study drug dose)+1
If assessment precedes first dose of drug then
(date of assessment) – (date of first study drug dose)
There is no Study Day 0.  Study Day 1 is the date of first dose and 
study day -1 is the day before the first dose.
Baseline
For change from baseline analyses, baseline value is defined as the last 
reported measure on or before the first dose date (prior to the dose 
administration), unless otherwise specified.
For change from baseline within a cycle, baseline value is defined as 
the measure prior to the first dose of that cycle, unless otherwise 
specified.
If more than one pre-dose measures are available, they may be 
averaged if appropriate.
Entered
Patients who have signed the informed consent document (ICD).
Enrolled
Patients who have been assigned to a study treatment and have 
received at least one dose of study treatment.


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6.2.
Handling of Dropouts or Missing Data
Missing data, except dates, will not be imputed.  Historical data such as historical diagnosis, 
historical illness, pre-existing conditions and prior therapies should be collected in a sufficiently 
informative way.  For example, in order to be considered as historical illness, events occurring in 
the same year as study entry should have at least a known month and year for the end date, while 
events occurring in previous years should have at least a known year for the end date.  When 
dates need to be imputed, missing days will be replaced with 15th of the month and missing 
day/month with 01 JULY.  
Patients who withdraw from the study before receiving study drug will be replaced and will not 
be included in the safety or efficacy assessments unless the withdrawl is due to a safety issue that 
is possibly related to study procedure.
In the following situations, patients will be considered non-evaluable and may be replaced to 
ensure that enough patients complete one cycle of therapy at each dose level, unless accrual to 
that cohort has stopped due to a DLT:
1. Any patient who is discontinued from the study before completing one cycle of therapy 
unless they experience a DLT prior to withdrawal. 
2. Patients who are not evaluable for PK, but who complete one cycle of therapy.
6.3.
Population for Analysis
Safety analyses will be conducted on all patients who have received at least one dose of 
LY3076226, regardless of whether they are deemed evaluable for the assessment of a dose level.
PK analyses will be conducted on patients who have received at least one dose of LY3076226 
and have sufficient samples collected to allow the estimation of LY3076226 PK parameters.
PD analyses will be conducted on subjects who have received at least one dose of LY3076226 
and have sufficient samples collected to allow the assessment of PD. 
6.4.
Patient Disposition
A detailed description of patient disposition will be provided.  It will include summaries of the 
number and percentage of patients entered into the study, enrolled in the study, completing the 
study, and reasons for discontinuation from study treatment, as well as discontinuation from the 
study.  Patients completing the study are defined as patients who received tumor assessments
after 3 cycles.  All patients entered in the study will be included in the summary.  Reason for 
discontinuation from both study treatment and the study will be listed by the pre-determined
categories.  If the reason for discontinuation is adverse event (AE) or death, the associated AE or 
cause of death will be reported.
6.5.
Patient Characteristics
Patient characteristics will be summarized and listed for all patients enrolled and will include:


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
Patient demographics, including age, sex, race, ethnicity, screening height and weight, 
and screening body mass index (BMI).

Baseline disease characteristics, including initial pathological diagnosis, basis for initial 
diagnosis, disease stage at initial diagnosis and Eastern Cooperative Oncology Group 
(ECOG) performance status.

Prior disease-related therapies including systemic, radiotherapy and cancer surgeries, if 
known, including dose, best response, date of progression.
Alcohol and tobacco historical consumption will be summarized.  Other patient characteristics 
will be summarized as deemed appropriate.
6.6.
Treatment Compliance
LY3076226 will be administered intravenously at the investigational site under the direction of 
the investigator.  As a result, a patient’s compliance with study drug administration is ensured. 
6.7.
Concomitant Therapy
All medications will be coded to the generic preferred name according to the current World 
Health Organization (WHO) drug dictionary.  All concomitant medications will be listed and 
summarized using the preferred name by cohort and overall for all patients on therapy.  If the 
concomitant medication use is due to an adverse event (AE), the associated National Cancer 
Institute’s (NCI) Common terminology Criteria for Adverse Events (CTCAE) Version 4.0 term 
will be listed.
6.8.
Safety Analyses
All patients who receive at least one dose of LY3076226 will be evaluated for safety and 
toxicity. 
6.8.1. Extend of Exposure
Study drug exposure information will be summarized by cohort and overall for patients on 
therapy, including cycles received per subject, duration on therapy, and cumulative dose.
Dose adjustment information will be summarized by cohort and overall for patients on therapy, 
including dose reductions, dose delays, dose omissions, dose increases, and the reasons leading 
to dose adjustments. 
Dose intensity, defined as the actual amount of drug taken per week, and relative dose intensity, 
defined as the actual amount of drug taken/planned amount of drug taken×100%, will also be 
summarized by cohort and overall.
6.8.2. Dose Limiting Toxicity
Dose limiting toxicities (DLTs) will be summarized and listed by cohort and overall for the 
safety population.


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Dose-equivalent toxicities (DETs) will also be summarized and listed by cohort and overall for 
the safety population.
6.8.3. Adverse Events
AE terms and severity grades will be assigned by the investigator using CTCAE Version 4.0.  In 
addition, AE verbatim text will also be mapped by the sponsor or designee to corresponding 
terminology within the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  
AEs will be reported using a unified CTCAE/MedDRA reporting process:

The CTCAE v4.0 term reported by the investigator will be mapped to the MedDRA 
preferred term (PT) and system organ class (SOC) of the corresponding MedDRA lowest 
level term (LLT), unless the reported CTCAE term is “Other-specify”.

If the reported CTCAE term is “Other-specify” the MedDRA LLT, PT and SOC mapped 
from the verbatim AE term will be used

All listings and summaries will use the CTCAE terms when available or the MedDRA 
LLT, along with the MedDRA PT resulting from this process.
A treatment emergent adverse event (TEAE) is defined as any AE that begins on or after the day 
of the first dose of LY3076226 or any pre-existing condition that increases in CTCAE grade on 
or after the day of the first dose of LY3076226.  Comparisons of pre-existing conditions to 
treatment events at the LLT level will be used in the treatment-emergent computation.
The number of patients who experienced a TEAE, SAE, or TEAE possibly related to study drug, 
will be summarized.  TEAEs will be summarized by SOC, by PT terms of decreasing frequency 
within SOC, and by maximum CTCAE grade and grade categories.
Historical illnesses are defined as events which ended before completion of the screening visit.  
Pre-existing conditions are defined as AEs that begin but do not resolve prior to the first dose of 
study drug is administered.  The pre-existing conditions will be presented by patient and can be 
combined with the adverse event listing, so that the history of the pre-existing conditions/adverse 
events can be traced.  Historical illnesses and pre-existing conditions will be summarized and 
listed by cohort and overall for all patients on therapy.
6.8.4. Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events
A summary of deaths will be presented for all patients who died on study.  Reasons for death 
will be summarized separately for deaths on therapy, within 30 days of discontinuation of study 
therapy and after 30 days of discontinuation of study therapy.  Other listings include:

Listing of Deaths

Listing of Serious Adverse Events

Listing of Subjects who Discontinued due to Adverse Events of Death


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6.8.5. Clinical Laboratory Evaluation
Abnormal laboratory parameters will be listed by cycle for patients on therapy.  In addition to the 
investigator-reported AEs, relevant hematology and chemistry laboratory values will be graded 
according to CTCAE v4.0.  These abnormal lab parameters with derived CTCAE grades will be
summarized by visit and cohort.
6.8.6. Vital Signs and Other Physical Findings
All vital signs data, height and weight will be summarized and listed by visit/time points and 
cohort for patients on therapy.
6.8.7. Electrocardiograms
Electrocardiogram (ECG) data will be summarized by visit and parameter for patients on 
therapy.  Any abnormal ECG data will be listed by patient.  Number and percentage of subjects 
with AEs that could be associated with abnormal ECGs will be presented, if appropriate.
The number of patients meeting the following criteria with respect to QTc will be presented for 
maximum on-study value:

QTc, >480 to 500 msec, and >500 msec and delta QTc >30 to 60 msec, and >60 msec.
All instances when a patient met the above criteria will be listed.  Maximum absolute and change 
from baseline QTc data will be summarized as a continuous variable.  Frequency of patients with 
Normal (≤480 msec) or High (>480 msec) QT/QTc interval at baseline and post baseline 
nominal time points will be summarized by shift table.  Summaries of other ECG parameters (for 
example, RR, PR, and QRS) will be presented, if appropriate. 
6.9.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be conducted on patients who have received at least one dose of 
the study drug and have had adequate samples collected.
Pharmacokinetic parameter estimates for conjugated LY3076226 and total LY3076226 IgG and 
metabolites DM4 and DM4-Me will be calculated by standard noncompartmental methods of 
analysis.  The primary parameters for analysis will be Cmax and AUC of conjugated LY3076226 
and total LY3076226 IgG and metabolites DM4 and DM4-Me.  Other noncompartmental 
parameters, such as t1/2, CL, and volume of distribution (V) may be reported.
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.
Pharmacokinetic parameter estimates will be evaluated to delineate effects of dose 
proportionality using methods described previously (Smith et al. 2000).  Log-transformed Cmax
and AUC estimates will be assessed to estimate ratios of geometric means and the corresponding 
90% confidence intervals (CIs).


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6.10. Pharmacodynamic Analyses
Pharmacodynamic data will be summarized by dose, and time from dose.  Potential PD markers-
versus-time data will be presented graphically for each patient and summarized by dose.  
Absolute and/or relative change from baseline may be evaluated.  Data may be log-transformed 
prior to summarizing, if necessary.  The interpatient and intrapatient variability of the PD 
markers may also be assessed where appropriate.
If data allow, a PK/PD analysis may also be performed, wherein PD data from all patients would 
be analyzed using linear and/or nonlinear fixed and mixed effects models as appropriate.
6.11. Immunogenicity Analyses
Immunogenicity data will be summarized by dose, drug concentrations, and time from dose.
If the data allow, immunogenicity data from all patients may also be analyzed using linear and/or 
nonlinear fixed and mixed effects models as appropriate.
6.12. Efficacy Analyses
The study is not designed to make an efficacy assessment.  However, any tumor response data 
will be listed and summarized. Particularly, the antitumor effect will be summarized by the 
overall response rate (ORR, defined by the total number of responses divided by the number of 
patients on therapy) and disease control rate (defined by the total number of stable disease + 
responses divided by the number of patients on therapy) by cohort and overall.  Mean, median, 
range, and exact 90% confidence intervals (CI) will be provided.  A patient is considered to have 
a tumor response if they achieve a confirmed complete response (CR) or partial response (PR)
according to RECIST 1.1 or lymphoma criteria (Cheson et al. 2007) or a confirmed stringent 
complete response (sCR), CR, very good partial response (VGPR) or PR according to multiple 
myeloma (IMWG) criteria (Rajkumar et al, 2011).  Reported lesion measurement data, including 
sum of target lesions, change and/or percent change form baseline sum at each visit will be listed 
for all patients on therapy.  Investigator-determined response by cycle will be listed.
Time-to-event variables, such as progression-free survival (PFS) and duration of response, will 
be listed and summarized.  PFS time is defined as the time from the first dose of the study drug 
to progressive disease (PD, either due to objective progressive disease or symptomatic 
deterioration) or death due to any cause, occurring without observed disease progression.  
Duration of response (DoR) is defined as the time from the first assessment of any tumor 
response to PD or death due to any cause, occurring without observed disease progression.  
Patients not known to have progressed or died while on study will have their PFS and DoR time 
censored at the date of the last objective progression-free disease assessment.  Patients for whom 
there is no record of progression, death, or post baseline radiographic assessment will have their 
PFS time censored on the day of first dose of any study drug.  The Kaplan-Meier method 
(Kaplan and Meier 1958) will be used to estimate the survival curves, medians with 90% CI, and 
PFS rates at various time points if applicable.  For Part C, time-to-event variables may be 
summarized by different tumor types if the data warrant.


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6.13. Tailoring Biomarker Analyses
Biomarker assessments in this study will focus on identifying markers and/or marker signatures 
that may indicate the patients most likely to respond or be resistant to LY3076226.  Exploratory 
analysis may be conducted using blood, urine, and tumor tissue to explore potential biomarkers 
related to LY3076226 mechanism of action, the FGFR3 pathway, DM4 mechanism of action, 
and the cancer pathobiology, to better understand relationship with clinical outcomes.  Tumor 
tissue samples may be analyzed to explore potential tumor gene signature(s) associated with 
response or resistance to LY3076226 therapy.
In all analyses, adjustments may be made to account for other baseline patient characteristics, 
safety, and PK/PD data.  Unless otherwise stated, given the small sample sizes involved, 
statistical analysis results will be considered exploratory and will not consider multiple 
comparison adjustments.
6.14. Protocol Violations
All major protocol violations will be summarized by cohort and reason.  These violations will 
include those defined by, for example:

Inclusion/Exclusion Criteria

Dosing

Noncompliance with other protocol procedures

Informed consent/assent process
6.15. Interim Analyses and Data Monitoring
Once the LY3076226 MTD is defined for Part A, an interim analysis will be performed prior to 
opening Parts B and C.
At the end of Parts B and C, an analysis may be conducted to review available safety, PK, and 
efficacy data once all evaluable patients have either completed 3 cycles of study treatment or 
discontinued from the study treatment.
Because this is a dose-finding study, data will be reviewed on a cohort-by-cohort basis during the 
study, until the MTD is determined for Part A.  The purpose of these cohort-by-cohort reviews is 
to evaluate the safety data and any available PK data at each dose level and determine if 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.
In Parts B and C, if a DLT-equivalent toxicity occurs in one third or more of patients during 
Cycle 1 (with a minimum of 6 patients enrolled); a data review will be performed to determine 
whether to continue at the current LY3076226 dose or whether the dose of LY3076226 should 
be reduced.  Refer to Protocol Section 7.2.3 for more details.


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If an unplanned interim analysis is deemed necessary, the sponsor will determine if it is 
necessary to amend the protocol.
6.16. Annual Report Analyses
The following reports are needed as requested for annual reporting purposes.
Clinical Investigator brochure:

Summary of SAE

Summary of Deaths

Listing and Summary of TEAE

Listing of Subjects Who Discontinued Due to Adverse Event or Death
Development Safety Update Report:

Cumulative Subject Exposure by Age Group and Sex

Cumulative Subject Exposure by Racial Group

Estimated Cumulative Subject Exposure

Exposure Information

Listing of Discontinuations Due to Adverse Event During the Reporting Period

Listing of Subjects Who Died During the Reporting Period
6.17. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:
Summary of AEs, provided as a dataset which will be converted to an XML file.  Both SAEs 
and ‘Other’ AEs are summarized by MedDRA preferred term (PT) within treatment group.

An AE is considered ‘Serious’ whether or not it is a treatment emergent adverse event 
(TEAE).

An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each SAE and ‘Other’ AE, for each term and treatment group, the following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.


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
Adverse event reporting is consistent with other document disclosures for example, the 
CSR, manuscripts, and so forth.  
A participant flow will be created that will describe how many entered patients completed the 
study, and for those who did not, the frequency of each reason for not completing.  This analysis 
will be based on study discontinuation, not treatment discontinuation.  


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7.
References
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Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai 
K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on 
Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-
586.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours:  revised RECIST guideline (version 1.1). 
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Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
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