Clinical trial NCT02737072
Conditions: Solid Tumor
Keywords: immuno-oncology
Sponsor: Eli Lilly and Company
Start date: 2016-09-01; Completion date: 2017-09-25
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the safety and tolerability of chemokine (C-X-C Motif) receptor 4 (CXCR4) peptide antagonist LY2510924 and durvalumab for phase 1a and 1b in participants with advanced refractory solid tumors.

Detailed description:

Arms: arm 1: 20 milligrams (mg) LY2510924 given subcutaneously (SQ) once daily in combination with 1500 mg durvalumab given intravenously (IV) on Day 1 of each cycle (28 days). arm 2: 30 mg LY2510924 given SQ once daily in combination with 1500 mg durvalumab given IV on Day 1 of each cycle (28 days). arm 3: 40 mg LY2510924 given SQ once daily in combination with 1500 mg durvalumab given IV on Day 1 of each cycle (28 days).
Interventions: intervention 1: LY2510924 intervention 2: Durvalumab
Intervention descriptions: intervention 1: Administered SQ intervention 2: Administered IV

Protocol documents:
Prot_000.pdf: 
Protocol I2V-MC-CXAD (b)
Protocol I2V-MC-CXAD (b) A Phase 1a/1b Study of CXCR4 Peptide Antagonist 
(LY2510924) Administered in Combination with the Anti-PD-L1 Antibody, Durvalumab 
(MEDI4736), in Advanced Refractory Solid Tumors  
NCT02737072 
Approval Date: 12-Oct-2016 


I2V-MC-CXAD(b) Phase 1 Oncology Protocol
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1.
Protocol I2V-MC-CXAD(b)
A Phase 1a/1b Study of CXCR4 Peptide Antagonist 
(LY2510924) Administered in Combination with the 
Anti-PD-L1 Antibody, Durvalumab (MEDI4736), in 
Advanced Refractory Solid Tumors
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 
LY2510924 in combination with durvalumab (MEDI4736), unless such persons are bound 
by a confidentiality agreement with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  this document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY2510924 and Durvalumab (MEDI4736)
This is a multicenter, nonrandomized, open-label, dose-escalation Phase 1a study of 
LY2510924 combined with durvalumab (MEDI4736) in patients with advanced refractory 
solid tumors followed by an open-label, 2-expansion-arms, Phase 1b study in patients with 
advanced refractory pancreatic and ovarian cancer.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on: 22 February 2016 
Amendment (a) Electronically Signed and Approved by Lilly:  21 July 2016
Amendment (b) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 12-Oct-2016 GMT


I2V-MC-CXAD(b) Phase 1 Oncology Protocol
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LY2510924/durvalumab
2.
Synopsis
The chemokine (C-X-C Motif) receptor 4 (CXCR4) and its only known ligand, α-chemokine 
stromal cell-derived factor-1 (SDF-1) are believed to play an important role in the regulation of 
organ-specific metastasis, as well as tumor growth, invasion, survival, and angiogenesis. 
CXCR4 is functionally expressed or overexpressed in a variety of solid tumor cancers, 
lymphoma, and chronic lymphocytic leukemia (Balkwill 2004; Peng et al. 2015).  Within 
hypoxic areas of tumors, both SDF-1 secretion by fibroblasts and CXCR4 expression on tumor 
cells increase, which stimulate tumor cell growth, migration, and invasion.  SDF-1 promotes 
tumor growth in a paracrine fashion by directly stimulating tumor cell proliferation and survival 
via CXCR4.  Recently, CXCR4 was demonstrated to play a role in cancer immunotherapy via 
T-cell mobilization and redistribution in the tumor microenvironment (Righi et al. 2011; Feig 
et al. 2013; Gil et al. 2014).
Durvalumab (MEDI4736) is in development as a potential anticancer therapy for patients with 
advanced solid tumors and hematological malignancies.  Durvalumab is a human monoclonal 
antibody (mAb) of the immunoglobulin G1 kappa (IgG1κ) subclass that inhibits binding of 
programmed cell death–ligand 1 (PD-L1) (B7 homolog 1 [B7-H1], cluster of differentiation 
[CD]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). Partial efficacy data 
are available for the ongoing Phase 1/2 Study CD-ON-MEDI4736-1108 in patients with solid 
tumors (of whom, 456 were response evaluable).  Across the PD-L1-positive tumors (n=383 of 
456 patients), overall response rate (ORR) was highest (>10%) for bladder cancer (33.3%; 1 of 
3 response evaluable patients), advanced cutaneous melanoma (33.3%; 1 of 3 response evaluable 
patients), hepatocellular carcinoma (HCC) (33.3%; 1 of 3 response evaluable patients), non–
small-cell lung cancer (NSCLC) (26.7%; 23 of 86 response evaluable patients), and squamous 
cell carcinoma of the head and neck (SCCHN) (18.2%; 4 of 22 response evaluable patients).  
Further, in the PD-L1-positive subset, disease control rate (DCR)-24w was highest (>10%) in 
advanced cutaneous melanoma (66.7%), NSCLC (36.0%), HCC (33.3%), bladder cancer 
(33.3%), and SCCHN (18.2%). While the ORR in these tumor types are appreciable, other 
indications have either low to no efficacy with PD-L1 treatment alone, possibly due to lack of 
immune cell infiltration in the tumor microenvironment. 
The combination of CXCR4 inhibitor with anti-PD-L1 immunotherapy has shown increased 
infiltration of T cells into tumors and tumor regression in an in vivo pancreatic cancer mouse 
model (Feig et al. 2013).  This study will investigate the effects of CXCR4 inhibition 
(LY2510924) in combination with PD-L1 inhibition (durvalumab).  
This study is a Phase 1a/1b open-label study that will be conducted in 2 parts.  The Phase 1a
portion of this study will consist of a dose assessment of the safety and tolerability of 
LY2510924 administered at 20, 30, or 40 mg subcutaneously (SQ) daily in combination with 
durvalumab 1500 mg intravenously (IV) once every 28 days in patients with advanced refractory 
solid tumors. The LY2510924 dose in the Phase 1b portion of this study will be based on 
Phase 1a results.  The Phase 1b portion will include expansion arms in 2 indications, pancreatic 
and ovarian cancer (N=15 each arm). Enrollment will be complete when the expansion arms 


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LY2510924/durvalumab
have reached the prespecified enrollment target.  Safety and efficacy analysis of each expansion
arm will be performed independently of the other arm.  
Clinical Protocol Synopsis:  Study I2V-MC-CXAD
Name of Investigational Product:  LY2510924 and durvalumab (MEDI4736) 
Title of Study:  A Phase 1a/1b Study of CXCR4 Peptide Antagonist (LY2510924) Administered in Combination 
with the Anti-PD-L1 Antibody, Durvalumab (MEDI4736), in Advanced Refractory Solid Tumors
Number of Planned Patients:
Phase 1a:  approximately 12-15 patients
Phase 1b:  approximately 30 patients
Phase of Development:  
1a/1b
Length of Study:  Approximately 2 years
Planned first patient visit:  August 2016               Planned last patient visit:  August 2018
Objectives:  
Primary objective for the dose escalation:  To assess the safety and tolerability of LY2510924 SQ daily in 
combination with durvalumab by identifying dose-limiting toxicities (DLTs) and the maximum-tolerated dose 
(MTD) of the combination in patients with advanced (metastatic and/or unresectable) solid tumors. 
Primary objective for the dose expansion: To assess the safety of LY2510924 SQ daily in combination with 
durvalumab in patients with advanced pancreatic and ovarian cancers.  
Secondary objectives:

To characterize the pharmacokinetics (PK) of LY2510924 and durvalumab when co-administered

To characterize the immunogenicity of durvalumab when administered in combination with LY2510924

To assess the antitumor activity of the combination of LY2510924 and durvalumab in patients with advanced 
solid tumors 
Exploratory objectives:  
•
To examine biomarkers, including pharmacodynamic markers, relevant to LY2510924 and durvalumab, 
including but not limited to, immune cells/immune functioning, drug targets, cancer-related pathways and the 
disease state, and to correlate these markers with clinical outcome
Study Design:  This is a Phase 1a/1b open-label study that will be conducted in 2 parts.  The first part (Phase 1a) of 
the study will consist of a dose-escalation assessment of the safety and tolerability of LY2510924 administered with 
durvalumab in patients with advanced refractory solid tumors.  The second part (Phase 1b) of the study will include 
2 expansion arms in advanced pancreatic cancer (N=approximately 15 patients) and ovarian cancer 
(N=approximately15 patients), all receiving LY2510924 (dose determined from Phase 1a) with durvalumab.  


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LY2510924/durvalumab
Diagnosis and Main Entry Criteria:
Inclusion:

Phase 1a: Have a histologic or cytological confirmed advanced solid tumor (see American Joint Committee on 
Cancer Staging Criteria; Edge et al. 2009) and 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 the patient has refused available standard therapies.  

Phase 1b: Histologic or cytologic confirmation of advanced cancer in the following tumor types:
o
Pancreatic cancer
o
Cytologically or histologically confirmed pancreatic adenocarcinoma (excluding other pancreatic 
malignancies [eg, acinar cell carcinomas, adenosquamous carcinomas, and neuroendocrine islet cell 
neoplasms])
o
Metastatic disease or locally advanced, unresectable disease
o
Have had disease progression, be refractory or intolerant to no more than 2 prior systemic regimens for 
locally advanced or metastatic pancreatic cancer.  Patients who have received prior neoadjuvant therapy 
and who now have metastatic disease, must receive FOLFIRINOX, FOLFOX, single-agent 
gemcitabine, gemcitabine/nab-paclitaxel, or TS-1 (tegafur gimeracil oteracil potassium) prior to 
enrollment on this study.  
o
Ovarian cancer
o
Cytologically or histologically proven epithelial ovarian cancer (except borderline ovarian tumor 
histology), fallopian tube cancer, or primary peritoneal cancer with evidence of recurrence or refractory 
disease, which is advanced and not amenable to curative surgery or radiotherapy (International 
Federation of Gynecology and Obstetrics Staging; Odicino et al. 2008).
o
Have recurrence of cancer at least 6 months after completion of first-line platinum-based therapy.  
o
Have received chemotherapy for recurrence of disease, but not exceeding 4 lines of therapy during 
which time disease may be platinum sensitive or resistant.

Have provided tissue from a newly obtained core or excisional biopsy of a tumor lesion or a recent biopsy 
defined by ≤3 years since last documented progression of disease. (Note:  patients for whom newly obtained 
samples cannot be obtained such as in cases of inaccessibility or patient safety concern, an archived specimen 
can be submitted upon agreement from sponsor and if not restricted by local regulations)  
o
For ovarian expansion arm only: Be able to provide tissue (newly obtained core or excisional biopsy of 
tumor lesion) from an on-treatment biopsy for biomarker analysis.  

Have at least 1 measurable lesion assessable using standard techniques by Response Evaluation Criteria in Solid 
Tumours (RECIST) v1.1 (Eisenhauer et al. 2009).
Exclusion:

Active autoimmune disorders, or prior documented severe autoimmune or inflammatory disorders requiring 
immunosuppressive treatment (including inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis 
with the exception of diverticulosis, irritable bowel syndrome, or other serious gastrointestinal chronic 
conditions associated with diarrhea); systemic lupus erythematosus; Wegener Granulomatosis (with 
polyangiitis), Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis, etc).  The following are exceptions to 
this criterion:  vitiligo or alopecia, diabetes mellitus type I or resolved childhood asthma/atopy; hypothyroidism 
(eg, following Hashimoto syndrome) stable on hormone replacement; psoriasis not requiring systemic treatment; 
any chronic skin condition that does not require systemic therapy; or celiac disease controlled by diet alone. 
Patients without active disease in the last 5 years may be included but only after consultation with the study 
physician.

Require escalating or chronic supraphysiologic doses of corticosteroids (>10 mg/day of prednisone or an 
equivalent corticosteroid) for control of their disease or immunosuppressive agents (eg, cyclosporine) for any 
reason.

Have had prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-cytotoxic T lymphocyte-associated 


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LY2510924/durvalumab
antigen-4 antibody (including but not limited to ipilimumab, durvalumab or tremelimumab) or any other 
antibody or drug specifically targeting T-cell costimulation or checkpoint pathways such as CD137, GITR, 
TIM-3, and LAG3.
Test Product, Dosage, and Mode of Administration:  A cycle is 28 days in duration.
LY2510924 at 20 mg, 30 mg, or 40 mg self-administered SQ once daily in Phase 1a; LY2510924 will be self-
administered in a similar fashion in Phase 1b at the selected Phase 1a dose.
Durvalumab:  IV administration of durvalumab 1500 mg on Day 1 of each cycle for Phase 1a and Phase 1b.
Planned Duration of Treatment: Patients will receive study therapy until the patient fulfills 1 of the criteria for 
study discontinuation.  Patients may continue on combination therapy beyond initial radiological disease progression 
in the absence of clinically significant deterioration.  If a patient experiences an adverse event (AE) that requires the 
patient be discontinued from durvalumab or LY2510924, the patient should be discontinued from both study drugs.
Criteria for Evaluation:  
Safety:  Hematology, clinical chemistry, urinalysis, vital sign collection, weight, electrocardiograms (ECGs), 
echocardiography (screening for all patients; subsequently if clinically indicated), physical examinations, 
concomitant medication collection, dose adjustments, AE/DLT/serious adverse events (SAE) collection using 
International Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.  
Efficacy:  Eastern Cooperative Oncology Group (ECOG) performance status, tumor assessment via RECIST v 1.1.  
Biomarkers/Pharmacodynamic:  Blood collection, tumor biopsies.
Pharmacokinetic:  Concentrations of LY2510924 and durvalumab in plasma or serum will be assayed using validated 
methods.
Immunogenicity:  Immunogenicity will be assessed by a validated assay designed to detect antidrug antibodies 
(ADAs) in the presence of durvalumab.  
Statistical Methods:  
Statistical:  Up to approximately 45 patients may be enrolled in this study.  The Bayesian model-based, toxicity-band 
method will be followed to assist dose escalation during Phase 1a. The sample size for Phase 1a will primarily be 
limited by the incidence of DLTs.  The anticipated sample size for Phase 1a ranges from approximately 12 to 
15 patients.  The sample size of approximately 15 patients per tumor type in Phase 1b has been selected to allow 
adequate assessment of safety at the recommended dose level. The first tumor evaluation will occur at 2 months.
Safety:  All patients who receive at least 1 dose of either study drug will be evaluated for safety. Summaries and 
listings for all safety data collected will be provided.  
Efficacy:  Tumor response data will be summarized by the best overall response, overall response rate and disease 
control rate. Time-to-event variables such as progression-free survival, time to response, duration of response and 
overall survival will also be summarized and the Kaplan-Meier method will be used to estimate the survival curves, 
medians, and survival rates as applicable.
Biomarkers/Pharmacodynamic:  Exploratory biomarkers will be summarized and assessed for correlations with 
clinical outcomes.  Biomarker relationships by tumor type, changes in biomarker levels at baseline and over time, and 
differences among dose levels or exposure will be explored as possible.  
The pharmacodynamic effect from all patients undergoing pharmacodynamic assessments will be explored.
Pharmacokinetic:  Summary statistics will be tabulated for the PK parameters of LY2510924 and durvalumab by 
dose and study day.  
Immunogenicity:  Immunogenicity incidence will be summarized, and correlation to durvalumab, activity, and safety 
will be assessed as appropriate, respectively. The measures that will be analyzed include baseline presence and level 
of ADA, treatment-emergent ADA, levels of neutralizing ADA, and incidence and levels of ADA-related to 
infusion-related reactions (IRR).


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3.
Table of Contents
Section
Page
1.
Protocol I2V-MC-CXAD(b) A Phase 1a/1b Study of CXCR4 Peptide 
Antagonist (LY2510924) Administered in Combination with the 
Anti-PD-L1 Antibody, Durvalumab (MEDI4736), in Advanced 
Refractory Solid Tumors.....................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................6
4.
Abbreviations and Definitions...........................................................................................13
5.
Introduction ......................................................................................................................18
5.1.
Cancer Immunotherapy................................................................................................18
5.1.1.
Immune Checkpoint Inhibitors Targeting PD-1/PD-L1.........................................18
5.1.2.
Rationale for Combination Therapy and Selection of 
Expansion Tumor Types ......................................................................................18
5.2.
Rationale for Protocol Amendment (a).........................................................................19
5.3.
Rationale for Protocol Amendment (b).........................................................................20
5.4.
Objectives ....................................................................................................................21
5.4.1.
Primary Objective ................................................................................................21
5.4.2.
Secondary Objectives...........................................................................................22
5.4.3.
Exploratory Objectives.........................................................................................22
5.5.
General Introduction to LY2510924 and Durvalumab ..................................................22
5.5.1.
LY2510924..........................................................................................................22
5.5.1.1.
LY2510924 Chemokines, SDF-1, and CXCR4 ...............................................22
5.5.1.2.
CXCR4 Peptide Antagonist LY2510924 and Its 
Mechanism of Action .....................................................................................23
5.5.1.3.
Summary of Clinical Experience ....................................................................23
5.5.1.4.
Biomarkers.....................................................................................................24
5.5.2.
Durvalumab .........................................................................................................24
5.5.2.1.
Programmed Cell Death–Ligand 1 (PD-L1)....................................................24
5.5.2.2.
Background on Durvalumab ...........................................................................25
5.5.2.3.
Summary of Nonclinical Experience...............................................................25
5.5.2.4.
Summary of Clinical Experience ....................................................................25
5.6.
Rationale for Selection of Dose....................................................................................27
6.
Investigational Plan...........................................................................................................30
6.1.
Study Population..........................................................................................................30
6.1.1.
Screening Procedures...........................................................................................30
6.1.2.
Inclusion Criteria .................................................................................................30


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6.1.3.
Exclusion Criteria ................................................................................................34
6.2.
Summary of Study Design............................................................................................36
6.2.1.
Study Completion and End of Trial......................................................................39
6.2.2.
Definitions of Study Periods.................................................................................39
6.2.3.
Continued Access.................................................................................................40
6.3.
Discontinuations ..........................................................................................................40
6.3.1.
Discontinuation of Patients Inadvertently Enrolled...............................................40
6.3.2.
Discontinuation of Patients from Study or Study Drug .........................................41
6.3.3.
Discontinuation of Study Sites .............................................................................42
6.3.4.
Discontinuation of the Study................................................................................42
7.
Treatment..........................................................................................................................43
7.1.
Materials and Supplies .................................................................................................43
7.1.1.
LY2510924..........................................................................................................43
7.1.2.
Durvalumab (MEDI4736) ....................................................................................43
7.2.
Study Drug Administration ..........................................................................................43
7.2.1.
Dosing Schedule ..................................................................................................44
7.2.1.1.
LY2510924 ....................................................................................................44
7.2.1.2.
Durvalumab....................................................................................................44
7.2.2.
Phase 1a Dose Escalation.....................................................................................46
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum-
Tolerated Dose Definition...............................................................................47
7.2.2.2.
Dose-Escalation Method.................................................................................48
7.2.3.
Phase 1b Expansion .............................................................................................49
7.2.4.
DLT-Equivalent Toxicity.....................................................................................50
7.2.5.
Dose Adjustments, Delays, or Discontinuation from Study 
Drug.....................................................................................................................50
7.2.5.1.
LY2510924 Dose Adjustments, Delays, and 
Discontinuation for Phase 1a and 1b...............................................................50
7.2.5.1.1.
LY2510924 Dose Adjustments and Delays ...............................................50
7.2.5.1.2.
Discontinuation from LY2510924.............................................................51
7.2.5.2.
Durvalumab Dose Adjustments, Delays, and 
Discontinuation for Phase 1a and 1b...............................................................51
7.2.5.3.
Dose Delays for Reasons Not Related to Study 
Treatment .......................................................................................................52
7.3.
Method of Assignment to Treatment ............................................................................52
7.4.
Blinding .......................................................................................................................52
7.5.
Concomitant Therapy...................................................................................................52
7.5.1.
Restrictions during Study.....................................................................................53
7.6.
Treatment Compliance .................................................................................................54


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7.6.1.
LY2510924 Compliance ......................................................................................54
7.6.2.
Durvalumab Compliance......................................................................................55
7.6.3.
Evaluable Phase 1a Patients .................................................................................55
8.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data 
Collection .........................................................................................................................56
8.1.
Safety Evaluations........................................................................................................56
8.1.1.
Safety Data Collection and Review ......................................................................56
8.1.2.
Adverse Events ....................................................................................................56
8.1.2.1.
Serious Adverse Events ..................................................................................58
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting .....................................59
8.1.2.2.1.
Prior to Administration of Study Drugs.....................................................59
8.1.2.2.2.
On Therapy...............................................................................................59
8.1.2.2.3.
Follow-Up Visit........................................................................................59
8.1.2.3.
Adverse Events of Special Interest for Durvalumab........................................60
8.1.2.4.
Reporting Adverse Events of Special Interest .................................................61
8.1.2.5.
Suspected Unexpected Serious Adverse Reactions..........................................61
8.1.2.6.
Summary of Adverse Event/Serious Adverse Event 
Reporting Guidelines......................................................................................61
8.1.3.
Other Safety Measures .........................................................................................62
8.1.3.1.
Electrocardiograms.........................................................................................62
8.1.3.2.
Echocardiography...........................................................................................63
8.1.4.
Safety Monitoring ................................................................................................64
8.1.5.
Complaint Handling.............................................................................................64
8.2.
Sample Collection and Testing.....................................................................................64
8.2.1.
Samples for Study Qualification and Health Monitoring.......................................65
8.2.2.
Samples for Drug Concentration Measurements 
Pharmacokinetics/Pharmacodynamics..................................................................65
8.2.2.1.
Pharmacokinetic Samples...............................................................................65
8.2.3.
Samples for Tailoring and Pharmacodynamic Biomarkers....................................66
8.2.3.1.
Blood Samples................................................................................................66
8.2.3.2.
Tumor Tissue .................................................................................................67
8.2.4.
Samples for Pharmacogenetics .............................................................................68
8.2.5.
Samples for Immunogenicity Research.................................................................68
8.3.
Efficacy Evaluations ....................................................................................................69
8.3.1.
RECIST Version 1.1 with Confirmatory Scan for Disease 
Progression ..........................................................................................................69
8.3.1.1.
Rationale for RECIST Version 1.1 with Confirmatory 
Scan for Disease Progression..........................................................................69


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8.3.1.2.
Application of RECIST Version 1.1 with Confirmatory 
Scan for Disease Progression..........................................................................70
8.4.
Procedure/Sampling Compliance..................................................................................71
9.
Data Management Methods...............................................................................................72
9.1.
Data Quality Assurance................................................................................................72
9.2.
Data Capture Systems ..................................................................................................72
9.2.1.
Case Report Form ................................................................................................72
9.2.2.
Ancillary Data......................................................................................................73
10.
Data Analyses...................................................................................................................74
10.1. General Considerations ................................................................................................74
10.2. Patient Disposition .......................................................................................................75
10.3. Patient Characteristics ..................................................................................................75
10.4. Safety Analyses............................................................................................................75
10.5. Pharmacokinetic Analyses............................................................................................75
10.6. Biomarker Analyses.....................................................................................................76
10.7. Pharmacokinetic/Pharmacodynamic Analyses..............................................................76
10.8. Immunogenicity...........................................................................................................76
10.9. Efficacy........................................................................................................................76
10.10. Interim Analyses ..........................................................................................................76
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................78
11.1. Informed Consent.........................................................................................................78
11.2. Ethical Review.............................................................................................................78
11.3. Regulatory Considerations ...........................................................................................78
11.3.1.
Investigator Information.......................................................................................79
11.3.2.
Protocol Signatures ..............................................................................................79
11.3.3.
Final Report Signature .........................................................................................79
12.
References ........................................................................................................................80


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List of Tables
Table
Page
Table CXAD.7.1.Durvalumab Hold and Infusion Times ...........................................................45
Table CXAD.7.2.Dose Adjustments of LY2510924..................................................................51
Table CXAD.7.3 Acceptable Methods of Contraception ...........................................................54
Table CXAD.8.1.Adverse Event and Serious Adverse Event Reporting Guidelines for 
Study CXAD .................................................................................................62
Table CXAD.8.2.Summary of Response Assessment by RECIST, RECIST with 
Confirmatory Scan for Progressive Disease, and irRC ...................................70
Table CXAD.10.1.
Estimated Incidence Rate and Its Two-Sided 95% Confidence 
Interval..........................................................................................................74


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List of Figures
Figure
Page
Figure CXAD.6.1.
CXAD study design..................................................................................37


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List of Attachments
List of Protocol Attachments
Attachment
Page
Attachment 1.
Protocol CXAD Study Schedule ....................................................................84
Attachment 2.
Protocol CXAD Clinical Laboratory Tests.....................................................92
Attachment 3.
Protocol CXAD Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ..................................................................................................94
Attachment 4.
Protocol CXAD Pharmacokinetic, Pharmacodynamic, Immunogenicity, 
and Biomarker Sampling Schedule ................................................................95
Attachment 5.
Protocol CXAD Data Sharing and Sample Testing Schedule .........................99
Attachment 6.
Protocol CXAD Recommendations for Reporting 
Serious Adverse Events ...............................................................................101
Attachment 7.
Protocol CXAD ECOG Performance Status.................................................102
Attachment 8.
Protocol CXAD Creatinine Clearance Formula............................................103
Attachment 9.
Protocol CXAD Bayesian Model-Based, Toxicity-Band Method for 
Phase 1a Dose Escalation.............................................................................104
Attachment 10.
Protocol CXAD RECIST Version 1.1..........................................................111
Attachment 11.
Protocol CXAD Durvalumab Monotherapy Dosing Modification and 
Toxicity Management Guidelines for Immune-Mediated, 
Infusion-Related, and Non-Immune–Mediated Reactions ............................118
Attachment 12. Protocol CXAD Echocardiographic Guidelines ...........................................139
Attachment 13.
Protocol CXAD
Protocol Amendment I2V-MC-CXAD(b) Summary
A Phase 1a/1b Study of CXCR4 Peptide Antagonist (LY2510924) 
Administered in Combination with the Anti-PD-L1 Antibody, 
Durvalumab (MEDI4736), in Advanced Refractory Solid Tumors...............144


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4.
Abbreviations and Definitions
Term
Definition
ADA
antidrug antibody
ADA
antidrug antibody
AE
adverse event:  any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not 
necessarily have a causal relationship with this treatment.  An adverse event 
(AE) can therefore be any 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.
AESI
adverse event of special interest 
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC
area under the plasma drug concentration-time curve
AUCss
AUC at steady state 
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).
blinding/masking
a procedure in which one or more parties to the study are kept unaware of the 
treatment assignment(s).  Unless otherwise specified, blinding will remain in 
effect until final database lock.  Single-blinding usually refers to the patient(s) 
being unaware, and double-blinding usually refers to the patient(s), 
investigator(s), monitor(s), and in some cases select sponsor personnel, being 
unaware of the treatment assignment(s).
CD
cluster of differentiation
CE
carboplatin/etoposide
CI
confidence interval
CL/F (or CL)
apparent systemic clearance
Cmax
maximum observed concentration


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Cmax,ss
Cmax at steady state 
collaborator
For this study, collaborator is defined as AstraZeneca (London, United 
Kingdom).
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.
confirmation
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that Lilly is 
confident that results are accurate.  Confirmation will either occur immediately 
after initial testing or will require that samples be held to be retested at some 
defined time point, depending on the steps required to obtain confirmed results.
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
CSF
cerebrospinal fluid
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CXCR4
chemokine (C-X-C Motif) receptor 4
DCR
disease control rate
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
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 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.
GCP
good clinical practice
GTP
guanosine-5'-triphosphate
HCC
hepatocellular carcinoma
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
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.
interim analysis
an analysis of clinical study data that is conducted before the final reporting 
database is authorized for data lock.
intravenous
IV
investigational 
product (IP)
a pharmaceutical form of an active substance or placebo being tested or used as 
a reference in a clinical trial.  Investigational product includes a product with a 
marketing authorization when:
1.
used or assembled (formulated or packaged) in a way different from 
the authorized form
2.
used for an unauthorized indication or
3.
used to gain further information about the authorized form
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
irRC
immune-related response criteria
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.


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LV
left ventricular
LVEF
left ventricular ejection fraction
mAb
human monoclonal antibody
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 patients, relevant 
SOPs, International Conference on Harmonisation Good Clinical Practice 
guidelines (ICH-GCP), and all applicable laws (for example, privacy and data 
protection) and regulations.  
MRI
magnetic resonance imaging
MTD
maximum-tolerated dose
NCI
National Cancer Institute
NSCLC
non–small-cell lung cancer
open-label
A study in which there are no restrictions on knowledge of treatment allocation, 
therefore the investigator and the study participants are aware of the drug 
therapy received during the study.
ORR
overall response rate
patient
a subject with a defined disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PET
positron emission tomography
PK
pharmacokinetic
PR
partial response
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
rescreen
to screen a patient who was previously declared a screen failure for the same 
study
SAE
serious adverse event


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SCCHN
squamous cell carcinoma of the head and neck
SCLC
small cell lung cancer
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 diagnostic procedures and/or tests (for example, blood 
draws).  For this type of screening, informed consent for these screening 
procedures and/or tests shall be obtained; this consent may be separate from 
obtaining consent for the study.
screen failure
a patient who does not meet one or more criteria required for participation in a 
trial
SD
stable disease
SDF-1
stromal cell-derived factor-1
sPD-L1
soluble programmed cell death ligand 1
sponsor
the party who takes responsibility for the initiation, management and/or 
financing of a clinical study.
SQ
subcutaneous
study completion
This study will be considered complete after the final analysis (to occur no more 
than 12 months after last patient enters treatment) and evaluation of the primary 
objective and secondary objectives have been performed.
SUSAR
suspected unexpected serious adverse reactions
t1/2
half-life
TPO
third-party organization
ULN
upper limit of normal
v
version
WT
body weight


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5.
Introduction
5.1.
Cancer Immunotherapy
Immune responses directed against tumors are one of the body’s natural defenses against the 
growth and proliferation of cancer cells. However, over time and under pressure from immune 
attack, cancers develop strategies to evade immune-mediated killing allowing them to develop 
unchecked. One such mechanism involves upregulation of surface proteins that deliver 
inhibitory signals to cytotoxic T cells. Programmed cell death–ligand 1 (PD-L1) is one such 
protein, and is upregulated in a broad range of cancers with a high frequency. In a number of 
these cancers, including lung (Mu et al. 2011), renal (Thompson et al. 2005; Thompson et al.
2006; Krambeck et al. 2007), pancreatic (Nomi et al. 2007; Loos et al. 2008; Wang et al. 2010), 
ovarian cancer (Hamanishi et al. 2007), and hematologic malignancies (Andorsky et al. 2011; 
Brusa et al. 2013) tumor cell expression of PD-L1 is associated with reduced survival and an 
unfavorable prognosis.
5.1.1. Immune Checkpoint Inhibitors Targeting PD-1/PD-L1
The programmed cell death 1 (PD-1) receptor-ligand interaction is a major pathway hijacked by 
tumors to suppress immune control.  The normal function of PD-1, expressed on the cell surface 
of activated T cells under healthy conditions, is to down-modulate unwanted or excessive 
immune responses, including autoimmune reactions.  Immune checkpoints, such as PD-1 and 
PD-L1, have been targeted with antagonist mAbs, such as PD-1 antibodies nivolumab and 
pembrolizumab and PD-L1 antibody durvalumab (MEDI4736).  
5.1.2. Rationale for Combination Therapy and Selection of Expansion
Tumor Types
PD-1 inhibitors provide the opportunity to restore T-cell immunity via blocking both its 
inhibitory interactions with PD-L1 and PD-L2.  In settings of chronic stimulation, as in cancer, 
PD-L1 signals through T-cell PD-1 to “turn off” T cells in order to minimize damage to healthy 
tissue. Blocking PD-1/PD-L1 allows T cells to maintain their effector function. However, in an 
immunocompetent pancreatic mouse tumor model single-agent anti-PD-L1 did not induce tumor 
regression due to lack of immune cells; CXCR4 blockade ensures adequate T cells are present in 
the tumor microenvironment (Feig et al. 2013). Thus blockade of both chemokine (C-X-C 
Motif) receptor 4 (CXCR4) and PD-L1 has the potential to reverse the immune escape associated 
with these molecules in cancer and to potentially provide immune restoration to improve tumor 
control. The combination of CXCR4 and PD-1/PD-L1 inhibition is hypothesized to provide 
antitumor activity because CXCR4 inhibition may promote T-cell accumulation and synergize 
with anti-PD-L1, thereby inducing cancer regression through T-cell regulation.  
The combination may be potentially effective in several tumor types, including pancreatic and 
ovarian cancers. A preclinical autochthonous model of pancreatic ductal adenocarcinoma 
demonstrated that the addition of a CXCR4 inhibitor (AMD3100) resulted in the inhibition of 
α-chemokine stromal cell–derived factor-1 (SDF-1; also known as CXCL12), the ligand to 
CXCR4 receptor, promotion of T-cell accumulation in the tumor and synergism with 


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anti-PD-L1, inducing cancer regression through T-cell regulation (Feig et al. 2013).  These 
studies along with increased expression of CXCR4 in pancreatic cancer (Marchesi et al. 2004) 
support this tumor type as an indication for the combination of LY2510924 and durvalumab.  
Similarly, ovarian cancer also has been shown to have increased expression of CXCR4 (Scotton 
et al. 2002).  High CXCR4 expression has been associated with poor prognosis in ovarian cancer
(Liu et al. 2014). In an immunocompetent mouse model of epithelial ovarian cancer, treatment 
of tumors with selective CXCR4 antagonist, AMD3100, resulted in selective reduction of 
intratumoral FoxP3+ regulatory T cells, which are involved in the inhibition of tumor infiltrating 
lymphocytes (Righi et al. 2011). Therefore, these studies warrant further investigation of ovarian 
cancer as another indication for the combination of LY2510924 and durvalumab.
This study is a Phase 1a/1b open-label study that will be conducted in 2 parts.  The Phase 1a
portion of this study will consist of a dose assessment of the safety and tolerability of 
LY2510924 administered at 20, 30, or 40 mg subcutaneously (SQ) daily in combination with 
durvalumab 1500 mg intravenously (IV) once every 28 days in patients with advanced refractory 
solid tumors. The LY2510924 dose in the Phase 1b portion of this study will be based on the 
Phase 1a results.  The Phase 1b portion will include expansion arms in 2 indications, pancreatic 
and ovarian cancer (N=approximately 15 patients in each arm). Enrollment will be complete 
when the expansion arms have reached the prespecified enrollment target.  Safety and efficacy 
analysis of each expansion arm will be performed independently of the other arm.  
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.
5.2.
Rationale for Protocol Amendment (a)
The I2V-MC-CXAD protocol was amended to make the following changes:  

include FOLFOX as an accepted prior therapy for pancreatic cancer

allow for enrollment of patients with celiac disease if their disease is controlled only with 
diet 

add echocardiography at baseline to document initial left ventricular (LV) function.  
Additionally, echocardiography may be performed on-study as clinically indicated to 
determine left ventricular ejection fraction (LVEF)/LV dysfunction and any change in 
cardiac size or function.  An echocardiography guidance was included as a protocol 
attachment (Attachment 12).

exclude patients with history of QT interval prolongation, history of uncontrolled cardiac 
arrhythmias or congenital long QT syndrome, or who require drugs known to cause QT 
prolongation

change the exclusion criterion for mean QTc interval from ≥470 ms to ≥450 ms to align 
with ICH E14 guidelines

observe the initial patient in the 40-mg cohort in Phase 1a for 2 weeks, after which 
additional patients will be enrolled after notification from the sponsor.  This allows for a 


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safety assessment prior to enrolling subsequent patients since this dose level has not 
previously been investigated.

clarify that final analysis will be conducted no more than 12 months after the last patient 
enters treatment

allow dose interruption up to 12 weeks.  Management of immune-mediated adverse 
events (AEs), including steroid tapering, allows a 12-week window for resolution before 
discontinuing study treatment.  

add dose-limiting toxicity (DLT) and LY2510924 discontinuation criteria of ≥Grade 3 
QT prolongation AE per Common Terminology Criteria for Adverse Events (CTCAE)
criteria 

clarify an exclusion to the DLT list.  Grade 3 thrombocytopenia not associated with 
bleeding that requires clinically significant medical intervention and improves by at least 
1 grade within 3 days is not considered a DLT.

clarify LY2510924 dose adjustments, delays, and discontinuations and revise a 
discontinuation criterion from LY2510924 treatment.  Patients with combined elevated 
aspartate aminotransferase (AST)/alanine aminotransferase (ALT) AND total bilirubin 
values meeting discontinuation parameters as described in the DLT definition should be 
considered for permanent discontinuation based on clinical judgment.

include scheduled electrocardiogram (ECG) assessments to assess QT interval length
periodically during study therapy

make minor clarifications and changes.  
5.3.
Rationale for Protocol Amendment (b)
The I2V-MC-CXAD protocol (a) was amended to make the following changes:  

Section 5.5.2.4:  Clinical safety information on durvalumab updated.

Section 6.1.3: Exclusion Criterion [16] expanded to include previous participation in any 
randomized controlled trial that included arms with an anti-PD-1, anti-PD-L1, 
anti-PD-L2, or anti-cytotoxic T lymphocyte-associated antigen-4 antibody or any other 
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways such 
as CD137, GITR, TIM-3, and LAG3, rather than only either durvalumab or 
tremelimumab.  

Synopsis and Section 6.2:  Clarified that patients will be allowed to continue until they 
fulfill 1 or more of the study discontinuation criteria.  

Sections 6.2 and 8.3.1.2: Clarified that patients will not be permitted to continue study 
therapy if progression occurs after confirmed response.    

Section 7.2.2.1: Added or modified existing DLT criteria to:
o
Grade 3 leukocytosis (leukocytes >100,000/µL) of any duration, or 
leukocytosis/granulocytosis causing clinical symptoms
o
Any Grade 4 non-laboratory AE
o
Any Grade 3 laboratory value, and modified stipulations that the abnormal value 
must be associated with clinically significant symptoms and persist for >7 days
o
Any Grade 4 laboratory abnormalities


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
Section 7.2.2.2:  For Phase 1a, any DLT-equivalent toxicities observed in Cycle 2 and 
beyond will also be considered in dose escalation and determining MTD/recommended 
Phase 2 dose.  Additionally, if the DLT observation period is extended to Cycle 2, 
patients discontinuing Cycle 2 in the absence of DLT-equivalent toxicity will be 
evaluable for DLT assessments.

Section 7.2.4:  Wording added that for Phase 1a and 1b, the DLT observation period will 
be extended to Cycle 2 if a DLT-equivalent toxicity is observed during Cycle 2 in any 
cohort in Phase 1a.   

Table CXAD.7.2: Dose adjustment of LY2510924 to align with newly added DLT 
criterion for leukocytosis.

Section 8.1.3.1:  Typographical error was corrected.

Section 8.3.1.2: Patients with a decline in Eastern Cooperative Oncology Group (ECOG)
performance status >1 will not be permitted to continue study treatment after confirmed 
progression of disease.

Section 10.10:  Wording added that if the DLT-observation period is extended to 2 cycles 
during Phase 1a, analysis will include DLT-equivalent toxicities occurring in Cycle 2.

Attachment 1 and Attachment 4 Correction: For serum, plasma, and whole blood 
samples for biomarkers, baseline whole blood samples must be collected ≤7 days prior to 
Cycle 1 Day 1.

Attachment 4 Correction: immunogenicity samples will be collected 90 days post 
durvalumab treatment.  

Attachment 11: Durvalumab dose modification guidelines have been updated.
Attachment 13 contains a detailed list of changes made in this amendment.  Some minor editorial 
changes may not be listed.
5.4.
Objectives
5.4.1. Primary Objective
Dose Escalation
The primary objective of the dose-escalation part of this study is to assess the safety and 
tolerability of LY2510924 SQ daily in combination with durvalumab by identifying DLTs and 
the maximum-tolerated dose (MTD) of the combination in patients with advanced (metastatic 
and/or unresectable) solid tumors.  
Dose Expansion
The primary objective of the dose-expansion part of this study is to assess the safety of 
LY2510924 SQ daily in combination with durvalumab in patients with advanced pancreatic and 
ovarian cancers.  


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5.4.2. Secondary Objectives
The secondary objectives of this study are:  

To characterize the pharmacokinetics (PK) of LY2510924 and durvalumab when 
co-administered

To characterize the immunogenicity of durvalumab when administered in combination with 
LY2510924 

To assess the antitumor activity of the combination of LY2510924 and durvalumab in 
patients with advanced solid tumors  
5.4.3. Exploratory Objectives 
The exploratory objective of this study is to examine biomarkers, including pharmacodynamic 
markers, relevant to LY2510924 and durvalumab, including but not limited to, immune 
cells/immune functioning, drug targets, cancer-related pathways and the disease state, and to
correlate these markers with clinical outcome.  
5.5.
General Introduction to LY2510924 and Durvalumab
5.5.1. LY2510924
5.5.1.1.
LY2510924 Chemokines, SDF-1, and CXCR4
Chemokines are important molecules that guide the migration of cells from one tissue to another.  
The CXCR4 is a transmembrane G-protein–coupled receptor. CXCR4 and its only known 
ligand, α-chemokine stromal-cell derived factor-1 (SDF-1) are believed to play an important role 
in the regulation of organ-specific metastasis, as well as tumor growth, invasion, survival, and 
angiogenesis (Balkwill 2004; Peng et al. 2015). The CXCR4/SDF-1 axis is involved in the 
migration of hematopoietic stem cells and lymphocytes, and both are required for normal murine 
fetal development (Balkwill 2004).  SDF-1 is expressed widely throughout the body, and SDF-1 
concentrations in the tissue play an important role in signaling whether CXCR4+ cells should 
stay in their present environment or migrate to other tissues.  For instance, if local SDF-1 
concentrations increase in response to a stimulus, CXCR4+ cells may follow the gradient to the 
SDF-1-rich environment.  Similarly, static concentrations of SDF-1 will prevent the migration of 
CXCR4+ cells from the tissue; however, blocking the interaction of SDF-1 with CXCR4 results 
in rapid mobilization of stem cells and leukocytes into the peripheral blood.
CXCR4 is functionally expressed or overexpressed in a variety of solid tumor cancers, 
lymphoma, and chronic lymphocytic leukemia (Balkwill 2004; Peng et al. 2005).  Within 
hypoxic areas of tumors, both SDF-1 secretion by fibroblasts and CXCR4 expression on tumor 
cells increase, which stimulate tumor cell growth, migration, and invasion.  SDF-1 promotes 
tumor growth in a paracrine fashion by directly stimulating tumor cell proliferation and survival 
via CXCR4.  Stromal cells in tissues such as bone, liver, and lungs secrete SDF-1, creating a 
concentration gradient that induces directional migration of CXCR4 expressing cancer cells 
toward these tissues (Kucia et al. 2005). Recently, CXCR4 was demonstrated to play a role in 


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cancer immunotherapy via T-cell mobilization and redistribution in the tumor microenvironment 
(Righi et al. 2011; Feig et al. 2013; Gil et al. 2014).
More information about the known and expected benefits, risks and reasonably anticipated AEs 
may be found in the Investigator’s Brochure (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 also be found in the IB.
5.5.1.2.
CXCR4 Peptide Antagonist LY2510924 and Its Mechanism of Action
LY2510924 is a potent and selective peptide antagonist of CXCR4 in vitro and in vivo and 
inhibits SDF-1 binding to CXCR4 in human, monkey, mouse, and rat cells.  LY2510924 
inhibited SDF-1α binding to human CXCR4 in a dose-dependent manner in 2 different tumor 
cell lines (leukemia and lymphoma) with an IC50 of 0.0797 to 0.3016 nM (Peng et al. 2015).  
LY2510924 is specific for CXCR4, blocks binding of SDF-1α to CXCR4, and does not 
demonstrate agonist activity.  In an in vitro ligand-binding assay, LY2510924 did not bind to 
CCR1, CCR2, CXCR2 and CXCR3, serotonin, dopamine, or specific opioid receptors; however, 
in a cell surface receptor mini-panel, LY2510924 significantly inhibited Alpha 2 adrenergic, 
Ghrelin, muscarinic, NK2, and opioid (nonspecific) receptors at 10 M.  LY2510924 inhibited 
SDF-1 binding to CXCR4 of monkey, mouse, and rat in a dose-dependent manner with IC50 of 
0.097, 2.832, and 2.218 nM, respectively.  In vitro, SDF-1α induces guanosine-5'-triphosphate 
(GTP) binding and initiates a signaling cascade that results in chemotaxis in a dose-dependent 
manner; however, under identical conditions, LY2510924 interaction with CXCR4 does not 
cause GTP binding or chemotaxis, confirming that LY2510924 has no apparent agonist activity.  
5.5.1.3.
Summary of Clinical Experience
I2V-MC-CXAA (CXAA) study was a multicenter, nonrandomized, open-label, dose-escalation 
Phase 1 study of SQ LY2510924 in patients with advanced or metastatic cancer for whom no 
treatment of higher priority existed.  Study CXAA consisted of a dose-escalation phase, followed 
by a dose-confirmation phase.  Elevated CD34+ counts were seen in patients treated in CXAA 
study in a dose-dependent manner. The PK/pharmacodynamic modelling based on CD34+ cells 
from CXAA study indicated a plateau in the increase of CD34+ in peripheral blood for the dose 
levels above 20 mg but this was based on dose levels up to 30 mg only (n=7 patients treated at 
this dose on CXAA study, refer to Section 5.6 for further details). There were 9 SAEs 
experienced by 7 subjects (study disease [3 subjects]; and abdominal abscess, cerebellar tumor, 
dyspnea, chest pain, pulmonary embolism, and respiratory arrest [each 1 subject]); none of the 
SAEs were related to study drug.  Six subjects (13.3%) died within 30 days of their last dose of 
study drug; none of the deaths were related to study drug. Five subjects (2 subjects from each 
the 2.5 and 20 mg/day dose cohort and 1 subject from the 1.0 mg/day cohort) died due to study 
disease; 1 subject (10 mg/day dose cohort) died due to an SAE (respiratory arrest). 
Two Phase 2 combination studies have been completed; studies in renal cell carcinoma (RCC, 
12V-MC-CXAB [CXAB]) and small cell lung cancer (SCLC, 12V-MC-CXAC [CXAC]) in 
which 119 patients received LY2510924 in combination with the standard of care at a dose of 
20 mg daily SQ.  In Study CXAB (RCC), LY2510924 was administered with sunitinib 


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LY2510924/durvalumab
(72 patients) versus sunitinib alone (36 patients). The most frequent treatment-emergent adverse 
events (TEAEs) reported in the LY2510924 + sunitinib arm versus sunitinib-alone arm were 
fatigue (69.4% vs 55.6%), nausea (48.6% vs 50%), diarrhea (38.9% vs 52.8%), anemia (34.7% 
vs 16.7%), dysgeusia (31.9% vs 30.6%), thrombocytopenia (27.8% vs 22.2%), rash (26.4% vs 
11.1%, vomiting (25% vs 22.2%), dizziness (23.6% vs 19.4%), mucosal inflammation (23.6% vs 
27.8%), decreased appetite (23.6% versus 22.2%) and hypertension (22.2% versus 33.3%). All 
deaths on study were due to disease progression except for 1 patient in the LY2510924 and 
sunitinib arm who died due to an event unrelated to drug therapy. In Study CXAC (SCLC), 
LY2510924 was combined with carboplatin/etoposide (CE) (47 patients) versus CE only 
(43 patients).  The most common treatment-emergent AEs that occurred more frequently (>5%) 
in the LY2510924+CE arm than in the CE arm were anemia (62% vs 49%), vomiting (32% vs 
23%), leukopenia (28% vs 9%), back pain (19% vs 7%), injection site pain (19% vs 0%), 
exertional dyspnea (15% vs 2%), and dysgeusia (12% vs 2%). No patients in this study died 
during treatment due to AEs.  Both studies indicate that LY2510924 is able to be safely 
administered at this dose. However, neither study demonstrated sufficient efficacy of 
LY2510924 when given with standard of care for advanced RCC or SCLC.  
5.5.1.4.
Biomarkers
CXCR4 and SDF-1 interaction is critical for the retention of CD34+ stem cells and immune cells 
in bone marrow.  In preclinical models, treatment with LY2510924 showed significant 
pharmacodynamics effects by increasing CD34+ stem cells and white blood cells (including 
neutrophils and lymphocytes) in the circulation.  These pharmacodynamic effects were also 
observed in humans in a Phase 1 clinical study (Galsky et al. 2014).  Therefore, CD34+ stem 
cells and total white blood cells including neutrophils and lymphocytes can be used as 
exploratory pharmacodynamic biomarkers in this study.  
Additionally, the infiltration and distribution of T cells, and their relationship with tumor cells 
and stromal cells in the tumor microenvironment can be further explored as biomarkers.
5.5.2. Durvalumab
5.5.2.1.
Programmed Cell Death–Ligand 1 (PD-L1)
Programmed cell death–ligand 1 is part of a complex system of receptors and ligands that are 
involved in controlling T-cell activation. PD-L1 acts at multiple sites in the body to help 
regulate normal immune responses and is utilized by tumors to help evade detection and 
elimination by the host immune system tumor response. In the lymph nodes, PD-L1 on 
antigen-presenting cells binds to PD-1 or CD80 on activated T cells and delivers an inhibitory 
signal to the T cell (Keir et al. 2008; Park et al. 2010). This results in reduced T-cell activation 
and fewer activated T cells in circulation. In the tumor microenvironment, PD-L1 expressed on 
tumor cells binds to PD-1 and CD80 on activated T cells reaching the tumor. This delivers an 
inhibitory signal to those T cells, preventing them from killing target cancer cells and protecting 
the tumor from immune elimination (Zou and Chen, 2008). 


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5.5.2.2.
Background on Durvalumab
Durvalumab is being developed as a potential anticancer therapy for patients with advanced solid 
tumors. Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G1 kappa 
(IgG1κ) subclass that inhibits binding of programmed cell death–ligand 1 (PD-L1 (B7 homolog 
1 [B7-H1], cluster of differentiation [CD]274) to PD-1 (CD279) and CD80 (B7-1). Durvalumab
is composed of 2 identical heavy chains and 2 identical light chains, with an overall molecular 
weight of approximately 149 kDa. Durvalumab contains a triple mutation in the constant 
domain of the immunoglobulin (Ig) G1 heavy chain that reduces binding to complement protein 
C1q and the fragment crystallizable gamma (Fcγ) receptors involved in triggering effector 
function.  
5.5.2.3.
Summary of Nonclinical Experience
The nonclinical experience is fully described in the current version of the durvalumab IB.  
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction 
with PD-1 and CD80. Additionally, durvalumab demonstrated a lack of antibody-dependent 
cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in cell-based 
functional assays. 
5.5.2.4.
Summary of Clinical Experience 
Clinical experience with durvalumab is fully described in the current version of the durvalumab
IB.
As of 12 July 2015, a total of 1883 patients have been enrolled and treated in 30 ongoing 
durvalumab clinical studies, including 20 sponsored and 10 collaborative studies. Of the 
1883 patients, 1279 received durvalumab monotherapy, 440 received durvalumab in combination 
with tremelimumab or other anticancer agents, 14 received other agents (1 gefitinib, 
13 MEDI6383), and 150 have been treated with blinded investigational product. No studies have 
been completed or terminated prematurely due to toxicity.  
Pharmacokinetics and Product Metabolism 
Study CD-ON-MEDI4736-1108: As of 09 Feb 2015, PK data were available for 378 patients in 
the dose-escalation and dose-expansion phases of Study CD-ON-MEDI4736-1108 following 
treatment with durvalumab 0.1 to 10 mg/kg every 2 weeks (Q2W) or 15 mg/kg every 3 weeks 
(Q3W). The maximum observed concentration (Cmax) increased in an approximately 
dose-proportional manner over the dose range of 0.1 to 15 mg/kg. The area under the 
concentration-time curve (AUC) from 0 to 14 days increased in a greater than dose-proportional 
manner over the dose range of 0.1 to 3 mg/kg and increased dose-proportionally at ≥3 mg/kg.  
These results suggest durvalumab exhibits nonlinear PK likely due to saturable target-mediated 
apparent systemic clearance (CL) at doses <3 mg/kg and approaches linearity at doses ≥3 mg/kg. 
Near complete target saturation (soluble programmed cell death–ligand 1 [sPD-L1] and 
membrane bound) is expected with durvalumab ≥3 mg/kg Q2W. Exposures after multiple doses 
showed accumulation consistent with PK parameters estimated from the first dose. In addition, 


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PK simulations indicate that following durvalumab 10 mg/kg Q2W dosing, >90% of patients are 
expected to maintain PK exposure ≥40 g/mL throughout the dosing interval.  
As of 09 February 2015, a total of 388 patients provided samples for antidrug antibody (ADA)
analysis. Only 8 of 388 patients (1 patient each in 0.1-, 1-, 3-, and 15-mg/kg cohorts, and 
4 patients in 10-mg/kg cohort) were ADA positive with an impact on PK/pharmacodynamics in 
1 patient in the 3-mg/kg cohort.  
Safety 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumor types appeared to be associated with unique AEs. 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. Potential risks are 
events with a potential inflammatory mechanism which may require more frequent monitoring 
and/or unique interventions such as immunosuppressants and/or endocrine replacement therapy. 
These risks include gastrointestinal AEs such as colitis and diarrhea, pneumonitis, nephritis and 
acute renal failure; hepatic AEs such as hepatitis and liver enzyme elevations, and dermatitis;
and endocrinopathies such as hypo- and hyper-thyroidism, hypophysitis, and adrenal 
insufficiency.  Additional treatment-emergent immune-related events, including pancreatitis, 
neuropathy, and neuromuscular toxicity, have been reported with checkpoint inhibitor treatment.  
These events are manageable by available/established treatment guidelines as described in the 
study protocol.  
Adverse Event Profile of Durvalumab Monotherapy
Identified risks with durvalumab are diarrhea, increases in transaminases, pneumonitis, and 
colitis. 
Potential risks include endocrinopathies (hypo- and hyper-thyroidism, hypophysitis, and adrenal 
insufficiency), hepatitis/hepatotoxicity, neurotoxicities, nephritis, pancreatitis, dermatitis, 
infusion-related reactions, anaphylaxis, hypersensitivity or allergic reactions, and immune 
complex disease. Further information on these risks can be found in the current version of the 
durvalumab IB.
In monotherapy clinical studies, AEs (all grades) reported very commonly (≥10% of patients) are 
fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back pain, 
pyrexia, abdominal pain, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. 
Approximately 10% of patients experienced an AE that resulted in permanent discontinuation of 
durvalumab and approximately 3.5% of patients experienced an SAE that was considered to be 
related to durvalumab by the study investigator.
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 


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treatment guidelines for immune-mediated toxicity (see the Dosing Modification and Toxicity 
Management Guidelines in Attachment 11).
A detailed summary of durvalumab monotherapy AE data can be found in the current version of 
the durvalumab IB.
5.6.
Rationale for Selection of Dose
LY2510924
A dose range of 20, 30, and 40 mg of LY2510924 administered SQ daily was selected based on 
the overall clinical information from the 3 studies completed. In the first-in-human dose CXAA 
study, a predefined DLT criterion was used for the elevation of absolute neutrophil account 
(ANC >25 000) and 2 of 7 patients exceeded this level at the 30 mg dose during treatment. This 
led to the MTD dose of 20 mg. However, it is notable that high levels of ANC were not reported 
as clinically significant. In addition, the 2 Phase 2 studies, CXAB (RCC) and CXAC (SCLC),
did not show efficacy in combination with standard of care (SOC) at 20-mg dose. Therefore,
Lilly proposed to test higher dose levels of LY2510924 in this CXAD combination therapy 
setting by increasing the predefined ANC threshold criteria to 75 000. After the first patient is 
enrolled and receives study treatment in the 40-mg cohort, there will be a 2-week observation 
period, after which enrollment will continue after notification from the sponsor.
The PK/pharmacodynamic modelling based on CD34+ cells from Study CXAA indicated a 
plateau in the increase of CD34+ in peripheral blood for the dose levels above 20 mg but this 
was based on dose levels up to 30 mg only.  
Durvalumab
Monotherapy dose rationale
A durvalumab dose of 20 mg/kg Q4W is supported by in vitro data, nonclinical activity, clinical 
PK/pharmacodynamics, biomarkers, and activity data from Study 1108 in patients with advanced 
solid tumors and from a Phase 1 trial performed in Japanese patients with advanced solid tumor 
(D4190C00002).  
PK/Pharmacodynamic data
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging 
from 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W, durvalumab exhibited nonlinear (dose dependent) 
PK consistent with target-mediated drug disposition.  The PK approached linearity at ≥3 mg/kg 
Q2W, suggesting near complete target saturation (membrane bound and sPD-L1), and further 
shows that the durvalumab dosing frequency can be adapted to a particular regimen given the 
linearity seen at doses higher than 3 mg/kg.  The expected half-life (t1/2) with doses ≥3 mg/kg 
Q2W is approximately 21 days.  A dose-dependent suppression in peripheral sPD-L1 was 
observed over the dose range studied, consistent with engagement of durvalumab with PD-L1.  A 
low level of immunogenicity has been observed.  No patients have experienced 
immune-complex disease following exposure to durvalumab (further information on 
immunogenicity, please see the current durvalumab IB).  


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Data from Study D4190C00006 (Phase 1 trial in NSCLC patients using the combination of 
durvalumab and tremelimumab) also show an approximately dose-proportional increase in PK
exposure for durvalumab over the dose range of 3 to 20 mg/kg durvalumab every 4 weeks 
(Q4W) or Q2W (further information on PK observations in Study 006, please see the current 
durvalumab IB).  
The observed durvalumab PK data from the combination study were well in line with the 
predicted monotherapy PK data (5th median and 95th percentiles) for a Q4W regimen.  
A population PK model was developed for durvalumab using monotherapy data from Study 
1108 (N=292; doses=0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W (Ellis et al. 2008; Fairman et 
al. 2014).  Multiple simulations indicate that a similar overall exposure is expected following 
both 10 mg/kg Q2W and 20 mg/kg Q4W regimens, as represented by AUC at steady state 
(AUCss) 4 weeks).  Median Cmax at steady state (Cmax,ss) expected to be higher with 20 mg/kg 
Q4W (~1.5-fold) and median Ctrough,ss is expected to be higher with 10 mg/kg Q2W 
(~1.25-fold).  Clinical activity with the 20 mg/kg Q4W dosing regimen is anticipated to be 
consistent with 10 mg/kg Q2W with the proposed similar dose of 20 mg/kg Q4W expected to 
(a) achieve complete target saturation in majority of patients; (b) account for anticipated 
variability in PK, pharmacodynamics, and clinical activity in diverse cancer populations; 
(c) maintain sufficient PK exposure in case of ADA impact; and (d) achieve PK exposure that 
yielded maximal antitumor activity in animal models.  
Given the similar AUC and modest differences in median peak and trough levels at steady state, 
the observation that both regimens maintain complete sPD-L1 suppression at trough, and the 
available clinical data, the 20 mg/kg Q4W and 10 mg/kg Q2W regimens are expected to have 
similar efficacy and safety profiles, supporting further development with a dose of 20 mg/kg 
Q4W.  
Fixed Dosing
Population PK analysis indicated only minor impact of body weight on PK of durvalumab
(coefficient of ≤0.5). The impact of body weight-based (10 mg/kg Q2W) and fixed dosing 
(750 mg Q2W) of durvalumab was evaluated by comparing predicted steady-state PK 
concentrations (5th, median and 95th percentiles) using the population PK model. A fixed dose 
of 750 mg was selected to approximate 10 mg/kg (based on median body weight of ~75 kg). A 
total of 1000 patients were simulated using body weight distribution of 40 to 120 kg. Simulation 
results demonstrate that body weight-based and fixed dosing regimens yield similar median 
steady-state PK concentrations with slightly less overall between-subject variability with fixed 
dosing regimen.  
Similar findings have been reported by others (Ng et al. 2006; Wang et al. 2009; Zhang et al.
2012; Narwal et al. 2013).  Wang and colleagues (2009) investigated 12 mAbs and found that 
fixed and body size-based dosing perform similarly, with fixed dosing being better for 7 of 
12 antibodies (Wang et al 2009). In addition, they investigated 18 therapeutic proteins and 
peptides and showed that fixed dosing performed better for 12 of 18 in terms of reducing the 
between-subject variability in PK/pharmacodynamics parameters (Zhang et al. 2012). 


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A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors.  Given expectation of similar PK exposure and variability, we considered 
it feasible to switch to fixed dosing regimens.  Based on average body WT of 75 kg, a fixed dose 
of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is included in the current study
given the decreased frequency of Q4W compared to Q2W regimen leading to further ease of use.  
Fixed dosing of durvalumab is recommended only for patients with >30 kg body weight due to 
endotoxin exposure.  


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6.
Investigational Plan
6.1.
Study Population
6.1.1. Screening Procedures
Patients who do not meet the criteria for participation within the 28-day screening period (screen 
failure) may be rescreened with the approval of the study manager (see below).  Note that 
repeating laboratory tests during the 28-day screening period does not constitute rescreening (any 
test that does not meet eligibility may be repeated within the 28-day period and not considered a 
rescreening).  Results of the repeat screening do not have to be received within the 28-day 
period.  Screening laboratory tests may not be repeated more than twice in order to meet 
eligibility during the 28-day screening period.  If a repeat laboratory value meets eligibility, that 
test must be repeated again to confirm eligibility.
After the initial 28-day screening period, a patient may be rescreened.  The interval between 
rescreenings should be at least 1 week.  If a patient does not meet eligibility within the first 
28-day screening period, the patient may be rescreened beginning on Day 35.  Rescreening may 
occur up to 2 times after the initial screening, if needed.  Each time rescreening is performed, the 
patient must sign a new informed consent form (ICF) and will be assigned a new identification 
number.  All required tests including laboratory tests, ECGs, and computed tomography (CT) 
scans with contrast must be repeated in patients who are rescreened in a new 28-day period.
Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as 
protocol waivers or exemptions) is not permitted.  Any missing laboratory or test results 
precludes patient from being enrolled on this study until those laboratory or test results are 
available.  Local laboratories will be used to assess eligibility.  
6.1.2. 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]
Phase 1a: Have histologic or cytologic confirmation of advanced solid tumor
(see American Joint Committee on Cancer Staging Criteria; Edge et al. 2009), 
and 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 the patient has refused available standard 
therapies.
[2]
Phase 1b: Histologic or cytologic confirmation of advanced cancer in the 
following tumor types:
a) Pancreatic cancer

Cytologically or histologically confirmed pancreatic adenocarcinoma (excluding 
other pancreatic malignancies [eg, acinar cell carcinomas, adenosquamous 
carcinomas, and neuroendocrine islet cell neoplasms])

Metastatic disease or locally advanced, unresectable disease


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
Have had disease progression, be refractory or intolerant to no more than 2 prior 
systemic regimens for locally advanced or metastatic pancreatic cancer.  Patients 
who have received prior neoadjuvant therapy and who now have metastatic 
disease, must receive FOLFIRINOX, FOLFOX, single-agent gemcitabine, 
gemcitabine/nab-paclitaxel, or TS-1 (tegafur gimeracil oteracil potassium) prior to 
enrollment on this study.  
b) Ovarian cancer

Cytologically or histologically proven epithelial ovarian cancer (except borderline 
ovarian tumor histology), fallopian tube cancer, or primary peritoneal cancer with 
evidence of recurrence or refractory disease, which is advanced and not amenable 
to curative surgery or radiotherapy (International Federation of Gynecology and 
Obstetrics [FIGO] Staging; Odicino et al. 2008).

Have recurrence of cancer at least 6 months after completion of first-line 
platinum-based therapy.

Have received chemotherapy for recurrence of disease, but not exceeding 4 lines 
of therapy during which time disease may be platinum sensitive or resistant.
[3]
Have at least 1 measurable lesion assessable using standard techniques by 
Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 (Eisenhauer 
et al. 2009; Attachment 10). Positron emission tomography (PET) scans and 
ultrasounds may not be used for diagnostic purposes.
[4]
Are 18 years of age.
[5]
Have a minimum body weight of >30 kg.


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[6]
Have adequate organ function, as defined below:
System
Laboratory Value
Hematologic
ANC
1.5 × 109/L
Platelets
100 × 109/L
Hemoglobin
9g/dL or 5.6 mmol/L
Patients may receive erythrocyte transfusions to achieve this 
hemoglobin level at the discretion of the investigator (at 
least 3 days before starting treatment with study drug).  
Initial treatment must not begin until 2 days after the 
erythrocyte transfusion and after the confirmation of 
hemoglobin level ≥9 g/dL.
INR or PT
1.5 × ULN, unless patient is receiving stable dose 
anticoagulant therapy (these patients are eligible as long as 
PT or INR is within therapeutic range of the intended use 
of the anticoagulant).  
Partial Thromboplastin Time (PTT) or 
Activated Partial Thromboplastin Time 
(aPTT)
PTT or aPTT ≤5 seconds above ULN, unless patient is 
receiving anticoagulant therapy, where the PTT or aPTT is 
within therapeutic range of intended use of anticoagulants.
Hepatic
Total bilirubin
1.5 × ULN except patients with Gilbert’s Syndrome who 
must have a total bilirubin level of <3.0 × ULN and will be 
allowed only in consultation with their physician.
ALT and AST
2.5 × ULN OR
5 × ULN if the liver has tumor involvement
Albumin
3g/dL
Renal
Calculated creatinine clearance (see 
Attachment 8)
Serum creatinine CL >40 mL/min by the Cockcroft-Gault 
formula (Cockcroft and Gault, 1976) or by 24 hour urine 
collection for determination of creatinine clearance
Urine protein
<2+ on dipstick or routine urinalysis.  If urine dipstick or 
routine analysis indicates proteinuria 2+, then a 24-hour 
urine must be collected and must demonstrate <2 g of 
protein in 24 hours to allow participation in the study.
Thyroid function
TSH OR free T4 within normal limits
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; ANC = absolute 
neutrophil count; CL = clearance; INR = international normalized ratio of prothrombin time; 
PT = prothrombin time; TSH = thyroid stimulating hormone; ULN = upper limit of normal.
[7] Have a performance status of 0 or 1 on the ECOG scale (refer to
Attachment 7).


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[8]
Have discontinued all previous treatments for cancer for at least 14 days and 
recovered from the acute effects of therapy.  Patients must have discontinued 
from previous treatments, as shown below:
Previous Treatment
Length of Time Prior to First Dose of Study Treatment
Cytotoxic therapies or targeted agents 
that are small molecule inhibitors 
2 weeks
Mitomycin-C or nitrosoureas
>42 days
Biologic agents (for example, 
antibodies)
2 weeks
Radiotherapy
4 weeks
Limited field radiotherapy
2 weeks 
Major surgery, excluding biopsy
Patients with recent major surgery must have occurred 
>28 days prior to screening) must have recovered, in the 
opinion of the investigator, from the toxicity and/or 
complications from the intervention before starting 
therapy.
Study drug with an investigational 
product or nonapproved use of a drug or 
device
2 weeks
NOTE:  At the discretion of the investigator, patients with hormone-refractory prostate cancer who are 
stable on gonadotropin-releasing hormone (GnRH) agonist therapy or patients with breast cancer 
who are stable on anti-estrogen therapy (for example, an aromatase inhibitor) may continue that 
treatment while enrolled in this study.
[9]
Have provided tissue from a newly obtained core or excisional biopsy of a 
tumor lesion or a recent biopsy defined by 3 years since last documented 
progression of disease.  (Note: patients for whom newly obtained samples 
cannot be obtained such as in cases of inaccessibility or patient safety 
concern, an archived specimen can be submitted upon agreement from 
sponsor and if not restricted by local regulations.)  
For ovarian expansion arm only: Be able to provide tissue (newly obtained 
core or excisional biopsy of tumor lesion) from an on-treatment biopsy for 
biomarker analysis.  
[10] Are male patients who are sterile (including vasectomy confirmed by 
post-vasectomy semen analysis) or agree use of an effective method of 
contraception and not to donate sperm or practice total abstinence from 
heterosexual activity, starting with the first dose of study treatment, during the 
study, and for at least 6 months following the last dose of study treatment, or 
longer, if determined by country requirements;  
[11] Female patients must either be of nonreproductive potential (ie, 
postmenopausal by history: ≥60 years old and no menses for ≥1 year without 
an alternative medical cause; OR history of hysterectomy, OR history of 
bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a 
negative serum pregnancy test upon study entry.  


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[12] Have an estimated life expectancy of ≥12 weeks, in the judgment of the 
investigator.
[13] Capable and willing to learn to self-administer LY2510924, or have a 
caregiver who is willing to learn and able to administer LY2510924 by SQ 
injection.  
6.1.3. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[14] Have a serious concomitant systemic disorder or laboratory abnormality that
would compromise interpretation of results or the patient’s ability to adhere to 
the protocol

Including active infection with human immunodeficiency virus (HIV) 
(HIV 1/2 antibodies)

Active infection with hepatitis B virus (positive hepatitis B surface antigen 
[+HBsAg]), or hepatitis C virus (HCV)

Known history of previous clinical diagnosis of tuberculosis

History of primary immunodeficiency

Have prior or second concurrent primary malignancies that, in the 
judgment of the investigator and Lilly, may affect the interpretation of 
results. Patients with carcinoma in situ of any origin and patients with 
prior malignancies who are in remission and whose likelihood of 
recurrence is very low (such as basal cell carcinoma), as judged by the 
Lilly clinical research physician (CRP) or designee, are eligible for this 
study.  

Active autoimmune disorders, or prior documented severe autoimmune or 
inflammatory disorders requiring immunosuppressive treatment (including 
inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis 
with the exception of diverticulosis, irritable bowel syndrome, or other 
serious gastrointestinal chronic conditions associated with diarrhea); 
systemic lupus erythematosus; Wegener Granulomatosis (with 
polyangiitis), Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis, 
etc).  The following are exceptions to this criterion:
o
Patients with vitiligo or alopecia
o
Patients with diabetes mellitus type I or resolved childhood 
asthma/atopy
o
Patients with hypothyroidism (eg, following Hashimoto syndrome) 
stable on hormone replacement, or psoriasis not requiring systemic 
treatment 


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o
Any chronic skin condition that does not require systemic therapy
o
Patients with celiac disease controlled by diet alone
o
Patients without active disease in the last 5 years may be included but 
only after consultation with the study physician

Patients requiring escalating or chronic supraphysiologic doses of 
corticosteroids (>10 mg /day of prednisone or an equivalent 
corticosteroid) for control of their disease or immunosuppressive agents 
(eg, cyclosporine) for any reason are excluded.  Patients with resolved 
childhood asthma/atopy are eligible.  Patients who require intermittent use 
of bronchodilators or local steroid injections would not be excluded from 
the study.  Patients with hypothyroidism stable on hormone replacement, 
Raynaud’s syndrome or Sjögren’s syndrome will not be excluded from the 
study

Have a bowel obstruction, history or presence of inflammatory 
enteropathy or extensive intestinal resection (hemicolectomy or extensive 
small intestine resection, either condition with chronic diarrhea), Crohn’s 
disease, ulcerative colitis, or chronic diarrhea

Have evidence of interstitial lung disease that is symptomatic or may 
interfere with the detection or management of suspected drug-related 
pulmonary toxicity or active, noninfectious pneumonitis

Have an active infection 

Have moderate or severe cardiovascular disease:  
o
Have the presence of cardiac disease, including a myocardial 
infarction or any other arterial thrombotic event including 
cerebrovascular accident or transient ischemic attack within 6 months 
prior to study entry, unstable angina pectoris, New York Heart 
Association Class III/IV congestive heart failure, aneurysm of major 
vessels or heart, left ventricular (LV) ejection fraction <50% 
(echocardiographic evaluation based on institutional lower limit of 
normal performed within 28 days of first dose), or uncontrolled 
hypertension; 
o
Have a history of QT interval prolongation, history of uncontrolled 
cardiac arrhythmias, congenital long QT syndrome, or who require 
drugs known to cause QT prolongation;


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o
Have valvulopathy that is severe, moderate, or deemed clinically 
significant; or documented major ECG abnormalities that are clinically 
significant at the investigator’s discretion(for example, symptomatic or 
sustained atrial or ventricular arrhythmias, second- or third-degree 
atrioventricular block, bundle-branch blocks, ventricular hypertrophy, 
or recent myocardial infarction; or a mean QT interval corrected for 
heart rate (QTc) is ≥450 ms calculated using Fridericia’s Correction, 
confirmed on triplicate ECG);  
[15] Have had prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-
cytotoxic T lymphocyte-associated antigen-4 antibody (including but not 
limited to ipilimumab, durvalumab, or tremelimumab) or any other antibody 
or drug specifically targeting T-cell co-stimulation or checkpoint pathways 
such as CD137, GITR, TIM-3, and LAG3.
[16] Previous participation in any randomized controlled trial that included arms 
with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-cytotoxic T 
lymphocyte-associated antigen-4 antibody (including but not limited to 
ipilimumab, durvalumab, or tremelimumab) or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathways such as 
CD137, GITR, TIM-3, and LAG3, irrespective of actual treatment received on 
the trial.
[17] Female patients who are pregnant, breastfeeding or male or female patients of 
reproductive potential who are not employing an effective method of birth 
control.
[18] Have received a live vaccine within 30 days before the first dose of study 
treatment.  Examples of live vaccines include, but are not limited to, the 
following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, 
Bacillus Calmette–Guérin, and typhoid vaccine.  Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed; however, 
intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and 
are not allowed.
[19] Have symptomatic or uncontrolled brain metastases, spinal cord compression 
or leptomeningeal disease requiring concurrent treatment, including but not 
limited to surgery, radiation and/or corticosteroids (patients receiving 
anticonvulsants are eligible).
[20] Have a history of allergy or hypersensitivity to study drug components
6.2.
Summary of Study Design
This is an open-label Phase 1a/1b study that will be conducted in 2 parts.  The first part 
(Phase 1a) of the study will consist of a dose-escalation assessment of the safety and tolerability 
of LY2510924 administered with durvalumab (MEDI4736) with advanced refractory solid 
tumors (Figure CXAD.6.1).  The second part (Phase 1b) of the study will be disease restricted to 
include 2 expansion arms in advanced pancreatic cancer (N=approximately 15 patients) and


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ovarian cancer (N=approximately 15 patients), all patients receiving LY2510924 (dose 
determined from Phase 1a) with durvalumab. The 2 expansion arms may open either in parallel 
or in a staggered fashion, which will be determined after dose escalation is complete.  
Abbreviations:  approx. = approximately; I/E = inclusion/exclusion criteria; 
IV = intravenous; LY = LY2510924; Ph1a = Phase 1a; 
PK/PD = pharmacokinetic/pharmacodynamic; pts = patients; MTD = maximum-
tolerated dose; SQ = subcutaneous.
Figure CXAD.6.1.
CXAD study design.
Dose escalation for LY2510924 in combination with durvalumab in Phase 1a will be driven by 
an adaptive model-based dose-escalation scheme (Neuenschwander et al. 2008) to assist in the 
estimation of DLT rate at recommended dose levels. It provides quantitative guidance on the 
determination of the dose level and provides a lower under-dosing rate and a higher MTD 
selection rate than the traditional 3+3 method.  The starting dose level will be 20 mg. 
Subsequent dose levels will reflect a maximum increment of 10 mg from the prior dose level. At 
the 40-mg dose level, the first patient will be treated and observed for 2 weeks, after which 
additional patients will be enrolled following notification from the sponsor. If the MTD has not 
yet been reached at the highest dose level of 40 mg, then additional dose levels may be 


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investigated based on both safety and the available PK data. Further information on the dose-
escalation method is given in Section 7.2.2.
To determine the MTD of LY2510924, 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 modelling techniques, if data warrant. 
The actual sample size of the dose escalation (Phase 1a) will primarily be limited by the 
incidence of DLTs. Under the adaptive scheme, each dose level will enroll 3 patients initially 
(see note above on initial enrollment into the 40-mg dose level), and additional patient cohorts 
may be enrolled in case of DLT.  The anticipated sample size for Phase 1a ranges from 
approximately 12 to 15 patients, depending on the incidence of DLTs. Each expansion arm in 
Phase 1b will enroll approximately 15 patients. The overall sample size is estimated to be 
approximately 45 patients.
Patients will have regularly scheduled study visits at the clinical site, including disease 
assessment with CT and/or magnetic resonance imaging (MRI), as appropriate (Attachment 1).
Treatment decisions related to patient management and whether to treat a patient with advanced 
refractory solid tumors with additional cycles of study therapy will be based on RECIST v1.1.  
Continuation with study treatment beyond confirmed radiographic progression may be made on a 
case-by-case basis for patients who are believed to be clinically benefiting from protocol therapy 
and both the investigator and sponsor, in consultation with collaborator (AstraZeneca, London, 
United Kingdom), agree that continuing protocol therapy is in the patient’s best interest.  Patients 
will not be permitted to continue study therapy if progression occurs after confirmed response 
(complete response [CR] or partial response [PR] as defined by RECIST v1.1) in the target 
lesions (regardless of the appearance of new lesions), ie, the response and progression events 
both occurred in the target lesions while receiving study therapy.
At the sponsor’s discretion, scans and measurements may be collected and reviewed by 
independent radiologists using RECIST v1.1 at a later date, or at any time during the study.  
Study treatment will continue until the patient fulfills 1 of the criteria for study discontinuation 
(Section 6.3).  Patients may continue on combination therapy beyond initial radiological disease 
progression in the absence of clinically significant deterioration (Section 8.3.1.2).  If a patient 
experiences an AE that requires the patient be discontinued from durvalumab or LY2510924, the 
patient should be discontinued from both study drugs (Section 7.2.5).  
Patients who have discontinued from combination treatment will enter the Post Discontinuation
Follow-Up Period with visits at approximately 30, 60, and 90 days.  If a patient has discontinued 
treatment for reasons other than disease progression, tumor assessments should continue every 
8 weeks until confirmed disease progression occurs, initiation of a new anticancer therapy, the 
patient dies, or is lost to follow-up.  Patients will be followed for survival at least every 12 weeks 
(±7 days) until death or study completion.  This follow-up may occur through a phone call, 
email, or visit by the patient or the patient's caretaker.


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Refer to Attachment 1 for the Study Schedule.
6.2.1. Study Completion and End of Trial
This study will be considered complete after the final analysis (occurring no more than 
12 months after last patient enters treatment) and evaluation of the primary objective and 
secondary objectives have been performed for the expansion arm(s) in the Phase 1b portion.  
Investigators will continue to follow the Schedule of Events (Attachment 1) for all patients, until 
notified by Lilly that study completion has occurred.
The end of trial occurs after study completion, and after the last patient has discontinued study 
treatment and completed the 90-day follow-up (if applicable).  End of trial refers to the date of 
the last visit or last scheduled procedure for the last patient (includes follow-up periods).  
6.2.2. Definitions of Study Periods 
Terms used to describe the periods during the study are defined below:

Baseline/Screening:  begins when the ICF is signed, and ends at the first study treatment 
(defined as receiving any study drug); if no study treatment is given, baseline/screening 
ends with the decision not to enroll.  Lasts up to 28 days.

Study Period:  The overall study period for Study CXAD begins the day of the first 
patient’s first dose of study treatment and ends at overall study completion (as defined in 
a bullet below).
o
Study Treatment Period:  begins with the day of the patient’s first study 
treatment and ends the day the patient and investigator agree that the patient will 
discontinue study treatment (discontinuation of assigned study drug(s); 
Section 6.3).  Individual patients who enroll in Study CXAD may continue 
treatment until they have confirmed progressive disease or discontinued study 
treatment for any other reason.
o
Post Discontinuation Follow-Up Period:  consists of the following phases:  

30-Day Short-Term (Safety) Follow-Up:  begins the day after the patient 
and the investigator agree that the patient will discontinue study treatment 
and ends with the short-term follow-up visit, to occur approximately 
30 days thereafter.  

60-Day Short-Term (Safety) Follow-Up begins the day after the 30-day 
follow-up visit and lasts approximately 30 days or approximately 60 days 
after the patient and the investigator agree that the patient will discontinue 
study treatment.

90-Day Short-Term (Safety) Follow-Up begins the day after the 60-day 
follow-up visit and lasts approximately 30 days or approximately 90 days 
after the patient and investigator agree that the patient will discontinue 
study treatment.  

Long-term Follow-up begins the day after 90-day follow-up is completed 
and continues until the patient’s death or end of trial (approximately every 
12 weeks ±7 days the patient will be contacted).  


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
Study Completion for Study CXAD:  occurs after the final analysis (occurring no more 
than 12 months after last patient enters treatment) and evaluation of the primary objective 
and secondary objectives have been performed.  Investigators will continue to follow the 
Schedule of Events (Attachment 1) for all patients, until notified by Lilly that study 
completion has occurred.

Continued Access Period:  begins after study completion and ends at End of Trial.  In 
the continued access period, patients may continue the current study treatment after study 
completion, as long as they experience ongoing clinical benefit (details in Section 6.2.3).
o
Patients who are in 30-day short-term follow-up when the continued access period 
begins will complete the 30-day short-term follow-up visit and then discontinue 
from the study.
o
Patients who are in 60-day short-term follow-up when the continued access period 
begins will complete the 60-day short-term follow-up visit and then discontinue 
from the study.
o
Patients who are in 90-day short-term follow-up when the continued access period 
begins will complete the 90-day short-term follow-up visit and then discontinue 
from the study.
o
Patients who are in long-term follow-up when the continued access period begins 
will discontinue from the study.

End of Trial:  The term “end of trial” refers to the date of the last visit or last scheduled 
procedure for the last patient (includes follow-up periods).  The end of trial occurs after 
study completion, and after the last patient has discontinued study treatment and 
completed the 90-day follow-up (if applicable).  
6.2.3. Continued Access
The continued access period is defined in Section 6.2.1.  
Attachment 1 presents AE/SAE data collection and the necessary continued access follow-up 
visits, to occur after the decision is made to discontinue from the continued access period, or 
when the patient starts a new anticancer therapy, whichever happens first.
6.3.
Discontinuations
The reason for and date of discontinuation from study treatment will be collected for all patients.  
The date of discontinuation (for any of the above reasons) from study treatment is to be reported 
on the case report form (CRF).  Patients who discontinue from study treatment will have follow-
up procedures performed as shown in the Study Schedule (Attachment 1).
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.
6.3.1. Discontinuation of Patients Inadvertently Enrolled
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 


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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 CRP or designee 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 or designee agrees 
with the investigator that it is medically appropriate for that patient. The patient may not 
continue on study treatment if the Lilly CRP or designee 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 or designee to allow the inadvertently enrolled 
patient to continue in the study with or without investigational product.
6.3.2. Discontinuation of Patients from Study or Study Drug 
Patients who are discontinued from the study drug(s) early will have follow-up procedures 
performed as shown in the Study Schedule (Attachment 1).
In addition, patients will be discontinued from the study drugs 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(s)
o
if the patient, for any reason, requires treatment with another therapeutic 
agent that has been demonstrated to be effective for treatment of the study 
indication, discontinuation from the study drug(s) occurs prior to 
introduction of the other agent

Patient Decision
o
the patient or the patient’s designee (for example, legal guardian) requests to 
be discontinued from the study or study drug

Sponsor Decision
o
Lilly, in consultation with the collaborator, 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 confirmed evidence of progressive disease by RECIST v1.1. In the 
setting of disease progression, the patient will discontinue from study drug(s); 
however, the patient will continue to be followed on study.  In the setting of 
unconfirmed/equivocal progression, the patient should remain on study treatment 


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until the next assessment period or up to 12 weeks after consultation with a Lilly 
physician. See Section 8.3.1.2 for additional details.

The patient is noncompliant with study procedures and/or treatment (Section 7.6).

The patient experiences unacceptable toxicity. Note:  If the patient discontinues 
from 1 study drug, the patient should also discontinue from the other study drug.  

Patient has a dosing interruption of either study drug of >12 weeks.  

The patient becomes pregnant.
The reason for and date of discontinuation from study treatment will be collected for all patients.  
The date of discontinuation (for any of the above reasons) from study treatment is to be reported 
on the case report form (CRF).  Patients who discontinue from study treatment will have 
follow-up procedures performed as shown in the Study Schedule (Attachment 1).
6.3.3. 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.
6.3.4. 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
7.1.1. LY2510924
LY2510924 for Injection, 20mg/mL will be supplied as a single use sterile clear solution 
formulation in 2 mL glass vials.  Each vial contains 1.15 mL of a 20 mg/mL LY2510924 
solution.  The excess solution is supplied to facilitate the withdrawal of a 20-mg unit dose.  
One mL will be drawn from each vial to deliver 20 mg of LY2510924.  The LY2510924 drug 
product contains no antimicrobial preservative.
The drug product is composed of LY2510924 and the inactive ingredients sodium citrate 
dihydrate, citric acid monohydrate, sodium chloride, sterile water for injection with sodium 
hydroxide and/or hydrochloric acid used if necessary for pH adjustment.  Vials of LY2510924 
for Injection, 20mg/mL, must be stored refrigerated (2°C to 8°C). 
Clinical study materials will be labeled according to the country’s regulatory requirements.  
7.1.2. Durvalumab (MEDI4736)
Durvalumab (MEDI4736) will be supplied as a 500-mg vial solution for infusion.  The solution 
contains 50 mg/mL durvalumab, 26 mM histidine/histidine‑hydrochloride, 275 mM trehalose 
dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; it has a pH of 6.0.  The nominal fill 
volume is 10 mL.  Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must 
not be frozen.
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
designated study manager using aseptic technique.  Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed:  

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. 
Infusion solutions must be allowed to equilibrate to room temperature prior to commencement of 
administration.  Durvalumab does not contain preservatives and any unused portion must be 
discarded.
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 agents and planned duration of each 
individual’s treatment to the site personnel and patient/legal representative,

verifying that instructions are followed properly, 


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
maintaining accurate records of study drug dispensation, destruction, and collection, and
returning or destroying all unused medication to Lilly or its designee at the end of the 
study.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug(s) so that the situation can be assessed.
7.2.1. Dosing Schedule
This study defines 1 cycle as 4 weeks or 28 days.  
LY2510924 will be self-administered prior to the start of durvalumab infusion on the days both 
drugs are given together.
7.2.1.1.
LY2510924
In Phase 1a, LY2510924 will be self-administered SQ at rotated injection sites every day for 
28 days as outlined in a dose escalation schema; in Phase 1b, LY2510924 will be
self-administered SQ for 28 days at the selected Phase 1a dose.  
Approximately 30 minutes prior to dose administration, the vials should be removed from the 
refrigerated storage area 2°C to 8°C and allowed to equilibrate to ambient room temperature 
prior to injection.  Study drug must be administered within 6 hours after removal from the 
refrigerated storage area.
Doses that are missed should not be made up.  
On Day 1 of Cycles 1 to 4 and Cycle 6, LY2510924 should be self-administered at the clinic 
(time and date recorded) after a blood sample is taken for LY2510924 PK but prior to the 
start of durvalumab.  Additionally, on Cycle 1 Days 2, 15, and 16, LY2510924 should be 
self-administered at the clinic (time and date recorded) after a blood sample is taken for 
LY2510924 PK.  
7.2.1.2.
Durvalumab
Each patient will receive IV administration of durvalumab 1500 mg on Day 1 of each cycle.  
This administration will be given at least 30 minutes after LY2510924.
Preparation of durvalumab doses for administration with an IV bag
The preparation of infusion bags should be done under aseptic conditions by trained personnel.
A dose of 1500 mg durvalumab will be administered using an IV bag containing 0.9% (w/v) 
saline or 5% (w/v) dextrose, with a final durvalumab concentration ranging from 1 to 20 mg/mL, 
and delivered through an IV administration set with a 0.2- or 0.22-μm in-line filter.  Remove 
30.0 mL of IV solution from the IV bag prior to addition of durvalumab.  Next, 30.0 mL of 
durvalumab (ie, 1500 mg of durvalumab) is added to the IV bag such that final concentration is 
within 1 to 20 mg/mL (IV bag volumes 100 to 1000 mL).  Mix the bag by gently inverting to 
ensure homogeneity of the dose in the bag.


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Prior to the start of the infusion, ensure that the bag contents are at room temperature to avoid an 
infusion reaction due to the administration of the solution at low temperatures.
Vials should be used for specific patients and should not be shared between patients.
Dose administration
Durvalumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral or central vein.  
Following preparation of durvalumab, the entire contents of the IV bag should be administered 
as an IV infusion over approximately 60 minutes (±5 minutes), using a 0.2, or 0.22-μm in-line 
filter.
The IV line should be flushed with a volume of IV solution (0.9% [w/v] saline or 5% [w/v] 
dextrose) equal to the priming volume of the infusion set used after the contents of the IV bag are 
fully administered, or complete the infusion according to institutional policy to ensure the full 
dose is administered and document if the line was not flushed.  
Since the compatibility of durvalumab with other IV medications and solutions, other than 0.9% 
(w/v) saline or 5% (w/v) dextrose, is not known, the durvalumab solution should not be infused 
through an IV line in which other solutions or medications are being administered.
Standard infusion time is approximately 1 hour.  However, if there are interruptions during 
infusion, the total allowed time should not exceed 8 hours at room temperature as shown in 
Table CXAD.7.1.  
Table CXAD.7.1.
Durvalumab Hold and Infusion Times
Maximum time from needle puncture to start of administration
4 hours at room temperature, 24 hours at 2°C to 8°C
Maximum time for IV bag infusion, including interruptions
8 hours at room temperature
Abbreviation:  IV = intravenous.  
In the event that either preparation time or infusion time exceeds the time limits outlined in 
Table CXAD.7.1, a new dose must be prepared from new vials.  Durvalumab does not contain 
preservatives, and any unused portion must be discarded.
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have been 
observed.
Monitoring of dose administration
Patients will be monitored during and after the infusion with assessment of vital signs.  
On durvalumab treatment days, measure blood pressure, pulse, temperature, and respiratory rate 
prior to the first infusion of the day, and as clinically indicated.


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
Measure blood pressure, pulse, temperature, and respiratory rate after the LY2510924 
injection (but prior to the durvalumab infusion), and as clinically indicated.

Measure blood pressure, temperature, and pulse at the following time points (based on a 
standard 60 (±5)-minute infusion):
o
before the start of infusion (up to 30 minutes prior)
o
during the infusion at 30 (±5) minute intervals, including when the infusion might 
be prolonged due to an interruption
o
at the end of infusion at 60 (±5) minutes
o
during the 1-hour post-infusion observation period, 30 (±5) and 60 (±5) minutes 
after the end of infusion
If the infusion takes longer than 60 minutes, then blood pressure, temperature, and pulse 
measurements should follow the principles described here or more frequently if clinically 
indicated.  
A 1-hour observation period is required after all durvalumab infusions.  If the patient shows no 
evidence of an infusion-related reaction (IRR) with the first 2 infusions of each study drug, then 
for subsequent infusions, no observation period is required after each subsequent infusion.  In the 
event an IRR occurs thereafter, the 1-hour observation between infusions should be reinstituted.
In the event of a ≤Grade 2 IRR, the infusion rate of study drug may be decreased by 50% or 
interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial rate 
until completion of the infusion.  For patients with a ≤Grade 2 IRR, subsequent infusions may be 
administered at 50% of the initial rate.  Acetaminophen and/or an antihistamine (eg, 
diphenhydramine) or equivalent medications per institutional standard may be administered at 
the discretion of the investigator.  If the IRR is ≥Grade 3 or higher in severity, both study drugs
will be discontinued.
In the event of an IRR, blood samples will be collected for both PK (durvalumab and 
LY2510924) and immunogenicity (durvalumab) analysis at the following time points:  (i) as 
close as possible to the onset of the IRR, (ii) at the resolution of the IRR, and (iii) 30 days 
following the IRR.
As with any antibody, allergic reactions to dose administration are possible.  Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis.  The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit patients to an intensive care unit if necessary.
7.2.2. Phase 1a Dose Escalation 
The MTD of LY2510924 determined during Phase 1a will be used for Phase 1b.  
Three dose levels will be investigated in Phase 1a (Figure CXAD.6.1).  Dose escalation is 
described in Section 7.2.2.2.


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Because Phase 1a is the dose-escalation part of the study, data will be evaluated on an ongoing 
basis until the MTD is determined. Safety data, in particular AEs, will be the primary criteria for 
the dose escalation.  No dose escalation can occur without prior discussion and agreement 
between the investigator and the Lilly study team in consultation with the collaborator.
No intrapatient dose escalation or reduction is allowed during Phase 1a.  
Dose escalation will be based on the number of DLTs experienced during Cycle 1.
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum-Tolerated Dose 
Definition 
A DLT is defined as 1 of the following AEs reported during the Phase 1a DLT observation 
period, if considered to be definitely, probably, or possibly related to either study regimen by the 
investigator; and fulfills any 1 of the following criterion using National Cancer Institute (NCI)
CTCAE version (v) 4.03:
1. Non-laboratory abnormalities (clinical toxicity):
a.
Any Grade 4 immune-related AE (Attachment 10)
b. Any Grade 4 non-laboratory AE
c.
Any CTCAE Grade ≥3 QT prolongation AE
d. Any ≥Grade 3 colitis or noninfectious pneumonitis irrespective of duration 
e.
Any Grade 3 immune-related AE (excluding colitis, QT prolongation, or 
pneumonitis) (Attachment 10) that does not downgrade to Grade 2 within 3 days 
after onset of the event despite optimal medical management including systemic 
corticosteroids, or does not downgrade to ≤Grade 1 or baseline within 14 days
f.
Any Grade 2 pneumonitis that does not resolve to ≤Grade 1 within 3 days of the 
initiation of maximal supportive care, including corticosteroid therapy
g. Grade 3 toxicity lasting an extended period of time despite optimal supportive 
care (for example, nausea, vomiting, and diarrhea lasting >3 days; fatigue lasting 
>7 days)
2. Laboratory abnormalities:
a.
Any Grade 3 laboratory value if:
i.
Medical intervention is required to treat the patient, or
ii.
Associated with clinically significant symptoms.  Examples include but are 
not limited to, Grade 3 thrombocytopenia if associated with bleeding and 
requires platelet transfusion, Grade 3 febrile neutropenia, or
iii.
The abnormality persists for >7 days (excluding amylase and lipase)
b. Any Grade 4 laboratory abnormalities
c.
Liver transaminase elevation >8 × upper limit of normal (ULN) or total bilirubin 
>5 × ULN
Note:  Liver test abnormality:  For HCC patients and patients with liver metastasis 
who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by 
2-fold greater than baseline and lasts for >7 days


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d. ANC >75,000/µL or Grade 3 leukocytosis (leukocytes >100,000/µL) of any 
duration, or leukocytosis/granulocytosis causing clinical symptoms
3. Grade 5 toxicity (that is, death)
4. Any other significant toxicity deemed by the primary investigator and Lilly clinical 
research personnel to be dose limiting, for example:
a.
Any toxicity that is possibly related to study treatment that requires the 
withdrawal of the patient from the study during Cycle 1 (including Day 15), or
b. A delay of >14 days in initiating Cycle 2 due to persistent Grade >2 toxicities
5. Any other Grade 3 toxicity, except for the exclusions listed below.
The definition excludes the following conditions:

Toxicity that is clearly and directly related to the primary disease or to another etiology is 
excluded from this definition

Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the patient is asymptomatic

Grade 3 inflammatory reaction attributed to a local antitumor response (for example, 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.)

Concurrent vitiligo or alopecia of any AE grade

Grade 3 IRR (first occurrence and in the absence of steroid prophylaxis) that resolves 
within 6 hours with appropriate clinical management

Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days. Note:  Grade 3 or Grade 4 febrile
neutropenia will be a DLT regardless of duration or reversibility.

Grade 3 or 4 lymphopenia

Grade 3 thrombocytopenia that is not associated with bleeding that requires clinically 
significant medical intervention and improves by at least 1 grade within 3 days

Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or
symptoms and are reversed with appropriate maximal medical intervention within 3 days
7.2.2.2.
Dose-Escalation Method
Adaptive scheme, with incorporation of a Bayesian model-based, toxicity-band method 
(Neuenschwander et al. 2008), will be used to assess the safety of LY2510924 given in 
combination with durvalumab. 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. The 
dose recommendation relies on maximizing the probability of targeted toxicity while controlling 
the probability of excessive or unacceptable toxicity. This method will be applied to the 
observed data on an ongoing basis throughout the dose escalation. The toxicity-band method 
will stop early 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 or designee in consultation 
with collaborator will consider the model recommendation, the observed DLT rate, and any 


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DLT-equivalent toxicities observed in Cycle 2 and beyond at each cohort to determine the next 
dose level and determine when to stop dose escalation. Safety data, in particular, DLTs, will be 
the primary criteria for dose escalation. In addition, if available at the time of the dose-escalation 
decision, PK 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/pharmacodynamics. No dose escalation can occur without prior discussion and agreement 
between the investigator and the Lilly CRP or designee in consultation with collaborator; the 
decision will be documented in writing.  
The dose levels for dose escalation are provided in Figure CXAD.6.1. The starting dose level 
will be 20 mg. The 20-mg and 30-mg dose levels will enroll 3 patients initially. The 40-mg 
dose level will enroll and treat 1 patient initially.  After a 2-week observation period, the 
additional patients will be enrolled after notification from the sponsor.  For all dose levels after 
the initial 3 patients have been enrolled, additional patients (at that dose level) may be enrolled in 
case of DLT. If deemed necessary, additional dose levels may be explored after discussion 
between the investigator and the Lilly CRP or designee in consultation with collaborator. The 
toxicity-band method has the ability to accommodate additional dose levels naturally.  The DLT 
observation period will last for 4 weeks or to the completion of Cycle 1.  Additional patients will 
be enrolled in a cohort to achieve the minimum of 3 evaluable patients if dropouts or dose 
interruptions occur that result in a patient being nonevaluable for DLTs due to nonmedical
reasons.  Patients who withdraw from the study during the DLT observation period for reasons 
other than a DLT may be replaced within the same dose level.  For the purpose of making 
decisions on dose escalation from a safety perspective, patients will be considered evaluable 
(DLT-evaluable population) if they have either completed the DLT-observation period (Cycle 1) 
and received the scheduled durvalumab dose and at least 75% of LY2510924 doses in Cycle 1 or 
have discontinued study treatment or study participation before completing Cycle 1 due to a 
DLT. If the DLT-observation period is extended to Cycle 2, patients who discontinued during 
Cycle 2 in the absence of DLT-equivalent toxicity will be considered evaluable for DLT 
assessment.
Details regarding the toxicity-band method for this study are provided in Attachment 9.
7.2.3. Phase 1b Expansion 
The Phase 1b part of the study will include 2 expansion arms (pancreatic cancer 
[N=approximately15 patients] and ovarian cancer [N=approximately15 patients]).  
Once the safety profile of all doses tested has been characterized and the MTD of combined 
administration of LY2510924 and durvalumab has been defined in the Phase 1a part of the study, 
the expansion arms will be initiated.  
Treatment in the expansion arms will consist of 1500 mg durvalumab IV on Day 1 of each cycle 
and LY2510924 SQ daily at the dose determined in the Phase 1a part of the study. A cycle is 
28 days.  


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Continuous evaluation of toxicity in the expansion arms will be performed throughout 
enrollment in the expansion arms.  
7.2.4. DLT-Equivalent Toxicity
A DLT-equivalent toxicity is defined as an AE occurring during Cycle 2 and beyond in Phase 1a 
that would have met the criteria for a DLT if it had occurred during Cycle 1 or during any cycle 
in Phase 1b.  The DLT-observation period will be extended to Cycle 2 if a DLT-equivalent 
toxicity is observed during Cycle 2 in any cohort in Phase 1a.  For individual patients 
experiencing a DLT-equivalent toxicity, dose adjustments will be made as outlined in 
Section 7.2.5.  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 or designee in consultation with collaborator 
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.  
7.2.5. Dose Adjustments, Delays, or Discontinuation from Study Drug
7.2.5.1.
LY2510924 Dose Adjustments, Delays, and Discontinuation for Phase 1a
and 1b
If a patient has an immune-related AE that requires discontinuation of durvalumab per the dose 
modification table in Attachment 11, both drugs should be discontinued.  Once the 
immune-related AE has resolved to ≤Grade 1 or baseline, the investigator in consultation with 
the Lilly physician may resume combination treatment as indicated in Table CXAD.7.2. 
7.2.5.1.1. LY2510924 Dose Adjustments and Delays
During Phase 1a, intrapatient dose escalation or reduction of LY2510924 is not allowed.
During Phase 1b, 2 dose reductions of LY2510924 are allowed (depending on the starting dose:  
reduce 1 dose level if available or hold if not available). Reescalation is allowed once at the 
discretion of the investigator. If Grade 3/4 toxicity attributed to LY2510924 occurs after 
2 previous dose reductions, LY2510924 will be discontinued. If patients are discontinued from 
LY2510924, patients must also be discontinued from durvalumab.  
No dose reduction of LY2510924 will occur for myelosuppression. Granulocytosis was 
observed in patients receiving LY2510924 in the Phase 1 and 2 studies. Management of 
granulocytosis and nonhematologic toxicity is outlined in Table CXAD.7.2 and in the 
durvalumab dose-modification tables within Attachment 11.  


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Table CXAD.7.2.
Dose Adjustments of LY2510924
Event
Intervention
Dose Adjustment
Leukocytosis (ANC 
>75,000/µL or leukocytes 
>100,000/µL) 
1) Interrupt LY2510924 
2) Recheck WBC, ANC every
2 to 3 days until ANC 
decreases to <50,000/µL 
Reduce 1 dose level 
Injection site reaction, Grade 3 
1) Interrupt LY2510924 
2) Administer topical treatment 
as necessary 
Reduce 1 dose level 
Other nonhematologic
toxicities meeting treatment 
interruption criteria described 
in Attachment 11
1) Interrupt LY2510924 
2) Re-examine patient at least 
weekly until toxicity improves 
to ≤Grade 1 and consider 
restarting treatment according 
to the durvalumab 
dose-modification tables 
(Attachment 11)
Reduce 1 dose level 
Abbreviations:  ANC = absolute neutrophil cell; WBC = white blood cell.
7.2.5.1.2. Discontinuation from LY2510924
Patients with combined elevated AST/ALT AND total bilirubin values meeting discontinuation 
parameters as described in the DLT definition (Section 7.2.2.1) should be considered for 
permanent discontinuation based on clinical judgment.
If a patient has a documented CTCAE Grade ≥3 QT prolongation, the patient should be 
discontinued from study treatment. The investigator should consider (and may consult with a 
cardiologist) whether a patient with other evidence of QT prolongation, eg, QT/QTc interval 
≥501 msec and/or a change of >60 msec over baseline, should also be discontinued.
If a patient experiences an AE that requires the patient be discontinued from LY2510924, the 
patient should also be discontinued from durvalumab.  
7.2.5.2.
Durvalumab Dose Adjustments, Delays, and Discontinuation for
Phase 1a and 1b
Intrapatient dose escalation of durvalumab is not allowed in either Phase 1a or 1b.
If a patient has an immune-related AE that requires discontinuation of durvalumab per the 
dose-modification table in Attachment 11, both drugs should be discontinued.  Once the AE has 
resolved to ≤Grade 1 or baseline, the investigator in consultation with the Lilly physician may 
resume combination treatment.
For AEs that are considered at least partly due to administration of durvalumab, the following 
dose adjustment guidance may be applied:

Treat each of the toxicities with maximum supportive care (including holding the agent 
suspected of causing the toxicity where required).


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
If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of durvalumab along with appropriate continuing supportive care.  
If medically appropriate, dose modifications are permitted for durvalumab (Attachment 11).

All dose modifications should be documented with clear reasoning and documentation of 
the approach taken.
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued.
Based on the mechanism of action of durvalumab leading to T-cell activation and proliferation, 
there is the possibility of observing immune-related AEs during the conduct of this study.  
Potential immune-related AEs include immune-mediated enterocolitis, dermatitis, hepatitis, and 
endocrinopathies.  Patients should be monitored for signs and symptoms of immune-related AEs.  
In the absence of an alternative etiology (eg, infection or progressive disease) signs or symptoms 
of enterocolitis, dermatitis, hepatitis, and endocrinopathy should be considered to be 
immune-related.  
Dose-modification recommendations and toxicity management guidelines for immune-mediated 
reactions, for IRRs, and for nonimmune-mediated reactions are detailed in Attachment 11.
7.2.5.3.
Dose Delays for Reasons Not Related to Study Treatment
Dosing interruptions of either study drug of ≤1 week are also permitted for reasons not related to 
study treatment (for example, minor surgery, unrelated medical events, patient vacation, and/or 
holidays).  The reason for interruption should be documented on the CRF.
7.3.
Method of Assignment to Treatment
This study is open-label for Phase 1a and Phase 1b.  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/expansion arm for each patient.  
For Phase 1a, if investigators have eligible patients who have consented concurrently, more than 
3 patients may be entered at a particular dose level 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.
7.4.
Blinding
Not applicable. This is an open-label study.
7.5.
Concomitant Therapy
No other therapy, including routine use of growth factors or experimental medications (for 
example, immunotherapy or other not approved medication) will be permitted while the patients 
are on the study.  Growth factors and erythropoietin are allowed per American Society of 


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Clinical Oncology or National Comprehensive Cancer Network guidelines.  Granulocyte 
colony-stimulating factors must be discontinued at least 24 hours prior to the start of the next 
cycle of treatment.  Transfusions are permitted.  Patients may receive prophylactic steroids (such 
as, prednisolone, methylprednisolone or dexamethasone; see below for limits) to prevent 
transfusion reactions.  
Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, nonpalliative radiation therapy, or standard or investigational agents for treatment of 
pancreatic cancer) will not be allowed unless outlined elsewhere.  Any disease progression 
requiring other forms of specific antitumor therapy will necessitate early discontinuation from 
the study.  Appropriate documentation for all forms of premedications, supportive care, and 
concomitant medications must be captured on the CRF.  Replacement hormonal therapy initiated 
before study entry will be allowed.
Immunosuppressive medications will not be allowed including, but not limited to systemic 
corticosteroids at doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, 
azathioprine, and tumor necrosis factor-α blockers.  Use of immunosuppressive medications for 
the management of investigational product-related AEs, in patients with contrast allergies or for 
treatment of nonautoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a 
contact allergen) is acceptable.  Patients are also permitted the use of topical, ocular, intra-
articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption) unless 
outlined elsewhere.  Live attenuated vaccines within 30 days of durvalumab dosing are not 
permitted (ie, 30 days prior to the first dose, during treatment with durvalumab and for 30 days 
post discontinuation of durvalumab).  Inactivated vaccines, such as the injectable influenza 
vaccine, are permitted.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed (see Section 6.1.3).
Patients should receive full supportive care during the trial.  Concomitant palliative and 
supportive care for disease-related symptoms (including bisphosphonates and RANK-L 
inhibitors) is allowed if initiated prior to first dose of study therapy.  Prior palliative radiotherapy 
must have been completed at least 2 weeks prior to enrollment.  The potential for overlapping 
toxicities with radiotherapy and durvalumab currently is not known.  Therefore, palliative 
radiotherapy is not recommended while receiving durvalumab.  
All concomitant medications should be recorded throughout the patient’s participation in the 
study.
7.5.1. Restrictions during Study
Females of childbearing potential who are sexually active with a nonsterilized male partner must 
use effective contraception from screening, and must agree to continue using such precautions 
for 6 months following the last infusion of durvalumab; cessation of birth control after this point 
should be discussed with a responsible physician.  Male partners of a female patient must use 
male condom plus spermicide throughout this period.  If a barrier method of contraception is 


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used, 2 methods must be used as outlined in Table CXAD.7.3.  Periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of birth control.

Females of childbearing potential are defined as those who are not surgically sterile (ie, 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal (defined as 12 months with no menses without an alternative medical 
cause).

Patients must use 2 acceptable methods of effective contraception as described in 
Table CXAD.7.3.

Nonsterilized males who are sexually active with a female partner of childbearing 
potential must use 2 acceptable methods of effective contraception (see 
Table CXAD.7.3) from Day 1 and for 6 months after receipt of the final dose of 
durvalumab.
Table CXAD.7.3
Acceptable Methods of Contraception 
Barrier Methods
Intrauterine Device Methods
Hormonal Methods
Male condom plus spermicide
Copper T
Implants
Cap plus spermicide
Progesterone Ta
Hormone shot or 
injection
Diaphragm plus spermicide
Levonorgestrel-releasing intrauterine 
system (eg, Mirena®)a
Combined pill
Minipill
Patch
a
Also considered a hormonal method.
Patients should not donate blood while participating in this study or for 3 months after 
discontinuation of study treatment.  
7.6.
Treatment Compliance
7.6.1. LY2510924 Compliance
Patient compliance with LY2510924 will be assessed on Day 1 of each cycle (excluding 
Cycle 1).  Compliance will be assessed by direct questioning, review of diary, and counting any 
returned vials.  Deviations from the prescribed dosage regimen should be recorded on the CRF.  
On those study days that PK collection is scheduled (see Attachment 1 and Attachment 4), 
patients will wait to self-administer LY2510924 until they are in the clinic.  
For patients who are significantly noncompliant (<75% of expected study drug taken in a visit 
interval), investigative sites must counsel patients on the importance of study drug compliance 
and drug accountability.  Patients who are consistently out of the compliance range may be 
discontinued after discussion with Lilly CRP or designee.  A Lilly representative should be 
contacted upon the second instance of treatment noncompliance.  
The following procedures will be employed to ensure appropriate drug accountability:

Drug accountability will be emphasized at the start-up meeting.

Drug accountability will be monitored throughout the study.


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
Each patient should be instructed to return all study drug packaging and unused material to 
the study site at each visit.  The study site will keep a record of all drug dispensed to and 
returned by the patients throughout the study.  Study site personnel will return or destroy (as 
requested) all unused study drug for all patients.

In the Phase 1a and 1b part of the study, patients will keep a study diary for the entire 
treatment duration to document that they are taking LY2510924 as prescribed.
7.6.2. Durvalumab Compliance
Durvalumab 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.  
Patients should attend scheduled clinic visits and must comply with study criteria under their 
control.  Deviation(s) from the prescribed dosage regimen should be recorded on the CRF.
7.6.3. Evaluable Phase 1a Patients
For Phase 1a, any patient who discontinues from the study for nonmedical reasons before 
completing the first cycle of study treatment will be deemed nonevaluable for assessment of a 
dose level and may be replaced within the same dose level, unless they experience a DLT prior 
to withdrawal.  If the patient is noncompliant during Cycle 1 due to reasons other than 
drug-related toxicity, he or she will be considered nonevaluable and may be replaced.  
Nonevaluable patients may be replaced to ensure that 3 patients complete 1 cycle of therapy at 
each dose level, unless accrual to that cohort has stopped due to a DLT.  Safety analyses will be 
conducted on all patients who have received at least 1 dose of study drug, regardless of whether 
they are deemed evaluable for the assessment of a dose level.
For the purpose of making decisions on dose escalation from a safety perspective, patients will 
be considered evaluable if:

they have either completed the DLT observation period (Cycle 1) and

they have received the scheduled durvalumab dose in the first cycle, and

they took at least 75% of the cohort-specified doses of LY2510924
OR

they discontinued study treatment or study participation before completing Cycle 1 due to 
a DLT
Patients who are not evaluable for PK, but who complete 1 cycle of therapy, may be replaced 
upon consultation with the investigator(s) and the Lilly CRP or designee to ensure adequate PK 
data, unless accrual to that cohort has stopped due to a DLT.


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8. Safety, Pharmacokinetic, Pharmacodynamic, and 
Efficacy Data Collection
8.1.
Safety Evaluations
Safety is the primary endpoint of this Phase 1a/b study as determined by the NCI CTCAE v 4.03.  
All patients who receive at least 1 dose of LY2510924 or durvalumab will be evaluated for 
safety as measured by the occurrence of AEs, SAEs, deaths, and laboratory abnormalities, 
assessed during treatment and for 90 days in follow-up.
Patients will have regularly scheduled study visits at the clinical site as noted in Attachment 1, 
where safety assessments including AE collection, laboratory assessments, vital sign collection, 
and physical examinations will be performed.  
Imaging studies will be performed every 8 weeks or sooner if clinically indicated.  Liver 
function, as part of the routine clinical chemistry panel, will be tested every other week in 
Cycle 1 and every cycle thereafter.  
Study procedures and their timing are described in the Study Schedule (Attachment 1).  
Attachment 2 lists the specific tests that will be performed for this study.  
8.1.1. Safety Data Collection and Review
Investigators are responsible for monitoring the safety of patients who have entered into this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patient.  
The investigator is responsible for the appropriate medical care of the patient during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to study treatment or the study, or that caused the patient 
to discontinue before completing the study.  The patient should be followed until the event is 
resolved, the event is no longer considered to be drug-related, the event becomes stable or 
returns to baseline, a new treatment is initiated for the patient, or the patient dies or is lost to 
follow-up.  Frequency of AE and SAE follow-up evaluation is left to the discretion of the 
investigator.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  
Table CXAD.8.1 presents a summary of AE and SAE reporting guidelines.  Table CXAD.8.1
also shows which database or system is used to store AE and SAE data.
8.1.2. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical occurrence 
in a patient or clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 


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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, which 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 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, v 4.03) 
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 4.1 
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(s) 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 CRF the circumstances and data leading 
to any such dosage reduction or discontinuation of treatment.  
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, or study drug via CRF.


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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 therapy 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 in offspring of the patient

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.  
SAEs due to disease progression, including death, should not be reported as SAEs unless the 
investigator deems them to be possibly related to the study drug.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 


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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.  
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
8.1.2.2.1. Prior to Administration of Study Drugs
During 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 study (that is, 
have not received at least 1 dose of LY2510924 or durvalumab), only AEs and SAEs related to 
protocol procedures are required to be collected.  
8.1.2.2.2. On Therapy
All AEs and SAEs, regardless of relatedness to study drug(s) 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 the decision to discontinue the patient from study treatment is made.
8.1.2.2.3. Follow-Up Visit
All AEs and SAEs, regardless of relatedness to study drug(s) or protocol procedures, occurring 
during the 30-day, 60-day, and 90-day safety follow-ups occurring after last dose of combination 
treatment must be reported to Lilly or its designee (Attachment 1).  
Following the 30-, 60-, and 90-day follow-up assessments, patients who discontinue from study 
treatment for progressive disease will be followed only for survival, unless there is an ongoing 
AE or SAE that is possibly related to study drug or protocol procedures.  In this instance, the 
patient should be followed in subsequent follow-up visits until the event is resolved, the event is 
no longer considered to be drug-related, the event becomes stable or returns to baseline, a new 
treatment is initiated for the patient, or the patient dies or is lost to follow-up.  For patients who 
have discontinued study treatment for reasons other than progressive disease, these patients will 
be followed for survival, progression-free survival (PFS), time and duration of response, and best 
overall response (BOR), unless they have started another treatment.  In that case, the patient will 
only be followed for survival.  Patients with an ongoing AE or SAE that is possibly related to 


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study drug or protocol procedures will be followed until the event is resolved, unless a new 
treatment is started.  
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 90-day follow-up visit, the follow-up visit duration may be 
shortened. In this case, the follow-up assessments should be completed prior to the initiation of 
the new therapy.
After the 90-day follow-up visit, AEs are not required to be reported unless the investigator feels 
the AEs were related to either study drug 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 in the Lilly Safety 
System.
8.1.2.3.
Adverse Events of Special Interest for Durvalumab
Adverse events of special interest (AESIs) are events of scientific and medical interest specific to 
the further understanding of the durvalumab safety profile and require close monitoring and 
rapid communication by the investigator to the sponsor.  Durvalumab AESIs may be serious or 
nonserious.  The rapid reporting of these AESIs allows ongoing analysis of these events in order 
to characterize and understand them in association with the use of this investigational product.
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy.  These 
AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-related AE is defined as an AE that is associated with drug 
exposure and is consistent with an immune-mediated mechanism of action and where there is no 
clear alternative etiology.  Serologic, immunologic, and histologic (biopsy) data, as appropriate, 
should be used to support an immune-related AE diagnosis.  Appropriate efforts should be made 
to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the 
immune-related AE.  
If the Investigator has any questions in regards to an AE being an immune-related AE, the 
Investigator should promptly contact the study CRP or designee.
AESIs observed with durvalumab include:

colitis

pneumonitis

ALT/AST increases / hepatitis / hepatotoxicity 

neuropathy / neuromuscular toxicity (ie, events of encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis)

endocrinopathy (ie, events of hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism)

dermatitis

nephritis


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
pancreatitis (or labs suggestive of pancreatitis - increased serum lipase , increased serum 
amylase)  

infusion-related reactions
Further information on these risks (eg, presenting symptoms) can be found in Attachment 11 and 
in the current version of the durvalumab IB.
8.1.2.4.
Reporting Adverse Events of Special Interest
AESIs require close monitoring and rapid communication to the sponsor.
Details regarding reporting of IRRs and hepatic function abnormalities are presented in 
Attachment 11.
Attachment 11 presents the dose-modification guidelines and guidance for management of 
AESIs for durvalumab AESIs.  Contact the Lilly CRP or designee if questions arise concerning 
AESIs.
8.1.2.5.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are not listed in the 
Development Core Safety Information (LY2510924 IB Section 7) or Summary of Data and 
Guidance for Investigator (durvalumab IB Section 6) and that the investigator identifies as 
related to study drug or procedure.  The United States 21 CFR 312.32, the European Union 
Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national regulatory 
requirements in participating countries require the reporting of SUSARs.  Lilly has procedures 
that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulatory regulations and the associated detailed guidances.
8.1.2.6.
Summary of Adverse Event/Serious Adverse Event Reporting Guidelines
The AE and SAE reporting guidelines are summarized in Table CXAD.8.1.


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Table CXAD.8.1.
Adverse Event and Serious Adverse Event Reporting Guidelines 
for Study CXAD
Timing
Types of AEs/SAEs Reported 
Collection 
Database
Lilly Safety 
System
Prestudy (baseline assessments)
(Starts at the signing of informed 
consent and ends just before the 
first dose of study drug)a
Preexisting conditions
All AEs
All SAEs 
x
x
x
x
On therapy
(Starts at first dose of study drug(s) 
and ends on the date the decision 
to discontinue the patient from 
study treatment is made
All AEs
All SAEs 
x
x
x
Follow-up visit 
(Starts just after the date the 
decision to discontinue the patient 
from study treatment is made and 
ends when end of study safety 
assessments are completed [30, 60, 
and 90 days for short-term follow-
up])
All AEs
All SAEs 
x
x
x
Continued access period
All AEs 
All SAEs 
x
x
x
Continued access period follow-up
(30-, 60-, and 90-day continued 
access period follow-up)
All AEs 
All SAEs 
x
x
x
Subsequent follow-up visits, if 
necessary for patient monitoring 
Ongoing AEs possibly related to 
study drug(s), or protocol procedures
All SAEs related to protocol 
procedures or study drug
x
x
x
Patient no longer on study
All SAEs related to protocol 
procedures or study drug that the 
investigator becomes aware of
x
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
a
If patients are not enrolled into the study (that is, have not received at least 1 dose of LY2510924 or 
durvalumab), only AEs and SAEs related to protocol procedures are required to be collected.
8.1.3. Other Safety Measures
8.1.3.1.
Electrocardiograms
For each patient, 12-lead digital triplicate ECGs will be collected according to the Study 
Schedule (Attachment 1).  Patients must be supine for approximately 5 to 10 minutes before 
ECG collection and remain supine but awake during ECG collection.  Consecutive replicate 
ECGs will be obtained at approximately 1-minute intervals.  The mean QT interval must be 
calculated using a corrected heart rate calculated from 1 baseline ECG using Fridericia’s
Correction and confirmed with the 2 additional baseline ECGs.  


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ECGs 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.  
ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at the
site as soon after the time of ECG collection as possible, and ideally while the patient is still 
present, to determine whether the patient meets entry criteria 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 1 of the replicate ECGs from each time point.  
All digital ECGs will be electronically transmitted to a central ECG laboratory designated by 
Lilly.  A cardiologist at the central ECG laboratory will then conduct a full over-read on 1 of the 
replicates (including all intervals) and QT/HR/RR in the other 2 replicates. A report based on
data from this over-read (confirmed ECG report) and any clinically significant findings will be
issued to the investigative site.  All data from the central ECG vendor’s over-reads will be placed
in the Lilly database for analytical and study report purposes.
It is recognized that ECG interpretations by the investigator (or qualified designee) and by the
cardiologist at the central ECG laboratory may be different.
When there are differences in
ECG interpretation between the investigator (or qualified designee) and the cardiologist at the
central ECG laboratory, the investigator’s (or qualified designee’s) interpretation will be used
for study entry and immediate patient management.
Interpretations from the cardiologist at the 
central ECG laboratory will be used for data analysis and report-writing purposes.
The investigator (or qualified designee) must document his/her review of 1 of the replicate
ECGs printed at the time of collection, the final over-read ECG report issued by the central ECG 
laboratory, and any alert reports.
QT prolongation that meets CTCAE Grade ≥3 criteria will be considered a DLT criterion in the 
Phase 1a portion of this trial; in the other parts of the study, this should be considered grounds 
for early withdrawal or discontinuation based on the investigator’s assessment. The investigator 
should consider the significance of other measures of QT prolongation and may wish to consult 
with a cardiologist to determine whether such AEs should be reported as an SAE or should result 
in withdrawal of the patient from the study.
8.1.3.2.
Echocardiography
Echocardiography is required at baseline to document initial LV function (Attachment 12).  
Additionally, echocardiography may be performed on-study as clinically indicated to determine 
LVEF/LV dysfunction and any change in cardiac size or function.


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Echocardiography will be locally assessed (within 28 days of Cycle 1 Day 1) by individuals who 
are qualified by experience or training.  Individuals so qualified should be identified at each site.  
The same person should be responsible for reading the echocardiography on any individual study 
patient.  
8.1.4. Safety Monitoring
The Lilly CRP or designee will monitor safety data throughout the course of the study.  
Representatives from Lilly Global Patient Safety will specifically monitor SAEs.  Lilly will 
review SAEs within time frames mandated by company standard operating procedures.  The 
Lilly CRP or designee will, as is appropriate, consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist, and periodically review:

trends in safety data,

laboratory analytes,

AEs, including monitoring of AESIs

DLTs and DLT-equivalent AEs 

If a study patient experiences elevated alanine aminotransferase (ALT) >5X upper limit 
of normal (ULN) and elevated total bilirubin >2X ULN, clinical and laboratory 
monitoring should be initiated by the investigator.  
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP or designee regarding collection of specific 
recommended clinical information and follow-up laboratory tests (Attachment 3).
8.1.5. Complaint Handling
Lilly collects complaints on study drugs used in clinical studies in order to ensure the safety of 
study participants, monitor quality, and facilitate process and product improvements.
Complaints related to concomitant drugs are reported directly to the manufacturers of those 
drugs in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
complaint process in accordance with the instructions provided for this study:

recording a complete description of the complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
8.2.
Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study.  


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Attachment 4 lists the PK, pharmacodynamic, immunogenicity, and biomarker sampling 
schedule.
8.2.1. Samples for Study Qualification and Health Monitoring
Blood samples will be collected to determine whether patients meet inclusion/ exclusion criteria 
and to monitor patient health.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
8.2.2. Samples for Drug Concentration Measurements 
Pharmacokinetics/Pharmacodynamics
PK and pharmacodynamic samples will be collected as specified in the Pharmacokinetic and
Pharmacodynamic Sampling Schedule (Attachment 4).  
8.2.2.1.
Pharmacokinetic Samples
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last patient visit for the study.
Blood samples to determine LY2510924 and durvalumab PK will be collected at times specified 
in Attachment 4.
Blood samples will be drawn from all patients for the assessment of LY2510924 in plasma and
durvalumab concentrations in serum (also known as bioanalytical samples).  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 the sponsor.  
Sampling times were selected to coincide with expected Cmax and minimum serum concentration 
(Cmin) and any additional PK analysis, and with consideration to draw minimum volume of 
blood from patients and ensure that the patients do not need to make an extra visit to provide 
these samples.
Instructions for the collection and handling of bioanalytical blood samples will be provided by 
the sponsor.  The actual date and time of LY2510924 administration must be recorded on the 
patient diary then reported on the CRF on the dates of interest (the most recent dose 
administration date and time:  1) prior to predose blood draw for PK, 2) prior to the first post-
dose sample, 3) after the 24-hour sample must be recorded on eCRF). In case of additional PK 
collected date and time of the dose administered prior to that draw should be recorded on the 
eCRF.


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The actual start and end date and time of durvalumab infusion administration must be recorded 
on the eCRF.  The actual date and time that each bioanalytical blood sample was drawn must be 
recorded on the laboratory accession page after the sample is drawn.
LY2510924 concentrations in plasma and durvalumab concentrations in serum samples will be 
measured using a validated assay methodology at a laboratory designated by the sponsor.
The remaining plasma from the bioanalytical samples collected for LY2510924 PK may be 
pooled and used for exploratory metabolism work as deemed appropriate.
8.2.3. Samples for Tailoring and Pharmacodynamic Biomarkers
Blood and tissue samples will be collected for biomarker research in this study. 
Required samples for biomarker research to be collected from all patients in this study are the 
following:

blood samples (plasma, serum and whole blood) (see Section 8.2.3.1 and Section 8.2.4)

tumor tissue (see Section 8.2.3.2)
o
a newly obtained core or excisional biopsy of a tumor lesion or a recent biopsy 
defined by 3 years since last documented progression of disease. If a fresh biopsy is 
obtained, an archival specimen, if available should also be submitted for comparison
(see Section 8.2.3.2).
o
newly obtained biopsy specimens collected during the study treatment period (see 
Section 8.2.3.2) (Phase 1b ovarian expansion arm only).  
Optional samples for biomarker research that should be collected from patients in the study 
where possible are the following:

newly obtained biopsy specimens collected during the study treatment period (Phase 1a 
and pancreatic expansion arm in Phase 1b).  
Sample collection including blood (plasma, serum, and whole blood) and tumor tissue will occur 
at specified time points as indicated in Attachment 4, where local regulations allow these 
samples are also described in the following sections.  
It is possible that biomarker data has already been generated from samples that were collected 
and analyzed prior to enrolling in this trial.  These data may have been generated from genetic 
analyses.  If available, these data may be requested from medical records for use in the research 
described in following sections.
8.2.3.1.
Blood Samples
Blood (plasma, serum, and whole blood) will be collected and may be used for research related 
to, but not limited to the drug targets, immune cells/immune functioning within disease state and 
cancer-related conditions, pathways associated with cancer and study drugs, variable response to 
LY2510924 and/or durvalumab, the mechanism of action of LY2510924 and/or durvalumab, 
and/or research methods or in validating diagnostic tools or assay(s) related to cancer.  Potential 
pharmacodynamic and/or circulating markers may include, but not limited to:  PD-L1+ cells,


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CD34+ stem cells and total white blood cells as well immune cell subsets characterization. 
Blood will be collected at times specified in Attachment 4. All samples will be coded with the 
patient number.  These samples and any data generated can be linked back to the patient only by 
the study site personnel.
Samples may be stored for a maximum of 15 years following last patient visit for the trial or for 
a shorter period if local regulations and/or ERBs impose shorter time limits, at a facility selected 
by the sponsor.  This retention period enables use of new technologies, response to questions 
from regulatory agencies, and investigation of variable response that may not be observed until 
later in drug development or when the drug is commercially available.  
8.2.3.2.
Tumor Tissue
Tissue collection will be required for biomarker research and enrollment into the study. To meet 
study eligibility criteria, and therefore mandatory for study participation, patients must have 
available tissue from a newly obtained core or excisional biopsy of a tumor lesion or a recent 
biopsy defined by 3 years since last documented progression of disease will be required. If a 
fresh biopsy is obtained, an archival specimen if available should also be submitted for 
comparison if not restricted by local regulations. In addition, newly obtained biopsy collected 
during the study treatment period is required if any accessible lesions remain (mandatory in 
Phase 1b ovarian expansion arm only, optional in Phase 1a and pancreatic expansion arm in 
Phase 1b). For patients for whom newly obtained samples cannot be obtained such as in cases of 
inaccessibility or patient safety concern, an archived specimen can be submitted upon agreement 
from Sponsor. Pre- and on-treatment assessments are critical for meaningful clinical data, paired 
biopsies are planned to be tested from baseline over time for changes in molecular markers to 
document any potential immunomodulatory activity of treatment in patients with LY2510924 
and durvalumab and should be performed if clinically feasible.
Pretreatment formalin-fixed paraffin-embedded (FFPE) tumor tissue should be in a whole block
or unstained slides. Blocks will be sectioned and returned to the site. Slides will not be returned.  
In addition to the biopsies and biomarker samples discussed in Sections 8.2.3.1 and 8.2.3.2, 
patients may be asked to undergo collection of an additional biopsy specimen and blood sample 
after treatment with study drug(s) has been initiated, including potentially after disease 
progression. Such additional biopsies are optional and should only be performed if clinically 
feasible. If these additional samples are requested, they will be used to further investigate 
biomarkers that may explain treatment response and resistance mechanisms.
Details for the handling and shipping of the tumor tissue will be provided by the sponsor in a 
separate document.  The tissue samples will be obtained using appropriate method. Tumor tissue 
should be submitted as a newly-acquired excisional or core needle (minimum 18 gauge) biopsy 
in formalin. Cytological or fine-needle aspiration specimens are not acceptable.  Due diligence 
should be used to ensure that tumor specimen (not normal adjacent or tumor margins) is 
provided.  Pathology reports accompanying the tissue may also be requested.  Each sample will 
be labeled with patient number and tissue of origin and be stored for up to 15 years after the last 
patient visit at a facility selected by the sponsor.


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Tumor tissue will be examined for biomarkers related to, but not limited the drug targets, disease 
process, immune cells/immune functioning within the disease state, and cancer-related 
conditions, pathways associated with cancer and study drugs, mechanism of action of 
LY2510924 and/or durvalumab, and/or research methods or in validating diagnostic tools or 
assays.  
Gene expression, sequencing and/or immunohistochemistry may be performed on these tissue 
samples to evaluate expansion in clonal T-cell populations and changes in immune cell 
infiltration, activation, modulation, microenvironment and changes in stromal and tumor biology 
in response to study treatment. The results of this analysis may be correlated with clinical 
efficacy data.  
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.  
8.2.4. Samples for Pharmacogenetics
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(s). 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 drugs
Samples will be destroyed according to a process consistent with local regulation.
8.2.5. Samples for Immunogenicity Research
Blood samples for immunogenicity testing will be collected to determine ADA production 
against durvalumab. The specific time points are listed in Attachment 4.  Sample collection, 
storage, and shipment instructions for blood samples will also be provided in the Central 
Laboratory Manual. Pretreatment and post-treatment samples will be collected and assayed for 


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the presence of ADA using an immunoassay. The number and percentage of patients with 
positive antidrug response will be summarized.  In the event of a study treatment-related infusion 
reaction, every effort should be made to collect blood samples for anti-durvalumab antibody 
determination, as well as blood samples for durvalumab serum concentration, as close to the 
onset of the reaction as possible, at the resolution of the event, and 30 days following the event.  
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 drugs.  
The duration allows the sponsor to respond to regulatory requests related to study drugs.
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:

CT scan

MRI
Each patient’s full extent of disease will also be assessed with:

Tumor measurement by RECIST v1.1 (Eisenhauer et al. 2009; Attachment 10).

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 for subsequent 
imaging, using the sample method that was used at baseline.  
8.3.1. RECIST Version 1.1 with Confirmatory Scan for Disease
Progression
8.3.1.1.
Rationale for RECIST Version 1.1 with Confirmatory Scan for Disease 
Progression
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy, including the following (Wolchok et al. 2009; Nishino et al. 2013):

Response to immunotherapy may be delayed.

Response to immunotherapy may occur after progressive disease by conventional criteria.

The appearance of new lesions may not represent progressive disease with 
immunotherapy.

Stable disease (SD) while on immunotherapy may be durable and represent clinical 
benefit.  


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Therefore, to adequately characterize additional patterns of response and progression specific to 
patients treated with immunotherapy, which cannot be captured by conventional criteria such as 
RECIST v1.1, alternative measures of tumor assessment have been developed:  1) RECIST v1.1 
with confirmatory scan for disease progression and 2) immune-related response criteria (irRC,
Wolchok et al. 2009).  For both measures 1) and 2) clinically stable patients may continue 
treatment until disease progression (per standard RECIST v1.1) is confirmed.  As the irRC are 
still being developed and validated for various tumor types, Study CXAD will use RECIST v1.1 
with confirmatory scan for disease progression, which may discourage the early discontinuation 
of study treatment and provide a more complete evaluation of its antitumor activity than would 
be seen with conventional response criteria.
Table CXAD.8.2 provides an overall comparison across the 2 measures of disease progression to 
be used in Study CXAD, and irRC.  
Table CXAD.8.2.
Summary of Response Assessment by RECIST, RECIST with 
Confirmatory Scan for Progressive Disease, and irRC
Used in Study CXAD
Not Used in Study CXAD
Definition
RECIST v1.1
RECIST v1.1 
with confirmatory scan for PD
irRC (Wolchok et al. 2009)
New lesion
The presence of 
new lesion defines 
progression
The presence of new lesion defines 
progression
The presence of new lesion 
does not define progression
The measurements of the new 
lesion(s) are included in the 
sum of the measurements
Confirmation of 
PD
Not required
PD, in the absence of clinically 
significant deterioration, requires 
confirmation with repeat imaging after 
>4 weeks.
After initial PD following RECIST 
v1.1, shift to “RECIST v1.1 with 
confirmatory scan for PD.”
Required
Abbreviations:  irRC = immune-related response criteria; progressive disease = PD; RECIST = Response Evaluation 
Criteria in Solid Tumors.
8.3.1.2.
Application of RECIST Version 1.1 with Confirmatory Scan for Disease 
Progression
For Study CXAD, based on the unique response to immunotherapy and guidelines from 
regulatory agencies (for example, the European Medicines Agency’s “Guideline on the 
evaluation of anticancer medicinal products in man” [EMA/CHMP/205/95/Rev.4] for immune 
modulating anticancer compounds), the following will be applied, in addition to standard 
RECIST v1.1 criteria:


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
If radiologic imaging verifies initial progressive disease, tumor assessment 
should be repeated ≥4 weeks later in order to confirm progressive disease in 
the absence of clinically significant deterioration.  Study treatment would 
continue between the initial assessment of progression and confirmation for 
progression.
NOTE:  “clinically significant deterioration” is considered to be rapid 
tumor progression that necessitates treatment with anticancer therapy other 
than study treatment, or symptomatic progression that requires urgent 
medical intervention (for example, central nervous system metastasis, 
respiratory failure due to tumor compression, spinal cord compression).

In the case of clinically significant deterioration, the patient will discontinue 
study treatment (Section 6.3.2).

For patients who continue to receive clinical benefit, and in the absence of 
clinically significant deterioration despite evidence of objective progressive 
disease with the confirmatory scan, the patient may continue study treatment at
the discretion of the investigator, in consultation with the Lilly CRP or 
designee.  Patients with a decline in ECOG performance status to >1 will not 
be permitted to continue study treatment after confirmed progression of 
disease.
NOTE:  In determining whether or not progression can be confirmed, the site 
study team should consider all target lesions, nontarget lesions, and new lesions.  
Patients will not be permitted to continue study therapy if progression occurs after 
confirmed response (CR or PR as defined by RECIST v1.1) in the target lesions 
(regardless of the appearance of new lesions), ie, the response and progression 
events both occurred in the target lesions while receiving study therapy.
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, pharmacodynamic samples, and efficacy 
measurements are given as targets, to be achieved within reasonable limits.  The scheduled time 
points may be subject to minor alterations; however, the actual collection time must be correctly 
recorded on the CRF.  
The scheduled collection times may be modified by the sponsor based on analysis of the safety 
and PK information obtained during the study.  


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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 board (IRB)/ERBs with direct access to the original source documents.
9.2.
Data Capture Systems
9.2.1. Case Report Form
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
CRF data collected by the third-party organization (TPO) will be encoded by the TPO and stored 
electronically in the TPO’s database system.  Validated data will subsequently be transferred to 
Lilly data warehouse, using standard Lilly file transfer processes.  For any data handled by the 
sponsor internally, it will be managed by the sponsor and stored electronically in the sponsor’s 
data warehouse.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system.  Data will subsequently be transferred from the central 
vendor to the Lilly data warehouse.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect patient-


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reported outcome measures (for example, a rating scale), a daily dosing schedule, or an event 
diary.
Attachment 5 contains a data sharing and sample testing schedule for this study.
9.2.2. Ancillary Data
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly data warehouse 
and TPO’s system.
ECG 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 data warehouse and TPO’s system.
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 45 patients may be enrolled in this multicenter, open-label Phase 1a/1b 
study. Patients will be enrolled into the Phase 1a cohorts sequentially without randomization to 
dose. The Bayesian model-based, toxicity-band method will be followed to assist dose 
escalation during Phase 1a. 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 under-dosing rate 
and a higher MTD selection rate, with a well-controlled overdosing rate at a prespecified 
criterion. Refer to Attachment 9 for more details. The sample size for Phase 1a will primarily be 
determined by the incidence of DLTs. The anticipated sample size for Phase 1a ranges from 
approximately 12 to 15 patients. The sample size of approximately 15 patients per tumor type in 
the Phase 1b expansion arm has been selected to allow adequate assessment of safety at the 
recommended dose level. It can provide adequate precision for the estimated incidence rate of 
the following quantities of interest:  (1) patients having a specified AE or (2) patients showing a 
response (PR/CR) to treatment. Example point estimates of incidence rates and corresponding 
2-sided 95% confidence intervals (CI) are summarized in Table CXAD.10.1. The values are 
provided as a reference for estimation rather than a basis of any decision criteria. The MTD may 
be revised based on the safety data obtained in Phase 1b (Iasonos and O’Quigley 2013).
Table CXAD.10.1.
Estimated Incidence Rate and Its Two-Sided 95% Confidence 
Interval
Number of Cases
(N=15)
Estimated Incidence Rate
95% Confidence Intervala
Lower Limit
Upper Limit
0
0.0
0.0
0.22
3
0.2
0.04
0.48
6
0.4
0.16
0.68
9
0.6
0.32
0.84
Abbreviation: N = number of patients.
a
95% Clopper-Pearson interval for binomial distribution with sample size of 15.
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/expansion arms 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. 
Also, 95% CI will be constructed for the estimates if appropriate.  Missing data will not be 
imputed.


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The interpretation of the study results will be the responsibility of the investigator along with the 
Lilly CRP or designee, pharmacokineticist, and statistician.  The CRP or designee 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.
10.3. Patient Characteristics
Patient characteristics will include a summary and/or listing of the following:

Patient demographics including, for example, age, sex, ethnicity/race, weight, and 
screening body mass index (BMI) will be reported.  

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 1 dose of either study drug will be evaluated for safety and 
toxicity.  AE terms and severity grades will be assigned by the investigator using CTCAE, 
version 4.03).
Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drug, and concomitant 
medications

dose adjustments

laboratory values 

vital signs and physical examinations

DLTs at each dose level 

ECGs
10.5. Pharmacokinetic Analyses
PK analyses will be conducted on patients who have received at least 1 dose of the study drugs
and have had samples collected.  
PK parameter estimates for LY2510924 will be calculated by standard noncompartmental 
methods of analysis. The primary parameters for analysis will be AUC of LY2510924.  Other 
noncompartmental parameters, such as time of t1/2, CL/F, and apparent volume of distribution 
(V/F) may be reported.  


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Summary statistics will be tabulated for the PK parameters of durvalumab.  
Population PK analyses for LY2510924 and/or durvalumab may be conducted using a population 
PK approach.  The relationship between LY2510924 and/or durvalumab exposure and selected 
safety outcomes, pharmacodynamics/biomarkers, and immunogenicity may be explored, if 
necessary.
10.6. Biomarker Analyses 
Exploratory biomarkers will be summarized and assessed for correlations with clinical outcomes.
Biomarker relationships by tumor type, changes in biomarker levels at baseline and over time, 
and differences among dose levels or exposure will be explored as possible.  
The pharmacodynamic effect from all patients undergoing pharmacodynamic assessments will 
be explored.  
10.7. Pharmacokinetic/Pharmacodynamic Analyses
PK/pharmacodynamic analyses for LY2510924 may be conducted as deemed necessary by 
Global PK/ pharmacodynamic management.  These analyses may include, but are not limited to, 
establishing relationships (or lack of) between exposure and pharmacodynamic biomarkers that 
were explored or confirmed in pharmacodynamic analyses (refer to Section 10.6).
10.8. Immunogenicity
Immunogenicity incidence will be tabulated, and correlation to durvalumab, activity, and safety 
will be assessed, as appropriate, respectively.  The measures that will be analyzed include 
baseline presence and level of ADA, treatment-emergent ADA, levels of neutralizing ADA, and 
incidence and levels of ADA related to IRRs.
10.9. Efficacy
Tumor response data will be provided by cohort/expansion arm (according to RECIST v1.1). 
Particularly, the antitumor effect will be summarized by best overall response, including the 
overall response rate (ORR) and disease control rate (DCR). A patient is considered to have a 
tumor response if they achieve a confirmed CR or PR. 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. The DCR will be estimated by dividing the total number of CR+PR+SD by the 
total number of enrolled patients. A 95% exact CI will be constructed to determine the level of 
precision of the ORR and DCR. Time-to-event variables such as PFS, time to response, duration 
of response and overall survival will be tabulated, and the Kaplan-Meier method (Kaplan and 
Meier 1958) will be used to estimate the survival curves, medians, and survival rates (eg, 
6-month survival rate) if applicable.
10.10.
Interim Analyses
Data will be reviewed on a cohort-by-cohort basis during Phase 1a of the study, until the MTD is 
determined. The purpose of these cohort-by-cohort reviews is to evaluate the cumulative safety 
data (Cycle 1 and all later cycles) at each dose level(s) that has/have enrolled study patients, and 


I2V-MC-CXAD(b) Phase 1 Oncology Protocol
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determine if a DLT has been observed that would suggest MTD has been met or exceeded. The 
investigators and the Lilly study team in consultation with collaborator will make the 
determination regarding dose escalation based upon their review of the safety and tolerability 
data as described in this protocol.  
Safety and/or PK data will be reviewed during the study if needed for dose escalation, 
modifications to the dose-escalation strategy or other design elements.
Once MTD is determined for Phase 1a, an interim analysis will be performed prior to opening 
Phase 1b.
In Phase 1b, 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 LY2510924 dose or whether the dose of LY2510924 should be 
reduced.  If the DLT-observation period is extended to 2 cycles during Phase 1a, this analysis 
will also include DLT-equivalent toxicities occurring in Cycle 2.
In Phase 1b, a safety review may occur for each expansion arm approximately 2 months after 
approximately 8 of the planned patients per arm start study therapy.  
If an unplanned interim analysis is deemed necessary, the sponsor will determine if it is 
necessary to amend the protocol.
Any interim analyses may be combined if they are expected to occur within approximately a 
month, and interim analyses may also be combined with the ongoing trial-level safety review or 
annual safety review for annual safety update reporting.
The final analysis and evaluation of the primary objective and the secondary objectives will be 
performed no more than 12 months after the last patient of each expansion arm starts study 
therapy, and the final analysis may be conducted separately for each expansion arm. A clinical 
study report might be created before the last patient visit.  In this case, all data until the data-
cutoff date will be used for the analysis of safety, efficacy, PK, and pharmacodynamic
biomarkers.  


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11. Informed Consent, Ethical Review, and 
Regulatory Considerations
11.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the study in a timely manner.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study and to document that the 
patient is satisfied with his or her understanding of the potential risks and benefits of 
participating in the study and desires to participate in the study.
The investigator is ultimately responsible for ensuring that informed consent is given by each 
patient or legal representative before the study is started.  This includes obtaining the appropriate 
signatures and dates on the ICF prior to the performance of any protocol procedures and prior to 
the administration of study drug.  
Lilly or its representatives must approve all ICFs before they are used at investigative sites(s).  
All ICFs must be compliant with the ICH guideline on GCP.  
11.2. Ethical Review
The sponsor or its representatives must approve all ICFs before they are used at investigative 
sites.  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.
Additionally, 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
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.


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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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Attachment 1.
Protocol CXAD Study Schedule


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Baseline, During and Poststudy Assessments  
 
Baseline 
Cycle 1 
Cycle 2 
Cycle 3-n 
Follow-Up 
Comments 
Relative Day 
Within a Cycle 
<28 
days 
<7 
days 
1 
15 
1 
1 
30 
day  
60 
day 
90 
day 
LT 
FUa 
Assessments to be performed at the times 
stipulated in the table and as clinically required 
in the management of the patient.  All 
assessments to be performed pre-infusion unless 
stated otherwise. 
Visits 
 
 
 
 
 
 
801 
802 
803 
804 
 
Informed 
Consent 
x 
 
 
 
 
 
 
 
 
 
Informed Consent Form signed (prior to 
performance of any protocol-specific 
tests/procedures). 
Medical 
History 
x 
 
 
 
 
 
 
 
 
 
Including alcohol/tobacco use and other relevant 
habits assessments. 
Physical 
Examination/ 
Vital Signs 
x 
 
x 
 
x 
x 
 
 
 
 
Full examination at baseline.  Focused 
examination at other time points.  During the 
study treatment period, occurs within 3 days 
prior to first day of each cycle.  Includes recent 
height (baseline only), weight, and vital signs 
(blood pressure, pulse, temperature, and 
respiratory rate [at baseline and as indicated in 
Section 7.2.1.2]).  See Section 7.2.1.2 for a 
detailed description of vital sign collection on 
study.   
ECHO 
x 
 
 
 
 
 
 
 
 
 
Local.  ECHOs may be performed on study as 
clinically indicated to determine LVEF/LV 
dysfunction and any change in cardiac size or 
function.   


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Baseline
Cycle 1
Cycle 2
Cycle 3-n
Follow-Up
Comments
Relative Day 
Within a Cycle
<28 
days
<7 
days
1
15
1
1
30 
day 
60
day
90 
day
LT 
FUa
Assessments to be performed at the times 
stipulated in the table and as clinically required 
in the management of the patient.  All 
assessments to be performed pre-infusion unless 
stated otherwise.
Visits
801
802
803
804
ECG
x
x
x
x
Obtain ECGs before any associated blood 
draws.
At baseline, triplicate ECG will be obtained, on 
which QTcF must be <450 ms (calculated from 
one ECG using Fridericia’s Correction Formula 
and confirmed with 2 additional ECGs).
Cycle 1 Day 1: ECG will be conducted 30 mins 
post LY2510924 dose.
Cycle 1 Day 15 and Cycle 2 Day 1: ECGs will 
be conducted predose.
All ECGs will be done in triplicate.  
Concomitant 
Meds
x
x
x
x
x
x
x
Throughout study as needed.
ECOG 
Performance 
Status
x
x
x
x
x
x
x
HIV, 
Hepatitis B, 
and 
Hepatitis C 
Testing
x
All tests completed locally.  
Hepatitis B (HBsAg, Anti-HBc)
Hepatitis C (Anti-HCV, HCV RNA)
Hematology
x
x
x
x
x
x
x
x
Local. Complete blood count with differential.
If any abnormalities, will follow beyond the 
30-day FUP, as clinically indicated


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Baseline
Cycle 1
Cycle 2
Cycle 3-n
Follow-Up
Comments
Relative Day 
Within a Cycle
<28 
days
<7 
days
1
15
1
1
30 
day 
60
day
90 
day
LT 
FUa
Assessments to be performed at the times 
stipulated in the table and as clinically required 
in the management of the patient.  All 
assessments to be performed pre-infusion unless 
stated otherwise.
Visits
801
802
803
804
Serum 
Chemistry and 
Liver Function 
Testing
x
x
x
x
x
x
x
x
Local and central. See Attachment 2.
If any abnormalities, will follow beyond the 
30-day FUP, as clinically indicated.  
To include liver enzyme panel.
Tumor 
Markers in 
Blood
x
x
x
x
x
x
x
Local. If applicable to tumor type of the patient
(eg, CEA in patients with colorectal cancer or 
CA125 in patients with ovarian cancer). Obtain 
predose, if dose administered.  
Coagulation 
x
Local. Includes prothrombin time, aPTT and
INR.  As clinically indicated on study and prior 
to any procedures (eg, tumor biopsy).
Thyroid 
Function Tests
x
x
x
x
x
x
x
Local. Includes TSH and fT4.  
Additionally, measure if there is clinical 
suspicion of an adverse event related to the 
endocrine system.
Urinalysis
x
x
x
x
x
x
x
Local. See Attachment 2.
If any abnormalities, will follow beyond the 
90-day FUP, as clinically indicated.
CTCAE v 4.03 
Grading
x
x
x
x
x
x
x
x
x
To be reported only after study eligibility is 
confirmed.  Throughout study as needed.  Refer 
to Section 8.1.2.6 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.
Urine or 
Serum 
Pregnancy 
Test
x
Local. As clinically indicated while on study.


I2V-MC-CXAD(b) Phase 1 Oncology Protocol
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Baseline
Cycle 1
Cycle 2
Cycle 3-n
Follow-Up
Comments
Relative Day 
Within a Cycle
<28 
days
<7 
days
1
15
1
1
30 
day 
60
day
90 
day
LT 
FUa
Assessments to be performed at the times 
stipulated in the table and as clinically required 
in the management of the patient.  All 
assessments to be performed pre-infusion unless 
stated otherwise.
Visits
801
802
803
804
Tumor Tissue 
3
yrs
prior
D7
Central. Core or excisional biopsy of a tumor 
lesion or a recent biopsy defined by 3 years 
since last documented progression of disease.  
Patients for whom newly obtained samples 
cannot be obtained such as in cases of 
inaccessibility or patient safety concern, an 
archived specimen can be submitted upon 
agreement from sponsor. If a fresh biopsy is 
obtained, an archival specimen (if available) 
should also be submitted for comparison.  
On-treatment sample (Cycle 2 Day 7 ±7 days): 
mandatory for ovarian expansion arm (Phase 1b), 
optional in Phase 1a and pancreatic expansion 
arm in Phase 1b.  
PK Sampling 
D1 
& 2
D15 
& 16
x
C3, C4, & C6
x
See PK Sampling Attachment 4 for exact timing.
Serum, 
Plasma, and 
Whole Blood 
Samples for 
Biomarkers
x
See Attachment 4 for exact timing.
x
Baseline sample for whole blood only, and must 
be collected ≤7 days prior to Cycle 1 Day 1.
See Attachment 4 for exact timing.
Radiological 
Tumor 
Assessment
x
x
x
Local. CT scans will begin within 7 days prior 
to starting Cycle 3 and every other cycle 
afterwards including follow-up (approximately 
8 weeks apart).


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Baseline
Cycle 1
Cycle 2
Cycle 3-n
Follow-Up
Comments
Relative Day 
Within a Cycle
<28 
days
<7 
days
1
15
1
1
30 
day 
60
day
90 
day
LT 
FUa
Assessments to be performed at the times 
stipulated in the table and as clinically required 
in the management of the patient.  All 
assessments to be performed pre-infusion unless 
stated otherwise.
Visits
801
802
803
804
Blood for 
pharmaco-
genetics
x
It is highly recommended to draw the whole 
blood sample on Cycle 1 Day 1 prior to the first 
dose; however, it can be collected later during 
the study if necessary.
Other safety or 
laboratory 
assessments; 
for example, 
immuno-
genicity
x
C4
x
Note:  Day 1 sample should be taken prior to 
durvalumab and LY2510924.
Survival/ 
subsequent 
anticancer 
therapy
x
x
x
x
At long-term FUP, at least every 12 weeks
±7days until patient’s death or study completion.
Durvalumab
x
x
x
In clinic on Day 1 of each cycle.
LY2510924
Days 1-28
Days 1-
28
Days 1-28
LY2510924 will be self-administered SQ daily.  
On Cycle 1 Days 1, 2, 15 and 16 and on Cycles 2 
to 4 Day 1, LY2510924 should be taken at the 
clinic (time and date recorded) after a blood 
sample is taken for LY2510924 PK but prior to 
the start of durvalumab (refers to Day 1 of each 
cycle only).  
Dispense study 
drugs and 
assess 
compliance
x
x
x
Collect drug diary prior to dispensing study drug
for cycle.


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Baseline
Cycle 1
Cycle 2
Cycle 3-n
Follow-Up
Comments
Relative Day 
Within a Cycle
<28 
days
<7 
days
1
15
1
1
30 
day 
60
day
90 
day
LT 
FUa
Assessments to be performed at the times 
stipulated in the table and as clinically required 
in the management of the patient.  All 
assessments to be performed pre-infusion unless 
stated otherwise.
Visits
801
802
803
804
Dispense/
collect patient 
diaries 
x
x
x
Patients will complete diaries once per cycle.  
Abbreviations:  aPTT = activated partial thromboplastin time; C = cycle; CEA = carcinoembryonic antigen; CT = computer tomography; CTCAE = Common 
Terminology Criteria for Adverse Events; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FUP = follow-up 
HBsAg = hepatitis B surface antigen; HBc = hepatitis B core antibody; HCV =hepatitis C virus; HIV = human immunodeficiency virus; INR = international 
normalized ratio of prothrombin time; LTFU = long-term follow-up; n = cycle number; LV = left ventricular; LVEF = left ventricular ejection fraction; 
PK = pharmacokinetic; QTcF = Fridericia’s formula corrected QT interval; RNA = ribonucleic acid; SAE = serious adverse event; SQ = subcutaneous; 
TSH = thyroid-stimulating hormone; yrs = years.
a
Long-term follow-up begins the day after the 90-day follow-up is completed and continues until the patient’s death or end of trial (approximately every 
12 weeks ±7 days the patient will be contacted).


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Continued Access and Post Continued Access Assessments
Cycle n
Follow-Up (days)a
Comments
Relative Day Within a Cycle
1
30
60
90
Visit
501-5XX
901
902
903
CTCAE v 4.03 grading
x
x
x
x
To be reported only after study eligibility is confirmed.  Throughout study 
as needed.  Refer to Section 8.1.2.6 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.
Durvalumab
x
In clinic on Day 1 of each cycle.
Patients will continue to receive study drug(s) at the same dose and 
schedule as when in the main study.  
LY2510924
x
LY2510924 will be self-administered SQ daily.  
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; n = cycle number; SAE = serious adverse event; SQ = subcutaneous.
a
Continued access follow-up begins 1 day after the patient and the investigator agree that the patient will no longer continue treatment in the continued access 
period and lasts approximately 90 days.  No follow-up procedures will be performed for a patient who withdraws informed consent unless he or she has 
explicitly provided permission and consent.


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Attachment 2.
Protocol CXAD Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologyb
Clinical Chemistrya
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Mean corpuscular hemoglobin
Magnesium
Mean corpuscular hemoglobin concentration
Chloride
Mean corpuscular volume
Phosphorus
Erythrocyte count (RBC)
Potassium
Leukocytes (WBC)
Total and direct bilirubin
Neutrophilsc (% and absolute)
Alkaline phosphatase
Lymphocytes (% and absolute)
Alanine aminotransferase 
Monocytes (% and absolute)
Aspartate aminotransferase 
Platelets
Bicarbonate
Eosinophils
Blood urea nitrogen 
Basophils
Creatinine
Total protein
Coagulationb
Calcium
aPTT
Glucose, random 
PT
INR
Albumin
Urinalysisb
Clinical Chemistryd
Bilirubin
Serum Concentrations of:
Blood
Lactate dehydrogenase (LDH)
Color and appearance
Lipase
Glucose
Gamma glutamyl transferase (GGT)
Ketones
Creatine kinase
pH
Amylase
Protein
Specific gravity
Thyroid Function Testsb
Urine leukocyte esterase
Thyroid stimulating hormone
Free thyroxine (fT4)
Hepatitis B (HBsAg, Anti-HBc)b
Hepatitis C (Anti-HCV, HCV RNA)b
HIVb
Urine or serum (β-human chorionic gonadotropin 
(β-hCG) Pregnancy Test (females only)b


I2V-MC-CXAD(b) Phase 1 Oncology Protocol
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Clinical Laboratory Tests
Abbreviations:  aPTT = activated partial thromboplastin time; CRF = case report form; HBsAg = hepatitis B surface 
antigen; HBc = hepatitis B core antibody; HCV =hepatitis C virus; INR = international normalized ratio of 
prothrombin time; PT = prothrombin time; RBC = red blood cells; RNA = ribonucleic acid; WBC = white blood 
cells.
a
Local chemistry laboratory testing will be used to determine patient eligibility and decisions for treatment.  
Central chemistry laboratory testing will also be performed, and will be used for data analyses.
b
Local or investigator-designated laboratory.  Treatment decisions will be based on local laboratory results.
c
Neutrophils reported by automated differential hematology instruments include both segmented and band 
forms. When a manual differential is needed to report the neutrophils, the segmented and band forms should be 
added together and recorded on the CRF, unless the CRF specifically provides an entry field for bands.
d
Centrally only.


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Attachment 3.
Protocol CXAD Hepatic Monitoring Tests 
for Treatment-Emergent Abnormality
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP or designee regarding collection of specific 
recommended clinical information and follow-up laboratory tests.
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 or designee.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Activated partial thromboplastin 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-Actin antibody
AST
Anti-nuclear antibodya
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 laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Attachment 4.
Protocol CXAD Pharmacokinetic, 
Pharmacodynamic, Immunogenicity, and Biomarker
Sampling Schedule
Pharmacokinetic (PK) samples will be collected for both LY2510924 and durvalumab and 
immunogenicity (IK) samples will be collected for durvalumab only.  Predose sample for 
LY2510924 should be drawn as close as possible prior to the subcutaneous (SQ) injection of 
LY2510924, and that for durvalumab should be drawn as close as possible prior to start of 
durvalumab infusion (but can be drawn up to 1 hour or 60 minutes prior to the start of infusion). 
All post-dose blood draws for LY2510924 PK should be drawn in the preferred time windows 
listed in the table below. Exact clock reading for the time of blood draw should be recorded.  
While best effort should be done to draw the blood sample within the time window provided, it is 
more important to ensure that the predose sample for LY2510924 and durvalumab is actually 
collected before the administration of SQ injection and start of infusion, respectively, and post-
end of infusion sample for durvalumab should be collected after the infusion has actually 
completed.  It is also equally important to record actual date and time of blood collection for 
PK/IK sample on the Requisition Form after drawing the sample.  Sample collection for PK/IK 
must be from the opposite arm to that used for study drug infusion.  If drug was administered via 
a central venous catheter, the sample collection should be from a different site.
In addition, if a patient experiences an IRR, blood samples for anti-durvalumab antibody and PK 
should be drawn, with no more than 15 minutes’ time difference between PK and IK samples.  
Samples will be taken at the following time points:  (1) as soon as possible after the onset of the 
IRR, (2) at the resolution of the IRR, and (3) 30 days after the IRR.


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Pharmacokinetic, Pharmacodynamic, and Biomarker Sampling Schedule
Cycle
Day
PK 
Sampling 
Time for 
LY25109
24a
PK Sampling 
Time for 
Durvalumab
Durvalumab 
Immuno-
genicity
Blood for 
Pharmaco-
genetics
Tailoring and Pharmacodynamic Biomarker
Plasma for 
Exploratory 
Research
Serum for 
Exploratory 
Research
Whole Blood for 
Immunopheno-
typing Including 
CD34+ Countsc
and Other 
Exploratory 
Research
Tissue for PD-L1 and 
Exploratory Research
—
≤7 
days
X
X
1
1
Predoseb
X
X
X
X
(Core or excisional biopsy 
of a tumor lesion or a 
recent biopsy defined by 
3 years since last 
documented progression 
of disease)
1
1
0.5 hr +/-
15 min
10 min after 
end of 
infusion 
(+/-5 min)
1
1
2 hr +/-
30 min
X
1
1
4 hr +/-
30 min
X
1
1
6 hr +/-
30 min
1
1
8 hr +/-
30 min
1
2
24-30 hr 
post Day 
1 doseb
X
X
1
15
Predoseb
X
X


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Cycle
Day
PK 
Sampling 
Time for 
LY25109
24a
PK Sampling 
Time for 
Durvalumab
Durvalumab 
Immuno-
genicity
Blood for 
Pharmaco-
genetics
Tailoring and Pharmacodynamic Biomarker
Plasma for 
Exploratory 
Research
Serum for 
Exploratory 
Research
Whole Blood for 
Immunopheno-
typing Including 
CD34+ Countsc
and Other 
Exploratory 
Research
Tissue for PD-L1 and 
Exploratory Research
1
15
0.5hr +/-
15 min
1
15
2 hr +/-
30 min
X
1
15
4 hr +/-
30 min
X
1
15
6 hr +/-
30 min
1
15
8 hr+/-
30 min
1
16
24-30 hr 
post Day 
15 doseb
X
X
2
1
Predoseb
Predose 
(before start 
of infusion)
X
X
X
X
X
(On-treatment sample 
(Cycle 2 Day 7 ±7 days): 
mandatory for ovarian 
expansion arm (Phase 1b), 
optional in Phase 1a and 
pancreatic expansion arm 
in Phase 1b)
2
1
0.5 hr +/-
15 min
2
1
4 hr +/-
30 min
X
3
1
Predoseb
Predose 
(before start 
X
X
X


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Cycle
Day
PK 
Sampling 
Time for 
LY25109
24a
PK Sampling 
Time for 
Durvalumab
Durvalumab 
Immuno-
genicity
Blood for 
Pharmaco-
genetics
Tailoring and Pharmacodynamic Biomarker
Plasma for 
Exploratory 
Research
Serum for 
Exploratory 
Research
Whole Blood for 
Immunopheno-
typing Including 
CD34+ Countsc
and Other 
Exploratory 
Research
Tissue for PD-L1 and 
Exploratory Research
of infusion)
4
1
Predoseb
Predose 
(before start 
of infusion)
X
X
X
4
1
0.5-4 hr
10 min after 
end of 
infusion 
(+/-5 min)
6
1
Predoseb
Predose 
(before start 
of infusion)
30 
days 
post 
t/ment
X
X
90 
days 
post-
t/ment
Anytime
X
Abbreviations: EDTA = ethylenediaminetetraacetic; hr = hour; min = minute; PD-L1 = programmed cell death ligand 1; PK = pharmacokinetic; 
t/ment = treatment.
a
Samples of approximately 5 mL of whole blood will be drawn into EDTA tubes for measurement of LY2510924 in plasma.
b
Patients should be instructed ahead of time that LY2510924 should be taken at the clinic.
c
Includes CD34+ counts, absolute neutrophil count (ANC), absolute lymphocyte count (ALC).


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Attachment 5.
Protocol CXAD Data Sharing and Sample 
Testing Schedule
Data Sharing and Sample Testing Schedule
Study Procedures
Shared 
between the 
Two Parties
Not 
Shared
Timing to provide item 
(data/sample, etc.)
Party to Analyze 
Data/Sample
Clinical/oncologic history
X
Early Results Memo
Lilly
Vital signs/weight
X
Early Results Memo
Lilly
Physical examinations
X
Early Results Memo
Lilly
ECOG Performance Status
X
Early Results Memo
Lilly
12-Lead ECG 7
X
Early Results Memo
Lilly
Laboratory tests
X
Early Results Memo
Lilly
Pregnancy test – urine or serum
β-HCG 
X
Early Results Memo
Lilly
Other baseline physiological 
assessments
X
Early Results Memo
Lilly
Tumor Imaging -- assessment to 
support all efficacy analyses (to 
ensure compliance with 
SDTM 3.1.3)
X
Early Results Memo
Lilly
If collected, all radiologist 
reports — including tumor 
measurements and assessment of 
response and progression 
X
Early Results Memo
Lilly
Adverse events; all safety data
X
Early Results Memo
Lilly
Tumor and Blood Biomarker 
Assay(s) for exploratory analysis 
X
As soon as data is 
available during final 
analysis
Lilly
Tumor PD-L1 Biomarker Assay:  
scoring (including both dose 
finding cohorts and expansion 
arms)
X
As soon as possible but 
no longer than 
14 calendar days of the 
sample receipt
Partner
Tumor PD-L1 Methods and 
Validation
Xa
Within 1 month from the 
date the Tumor PDL-1
Biomarker Assay 
becomes available in the
marketplace
Partner
Durvalumab Immunogenicity 
(ADA) Data: results
X
As soon as data is 
available during planned 
interim and/or final 
analysis
Partner


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Study Procedures
Shared 
between the 
Two Parties
Not 
Shared
Timing to provide item 
(data/sample, etc.)
Party to Analyze 
Data/Sample
Durvalumab Immunogenicity 
(ADA) Data: methods and 
validation
Xa
N/A
Partner
Durvalumab PK: results
(plasma/serum concentration and 
PK parameters)
X
As soon as data is 
available during planned 
interim and/or final 
analysis
Partner
Durvalumab PK:  methods and 
validation
Xa
N/A
Partner
LY2510924 PK: results
(plasma/serum concentration and 
PK parameters)
X
As soon as data is 
available during planned 
interim and/or final 
analysis
Lilly
LY2510924 PK: methods and 
validation
Xa
N/A
Lilly
Abbreviations:  ADA = antidrug antibody; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; N/A = not applicable; PD-L1 = programmed cell death ligand 1; PK = pharmacokinetic; SDTM = Study 
Data Tabulation Model.  
a
In the event that the Regulatory Authorities require this information to be submitted along with the submission 
for Regulatory Approval for the use of the Lilly Compound in the Combination, Partner will provide this 
information directly to the Regulatory Authorities only for such purpose.


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Attachment 6.
Protocol CXAD Recommendations for 
Reporting Serious Adverse Events
Recommendations for Reporting Serious Adverse Events
When contacting Lilly to report a 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, relationship to study drug and protocol 
procedures.


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Attachment 7.
Protocol CXAD ECOG Performance Status
ECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able 
to carry out 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 CXAD Creatinine Clearance 
Formula
Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or 
by 24-hour urine collection for determination of creatinine clearance:
Males:
Creatinine CL 
(mL/min)
=
Weight (kg) x (140 – Age)       .
72 x serum creatinine (mg/dL)
Females:
Creatinine CL 
(mL/min)
=
Weight (kg) x (140 – Age)       x 0.85
72 x serum creatinine (mg/dL)
Source:  Cockcroft and Gault 1976.


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Attachment 9.
Protocol CXAD Bayesian Model-Based, 
Toxicity-Band Method for Phase 1a Dose Escalation
The need to minimize the number of patients treated below the biological active dose and the 
understanding of LY2510924 from earlier nonclinical and clinical studies supports a more 
efficient dose-escalation design for Study CXAD.  Therefore, the Bayesian model-based method 
is used in this trial to determine the next dose level, based on the predicted probabilities of dose-
limiting toxicity (DLT) rates.  The exact dose-escalation increment will be determined by the 
investigators in consultation with collaborator and Lilly CRP or designee 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 of CRM-Type Approaches
The Continual Reassessment Method (hereafter, 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 maximum 
tolerated dose (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 (EWOC) method 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 two-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, we
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 mayoccur in order to treat 
additional patients at intermediate doses below the MTD.
Dose Range and Reference Dose
Assuming that the starting dose level is20 mg,based on the preclinical data,the highest dose 
level that will be explored in this study is 40 mgand the reference dose in model (1.1) is chosen 
as  d∗=40 mg.


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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 ( , log ).  Based on preclinical experience of LY2510924, the prior 
median probability of DLT for the dose levels was determined as in Table App.1.Any 
intermediate dose level within the starting doses to 40 mgcan be explored.  
Table App.1. Prior Median Probability of Dose Limiting Toxicityat Each Dose Level
Dose (mg)
Median Probability of Dose Limiting Toxicity
10
0.06
20
0.12
30
0.18
40
0.26
For each dose, the minimally informative unimode 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 App.1 shows the median and the 95% confidence interval (CI)of the prior distribution of 
the DLT rate at each dose level.
Figure App.1.The prior distribution of the dose limiting toxicityrate at each dose level.
A bivariate normal distribution was derived on ( , log ) 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 ( , log ) have a bivariate normal distribution with mean=(-1.09,0.26), standard 
deviation=(2.17,0.51), and ρ=-0.89.


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Simulation Studies
We performed simulations 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 20 mg.

Maximum number of patients: 15 for toxicity-band method, and 15 for traditional 
3+3 method.

Rules for stopping early for toxicity-band method:  at least 6 patients have been 
treated at or near MTD or the probability of dose being in target band greater than
0.5 or at least 9 patients have been accrued.
Four scenarios were considered to represent a wide range of possible dose-toxicity relationships 
as shown in Figure App.2 and Table App.2.  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 20~33%
across scenarios.  Scenarios 1, 2 and 3 have MTD at 40 mg, and Scenario 4 has the MTD at 
30 mg.  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 App.2. The dose-toxicity relationships under each scenario.


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Table App.2.
The Dose-Toxicity Relationships
Dose (mg)
Scenarios
1
2
3
4
10
0.05
0.06
0.07
0.07
20
0.09
0.12
0.15
0.18
30
0.14
0.19
0.24
0.29
40
0.22
0.27
0.33
0.42
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 App.3.
Table App.3.
Comparison of Toxicity-Band and Traditional 3+3 Method
Abbreviations:  DLT = dose-limiting toxicity; MTD = maximum tolerated dose; Ph2 = Phase 2.
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 
underdosing 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 3+3 method, but strictly kept below the prespecified overdosing control 
criterion at 0.25.
Examples
Examples from Scenario 1 and Scenario 4 are provided here to illustrate how the toxicity-band 
method operates under certain circumstances.
Scenario 1
Scenario 2
Scenario 3
Scenario 4
Rate of Selected as MTD 
for Each Dose (mg/kg)
TB
3+3
TB
3+3
TB
3+3
TB
3+3
10 mg +durvalumab
0.064
0.087
0.121
0.14
0.196
0.175
0.253
0.24
20 mg + durvalumab
0.083
0.157
0.139
0.219
0.21
0.315
0.276
0.371
30 mg + durvalumab
0.164
0.227
0.194
0.276
0.22
0.265
0.249
0.262
40 mg + durvalumab
0.689
0.529
0.546
0.365
0.374
0.245
0.222
0.127
Rate of selecting Ph2 
Dose below true MTD
0.311
0.471
0.454
0.635
0.626
0.755
0.529
0.611
Rate of selecting Ph2 
Dose above true MTD
--
--
--
--
--
--
0.222
0.127
Rate of DLT events 
during the trial
0.164
0.165
0.199
0.211
0.240
0.259
0.270
0.302
Mean # Patients
14.5
10.4
14.1
10.1
13.6
9.6
13.2
9.0
Mean # Patients at true 
MTD
4.7
3.1
3.7
2.7
3.1
2.2
3.4
3.2


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Example 1
Scenario 2 has a true MTD at 40 mg with a DLT rate of 0.27 in Table App.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 40 mg after the 12th patient 
is treated (Figure App.3), although 2 DLTs are observed at 40 mg, and 40 mg will be declared as 
MTD after the 15th patient. The toxicity-band method is able to allocate more patients at the 
MTD dose level.
Figure App.3. A case study for Scenario 2.
Example 2
Scenario 4 has a true MTD at 30 mg with a DLT rate of 0.29 in Table App.2.  With a relatively 
steep 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 still 30 mg after the 9th 
patient is treated (Figure App.4), although 2 DLTs are observed at 30 mg, and 30 mg will be 
declared as MTD after the 15th patient, even though there are 3 DLTs observed. The 
toxicity-band method has also allocated more patients at the MTD dose level.


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Figure App.4. A case study for Scenario 4.
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 10.
Protocol CXAD RECIST Version 1.1
Response and progression will be evaluated in this study using the international criteria proposed 
by the New Response Evaluation Criteria in Solid Tumours (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 CT or MRI scan (slice thickness 5 mm) 

10-mm calliper measurement by clinical examination (nonmeasurable lesions if 
cannot be accurately measured with callipers)

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 nonmeasurable 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 examination that is not 
measurable by reproducible imaging techniques.
Special Considerations for Lesion Measurability
Bone Lesions:  

Bone scan, PET scan, or plain films are not considered adequate imaging 
techniques to measure bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI, can be considered measurable lesions if the soft tissue component 
meets the definition of measurability.

Blastic bone lesions are nonmeasurable.


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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 nonmeasurable unless there has been 
demonstrated progression in the lesion.  
Baseline Documentation of Target and Nontarget 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. Nonnodal 
target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and should be able to 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 CRF in millimeters (or 
decimal fractions of centimeters [cm]).
Nontarget Lesions
All other lesions (or sites of disease) are identified as nontarget lesions (chosen based on their 
representativeness of involved organs and the ability to be reproduced in repeated measurements) 
and should be recorded at baseline.  Measurement of these lesions are not required but should be 
followed as “present,” “absent,” or in rare cases “unequivocal progression.”  In addition, it is 
possible to record multiple nontarget lesions involving the same organ as a single item on the 
CRF (for example, multiple liver metastases recorded as 1 liver lesion).
Lymph nodes with short axis 10 mm but <15 mm should be considered nontarget lesions.  
Nodes that have a short axis <10 mm are considered nonpathological and are not recorded or 
followed.
Specifications by Methods of Measurement
All measurements should be recorded in metric notation, using a ruler or callipers 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 able to be assessed by clinical examination.  
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 enrolment 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 noncontrast 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 callipers (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 examination 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 from 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 1 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 CR 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 CR.  
Specific guidelines for both prostate-specific antigen response (in recurrent prostate cancer) and 
CA-125 response (in recurrent ovarian cancer) have been published.  
Cytology, Histology:  These techniques can be used to differentiate between PR and 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 


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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 SD in order to differentiate between response (or SD) and 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 CR or PR in target disease or when progression in bone is 
suspected.  
Response Criteria
Evaluation of Target Lesions
CR:  Disappearance of all target lesions.  Any pathological lymph nodes (whether target or 
nontarget) must have reduction in short axis to <10 mm.  Tumor marker results must have 
normalized.
PR:  At least a 30% decrease in the sum of diameter of target lesions, taking as reference the 
baseline sum diameters.
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 1 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.
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 Nontarget Lesions
Complete Response (CR):  Disappearance of all nontarget lesions and normalization of tumor
marker level.  All lymph nodes must be nonpathological or normal in size (<10-mm short axis).
Non-CR/Non-PD:  Persistence of 1 or more nontarget lesions and/or maintenance of tumor
marker level above the normal limits.


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PD:  Unequivocal progression of existing nontarget lesions.  The appearance of 1 or more new 
lesions is also considered progression.
Not Evaluable:  When a change in method of measurement from baseline occurs 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 nontarget disease and will also take into consideration the appearance 
of new lesions.  The best overall response will be calculated via an algorithm using the 
assessment responses provided by the investigator over the course of the trial.  
Time Point Response
It is assumed that at each protocol-specified time point, a response assessment occurs.  (When no 
imaging/measurement is conducted/made at all at a particular time point, the patient is not 
evaluable (NE) at that time point.)  Table App.4 provides a summary of the overall response 
status calculation at each time point for patients who have measurable disease at baseline.
Table App.4.
Time Point Response:  Patients with Target (Nontarget) Disease
Target Lesions
Nontarget 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 App.5 is to be used when patients have nonmeasurable disease only.
Table App.5.
Time Point Response:  Patients with Nontarget Disease Only
Nontarget 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; PD = progressive disease; NE = not evaluable.
a
non-CR/non-PD is preferred over SD for nontarget disease.  


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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 to 8 weeks is 
reasonable.  Normally, all target and nontarget sites are evaluated at each assessment using the 
same method.  However, bone scans may need to be repeated only when CR is identified in 
target disease or when progression in bone is suspected.  
Confirmatory Measurement/Duration of Response
Confirmation:
The main goal of confirmation of objective response in clinical trials is to avoid overestimating 
the response rate observed.  The confirmation of response is particularly important in 
nonrandomized trials where response (CR/PR) is the primary end point.  In this setting, to be 
assigned a status of PR/CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first 
met.  To confirm a response of CR, a full assessment of all target and nontarget lesions that were 
present at baseline must occur, including those measured by bone scan.  To confirm a PR or SD, 
a full assessment of target lesions that were present at baseline must occur; assessment of 
nontarget lesions 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).
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).  


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Independent Review of Response and Progression
When objective response (CR + PR) is the primary end point, and when key drug development 
decisions are based on the observation of a minimum number of responders, it is recommended 
that all claimed responses be reviewed by an expert(s) independent of the study.  If the study is a 
randomized trial, ideally reviewers should be blinded to treatment assignment.  


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Attachment 11.
Protocol CXAD Durvalumab Monotherapy 
Dosing Modification and Toxicity Management Guidelines 
for Immune-Mediated, Infusion-Related, and Non-Immune–
Mediated Reactions


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Pneumonitis
AEs of pneumonitis are of interest as pneumonitis has been reported with anti-PD-1 mAbs 
(Topalian et al. 2012).  Initial work-up should include high-resolution CT scan, ruling out 
infection, and pulse oximetry.  Pulmonary consultation is highly recommended.  
Guidelines for the management of patients with immune-mediated events including pneumonitis 
are outlined in the table below.
Infusion-Related Reactions
All infusion-related reactions occurring from the start of durvalumab infusion up to 48 hours 
after the infusion start time are considered AESIs. All infusion reactions are to be considered 
SAEs and should be reported as per the SAE reporting guidelines described in Section 8.1.2.6.  
Based on the mechanism of action of durvalumab leading to T-cell activation and proliferation, 
there is the possibility of observing immune-related AEs during the conduct of this study.  
Potential immune-related AEs include immune-mediated enterocolitis, dermatitis, hepatitis, and 
endocrinopathies.  Patients should be monitored for signs and symptoms of immune-related AEs.  
In the absence of an alternative etiology (eg, infection or PD) signs or symptoms of enterocolitis, 
dermatitis, hepatitis, and endocrinopathy should be considered to be immune-related.  
All AEs of possible infusion reactions are to be reported as IRRs, if occurring from the start of 
durvalumab infusion up to 48 hours after the infusion start time.
Hypersensitivity Reactions
Hypersensitivity reactions as well as infusion-related reactions have been reported with anti-PD-
L1 and anti-PD-1 therapy (Brahmer et al. 2012).  As with the administration of any foreign 
protein and/or other biologic agents, reactions following the infusion of mAbs can be caused by 
various mechanisms, including acute anaphylactic (immunoglobulin E-mediated) and 
anaphylactoid reactions against the mAb, and serum sickness.  Acute allergic reactions may 
occur, may be severe, and may result in death.  Acute allergic reactions may include 
hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, hypotonia, 
arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, hypertension, myalgia, 
vomiting and unresponsiveness.
Guidelines for management of patients with hypersensitivity (including anaphylactic reaction) 
and infusion-related reactions are outlined in the table below.
Hepatic Function Abnormalities (Hepatotoxicity)
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 
antibodies (Brahmer et al. 2012).  Inflammatory hepatitis has been reported in 3% to 9% of 
patients treated with anti-CTLA-4 monoclonal antibodies (eg, ipilimumab).  The clinical 
manifestations of ipilimumab-treated patients included general weakness, fatigue, nausea and/or 
mild fever and increased liver function tests such as AST, ALT, alkaline phosphatase, and/or 
total bilirubin.


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Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3x ULN 
and concurrent increase in total bilirubin to be greater than 2x ULN.  Concurrent findings are 
those that derive from a single blood draw or from separate blood draws taken within 8 days of 
each other.  Follow-up investigations and inquiries will be initiated promptly by the 
investigational site to determine whether the findings are reproducible and/or whether there is 
objective evidence that clearly supports causation by a disease (eg, cholelithiasis and bile duct 
obstruction with distended gallbladder) or an agent other than the investigational product.  
Guidelines for management of patients with hepatic function abnormality are outlined in the 
table below.
Cases where a patient shows an AST or ALT ≥3x ULN or total bilirubin ≥2xULN may need to 
be reported as SAEs.  These cases should be reported as SAEs if, after evaluation they meet the 
criteria for a Hy’s Law case or if any of the individual liver test parameters fulfill any of the SAE 
criteria.
Criteria for Hy’s Law (FDA 2009)

The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control drug 
or placebo 

Among study patients showing such aminotransferase elevations, often with 
aminotransferases much >3x ULN, one or more also show elevation of serum total 
bilirubin to >2x ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 

No other reason can be found to explain the combination of increased aminotransferases 
and total bilirubin, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or 
another drug capable of causing the observed injury.
Hepatic function abnormality
Hepatic function abnormality in a study patient, with or without associated clinical 
manifestations, is required to be reported as “hepatic function abnormal” within 24 hours of 
knowledge of the event to the sponsor, unless a definitive underlying diagnosis for the 
abnormality (eg, cholelithiasis or bile duct obstruction) that is unrelated to investigational 
product has been confirmed.

If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study patient 
will be based on the clinical judgment of the investigator.

If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study patient must be interrupted immediately.  Follow-up investigations and inquiries 
must be initiated by the investigational site without delay.
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by Lilly and collaborator.  


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Cardiovascular Disorders
For all cardiovascular AEs, CTCAE Grades 1 to 4, the investigator should consider consultation 
with a cardiologist experienced in the management of the specific AE being evaluated.
Gastrointestinal Disorders
Diarrhea/colitis is the most commonly observed treatment-emergent SAE when durvalumab is 
used as monotherapy.  In rare cases, colon perforation may occur that requires surgery 
(colectomy) or can lead to a fatal outcome if not properly managed.  Guidelines on management 
of diarrhea and colitis in patients receiving durvalumab are provided in the table below.
Endocrine Disorders
Immune-mediated endocrinopathies include hypophysitis, adrenal insufficiency, and hyper- and 
hypothyroidism.  Guidelines for the management of patients with immune-mediated endocrine 
events are provided in the table below.
Pancreatic Disorders
Immune-mediated pancreatitis includes autoimmune pancreatitis, and lipase and amylase 
elevation.  Guidelines for the management of patients with immune-mediated pancreatic 
disorders are provided in the table below.
Neurotoxicity
Immune-mediated nervous system events include encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis.  Guidelines for the management of patients 
with immune-mediated neurotoxic events are provided in the table below.
Nephritis
Consult with nephrologist.  Monitor for signs and symptoms that may be related to changes in 
renal function (eg, routine urinalysis, elevated serum blood urea nitrogen and creatinine, 
decreased creatinine clearance, electrolyte imbalance, decrease in urine output, proteinuria, etc).  
Patients should be thoroughly evaluated to rule out any alternative etiology (eg, disease 
progression, infections).
Steroids should be considered in the absence of clear alternative etiology even for low grade 
events (Grade 2), in order to prevent potential progression to higher grade event.  Guidelines for 
the management of patients with immune-mediated neurotoxic events are provided in the table 
below.


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MEDI4736 Monotherapy Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion Related, 
and Non Immune-Mediated Reactions - 19 August 2016 Version
1(17) 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation of study drug/study regimen 
based on CTC grade/severity (table below), permanently discontinue study 
drug/study regimen for the following conditions: 
•
Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per
day (or equivalent) within 12 weeks after last dose of study drug/study
regimen
•
Recurrence of a previously experienced Grade 3 treatment-related AE
following resumption of dosing
Grade 1 
Grade 2 
No dose modification 
Hold study drug/study regimen dose until Grade 2 resolution to 
Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
Study drug/study regimen can be resumed once event stabilizes to 
Grade ≤1 after completion of steroid taper. 
Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study drug/study 
regimen on the following conditions: 
1.
The event stabilizes and is controlled.
2.
The patient is clinically stable as per Investigator or treating
physician’s clinical judgement.
3.
Doses of prednisone are at ≤10 mg/day or equivalent.
Grade 3 
Depending on the individual toxicity, study drug/study regimen may 
be permanently discontinued. Please refer to guidelines below. 
Grade 4 
Permanently discontinue study drug/study regimen. 
Note: For Grade ≥3 asymptomatic amylase or lipase levels, hold study drug/study 
regimen, and if complete work up shows no evidence of pancreatitis, study 
drug/study regimen may be continued or resumed. 
Note: For Grade 3 and above asymptomatic amylase or lipase levels hold study 
drug/regimen and if complete work up shows no evidence of pancreatitis, may 
continue or resume study drug/regimen 
It is recommended that management of irAEs follows the guidelines presented in this 
table: 
− 
Patients should be thoroughly evaluated to rule out any alternative etiology 
(eg, disease progression, concomitant medications, and infections). 
− 
In the absence of a clear alternative etiology, all events should be considered 
potentially immune related. 
− 
Symptomatic and topical therapy should be considered for low-grade (Grade 1 
or 2, unless otherwise specified) events. 
− 
For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) events, 
promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If symptoms recur or worsen during corticosteroid tapering (28 days of taper), 
increase the corticosteroid dose (prednisone dose [eg, up to 2 to 4 mg/kg/day 
PO or IV equivalent]) until stabilization or improvement of symptoms, then 
resume corticosteroid tapering at a slower rate (>28 days of taper). 
− 
More potent immunosuppressives such as TNF inhibitors (eg, infliximab) 
(also refer to the individual sections of the irAE for specific type of 
immunosuppressive) should be considered for events not responding to 
systemic steroids. 
− 
Discontinuation of study drug/study regimen is not mandated for Grade 
3/Grade 4 inflammatory reactions attributed to local tumor response 
(eg, inflammatory reaction at sites of metastatic disease and lymph nodes). 
Continuation of study drug/study regimen in this situation should be based 
upon a benefit/risk analysis for that patient. 
AE  Adverse event; CTC  Common Toxicity Criteria; CTCAE  Common Terminology Criteria for Adverse Events; irAE  Immune-related adverse event; IV  intravenous; 
NCI  National Cancer Institute; PO  By mouth. 


Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Pneumonitis/ILD 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures as 
described below. 
− 
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up, and high- resolution CT scan. 
Grade 1 
(asymptomatic, clinical 
or diagnostic 
observations only; 
intervention not 
indicated) 
No dose modifications required. However, 
consider holding study drug/study 
regimen dose as clinically appropriate and 
during diagnostic work-up for other 
etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated. 
− 
Consider pulmonary and infectious disease consult. 
Grade 2 
(symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL) 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. 
For Grade 2 (mild to moderate new symptoms): 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Promptly start systemic steroids (eg, prednisone 1 to 
2 mg/kg/day PO or IV equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started 
− 
If still no improvement within 3 to 5 days despite IV 
methylprednisone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections (Category 2B 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
recommendation)a 
− 
Consider pulmonary and infectious disease consult. 
− 
Consider, as necessary, discussing with study physician. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; limiting 
self-care ADL; oxygen 
indicated) 
 
(Grade 4: life-
threatening respiratory 
compromise; urgent 
intervention indicated 
[eg, tracheostomy or 
intubation]) 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, 
life-threatening): 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Obtain pulmonary and infectious disease consult. 
− 
Hospitalize the patient. 
− 
Supportive care (eg, oxygen). 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 2 weeks dose) started. 
Caution: rule out sepsis and refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patients is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and, in particular, anti-PCP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections 
(Category 2B recommendation).a 
Diarrhea/Enterocolitis 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes in 
bowel habits such as increased frequency over baseline or 
blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs, and ileus). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, other medications, 
or infections), including testing for clostridium difficile toxin, 
etc. 
− 
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
prevent potential progression to higher grade event. 
− 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
Grade 1 
(stool frequency of 
<4 over baseline per 
day) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, American Dietetic 
Association colitis diet), and loperamide. Use probiotics as per 
treating physician’s clinical judgment. 
Grade 2 
(stool frequency of 4 to 
6 over baseline per day) 
Hold study drug/study regimen until 
resolution to Grade ≤1 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then study drug/study regimen can be 
resumed after completion of steroid 
taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, American Dietetic 
Association colitis diet), and loperamide and/or budesonide. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, GI consult 
should be obtained for consideration of further workup, such as 
imaging and/or colonoscopy, to confirm colitis and rule out 
perforation, and prompt treatment with IV methylprednisolone 
2 to 4 mg/kg/day started. 
− 
If still no improvement within 3 to 5 days despite 2 to 4 mg/kg 
IV methylprednisolone, promptly start immunosuppressives 
such as infliximab at 5 mg/kg once every 2 weeksa. Caution: it 
is important to rule out bowel perforation and refer to 
infliximab label for general guidance before using infliximab. 
− 
Consult study physician if no resolution to Grade ≤1 in 3 to 
4 days. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Grade 3 or 4 
(Grade 3: stool 
frequency of ≥7 over 
baseline per day; 
 
Grade 4: life 
threatening 
consequences) 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
− 
Monitor stool frequency and volume and maintain hydration. 
− 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (eg infliximab at 5 mg/kg 
once every 2 weeks). Caution: Ensure GI consult to rule out 
bowel perforation and refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Hepatitis (elevated 
LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB. 
− 
Evaluate for alternative etiologies (eg, viral hepatitis, disease 
progression, concomitant medications). 
Grade 1 
AST or ALT > to 3 × 
ULN and/or TB > to 
1.5 × ULN) 
No dose modifications. 
• 
If it worsens, then treat as Grade 2 
event. 
For Grade 1: 
− 
Continue LFT monitoring per protocol. 
Grade 2 
(AST or ALT > 3 to 5 × 
ULN and/or TB >1.5 to 
3.0 × ULN) 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
For Grade 2: 
− 
Regular and frequent checking of LFTs (eg, every 1 to 2 days) 
until elevations of these are improving or resolved. 
− 
If no resolution to Grade ≤1 in 1 to 2 days, discuss with study 
physician. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
regimen after completion of steroid 
taper. 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (mycophenolate mofetil)a Discuss with 
study physician if mycophenolate mofetil is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
Grade 3 or 4 
(Grade 3: AST or ALT 
>5 to 20 × ULN and/or 
TB >3.0 to 10 × ULN) 
 
(Grade 4: AST or ALT 
>20 × ULN and/or TB 
>10 × ULN) 
For Grade 3: 
For elevations in transaminases 
≤8 × ULN, or elevations in bilirubin 
≤5 × ULN: 
• Hold study drug/study regimen dose 
until resolution to Grade ≤1 or 
baseline 
• Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 or 
baseline within 14 days and after 
completion of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade ≤1 or 
baseline within 14 days 
For elevations in transaminases >8 × ULN 
or elevations in bilirubin >5 × ULN, 
discontinue study drug/study regimen. 
Permanently discontinue study drug/study 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy 
(mycophenolate mofetil). Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used. 
− 
Perform hepatology consult, abdominal workup, and imaging 
as appropriate. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
regimen for any case meeting Hy’s law 
criteria (AST and/or ALT >3 × ULN + 
bilirubin >2 × ULN without initial 
findings of cholestasis (ie, elevated 
alkaline P04) and in the absence of any 
alternative cause.b 
 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor for signs and symptoms that may be related to changes 
in renal function (eg, routine urinalysis, elevated serum BUN 
and creatinine, decreased creatinine clearance, electrolyte 
imbalance, decrease in urine output, or proteinuria). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression or infections). 
− 
Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2), in 
order to prevent potential progression to higher grade event. 
Grade 1 
(Serum creatinine > 1 
to 1.5 × baseline; > 
ULN to 1.5 × ULN) 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly and any accompanying 
symptoms. 
• 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
• 
If creatinine worsens, depending on the severity, treat 
as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
Grade 2 
(serum creatinine >1.5 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline.  
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
to 3.0 × baseline; >1.5 
to 3.0 × ULN) 
• 
If toxicity worsens, then treat as 
Grade 3 or 4. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume study 
drug/study regimen after completion 
of steroid taper. 
electrolyte replacement, and diuretics. 
− 
Carefully monitor serum creatinine every 2 to 3 days and as 
clinically warranted. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone at 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4 
(Grade 3: serum 
creatinine 
>3.0 × baseline; >3.0 to 
6.0 × ULN; 
 
Grade 4: serum 
creatinine >6.0 × ULN) 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine on daily basis. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Rash 
(excluding bullous skin 
formations) 
Any Grade 
(refer to NCI CTCAE 
v 4.03 for definition of 
severity/grade 
depending on type of 
skin rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of dermatitis (rash and 
pruritus). 
− 
IF THERE IS ANY BULLOUS FORMATION, THE STUDY 
PHYSICIAN SHOULD BE CONTACTED AND STUDY 
DRUG DISCONTINUED. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, including oral antipruritics 
(eg, diphenhydramine or hydroxyzine) and topical therapy 
(eg, urea cream). 
Grade 2 
For persistent (>1 to 2 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to Grade ≤1 or 
baseline. 
• 
If toxicity worsens, then treat as 
Grade 3. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper. 
For Grade 2: 
− 
Obtain dermatology consult. 
− 
Consider symptomatic treatment, including oral antipruritics 
(eg, diphenhydramine or hydroxyzine) and topical therapy 
(eg, urea cream). 
− 
Consider moderate-strength topical steroid. 
− 
If no improvement of rash/skin lesions occurs within 3 to 
5 days or is worsening despite symptomatic treatment and/or 
use of moderate strength topical steroid, discuss with study 
physician and promptly start systemic steroids such as 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
Consider skin biopsy if the event is persistent for >1 to 2 weeks 
or recurs. 
 
 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
Grade ≤1 or baseline within 30 days, then 
permanently discontinue study drug/study 
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Consider skin biopsy (preferably more than 1) as clinically 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
regimen. 
 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
feasible. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
Discuss with study physician. 
Endocrinopathy 
(eg, hyperthyroidism, 
hypothyroidism, 
hypopituitarism, and 
adrenal insufficiency) 
Any Grade 
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
v4.03 for defining the 
CTC grade/severity) 
General Guidance 
For Any Grade: 
− 
Consult endocrinologist. 
− 
Monitor patients for signs and symptoms of endocrinopathies. 
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, hypotension, and weakness. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression including brain 
metastases, or infections). 
− 
Monitor and evaluate thyroid function tests: TSH, free T3 and 
free T4 and other relevant endocrine labs depending on 
suspected endocrinopathy. 
− 
If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (eg, thyroiditis, pancreatitis, hypophysitis, 
or diabetes insipidus), the investigator should send a blood 
sample for appropriate autoimmune antibody testing. 
 
Grade  1 
No dose modifications. 
For Grade 1 (including those with asymptomatic TSH elevation): 
− 
Monitor patient with appropriate endocrine function tests. 
− 
If TSH < 0.5 × LLN, or TSH >2 × ULN or consistently out of 
range in 2 subsequent measurements, include free T4 at 
subsequent cycles as clinically indicated and consider 
endocrinology consult. 
Grade 2 
For Grade 2 endocrinopathy other than 
hypothyroidism, hold study drug/study 
regimen dose until patient is clinically 
For Grade 2 (including those with symptomatic endocrinopathy): 
− 
Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
stable. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement can be retreated with study 
drug/study regimen on the following 
conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement. 
3. 
Doses of prednisone are ≤10 mg/day 
or equivalent. 
corticosteroids. 
− 
Initiate hormone replacement as needed for management. 
− 
Evaluate endocrine function, and as clinically indicated, 
consider pituitary scan. 
− 
For patients with abnormal endocrine work up, except for those 
with isolated hypothyroidism, consider short-term 
corticosteroids (eg, 1 to 2 mg/kg/day methylprednisolone or IV 
equivalent) and prompt initiation of treatment with relevant 
hormone replacement (eg, levothyroxine, hydrocortisone, or 
sex hormones). - 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
− 
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory assessments/MRI 
as clinically indicated. 
Grade 3 or 4 
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism, hold study 
drug/study regimen dose until 
endocrinopathy symptom(s) are 
controlled.  
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper. 
For Grade 3 or 4: 
− 
Consult endocrinologist. 
− 
Isolated hypothyroidism may be treated with replacement 
therapy without treatment interruption and without 
corticosteroids. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent 
− 
Administer hormone replacement therapy as necessary. 
− 
For adrenal crisis, severe dehydration, hypotension, or shock, 
immediately initiate IV corticosteroids with mineralocorticoid 
activity. 
− 
Once the patient is improving, gradually taper 
immunosuppressive steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment 
(refer to current NCCN guidelines for treatment of cancer-
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
related infections [Category 2B recommendation]).a 
− 
Discuss with study physician. 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre) 
Any Grade 
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v4.03 
for defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule out any alternative etiology 
(eg, disease progression, infections, metabolic syndromes, or 
medications). 
− 
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness). 
− 
Consider appropriate diagnostic testing (eg, electromyogram 
and nerve conduction investigations). 
− 
Perform symptomatic treatment with neurological consult as 
appropriate. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations above. 
Grade 2 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to Grade ≤1. 
For sensory neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to Grade ≤1. 
If toxicity worsens, then treat as 
Grade 3 or 4. 
Study drug/study regimen can be resumed 
once event improves to Grade ≤1 and 
after completion of steroid taper. 
For Grade 2: 
− 
Discuss with the study physician. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg, gabapentin or duloxetine). 
− 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 2 mg/kg/day 
prednisone PO or IV equivalent, consider additional workup 
and promptly treat with additional immunosuppressive therapy 
(eg, IV IG). 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 irAE does not resolve 
to Grade ≤1 within 30 days. 
For Grade 3 or 4: 
− 
Discuss with study physician. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
2 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and promptly treat 
with additional immunosuppressants (eg, IV IG). 
− 
Once stable, gradually taper steroids over ≥28 days. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients may 
unpredictably experience acute decompensations that can result 
in substantial morbidity or in the worst case, death. Special care 
should be taken for certain sentinel symptoms that may predict 
a more severe outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory insufficiency or 
autonomic instability. 
− 
Patients should be evaluated to rule out any alternative etiology 
(eg, disease progression, infections, metabolic syndromes or 
medications). It should be noted that the diagnosis of immune-
mediated peripheral neuromotor syndromes can be particularly 
challenging in patients with underlying cancer, due to the 
multiple potential confounding effects of cancer (and its 
treatments) throughout the neuraxis. Given the importance of 
prompt and accurate diagnosis, it is essential to have a low 
threshold to obtain a neurological consult. 
− 
Neurophysiologic diagnostic testing (eg, electromyogram and 
nerve conduction investigations, and “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated upon suspicion 
of such conditions and may be best facilitated by means of a 
neurology consultation. 
− 
It is important to consider that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered 
effective. Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive to IV IG. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Discuss with the study physician. 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
− 
Care should be taken to monitor patients for sentinel symptoms 
of a potential decompensation as described above. 
− 
Obtain a neurology consult unless the symptoms are very 
minor and stable. 
Grade 2 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if it does not resolve to Grade ≤1 
within 30 days or if there are signs of 
respiratory insufficiency or autonomic 
instability. 
For Grade 2: 
− 
Discuss with the study physician. 
− 
Care should be taken to monitor patients for sentinel symptoms 
of a potential decompensation as described above. 
− 
Obtain a neurology consult 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (eg, gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat myasthenia 
gravis. It is important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 
administered in a monitored setting under supervision 
of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG. Such 
decisions are best made in consultation with a 
neurologist, taking into account the unique needs of 
each patient. 
o 
If myasthenia gravis-like neurotoxicity is present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective. 
o 
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
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Specific Immune-mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
to IV IG. 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 irAE does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency or 
autonomic instability. 
 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Discuss with study physician. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain neurological consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat myasthenia 
gravis. They should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG. 
o 
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis. 
 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective. 
o 
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG. 
a 
ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
b 
FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE  Acetylcholine esterase; ADL  Activities of daily living; AE  Adverse event; ALP  Alkaline phosphatase test; ALT  Alanine aminotransferase; AST  Aspartate 
aminotransferase; BUN  Blood urea nitrogen; CT  Computed tomography; CTCAE  Common Terminology Criteria for Adverse Events; ILD  Interstitial lung disease; 
irAE  Immune-related adverse event; IG  Immunoglobulin; IV  Intravenous; GI  Gastrointestinal; LFT  Liver function tests; LLN  Lower limit of normal; MRI  Magnetic 
resonance imaging; NCI  National Cancer Institute; NCCN  National Comprehensive Cancer Network; PCP ; PO  By mouth; T3  Triiodothyronine; T4  Thyroxine; 
TB  Total bilirubin; TNF  Tumor necrosis factor; TSH  Thyroid-stimulating hormone; ULN  Upper limit of normal. 
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Infusion-related Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the discretion of investigator. 
− 
Monitor patients for signs and symptoms of infusion-related 
reactions (eg, fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (eg, generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the event. 
 
For Grade 2: 
The infusion rate of study drug/study regimen may be decreased 
50% or temporarily interrupted until resolution of the event. 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator. 
− 
Consider premedication per institutional standard prior to 
subsequent doses. 
− 
Steroids should not be used for routine premedication of Grade ≤2 
infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per institutional 
standards (eg, IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid). 
CTCAE  Common Terminology Criteria for Adverse Events; IM  Intramuscular; IV  Intravenous; NCI  National Cancer Institute. 
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Non-immune-mediated Reactions 
Severity Grade of the Event 
(NCI CTCAE version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (ie, events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to 
≤Grade 1 or baseline within 14 days, resume study drug/study 
regimen administration.  Otherwise, discontinue study drug/study 
regimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the Sponsor.). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.” 
AE  Adverse event; CTCAE  Common Terminology Criteria for Adverse Events; NCI  National Cancer Institute. 
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Attachment 12.
Protocol CXAD Echocardiographic 
Guidelines


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Echocardiography (ECHO)
In this study, ECHO images will be acquired to screen patients for eligibility to enter the study,
ie, baseline normal cardiac structure and function, normal pulmonary artery pressure, and 
absence of significant valvular disease (defined herein as no valvular regurgitation except for 
mild tricuspid, mild mitral, or mild aortic regurgitation, and no more than mild mitral or aortic 
valvular stenosis).  ECHO should also be performed if clinically indicated in the opinion of the 
investigator to manage any cardiovascular or cardiopulmonary AEs. Determination of normalcy 
status requires objective evaluation of cardiac chamber size and function and attention to the use 
of appropriate techniques in the performance of the ECHO examinations, in particular the use of 
standardized settings during the acquisitions of color flow Doppler imaging.  Therefore, because 
quantitative ECHO is the goal, stringent criteria for image quality and reproducibility are 
essential.
In addition to qualitative assessment of valvular regurgitation when or if detected (trace, mild, 
moderate, or severe according to Singh et al. 1999 and Zoghbi et al. 2003) and 
qualitative/quantitative assessment of valvular stenosis when or if detected (mild, moderate, or 
severe, using mean and peak pressure gradient in mm Hg and orifice area in cm2 as applicable), 
other ECHO parameters to be serially quantified are LV cavity size (diameters, volumes), LVEF, 
LV mass and mass index, diastolic function based on mitral flow velocity, mitral deceleration 
time, pulmonary venous flow pattern, tissue Doppler, extrapolation of LV end-diastolic pressure 
by E/Em, left atrial volume index, and extrapolation of pulmonary artery systolic pressure when 
obtainable.  
An ECHO with no clinically significant abnormalities is one defined specifically as one in which
the LV (Schiller et al. 1989) internal dimension in diastole should be 2.8 cm/m2, the left atrial 
(Tsang et al. 2002) end-systolic volume should be 36 mL/m2, the LVEF (Oh et al. 2006) should 
be 50% without regional wall motion abnormalities, 2-dimensional ECHO-derived LV mass 
index should be 115 g/m2 for males and 99 g/m2 for females, the pulmonary artery pressure 
should be normal (tricuspid regurgitation jet velocity 2.5 m/s and/or pulmonary valve flow 
acceleration time 120 ms), the LV diastolic function (Khouri et al. 2004) should be normal 
(screening:  mitral deceleration time 150 ms and 250 ms, mitral E/A ratio 0.75 and 1.5, 
mitral E velocity divided by Doppler mitral annular velocity [E/Em] <15), and no evidence for 
pericardial or congenital heart disease.  In addition, there should be no evidence for more than 
mild mitral or aortic stenosis (mitral valve area should be >2.0 cm2, and aortic valve area should 
be >1.5 cm2) and no evidence of more than mild mitral or aortic regurgitation (Singh et al. 1999; 
Zoghbi et al. 2003).  Patients enrolled in the study may have evidence for tricuspid (trace or 
mild), pulmonary, mitral (trace or mild), or aortic (trace or mild) regurgitation by Doppler 
techniques (Singh et al. 1999; Zoghbi et al. 2003).
References
Khouri SJ, Maly GT, Suh DD, Walsh TE. A practical approach to the echocardiographic 
evaluation of diastolic function. J Am Soc Echocardiogr. 2004;17(3):290-297.


I2V-MC-CXAD(b) Phase 1 Oncology Protocol
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Oh JK, Seward JB, Tajik AJ. The echo manual. 3rd ed. Philadelphia: Lippincott, Williams & 
Wilkins; 2006.
Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, 
Reicheck N, Sahn D, Schnittger I, Silverman NH, Tajik AJ. Recommendations for quantitation 
of the left ventricle by two-dimensional echocardiography: American Society of 
Echocardiography Committee on Standards, Subcommittee on Quantitation of 
Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2(5):358-367.
Singh JP, Evans JC, Levy D, Larson MG, Freed LA, Fuller DL, Lehman B, Benjamin EJ. 
Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the 
Framingham Heart Study). Am J Cardiol. 1999;83(6):897-902.
Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as 
morphophysiologic expression of left ventricular diastolic dysfunction and relation to 
cardiovascular risk burden. Am J Cardiol. 2002;90(12):1284-1289.
Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Craft CD, Levine RA, 
Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski H, Stewart WJ, Waggoner A, 
Weissman NJ; American Society of Echocardiography. Recommendations for evaluation of 
the severity of native valvular regurgitation with two-dimensional and Doppler 
echocardiography. J Am Soc Echocardiogr. 2003;16(7):777-802.


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Appendix:  Qualitative and Quantitative Parameters for Grading Valvular 
(Mitral and Aortic) Regurgitation Severity
Please refer to references below for information on qualitative and quantitative parameters for 
grading valvular (mitral and aortic) regurgitation severity.
Singh JP, Evans JC, Levy D, Larson MG, Freed LA, Fuller DL, Lehman B, Benjamin EJ. 
Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the 
Framingham Heart Study). Am J Cardiol. 1999;83(6):897-902.
Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Craft CD, Levine RA, 
Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski H, Stewart WJ, Waggoner A, 
Weissman NJ; American Society of Echocardiography. Recommendations for evaluation of 
the severity of native valvular regurgitation with two-dimensional and Doppler 
echocardiography. J Am Soc Echocardiogr. 2003;16(7):777-802.
References
Henson JW, Ulmer S, Harris GJ. Brain tumor imaging in clinical trials. AJNR Am J Neuroradiol.
2008:29(3):419-424.
Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, 
Camphausen K, Park J, Albert PS, Fine HA. Phase II trial of single-agent bevacizumab 
followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J 
Clin Oncol. 2009;27(5):740-745.
Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell.
2003;113(6):685-700.
Sorensen AG, Batchelor TT, Wen PY, Zhang WT, Jain RK. Response criteria for glioma. Nat 
Clin Pract Oncol. 2008;5(11):634-644.
Sorensen AG, Patel S, Harmath C, Bridges S, Synnott J, Sievers A, Yoon YH, Lee EJ, Yang 
MC, Lewis RF, Harris GJ, Lev M, Schaefer PW, Buchbinder BR, Barest G, Yamada K, Ponzo 
J, Kwon HY, Gemmete J, Farkas J, Tievsky AL, Ziegler RB, Salhus MR, Weisskoff R. 
Comparison of diameter and perimeter methods for tumor volume calculation. J Clin Oncol.
2001;19(2):551-557.
Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub 
T, Mesirov JP, Alexe G, Lawrence M, O'Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler 
W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, 
Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN, 
Cancer Genome Atlas Research Network. Integrated genomic analysis identifies clinically 
relevant subtypes of glioblastoma characterised by abnormalities in PDGFRA, IDH1, EGFR, 
and NF1. Cancer Cell. 2010;17(1):98-110.
Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason 
W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Phase III study of 
enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J 
Clin Oncol. 2010;28(7):1168-1174.


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Wong ET, Gautam S, Malchow C, Lun M, Pan E, Brem S. Bevacizumab for recurrent 
glioblastoma multiforme: a meta-analysis. J Natl Compr Canc Netw. 2011;9(4):403-407.


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Attachment 13.
Protocol CXAD
Protocol Amendment I2V-MC-CXAD(b) Summary
A Phase 1a/1b Study of CXCR4 Peptide Antagonist 
(LY2510924) Administered in Combination with the 
Anti-PD-L1 Antibody, Durvalumab (MEDI4736), in 
Advanced Refractory Solid Tumors
Overview
Protocol I2V-MC-CXAD A Phase 1a/1b Study of CXCR4 Peptide Antagonist (LY2510924) 
Administered in Combination with the AntiPD-L1 Antibody, Durvalumab (MEDI4736), in 
Advanced Refractory Solid Tumors has been amended.  The new protocol is indicated by 
Amendment (b) and will be used to conduct the study in place of any preceding version of the 
protocol.
The I2V-MC-CXAD protocol (a) was amended to make the following changes:  

Section 5.5.2.4:  Clinical safety information on durvalumab updated.

Section 6.1.3: Exclusion Criterion [16] expanded to include previous participation in any
randomized controlled trial that included arms with an anti-PD-1, anti-PD-L1, anti-
PD-L2, or anti-cytotoxic T lymphocyte-associated antigen-4 antibody or any other
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways such
as CD137, GITR, TIM-3, and LAG3, rather than only either durvalumab or
tremelimumab.

Synopsis and Section 6.2:  Clarified that patients will be allowed to continue until they
fulfill 1 or more of the study discontinuation criteria.

Sections 6.2 and 8.3.1.2: Clarified that patients will not be permitted to continue study
therapy if progression occurs after confirmed response.

Section 7.2.2.1: Added or modified existing DLT criteria to:
o
Grade 3 leukocytosis (leukocytes >100,000/µL) of any duration, or
leukocytosis/granulocytosis causing clinical symptoms
o
Any Grade 4 non-laboratory AE
o
Any Grade 3 laboratory value, and modified stipulations that the abnormal value
must be associated with clinically significant symptoms and persist for >7 days
o
Any Grade 4 laboratory abnormalities

Section 7.2.2.2:  For Phase 1a, any DLT-equivalent toxicities observed in Cycle 2 and
beyond will also be considered in dose escalation and determining MTD/recommended
Phase 2 dose.  Additionally, if the DLT observation period is extended to Cycle 2,
patients discontinuing in Cycle 2 in the absence of DLT-equivalent toxicity will be
evaluable for DLT assessments.


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
Section 7.2.4:  Wording added that for Phase 1a and 1b, the DLT observation period will
be extended to Cycle 2 if a DLT-equivalent toxicity is observed during Cycle 2 in any
cohort in Phase 1a.

Table CXAD.7.2: Dose adjustment of LY2510924 to align with newly added DLT
criterion for leukocytosis.

Section 8.1.3.1:  Typographical error was corrected.

Section 8.3.1.2:  Patients with a decline in Eastern Cooperative Oncology Group (ECOG)
performance status >1 will not be permitted to continue study treatment after confirmed
progression of disease.

Section 10.10:  Wording added that if the DLT-observation period is extended to 2 cycles
during Phase 1a, analysis will include DLT-equivalent toxicities occurring in Cycle 2.

Attachment 1 and Attachment 4: Correction: For Serum, Plasma, and Whole Blood
Samples for Biomarkers, baseline whole blood samples must be collected ≤7 days prior
to Cycle 1 Day 1.

Attachment 4:  Correction: immunogenicity samples will be collected 90 days post
durvalumab treatment.

Attachment 11: Durvalumab dose modification guidelines have been updated.
A detailed list of changes made in this amendment is below. Some minor editorial changes may 
not be listed.


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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.
2.
Synopsis
...
Planned Duration of Treatment:  6 months or Patients will receive study therapy until the patient fulfills 1one of 
the criteria for study discontinuation.  Patients demonstrating a benefit from treatment may continue on combination 
therapy beyond initial radiological disease progression in the absence of clinically significant deterioration. 6 months 
if the patient and investigator feel that the patient is benefiting from treatment.  If a patient experiences an adverse 
event (AE) that requires the patient be discontinued from durvalumab or LY2510924, the patient should be 
discontinued from both study drugs.
…
5.2.
Rationale for Protocol Amendment (a)
…
Attachment 13 contains a detailed list of changes made in this amendment.  Some minor editorial 
changes may not be listed.
5.3.
Rationale for Protocol Amendment (b)
The I2V-MC-CXAD protocol (a) was amended to make the following changes:  

Section 5.5.2.4:  Clinical safety information on durvalumab updated.

Section 6.1.3: Exclusion Criterion [16] expanded to include previous participation in any
randomized controlled trial that included arms with an anti-PD-1, anti-PD-L1, anti-
PD-L2, or anti-cytotoxic T lymphocyte-associated antigen-4 antibody or any other
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways such
as CD137, GITR, TIM-3, and LAG3, rather than only either durvalumab or
tremelimumab.

Synopsis and Section 6.2:  Clarified that patients will be allowed to continue until they
fulfill 1 or more of the study discontinuation criteria.

Sections 6.2 and 8.3.1.2: Clarified that patients will not be permitted to continue study
therapy if progression occurs after confirmed response.

Section 7.2.2.1: Added or modified existing DLT criteria to:
o
Grade 3 leukocytosis (leukocytes >100,000/µL) of any duration, or
leukocytosis/granulocytosis causing clinical symptoms
o
Any Grade 4 non-laboratory AE
o
Any Grade 3 laboratory value, and modified stipulations that the abnormal value
must be associated with clinically significant symptoms and persist for >7 days
o
Any Grade 4 laboratory abnormalities

Section 7.2.2.2:  For Phase 1a, any DLT-equivalent toxicities observed in Cycle 2 and
beyond will also be considered in dose escalation and determining MTD/recommended


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Phase 2 dose.  Additionally, if the DLT observation period is extended to Cycle 2, 
patients discontinuing in Cycle 2 in the absence of DLT-equivalent toxicity will be 
evaluable for DLT assessments.

Section 7.2.4:  Wording added that for Phase 1a and 1b, the DLT-observation period will
be extended to Cycle 2 if a DLT-equivalent toxicity is observed during Cycle 2 in any
cohort in Phase 1a.

Table CXAD.7.2: Dose adjustment of LY2510924 to align with newly added DLT
criterion for leukocytosis.

Section 8.1.3.1:  Typographical error was corrected.

Section 8.3.1.2:  Patients with a decline in Eastern Cooperative Oncology Group (ECOG)
performance status >1 will not be permitted to continue study treatment after confirmed
progression of disease.

Section 10.10:  Wording added that if the DLT-observation period is extended to 2 cycles
during Phase 1a, analysis will include DLT-equivalent toxicities occurring in Cycle 2.

Attachment 1 and Attachment 4: Correction: For serum, plasma, and whole blood
samples for biomarkers, baseline whole blood samples must be collected ≤7 days prior to
Cycle 1 Day 1.

Attachment 4:  Correction: immunogenicity samples will be collected 90 days post
durvalumab treatment.

Attachment 11: Durvalumab dose modification guidelines have been updated.
Attachment 13 contains a detailed list of changes made in this amendment.  Some minor editorial 
changes may not be listed.
[Note:  With the addition of new Section 5.3 (above), subsequent heading numbers increased by 
the appropriate level through the end of Section 5: eg, 5.3 Objectives, now 5.4 Objectives.]
5.5.2.
Durvalumab
…
5.5.2.4.
Summary of Clinical Experience
…
Safety
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class.  No tumor types appeared to be associated with unique AEs.  
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. Potential risks are 
events with a potential inflammatory mechanism which may require more frequent monitoring 
and/or unique interventions such as immunosuppressants and/or endocrine replacement therapy. 
These risks include gastrointestinal AEs such as colitis and diarrhea, pneumonitis, nephritis and 
acute renal failure; hepatic AEs such as hepatitis and liver enzyme elevations and dermatitis; and 


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endocrinopathies such as hypo- and hyper-thyroidism, hypophysitis, and adrenal insufficiency.  
Additional treatment-emergent immune-related events, including pancreatitis, neuropathy, and 
neuromuscular toxicity, have been reported with checkpoint inhibitor treatment. Immune-related 
AEs, which are important risks of immune checkpoint inhibitors, have been observed with 
durvalumab and include colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular 
toxicity, endocrinopathy, dermatitis, and nephritis.  In addition, pancreatitis is an important 
potential risk particularly with durvalumab and tremelimumab combination therapy.    These 
events are manageable by available/established treatment guidelines as described in the study 
protocol.  
Adverse Event Profile of Durvalumab Monotherapy
Study CD-ON-MEDI4736-1108:  The safety profile of durvalumab monotherapy in the 
694 patients with advanced solid tumors treated at 10 mg/kg Q2W in Study 
CD-ON-MEDI4736-1108 has been broadly consistent with that of the overall 1279 patients who 
have received durvalumab monotherapy (not including patients treated with blinded 
investigational product) across the clinical development program.  The majority of 
treatment-related AEs were manageable with dose delays, symptomatic treatment, and in the 
case of events suspected to have an immune basis, the use of established treatment guidelines for 
immune-mediated toxicity.  As of 07 May 2015, among the 694 patients treated with durvalumab 
10 mg/kg Q2W in Study CD-ON-MEDI4736-1108, a total of 378 patients (54.5%) experienced a 
treatment-related AE, with the most frequent (occurring in ≥5% of patients) being fatigue 
(17.7%), nausea (8.6%), diarrhea (7.3%), decreased appetite (6.8%), pruritus (6.3%), rash 
(6.1%), and vomiting (5.0%).  A majority of the treatment-related AEs were Grade 1 or Grade 2 
in severity with ≥Grade 3 events occurring in 65 patients (9.4%).  Treatment-related ≥Grade 3 
events reported in 3 or more patients (≥0.4%) were fatigue (12 patients, 1.7%); increased AST 
(7 patients, 1.0%); increased gamma-glutamyltransferase (GGT; 6 patients, 0.9%); increased 
ALT (5 patients, 0.7%); and colitis, vomiting, decreased appetite, and hyponatremia (3 patients, 
0.4% each).  Six patients had treatment-related Grade 4 AEs (upper gastrointestinal hemorrhage, 
increased AST, dyspnea, neutropenia, colitis, diarrhea, and pneumonitis) and 1 patient had a 
treatment-related Grade 5 event (pneumonia).  Treatment-related SAEs that occurred in ≥2 
patients were colitis and pneumonitis (3 patients each).  A majority of the treatment-related 
SAEs were ≥Grade 3 in severity and resolved with or without sequelae.  AEs that resulted in 
permanent discontinuation of durvalumab were considered as treatment related in 18 patients 
(2.6%), with colitis being the most frequent treatment-related AE resulting in discontinuation 
(3 patients).  A majority of the treatment-related AEs resulting in discontinuation of durvalumab 
were ≥Grade 3 in severity and resolved with or without sequelae.  
Study D4191C00003/ATLANTIC:  The safety profile of durvalumab monotherapy in Study 
CD-ON-MEDI4736-1108 is generally consistent with that of Study D4191C00003/ATLANTIC 
in patients with locally advanced or metastatic non–small-cell lung cancer (NSCLC) treated with 
durvalumab 10 mg/kg Q2W.Identified risks with durvalumab are diarrhea, increases in 
transaminases, pneumonitis, and colitis. 


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Potential risks include endocrinopathies (hypo- and hyper-thyroidism, hypophysitis, and adrenal 
insufficiency), hepatitis/hepatotoxicity, neurotoxicities, nephritis, pancreatitis, dermatitis, 
infusion-related reactions, anaphylaxis, hypersensitivity or allergic reactions, and immune 
complex disease. Further information on these risks can be found in the current version of the 
durvalumab IB.
In monotherapy clinical studies, AEs (all grades) reported very commonly (≥10% of patients) are 
fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back pain, 
pyrexia, abdominal pain, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. 
Approximately 10% of patients experienced an AE that resulted in permanent discontinuation of 
durvalumab and approximately 3.5% of patients experienced an SAE that was considered to be 
related to durvalumab by the study investigator.
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see the Dosing Modification and Toxicity 
Management Guidelines in Attachment 11).
A detailed summary of durvalumab monotherapy AE data can be found in the current version of 
the durvalumab IB.
6.1.3.
Exclusion Criteria
…
[16] Previous participation in any randomized controlled trial that included arms 
with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-cytotoxic T lymphocyte-
associated antigen-4 antibody (including but not limited to ipilimumab, 
durvalumab, or tremelimumab) or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways such as CD137, GITR, 
TIM-3, and LAG3.either durvalumab or tremelimumab, irrespective of actual 
treatment received on the trial.
…
6.2.
Summary of Study Design
…
Treatment decisions related to patient management and whether to treat a patient with advanced 
refractory solid tumors with additional cycles of study therapy will be based on RECIST v1.1.  
Rare exceptions for cContinuation with study treatment beyond confirmed radiographic 
progression may be made on a case-by-case basis for patients who are believed to be clinically 
benefiting from protocol therapy and both the investigator and sponsor, in consultation with 
collaborator (AstraZeneca, London, United Kingdom), agree that continuing protocol therapy is 
in the patient’s best interest.  Patients will not be permitted to continue study therapy if 
progression occurs after confirmed response (complete response [CR] or partial response [PR] as 
defined by RECIST v1.1) in the target lesions (regardless of the appearance of new lesions), ie,


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the response and progression events both occurred in the target lesions while receiving study 
therapy.
At the sponsor’s discretion, scans and measurements may be collected and reviewed by 
independent radiologists using RECIST v1.1 at a later date, or at any time during the study.  
Study treatment will continue The planned duration of treatment is 6 months or until the patient 
fulfills 1 of the criteria for study discontinuation (Section 6.3).  Patients demonstrating a benefit 
from treatment may continue on combination therapy beyond initial radiological disease 
progression 6 months if the patient and investigator feel that the patient is benefiting from 
treatment in the absence of clinically significant deterioration (Section 8.3.1.2).  If a patient 
experiences an AE that requires the patient be discontinued from durvalumab or LY2510924, the 
patient should be discontinued from both study drugs (Section 7.2.5).  
…
6.3.2.
Discontinuation of Patients from Study or Study Drug
…
In addition, patients will be discontinued from the study drugs and/or from the study in the 
following circumstances:
…

The patient has confirmed evidence of progressive disease by RECIST v1.1.  In the
setting of disease progression, the patient will discontinue from study drug(s);
however, the patient will continue to be followed on study.  In the setting of
unconfirmed/equivocal progression, the patient should remain on study treatment
until the next assessment period or up to 12 weeks after consultation with a Lilly
physician. See Section 8.3.2.1 for additional details. Rare exceptions for
continuation with study treatment beyond confirmed radiographic progression may
be made on a case-by-case basis for patients who are believed to be clinically 
benefiting from protocol therapy and both the investigator and sponsor, in 
consultation with the collaborator, agree that continuing protocol therapy is in the 
patient’s best interest.  

…
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum-Tolerated 
Dose Definition
A DLT is defined as 1 of the following AEs reported during the Phase 1a DLT observation 
period, if considered to be definitely, probably, or possibly related to either study regimen by the 
investigator; and fulfills any 1 of the following criterion using National Cancer Institute (NCI) 
CTCAE version (v) 4.03:


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1. Non-laboratory abnormalities (clinicalNonhematologic toxicity):
a. Nonlaboratory:
ai. Any Grade 4 immune-related AE (Attachment 10) 
b. Any Grade 4 non-laboratory AE
cii. Any CTCAE Grade ≥3 QT prolongation AE
diii. …
gvi. Grade 3 toxicity lasting an extended period of time despite optimal supportive
care (for example, nausea, vomiting, and diarrhea lasting >3 days; fatigue lasting 
>7 days)
2b. Laboratory abnormalities:
ai. Any Grade 3 or Grade 4 laboratory value if:
i1.
Medical intervention is required to treat the patient, or
ii.
Associated with clinically significant symptoms.  Examples include but are
not limited to, Grade 3 thrombocytopenia if associated with bleeding and 
requires platelet transfusion, Grade 3 febrile neutropenia, or 
iii2. The abnormality persists for >7 14 days (excluding amylase and lipase)
b. Any Grade 4 laboratory abnormalities
cii. …
d. ANC >75,000/µL or Grade 3 leukocytosis (leukocytes >100,000/µL) of any
duration, or leukocytosis/granulocytosis causing clinical symptoms
2. Hematologic toxicity, as follows:
a.
Grade 4 toxicity lasting >7 days, or
b. Grade 3 thrombocytopenia if associated with bleeding and requires platelet
transfusion, or
c.
Grade 3 febrile neutropenia
d. ANC >75,000/µL
3. …
5. Any other Grade 3 nonhematological toxicity, except for the exclusions listed below.
…
7.2.2.2.
Dose-Escalation Method
…
During the dose-escalation period, the investigators and Lilly CRP or designee in consultation 
with collaborator will consider the model recommendation, and the observed DLT rate, and any 
DLT-equivalent toxicities observed in Cycle 2 and beyond at each cohort to determine the next 
dose level and determine when to stop dose escalation.  …
… For the purpose of making decisions on dose escalation from a safety perspective, patients
will be considered evaluable (DLT-evaluable population) if they have either completed the DLT-


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observation period (Cycle 1) and received the scheduled durvalumab dose and at least 75% of 
LY2510924 doses in Cycle 1 or who have discontinued study treatment or study participation 
before completing Cycle 1 due to a DLT.  If the DLT-observation period is extended to Cycle 2, 
patients who discontinued during Cycle 2 in the absence of DLT-equivalent toxicity will be 
considered evaluable for DLT assessment.
…
7.2.4.
DLT-Equivalent Toxicity
A DLT-equivalent toxicity is defined as an AE occurring during Cycle 2 and beyond in Phase 1a 
that would have met the criteria for a DLT if it had occurred during Cycle 1 or during any cycle 
in Phase 1b.  The DLT-observation period will be extended to Cycle 2 if a DLT-equivalent 
toxicity is observed during Cycle 2 in any cohort in Phase 1a. …
7.2.5.1.1.
LY2510924 Dose Adjustments and Delays
…
Table CXAD.7.2.
Dose Adjustments of LY2510924
Event
Intervention
Dose Adjustment
Cytosis Leukocytosis (ANC 
>75,000/µL or leukocytes 
>100,000/µL) 
1) Interrupt LY2510924
2) Recheck WBC, ANC every 
2 to 3 days until ANC 
decreases to <50,000/µL 
Reduce 1 dose level 
…
8.1.3.1.
Electrocardiograms
…
QT prolongation that meets CTCAE Grade ≥3 criteria will be considered a DLT criterion in the 
Phase 1ab portion of this trial; in the other parts of the study, this should be considered grounds 
for early withdrawal or discontinuation based on the investigator’s assessment.  …
8.3.1.
RECIST Version 1.1 with Confirmatory Scan for Disease Progression
8.3.1.1.
Rationale for RECIST Version 1.1 with Confirmatory Scan for Disease 
Progression
…
8.3.1.2.
Application of RECIST Version 1.1 with Confirmatory Scan for Disease 
Progression
For Study CXAD, based on the unique response to immunotherapy and guidelines from 
regulatory agencies (for example, the European Medicines Agency’s “Guideline on the 


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evaluation of anticancer medicinal products in man” [EMA/CHMP/205/95/Rev.4] for immune 
modulating anticancer compounds), the following will be applied, in addition to standard 
RECIST v1.1 criteria:

…

For patients who continue to receive clinical benefit, and in the absence of
clinically significant deterioration despite evidence of objective progressive 
disease with the confirmatory scan, the patient may continue study treatment at 
the discretion of the investigator, in consultation with the Lilly CRP or 
designee.  Patients with a decline in ECOG performance status to >1 will not 
be permitted to continue study treatment after confirmed progression of 
disease.
NOTE:  In determining whether or not progression can be confirmed, the site 
study team should consider all target lesions, nontarget lesions, and new lesions.  
Patients will not be permitted to continue study therapy if progression occurs after 
confirmed response (CR or PR as defined by RECIST v1.1) in the target lesions 
(regardless of the appearance of new lesions), ie, the response and progression 
events both occurred in the target lesions while receiving study therapy.
10.10.
Interim Analyses
Data will be reviewed on a cohort-by-cohort basis during Phase 1a of the study, until the MTD is 
determined.  The purpose of these cohort-by-cohort reviews is to evaluate the cumulative safety 
data (Cycle 1 and all later cycles) at each dose level(s) that has/have enrolled study patients, and 
determine if a DLT has been observed that would suggest MTD has been met or exceeded.  …
In Phase 1b, 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 LY2510924 dose or whether the dose of LY2510924 should be 
reduced.  If the DLT-observation period is extended to 2 cycles during Phase 1a, this analysis 
will also include DLT-equivalent toxicities occurring in Cycle 2.
…
Attachment 1.
Protocol CXAD Study Schedule


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Baseline, During and Poststudy Assessments 
Baseline
Cycle 1
Cycle 2
Cycle 3-n
Follow-Up
Comments
Relative Day 
Within a Cycle
<28 
days
<7 
days
1
15
1
1
30 
day 
60 
day
90 
day
LT 
FUa
Assessments to be performed at the times 
stipulated in the table and as clinically required 
in the management of the patient.  All 
assessments to be performed pre-infusion unless 
stated otherwise.
…
Serum, 
Plasma, and 
Whole Blood 
Samples for 
Biomarkers
x
See Attachment 4 for exact timing.
x
Baseline sample for whole blood only, and must 
be collected >≤7 days prior to Cycle 1 Day 1.
See Attachment 4 for exact timing.


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Attachment 4.
Protocol CXAD Pharmacokinetic, Pharmacodynamic, 
Immunogenicity, and Biomarker Sampling Schedule
…


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Pharmacokinetic, Pharmacodynamic, and Biomarker Sampling Schedule
Cycle
Day
PK 
Sampling 
Time for 
LY25109
24a
PK 
Sampling 
Time for 
Durvalumab
Durvalumab 
Immuno-
genicity
Blood for 
Pharmaco-
genetics
Tailoring and Pharmacodynamic Biomarker
Plasma for 
Exploratory 
Research
Serum for 
Exploratory 
Research
Whole Blood for 
Immunopheno-
typing Including 
CD34+ Countsc
and Other 
Exploratory 
Research
Tissue for PD-L1 and 
Exploratory Research
—
<≤7 
days
X
X
…
90 
days 
post-
t/ment
Anytime
X
X


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Attachment 11.
Protocol CXAD Durvalumab Monotherapy Dosing Modification and 
Toxicity Management Guidelines for Immune-Mediated, Infusion 
Related, and Non Immune–Mediated Reactions
[Note:  Formatting changes made to the table are not noted below.]


 
1
 
 
Immune-Mediated Reactions 
 
 
Dose Modifications 
Toxicity Management 
Immune-related 
Adverse Events 
(Overall 
Management For 
toxicities not noted 
below) 
Drug administration modifications of study drug/study regimen will be made 
to manage potential immune-related AEs based on severity of treatment- 
emergent toxicities graded per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation of study 
drug/regimen based on CTC grade/severity (table below) , permanently 
discontinue study drug/study regimen for  the following conditions: 
• 
Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone 
per day (or equivalent) within 12 weeks after last dose of study 
drug/regimen 
• 
Recurrence of a previously experienced Grade 3 treatment-related 
AE following resumption of dosing. 
It is recommended that management of irAEs follow the guidelines presented in 
this table 
- 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, concomitant medications, infections, 
etc.) 
- 
In the absence of a clear alternative etiology, all events should be 
considered potentially immune related. 
- 
Symptomatic and topical therapy should be considered for low-grade 
(Grade 1 or 2, unless otherwise specified) events 
- 
For persistent (greater than 3 to 5 days) low-grade (Grade 2) or severe 
(Grade ≥3) events promptly start prednisone 1-2mg/kg/day PO or IV 
equivalent 
- 
If symptoms recur or worsen during corticosteroid tapering 28 days of 
taper), increase the corticosteroid dose (prednisone dose [e.g. up to 2- 
4mg/kg/day PO or IV equivalent]) until stabilization or improvement 
of symptoms, then resume corticosteroid tapering at a slower rate (> 
28 days of taper) 
- 
More potent immunosuppressives such as TNF inhibitors (e.g. 
infliximab) – (also refer to the individual sections of the immune related 
adverse event for specific type of immunosuppressive) should be 
considered for events not responding to systemic steroids. 
- 
Discontinuation of study drug is not mandated for Grade 3 / Grade 4 
inflammatory reactions attributed to local tumour response (e.g. 
inflammatory reaction at sites of metastatic disease, lymph nodes etc.). 
Continuation of study drug in this situation should be based upon a 
benefit/risk analysis for that patient 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until Ggrade 2 
resolution to ≤ Grade 1 
• If toxicity worsens then treat as Grade 3 or Grade 4 
• If toxicity improves to baseline then treat at next 
scheduled treatment date 
Study drug/study treatment can be resumed at the next 
scheduled dose once event stabilizes to Ggrade ≤1  
and 5-7 days have passed after completion of steroid 
taper 
Patients with endocrinopathies who may require 
prolonged or continued steroid replacement can be 
retreated with study drug/study regimen on the 
following conditions: 1) the event stabilizes and is 
controlled , 2) the patient is clinically stable as per 
Investigator or treating physician’s clinical 
judgement, and 3) doses of prednisone are at less 
than or equal to 10mg/day or equivalent. 
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2
 
 
 
Grade 3 
Depending on the individual toxicity, may 
permanently discontinue study drug/study 
regimen. Please refer to guidelines below 
 
Grade 4 
Permanently discontinue study drug/study 
regimen 
Note: For Grade 3 and above asymptomatic amylase or lipase levels 
hold study drug/regimen and if complete work up shows no evidence of 
pancreatitis, may continue or resume study drug/regimen 
 
 
 
Grade of the 
Event (NCI 
CTCAE 
version 4.03) 
Dose Modifications 
Toxicity 
Management 
 
Pneumonitis/ILD 
Grade of 
Pneumonitis 
(CTCAE version 
4.03) 
General Guidance Any Grade 
- 
Monitor patients for signs and symptoms of pneumonitis or ILD 
(new onset or worsening shortness of breath or cough). Patients 
should be evaluated with imaging and pulmonary function tests 
including other diagnostic procedures as described below 
- 
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), laboratory 
work-up and high- resolution CT scan. 
Grade 1 
(Asymptomatic, 
clinical or 
diagnostic 
observations only, 
intervention not 
indicated)
No dose modification required. However, 
consider holding study drug/study regimen 
dosing as clinically appropriate and during 
diagnostic work-up for other etiologies 
For Grade 1 (Radiographic Changes Only) 
- 
Monitor and closely follow up in 2-4 days for clinical 
symptoms, pulse oximetry (resting and exertion) and 
laboratory work-up and then as clinically indicated 
- 
Consider pulmonary and  infectious disease consult 
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3
 
Grade 2 
(Symptomatic, 
medical 
intervention 
indicated, limiting 
instrumental ADL) 
Hold study drug/study regimen dose until 
Ggrade 2 resolution to ≤ Grade 1 
• If toxicity worsens then treat as Grade 3 or 
Grade 4 
• If toxicity improves to ≤ Grade 1, baseline 
For Grade 2 (Mild to Moderate New Symptoms) 
- 
Monitor symptoms daily and consider hospitalization 
- 
Promptly start systemic steroids (e.g., prednisone 1-
2mg/kg/day PO or IV equivalent) 
- 
Reimaging as clinically indicated 
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4
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
then the decision to reinitiate study 
drug/regimen at next scheduled 
treatment date will be based upon 
treating physician’s clinical 
judgment and after completion of 
steroid taper. 
Study drug/study treatment can be 
resumed at the next scheduled dose 
once event stabilizes to grade ≤1 
and 5-7 days have passed after 
completion of steroid taper 
-
If no improvement within 3-5 days, additional workup should be considered 
and prompt treatment with IV methylprednisolone 2-4mg/kg/day started 
- 
If still no improvement within 3-5 days despite IV methylprednisone at 2- 
4/g/kg/day, promptly start immunosuppressive therapy such as TNF 
inhibitors (e.g. infliximab at 5mg/kg every 2 weeks). Caution: Important to 
rule out sepsis and refer to infliximab label for general guidance before 
using infliximab 
- 
Once improving, gradually taper steroids over ≥28 days 4 weeks and 
consider prophylactic antibiotics, antifungal or anti PCP treatment (refer 
to current NCCN guidelines for treatment of cancer-related infections 
(Category 2B recommendation)iii 1 
- 
Consider pulmonary and infectious disease consult 
- 
Consider as necessary  discussing with study physician 
Grade 3 or 4 
(Grade 3: Severe 
symptoms; limiting 
self-care ADL; 
oxygen indicated; 
 
Grade 4: life 
threatening 
respiratory 
compromise, urgent 
intervention indicated 
[e.g. tracheostomy or 
intubation]) 
Permanently discontinue study 
drug/study regimen 
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, life threatening
- 
Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or 
equivalent 
- 
Obtain pulmonary and infectious disease consult 
- 
Hospitalize the patient 
- 
Supportive Care (oxygen, etc.) 
- 
If no improvement within 3-5 days, additional workup should be considered 
and prompt treatment with additional immunosuppressive therapy such as 
TNF inhibitors (e.g. infliximab at 5mg/kg every 2 weeks dose) started. 
Caution: rule out sepsis and refer to infliximab label for general guidance 
before using infliximab 
- 
Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and in particular, anti PCP treatment 
(please refer to current NCCN guidelines for treatment of cancer-related 
infections (Category 2B recommendation)iii 
 
1 ASCO Educational Book 2015. Michael Postow MD. “Managing Immune Checkpoint Blocking Antibody Side Effects” 
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5
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Diarrhea/ 
Enterocolitis 
Grade of Diarrhea 
(CTCAE version 
4.03) 
General Guidance Any Grade 
- 
Monitor for symptoms that may be related to diarrhea/enterocolitis 
(abdominal pain, cramping, or changes in bowel habits such as increased 
frequency over baseline or blood in stool) or related to bowel perforation 
(such as sepsis, peritoneal signs and ileus) 
- 
Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression, other medications, infections including testing for 
clostridium difficile toxin, etc.) 
- 
Steroids should be considered in the absence of clear alternative etiology, 
even for low grade events, in order to prevent potential progression to 
higher grade event 
- 
Use analgesics carefully; they can mask symptoms of perforation and 
peritonitis 
Grade 1 diarrhea 
(stool frequency of 
<4 over baseline per 
day) 
No dose modification 
For Grade 1 diarrhea : 
- 
Close monitoring for worsening symptoms 
- 
Consider symptomatic treatment including hydration, electrolyte 
replacement, dietary changes (e.g., American Dietetic Association colitis 
diet), and loperamide. Use of probiotics as per treating physician’s clinical 
judgment. 
Grade 2 diarrhea 
(stool frequency of 4- 
6 over baseline per 
day) 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 
• 
If toxicity worsens then treat as 
Grade 3 or Grade 4 
• 
If toxicity improves to ≤ Grade 
1, baseline then  treat at next 
scheduled treatment date 
• 
sStudy drug/study regimen can 
be resumed at the next 
scheduled dose once event 
stabilizes to grade ≤1 and 5-7 
days have passed after 
completion of steroid taper 
For Grade 2 diarrhea: 
- 
Consider symptomatic treatment including hydration, electrolyte 
replacement, dietary changes (e.g., American Dietetic Association colitis 
diet), and loperamide and/or budesonide 
- 
Promptly start  prednisone 1 to 2  mg/kg/day PO or IV equivalent 
- 
If event is not responsive within 3-5 days or worsens despite prednisone at 
1-2 mg/kg/day PO or IV equivalent, GI consult should be obtained for 
consideration of further workup such as imaging and/or colonoscopy to 
confirm colitis and rule out perforation, and prompt treatment with IV 
methylprednisolone 2-4mg/kg/day started. 
- 
If still no improvement within 3-5 days despite 2-4mg/kg IV 
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6
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
 
methylprednisolone, promptly start immunosuppressives such as 
(infliximab at 5mg/kg once every 2 weeks2). . Caution: Important to rule 
out bowel perforation and refer to infliximab label for general guidance 
before using infliximab 
- 
Consult study physician if no resolution to ≤ Grade 1 in 3-4 days 
- Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]) 
Grade 3 or 4 diarrhea 
 
(Grade 3: stool 
frequency of ≥7 over 
baseline per day; 
 
Grade 4: life 
threatening 
consequences) 
Permanently discontinue study 
drug/study regimen 
For Grade 3 or 4 diarrhea: 
- 
Promptly initiate empiric IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent 
- 
Monitor stool frequency and volume and maintain hydration 
- 
Urgent GI consult and imaging and/or colonoscopy as appropriate 
- 
If still no improvement within 3-5 days of IV methylprednisolone 2 to 
4mg/kg/day or equivalent, promptly start further immunosuppressives (e.g. 
infliximab at 5mg/kg once every 2 weeks). 
- 
Caution: Ensure GI consult to rule out bowel perforation and refer to 
infliximab label for general guidance before using infliximab. 
- Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]) 
 
 
 
 
 
2 ASCO Educational Book 2015 Michael Postow MD “Managing Immune Checkpoint Blocking Antibody Side Effects 
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7
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Hepatitis (Elevated 
LFTs) 
Infliximab should 
not be used for 
management of 
Immune Related 
Hepatitis 
Grade of Liver 
Function Test 
Elevation (CTCAE 
version 4.03) 
Any Grade 
 
 
 
 
 
 
No dose modification 
If  it worsens, treat as Grade 2 event 
- 
Monitor and evaluate liver function test: AST, ALT, ALP and total bilirubin 
- 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease progression, 
concomitant medications) 
Grade 1 
(AST or ALT > ULN 
to 3 times ULN 
and/or TB > ULN to 
1.5 times ULN) 
For Grade 1 AST or ALT and/or TB elevation 
- 
Continue LFT monitoring per protocol 
Grade 2 
(AST or ALT > 3 to 
5 times ULN and/or 
TB >1.5-3.0 times 
ULN) 
Hold Study drug/study regimen dose 
until grade 2 resolution to ≤ Grade 1 
• If toxicity worsens then treat as 
Grade 3 or Grade 4 
• If toxicity improves to ≤ Grade 1 
or baseline, resume  study 
drug/study regimen then treat at 
next scheduled treatment date 
• Study drug/study regimen can be 
resumed at the next scheduled dose 
once event stabilizes to grade ≤1 
and 5-7 days have passed after 
completion of steroid taper 
For Grade 2 AST or ALT and or TB elevation : 
- 
Regular and frequent checking of LFTs (e.g. every 1-2 days) until 
elevations of these are improving or resolved. 
- 
If no resolution to ≤ Grade 1 in 1-2 days, discuss with study physician. 
- 
If event is persistent (> 3-5 days) or worsens, promptly start prednisone 1- 
2mg/kg/day PO or IV equivalent. 
- 
If still no improvement within 3-5 days despite 1-2mg/kg/day of prednisone 
PO or IV equivalent, consider additional workup and prompt treatment 
with IV methylprednisolone 2-4mg/kg/day started. 
- If still no improvement within 3-5 days despite 2-4mg/kg/day of IV 
methylprednisolone, promptly start immunosuppressives (mycophenolate 
mofetil)3 . Discuss with study physician if mycophenolate mofetil is not 
available.  Infliximab should NOT be used. 
- Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
 
 
3 ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” , by Michael Postow MD 
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8
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
 
current NCCN guidelines for treatment of cancer-related infections [Category 
2B recommendation]) 
Grade 3 
(AST or ALT >5-20 
times ULN and/or TB 
> 3.0-10 times ULN 
For elevations in transaminases ≤ 8 × 
ULN, or elevations in bilirubin ≤ 5 
× ULN 
-Hold study drug/study regimen 
dose until resolution to ≤ Grade 1 
or baseline 
-Resume study drug/study regimen 
administration at the next 
scheduled dose if elevations 
downgrade ≤ Grade 1 or baseline 
within 14 days, and after 
completion of steroid taper 
Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to ≤ Grade 1 or 
baseline within 14 days 
For elevations in transaminases > 8 × 
ULN or elevations in bilirubin > 5 
× ULN, discontinue study 
drug/study regimen 
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria (AST 
and/or ALT > 
For Grade 3 or 4 AST or ALT and/or TB elevation:
- 
Promptly initiate empiric IV methylprednisolone at 1 to 4 mg/kg/day or 
equivalent 
- 
If still no improvement within 3-5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent , promptly start treatment with 
immunosuppressive therapy (mycophenolate mofetil) Discuss with study 
physician if mycophenolate is not available. Infliximab should NOT be 
used. 
 
- 
Hepatology consult, abdominal workup, and imaging as appropriate. 
 
- 
Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections [Category 
2B recommendation]) 
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9
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
3x ULN + bilirubin > 2x ULN 
without initial findings of 
cholestasis (i.e. elevated alkaline 
P04) and in the absence of any 
alternative causeiv 
 
Grade 4 
(AST or ALT > 20 
times ULN and/or TB 
> 10 times ULN) 
Permanently discontinue study 
drug/study regimen 
Nephritis or Renal 
Dysfunction 
(Elevated Serum 
Creatinine) 
Grade of Elevated 
Serum Creatinine 
(CTCAE version 
4.03) 
 
Any Grade 
General Guidance
- 
Consult with Nephrologist 
- 
Monitor for signs and symptoms that may be related to changes in renal 
function (e.g. routine urinalysis, elevated serum BUN and creatinine, 
decreased creatinine clearance, electrolyte imbalance, decrease in urine 
output, proteinuria, etc.) 
- 
Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression, infections etc.) 
- 
Steroids should be considered in the absence of clear alternative etiology 
even for low grade events (Grade 2) , in order to prevent potential 
progression to higher grade event 
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10
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 1 [Serum 
Creatinine > 1-1.5X 
baseline; > ULN to 
1.5X ULN] 
No dose modification 
For Grade 1 elevated creatinine: 
- 
Monitor serum creatinine weekly and any accompanying symptom 
• 
If creatinine returns to baseline, resume its regular monitoring per 
study protocol. 
• 
If it worsens, depending on the severity , treat as Grade 2 or Grade 
3 or 4 
- 
Consider symptomatic treatment including hydration, electrolyte 
replacement, diuretics, etc. 
Grade 2 [Serum 
Creatinine>1.5-3.0X 
baseline; >1.5X- 
3.0XULN] 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 or baseline  
• 
If toxicity worsens then treat as 
Grade 3 or Grade 4 
• 
If toxicity improves to ≤ Grade 
1 or baseline then resume 
study drug/study regimen after 
completion of steroid taper 
treat at next scheduled 
treatment date 
Study drug/study regimen can be 
resumed at the next scheduled 
dose once event stabilizes to 
grade ≤1 for 5-7 days have passed 
after completion of steroid taper 
For Grade 2 elevated creatinine: 
- 
Consider symptomatic treatment including hydration, electrolyte 
replacement, diuretics, etc. 
- 
Carefully monitor serum creatinine every 2-3 days and as clinically 
warranted 
- 
Consult Nephrologist and consider renal biopsy if clinically indicated 
- 
If event is persistent (> 3-5 days) or worsens, promptly start prednisone 1 
to 2 mg/kg/day PO or IV equivalent 
- 
If event is not responsive within 3-5 days or worsens despite prednisone at 
1-2 mg/kg/day PO or IV equivalent, additional workup should be 
considered and prompt treatment with IV methylprednisolone at 2-
4mg/kg/day started. 
- 
Once improving gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]). 
- 
When event returns to baseline, resume study drug/study regimen and 
routine serum creatinine monitoring per study protocol. 
Formatted Table
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11
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 3 or 4 
(Grade 3: Serum 
Creatinine > 3.0 X 
baseline; >3.0-6.0 X 
ULN 
 
Grade 4: Serum 
Creatinine > 6.0 X 
ULN) 
Permanently discontinue study 
drug/study regimen 
- 
Carefully monitor serum creatinine  on  daily basis 
- 
Consult Nephrologist and consider renal biopsy if clinically indicated 
- 
Promptly  start  prednisone 1 to 2  mg/kg/day PO or IV equivalent 
- 
If event is not responsive within 3-5 days or worsens despite prednisone at 
1-2 mg/kg/day PO or IV equivalent, additional workup should be 
considered and prompt treatment with IV methylprednisolone 2-
4mg/kg/day started. 
- Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation] 
Rash (excluding 
Bullous skin 
formations) 
Grade of Skin Rash 
(Please refer to 
NCICTCAE version 
4.03 for definition of 
severity/grade 
depending on type of 
skin rash) 
General Guidance Any Grade 
Monitor for signs and symptoms of dermatitis (rash and pruritus) 
**IF THERE IS ANY BULLOUS FORMATION, THE STUDY PHYSICIAN 
SHOULD BE CONTACTED AND STUDY DRUG DISCONTINUED** 
Grade 1 
No dose modification 
For Grade 1: 
- Consider symptomatic treatment including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea cream) 
Grade 2 
For persistent (> 1- 2 weeks) Grade 2 
events, hold scheduled study 
drug/study regimen until 
resolution to ≤ Grade 1 or 
baseline 
• 
If  toxicity worsens then treat 
For Grade 2 : 
- 
Obtain dermatology consult 
- 
Consider symptomatic treatment including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea cream) 
- 
Consider moderate-strength topical steroid 
- 
If no improvement of rash/skin lesions occurs within 3-5 days or is 
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12
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
as Grade 3
• 
If toxicity improves to Grade 
≤1 or baseline, then resume 
drug/study regimen after 
completion of steroid taper 
administration at next 
scheduled dose 
• 
Study drug/study regimen 
can be resumed at the next 
scheduled dose once event 
stabilizes to grade ≤1 and 5-7 
days have passed after 
l i
f
id
worsening despite symptomatic treatment and/or use of moderate strength 
topical steroid, discuss with study physician and promptly start systemic 
steroids prednisone  1-2 mg/kg/day PO or IV equivalent 
- Consider skin biopsy if persistent for >1-2 weeks or recurs 
Grade 3 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 or baseline 
If temporarily holding the study 
drug/study regimen does not 
provide improvement of the Grade 
3 skin rash to ≤ Grade 1 or 
baseline within 30 days, then 
permanently discontinue Study 
drug/study regimen 
For Grade 3 or 4: 
- 
Consult dermatology 
- 
Promptly initiate empiric IV methylprednisolone 1 to 4 mg/kg/day or 
equivalent 
- 
Consider hospitalization 
- 
Monitor extent of rash [Rule of Nines] 
- 
Consider skin biopsy (preferably more than 1) as clinically feasible. 
- 
Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]) 
- 
Discuss with Study Physician 
Grade 4 
Permanently discontinue study 
drug/study regimen 
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13
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Endocrinopathy 
(e.g., 
hyperthyroidism, 
hypothyroidism, 
hypopituitarism, 
adrenal 
insufficiency, etc.) 
Any Grade 
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade/severity) 
General Guidance
- 
Consult Endocrinologist 
- 
Monitor patients for signs and symptoms of endocrinopathies. Non-specific 
symptoms include headache, fatigue, behavior changes, changed mental 
status, vertigo, abdominal pain, unusual bowel habits, hypotension and 
weakness. 
- 
Patients should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression including brain metastases, infections, etc.) 
- 
Monitor and evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine labs depending on suspected endocrinopathy. 
- 
If a patient experiences an AE that is thought to be possibly of autoimmune 
nature (e.g., thyroiditis, pancreatitis, hypophysitis, diabetes insipidus), the 
investigator should send a blood sample for appropriate autoimmune 
antibody testing 
Grade 1 
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade 1) 
No dose modification 
For Grade 1: (including those with asymptomatic TSH elevation) 
- 
Monitor patient with appropriate endocrine function tests 
- 
If TSH < 0.5X LLN, or TSH >2X ULN or consistently out of range in 2 
subsequent measurements, include FT4 at subsequent cycles as clinically 
indicated and consider endocrinology consult. 
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14
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 2 
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade/severity 2) 
For Grade 2 endocrinopathy other 
than hypothyroidism, hold study 
drug/study regimen dose until 
subject is clinically stable 
• If toxicity worsens then treat as 
Grade 3 or Grade 4 
• If toxicity improves to baseline 
then treat at next scheduled 
treatment date 
Study drug/study regimen can be 
resumed at the next scheduled dose 
once event stabilizes and to grade 
≤1 and 5-7 days have passed after 
completion of steroid taper 
Patients with endocrinopathies who 
may require prolonged or 
continued steroid replacement can 
be retreated with study drug/study 
regimen on the following 
conditions: 1) the event stabilizes 
and is controlled,  ,2) the patient is 
clinically stable as per Investigator 
or treating physician’s clinical 
judgement, and 3) doses of 
prednisone are at less than or equal 
to 10mg/day or equivalent. 
For Grade 2: (including those with symptomatic endocrinopathy) 
- 
Isolated hypothyroidism may be treated with replacement therapy without 
treatment interruption and without corticosteroids 
- Initiate hormone replacement as needed for management 
- Evaluate endocrine function, and as clinically indicated, consider pituitary 
scan 
- For patients with abnormal endocrine work up, except for those with 
isolated hypothyroidism, consider short-term, corticosteroids (e.g., 1- 
2mg/kg/day methylprednisolone or IV equivalent) and prompt initiation of 
treatment with relevant hormone replacement (e.g. Levothyroxine, 
hydrocortisone, or sex hormones). - 
- Once improving, gradually taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti PCP treatment (please refer to 
current NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]) 
- For patients with normal endocrine work up (lab or MRI scans), repeat 
labs/MRI as clinically indicated. 
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15
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
Grade 3 or 4 
(Depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade/severity 3 or 4) 
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism, hold study 
drug/study regimen dose until 
endocrinopathy symptom(s) are 
controlled 
Resume study drug/study regimen 
administration if controlled at the next 
scheduled dose 
Study drug/study regimen can be 
resumed at the next scheduled dose 
once event stabilizes to grade ≤1 and 
5-7 days have passed after completion 
of steroid taper 
For Grade 3 or 4: 
- 
Consult endocrinologist 
- 
Isolated hypothyroidism may be treated with replacement therapy without 
treatment interruption and without corticosteroids 
- 
Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or 
equivalent 
- 
Administer hormone replacement therapy as necessary. 
- 
For adrenal crisis, severe dehydration, hypotension, or shock: immediately 
initiate intravenous corticosteroids with mineralocorticoid activity 
- 
Once improving, gradually taper immunosuppressive steroids over ≥28 
days 4 weeks and consider prophylactic antibiotics, antifungals and anti 
PCP treatment (please refer to current NCCN guidelines for treatment of 
cancer- related infections [Category 2B recommendation]) 
- 
Discuss with study physician 
Immune mediated 
Neurotoxicity (to 
include but not 
limited to limbic 
encephalitis . 
autonomic 
neuropathy, 
excluding 
Myasthenia Gravis 
and Guillain-Barre) 
Grade of 
Neurotoxicity 
Depending on the 
type of neurotoxicity 
, refer to NCI 
CTCAE version 4.03 
for defining the CTC 
grade/severity 
 
Any Grade 
General Guidance
- 
Patients should be evaluated to rule out any alternative etiology (e.g., 
disease progression, infections, metabolic syndromes and medications, etc.) 
- 
Monitor patient for general symptoms (headache, nausea, vertigo, behavior 
change, or weakness) 
- 
Consider appropriate diagnostic testing (e.g. electromyogram and nerve 
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16
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
 
conduction investigations)
- Symptomatic treatment with neurological consult as appropriate 
Grade 1 
No dose modifications 
See “Any Grade” recommendations above. 
Grade 2 
• 
For acute motor neuropathies 
or neurotoxicity, hold study 
drug/study regimen dose 
until resolution to ≤ Grade 1 
• 
For sensory 
neuropathy/neuropathic pain, 
consider holding study 
drug/study regimen dose 
until resolution to ≤ Grade 1. 
o If toxicity worsens then 
treat as Grade 3 or 
Grade 4 
o If toxicity improves to 
baseline then treat at 
next scheduled 
treatment date 
• 
Study drug/study regimen 
can be resumed at the next 
scheduled dose once event 
improves stabilizes to 
Ggrade ≤1 and 5-7 days have 
passed after completion of 
steroid taper 
- 
Discuss with the study physician 
- 
Obtain  Neurology Consult 
- 
Sensory neuropathy/neuropathic pain may be managed by appropriate 
medications (e.g., gabapentin, duloxetine, etc.) 
- 
Promptly start systemic steroids prednisone 1-2mg/kg/day PO or IV 
equivalent 
- 
If no improvement within 3-5 days despite 1-2mg/kg/day prednisone PO 
or IV equivalent consider additional workup and promptly treat with 
additional immunosuppressive therapy (e.g. IVIG) 
 
Grade 3 
• 
Hold Study drug/study 
regimen dose until resolution 
to ≤ Grade 1 
For Grade 3 or 4: 
- Discuss with study physician 
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17
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
• 
Permanently discontinue 
sStudy drug/study regimen 
if Grade 3 irAE does not 
resolve to ≤ Grade 1 within 
30 days. 
- 
Obtain Neurology Consult 
- 
Consider hospitalization 
- 
Promptly initiate empiric IV methylprednisolone 1 to 2 mg/kg/day or 
equivalent 
- 
If no improvement within 3-5 days despite IV corticosteroids, consider 
additional workup and promptly treat with additional immunosuppressants 
(e.g. IVIG) 
- 
Once stable, gradually taper steroids over ≥28 days 4 weeks 
Grade 4 
• 
Permanently discontinue 
study drug/study regimen 
Immune-mediated 
peripheral 
neuromotor 
syndromes, such as 
Guillain-Barre and 
Myasthenia Gravis 
 
General Guidance Any Grade 
- 
The prompt diagnosis of immune-mediated peripheral neuromotor 
syndromes is important, since certain patients may unpredictably 
experience acute decompensations which can result in substantial morbidity 
or in the worst case, death. Special care should be taken for certain sentinel 
symptoms which may predict a more severe outcome, such as prominent 
dysphagia, rapidly progressive weakness, and signs of respiratory 
insufficiency or autonomic instability 
- 
Patients should be evaluated to rule out any alternative etiology (e.g., 
disease progression, infections, metabolic syndromes and medications, 
etc.). It should be noted that the diagnosis of immune-mediated peripheral 
neuromotor syndromes can be particularly challenging in patients with 
underlying cancer, due to the multiple potential confounding effects of 
cancer (and its treatments) throughout the neuraxis. Given the importance 
of prompt and accurate diagnosis, it is essential to have a low threshold to 
obtain a neurological consult 
- 
Neurophysiologic diagnostic testing (e.g., electromyogram and nerve 
conduction investigations, and “repetitive stimulation” if myasthenia is 
suspected) are routinely indicated upon suspicion of such conditions and 
may be best facilitated by means of a neurology consultation 
Important to consider that the use of steroids as the primary treatment of 
Guillain-Barre is not typically considered effective. Patients requiring 
treatment should be started  with IVIG and followed by plasmapheresis if 
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18
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
 
not responsive to IVIG
Grade 1 
No dose modification 
- 
Discuss with the study physician 
- 
Care should be taken to monitor patients for sentinel symptoms of a 
potential decompensation as described above 
- 
Obtain a neurology consult unless the symptoms are very minor and stable 
Grade 2 
Hold study drug/study regimen dose 
until resolution to ≤ Grade 1 
Permanently discontinue study 
drug/study regimen if it does not 
resolve to ≤ Grade 1 within 30 days 
or if there are signs of respiratory 
insufficiency or autonomic 
instability 
Grade 2 
- 
Discuss with the study physician 
- 
Care should be taken to monitor patients for sentinel symptoms of a 
potential decompensation as described above 
- 
Obtain a Neurology Consult 
- 
Sensory neuropathy/neuropathic pain may be managed by appropriate 
medications (e.g., gabapentin, duloxetine, etc.) 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat Myasthenia Gravis. 
Important to consider that steroid therapy (especially with high 
doses) may result in transient worsening of myasthenia and should 
typically be administered in a monitored setting under supervision 
of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates for treatment 
with plasmapheresis or IVIG. Such decisions are best made in 
consultation with a neurologist, taking into account the unique 
needs of each patient. 
o 
If Myasthenia Gravis-like neurotoxicity present, consider starting 
acetylcholine esterase (AChE) inhibitor therapy in addition to 
steroids. Such therapy, if successful, can also serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE: 
o 
Important to consider here that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered effective. 
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19
 
 
 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
 
 
Patients requiring treatment should be started with IVIG and 
followed by plasmapheresis if not responsive to IVIG. 
Grade 3 
Hold study drug/study regimen dose 
until resolution to ≤ Grade 1 
Permanently discontinue Study 
drug/study regimen if Grade 3 
irAE does not resolve to ≤ Grade 1 
within 30 days or if there are signs 
of respiratory insufficiency or 
autonomic instability 
For severe or life threatening (Grade 3 or 4) events:
- 
Discuss with study physician 
- 
Recommend hospitalization 
- 
Monitor symptoms and obtain neurological consult 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to treat Myasthenia Gravis. It 
should typically be administered in a monitored setting under 
supervision of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates for treatment 
with plasmapheresis or IVIG. 
o 
If Myasthenia Gravis-like neurotoxicity present, consider starting 
acetylcholine esterase (AChE) inhibitor therapy in addition to 
steroids. Such therapy, if successful, can also serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE: 
Important to consider here that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered effective. 
Patients requiring treatment should be started with IVIG and 
followed by plasmapheresis if not responsive to IVIG 
Grade 4 
Permanently discontinue study 
drug/study regimen 
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20
 
 
Infusion-Related Reactions 
Severity Grade 
of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
- 
Management per institutional standard at the discretion of investigator 
- 
Monitor patients for signs and symptoms of infusion-related reactions (e.g., 
fever and/or shaking chills, flushing and/or itching, alterations in heart rate 
and blood pressure, dyspnea or chest discomfort, skin rashes etc.) and 
anaphylaxis (e.g., generalized urticaria, angioedema, wheezing, hypotension, 
tachycardia, etc.) 
Grade 1 
The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until resolution 
of the event 
For Grade 1 or Grade 2:
- 
Acetaminophen and/or antihistamines may be administered per institutional 
standard at the discretion of the investigator 
- 
Consider premedication per institutional standard prior to subsequent doses 
- 
Steroids should not be used for routine premedication of ≤Grade 2 infusion 
reactions  
Grade 2 
The infusion rate of study drug/study regimen may be 
decreased 50% or temporarily interrupted until resolution of 
the event 
Subsequent infusions may be given at 50% of the initial 
infusion rate 
Grade 3/4 
 
 
Permanently discontinue study drug/study regimen 
For Grade 3 or 4: 
 
Manage severe infusion-related reactions per institutional standards (e.g., IM 
epinephrine, followed by IV diphenhydramine and ranitidine, and IV 
glucocorticoid) 
I2V-MC-CXAD(b) Phase 1 Oncology Protocol
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21
 
 
 
 
 
Non-immune Mediated Reactions 
 
(Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician” 
CTC Grade/Severity 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modification 
Toxicity Management 
Any Grade 
Note: dose modifications are not required for adverse events not deemed to be related to study 
treatment (i.e. events due to underlying disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly as per institutional 
standard 
1 
No dose adjustment 
Treat accordingly as per institutional 
standard 
2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
Treat accordingly as per institutional 
standard 
3 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline within 
14 days, resume study drug/study regimen administration.  at next scheduled dose. Otherwise, 
discontinue study drug/study regimen 
Treat accordingly as per institutional 
standard 
4 
Discontinue Study drug/study regimen (Note for Grade 4 labs, decision to discontinue would be 
based on accompanying clinical signs/symptoms and as per Investigator’s clinical judgment and 
in consultation with the sponsor) 
Treat accordingly as per institutional 
standard 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.” 
 
AChE = acetylcholine esterase; ADA = American Dietetic Association; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; CT = computed tomography; GI = gastrointestinal; IDS=Infectious Disease Service; ILD = interstitial lung disease; IM = intramuscular; irAE = immune- 
related adverse event; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; PO = by mouth; TNF = tumor necrosis 
factor; TSH = thyroid stimulating hormone; ULN = upper limit of normal. 
I2V-MC-CXAD(b) Phase 1 Oncology Protocol
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22
 
 
 
 
ai ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD 
ibi FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation NCI CTCAE version 4.03 
iii ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD 
iv FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation 
I2V-MC-CXAD(b) Phase 1 Oncology Protocol
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LY2510924/durvalumab


Leo Document ID = a8c410fb-9772-49b2-b6fe-5ecfead974bf
Approver: 
Approval Date & Time: 12-Oct-2016 16:43:44 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 12-Oct-2016 23:08:02 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan I2V-MC-CXAD 
 
A Phase 1a/1b Study of CXCR4 Peptide Antagonist (LY2510924) Administered in Combination 
With the Anti-PD-L1 Antibody, Durvalumab (MEDI4736), in Advanced Refractory Solid 
Tumors   
 
NCT02737072 
 
Approval Date: 02-Jun-2016 
 


I2V-MC-CXAD Statistical Analysis Plan Version 1
Page 1
LY2510924
1.
Statistical Analysis Plan :  
A Phase 1a/1b Study of CXCR4 Peptide Antagonist
(LY2510924) Administered in Combination with the 
Anti-PD-L1 Antibody, Durvalumab (MEDI4736), in 
Advanced Refractory Solid Tumors
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities: this document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries..
LY2510924
This is a multicenter, nonrandomized, open-label, dose-escalation Phase 1a study of 
LY2510924 combined with MEDI4736 in patients with advanced refractory solid tumors 
followed by an open-label 2-expansion-arm Phase 1b study in patients with advanced 
refractory pancreatic cancer and ovarian cancer.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I2V-MC-CXAD
Phase 1
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 02-Jun-2016 GMT


I2V-MC-CXAD Statistical Analysis Plan Version 1
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan :   A Phase 1a/1b Study of CXCR4 Peptide 
Antagonist (LY2510924) Administered in Combination with the 
Anti-PD-L1 Antibody, Durvalumab (MEDI4736), in Advanced 
Refractory Solid Tumors.....................................................................................................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.
Summary of Study Design ..................................................................................................8
5.1.
Determination of Sample Size ........................................................................................8
5.2.
Method of Assignment to Treatment ..............................................................................9
6.
A Priori Statistical Methods ..............................................................................................11
6.1.
General Considerations ................................................................................................11
6.2.
Handling of Dropouts or Missing Data.........................................................................12
6.3.
Population for Analysis ................................................................................................12
6.4.
Patient Disposition .......................................................................................................12
6.5.
Patient Characteristics ..................................................................................................13
6.6.
Treatment Compliance .................................................................................................13
6.6.1.
LY2510924 Compliance ......................................................................................13
6.6.2.
MEDI4736 Compliance .......................................................................................13
6.7.
Concomitant Therapy...................................................................................................13
6.8.
Safety Analyses............................................................................................................14
6.8.1.
Extent of Exposure...............................................................................................14
6.8.2.
Dose Limiting Toxicity ........................................................................................14
6.8.3.
Adverse Events ....................................................................................................14
6.8.3.1.
Adverse Events of Special Interest for Durvalumab........................................15
6.8.4.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................15
6.8.5.
Clinical Laboratory Evaluation.............................................................................15
6.8.6.
Vital Signs and Other Physical Findings...............................................................16
6.8.7.
Electrocardiograms ..............................................................................................16
6.9.
Pharmacokinetic Analyses............................................................................................16
6.10. Biomarker Analyses.....................................................................................................17


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6.11. Pharmacokinetic/Pharmacodynamic Analyses..............................................................17
6.12. Immunogenecity Analyses ...........................................................................................17
6.13. Efficacy Analyses ........................................................................................................17
6.13.1.
Efficacy Analysis Variables (RECIST v.1.1)........................................................17
6.13.2.
Efficacy Analysis Variables (RECIST v1.1 with 
confirmatory scan for disease progression)...........................................................19
6.14. Protocol Violations.......................................................................................................21
6.15. Interim Analyses and Data Monitoring.........................................................................21
6.16. Annual Report Analyses...............................................................................................22
6.17. Clinical Trial Registry Analyses...................................................................................22
7.
References ........................................................................................................................24


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Table of Contents
Table
Page
Table CXAD.4.1.
Estimated Incidence Rate and Its Two-sided 95% Confidence Interval........9
Table CXAD.5.1.
Data Handling Conventions ......................................................................11
Table CXAD.5.2.
Rules for Determining Date of Progression or Censor for Progression-Free 
Survival
19


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Table of Contents
Figure
Page
Figure CXAD.4.1.
CXAD study design..................................................................................10


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3.
Revision History
SAP Version 1 was approved prior to the first visit when a subject receives study drug or any 
other protocol intervention. 


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4.
Study Objectives
4.1.
Primary Objective
Dose Escalation
The primary objective of the dose-escalation part of this study is to assess the safety and 
tolerability of LY2510924 SQ daily in combination with durvalumab by identifying dose-
limiting toxicities (DLTs) and the maximum-tolerated dose (MTD) of the combination in 
patients with advanced (metastatic and/or unresectable) solid tumors.  
Dose Expansion
The primary objective of the dose-expansion part of this study is to assess the safety of 
LY2510924 SQ daily in combination with durvalumab in patients with advanced pancreatic and 
ovarian cancers.    
4.2.
Secondary Objectives

To characterize the pharmacokinetics (PK) of LY2510924 and durvalumab when 
co-administered

To characterize the immunogenicity of durvalumab when administered in combination with 
LY2510924 

To assess the antitumor activity of the combination of LY2510924 and durvalumab in 
patients with advanced solid tumors  
4.3.
Exploratory Objectives 
The exploratory objective of this study is to examine biomarkers, including pharmacodynamic 
markers, relevant to LY2510924 and durvalumab, including but not limited to, immune 
cells/immune functioning, drug targets, cancer-related pathways and the disease state, and to 
correlate these markers with clinical outcome.  


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5.
Summary of Study Design
Study CXAD is a multicenter, nonrandomized, open-label, dose-escalation Phase 1a/1b study of 
LY2510924 combined with MEDI4736.  
This Phase 1a/1b study will be conducted in 2 parts.  The first part (Phase 1a) of the study will 
consist of a dose-escalation assessment of the safety and tolerability of CXCR4 administered 
with MEDI4736 with advanced refractory solid tumors (Figure CXAD.4.1).  The second part 
(Phase 1b) of the study will be disease restricted to include 2 expansion arms in advanced 
pancreatic cancer (N=approximately 15 patients) and ovarian cancer (N= approximately 15 
patients), all receiving LY2510924 (dose determined from Phase 1a) with MEDI4736.
Dose escalation for LY2510924 in combination with MEDI4736 in Phase 1a will be driven by an 
adaptive model-based dose-escalation scheme (Neuenschwander et al. 2008) to assist in 
estimation of DLT rate at recommended dose levels.  It provides quantitative guidance on the 
determination of the dose level and provides a lower underdosing rate and a higher MTD 
selection rate than traditional 3+3 method. The starting dose level will be 20 mg.  Subsequent 
dose levels will reflect a maximum increment of 10 mg from the prior dose level.  If the MTD 
has not yet been reached at the highest dose level of 40 mg, then additional dose levels may be 
investigated based on both safety and the available PK data.  The dose escalation method is
described in details in Attachment 9 of the protocol. 
5.1.
Determination of Sample Size
To determine the MTD of LY2510924, 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 (Phase 1a) will primarily be limited by the 
incidence of DLTs. Under the adaptive scheme, each dose level will enroll 3 patients initially 
and additional patient cohorts may be enrolled in case of DLT.  The anticipated sample size for 
Phase 1a ranges from approximately 12 to 15 patients, depending on the incidence of DLTs.  As 
shown in protocol Attachement 9, the mean number of patients in simulated trials using this dose 
escalation method was at most 15 patients.  Each expansion arm in Phase 1b will enroll
approximately 15 patients. The overall sample size is thus estimated to be approximately 45 
patients.
The sample size of 15 patients in Phase 1b has been selected to allow adequate assessment of
safety at the recommended dose level.  It can provide adequate precision for the estimated 
incidence rate of the following quantities of interest: (1) patients having a specified AE or (2) 
patients showing a response (PR/CR) to treatment.  Example point estimates of incidence rates 
and corresponding 2-sided 95% confidence intervals (CI) are summarized in Error! Reference 
source not found..  The values are provided as a reference for estimation rather than a basis of 
any decision criteria.  The MTD may be revised based on the safety data obtained in Phase 1b 
(Iasonos and O’Quigley 2013).


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Table CXAD.5.1.
Estimated Incidence Rate and Its Two-sided 95% Confidence 
Interval
Num. of Cases
(N=15)
Est. 
Rate
95% CIa
Lower Limit
Upper Limit
0
0.0
0.0
0.22
3
0.2
0.04
0.48
6
0.4
0.16
0.68
9
0.6
0.32
0.84
Abbreviations: CI = confidence interval; Est. = estimated; N = number of patients.
a
95% Clopper-Pearson interval for binomial distribution with sample size of 15
5.2.
Method of Assignment to Treatment
This study is open-label for Phase 1a and Phase 1b. 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/expansion arm for each patient.  
For Phase 1a, if investigators have eligible patients who have consented concurrently, more than 
3 patients may be entered at a particular dose level 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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Abbreviations:  approx. = approximately; I/E = inclusion/exclusion criteria; IV = intravenous; LY 
= LY2510924; Ph1a = Phase 1a; PK/PD = pharmacokinetic/pharmacodynamic; pts = patients; 
MTD = maximum-tolerated dose; SQ = subcutaneous.
Figure CXAD.4.1.
CXAD study design.


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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 feature of the protocol.  Any other change to the data analysis 
methods described in the protocol and the justification for making the change will be described 
in the clinical study report (CSR).
The following data handling conventions will be used in the analysis (see Table 
CXAD.6.1Error! Reference source not found.).
Table CXAD.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 measure is available, they may be averaged 
if appropriate.
Entered
Patients who have signed the informed consent form directly or 
through their legally acceptable representatives.
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 a historical illness, events occurring 
in the same year as study entry should have at least 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; all 
previous treatments for cancer should have at least known date, month, and year for the end date, 
in order to determine if inclusion criteria is met.  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 DLT-evaluable; otherwise, patients are 
considered DLT nonevaluble 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. Completed the DLT observation period (Cycle 1) and received the scheduled durvalumab 
dose and at least 75% of LY2510924 doses in Cycle 1;
2. discontinued study treatment or study participation before completing Cycle 1 due to a 
DLT.
6.3.
Population for Analysis
Safety and efficacy analyses will be conducted on all patients who have received at least one 
dose of the study treatment(s), regardless of whether they are deemed evaluable for the 
assessment of a dose level.
Pharmacokinetic (PK) analyses will be conducted on patients who have received at least one 
dose of the study treatment(s) and have sufficient samples collected to allow the estimation of
LY2510924 and MEDI4736 PK parameters.
Pharmacodynamic (PD) analyses will be conducted on subjects who have received at least one 
dose of the study treatment(s) 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 one cycle of study 
treatment or discontinue prior to doing so due to an AE classified as a DLT in Phase 1a and
patients who received two cycles of study treatment in Phase 1b.  All patients entered in the 
study will be included in the summary.  Reason for discontinuation from both study treatment 


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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.
Screen failures will be listed and summarized if appropriate.
6.5.
Patient Characteristics
Patient characteristics will be summarized and listed for all patients enrolled and will include:

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.

Historical substance consumption such as alcohol and tobacco use.  
Other patient characteristics will be summarized and listed as deemed appropriate.
6.6.
Treatment Compliance
6.6.1.
LY2510924 Compliance
Patient compliance with LY2510924 will be assessed on Day 1 of each cycle (excluding Cycle 
1).  Compliance will be assessed by direct questioning, review of diary, and counting any 
returned vials.  Patients are considered significantly noncompliant if <75% of expected study 
drug is taken in a visit interval.  Deviations from the prescribed dosage regimen should be 
recorded on the CRF.  On those study days that PK collection is scheduled, patients will wait to 
self-administer LY2510924 until they are in the clinic. For more details refer to Protocol Section 
7.6.1.
6.6.2.
MEDI4736 Compliance
MEDI4736 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.  
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.
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.


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6.8.
Safety Analyses
All patients who receive at least one dose of LY2510924 or durvalumumab will be evaluated for 
safety and toxicity. The National Cancer Institute Common Terminology Criteria for Adverse 
Events Version 4.0 (NCI-CTCAE v4.0) will serve as the reference document for choosing 
appropriate terminology for, and grading the severity of, all adverse events (AEs) and other 
symptoms.
Safety analyses will include summaries of the following:

adverse events, including severity and possible relationship to study drug

DLTs at each dose level

dose adjustments

laboratory values 

vital signs 

ECG readings

transfusions
6.8.1. Extent 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.
DLT-equivalent toxicities 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. 
Any minor version of CTCAE Version 4.0 (for example, CTCAE Version 4.03) may be used for 
this study.  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”.


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
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 study treatment or any pre-existing condition that increases in CTCAE grade 
on or after the day of the first dose of study treatment, and prior to the end of the short-term 
(safety) follow-up.  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 “Any grade” categories. Immune-related AEs 
may be tabulated if deemed appropriate.
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.
6.8.3.1.
Adverse Events of Special Interest for Durvalumab
AESIs for durvalumab include infusion-related reactions and immune-related AEs: colitis; 
pneumonitis; hepatotoxicity: ALT/AST increases/hepatitis/hepatotoxicity; 
neuropathy/neuromuscular toxicity; endocrinopathy; dermatitis; nephritis; and pancreatitis. 
6.8.4. Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events
A summary of deaths will be presented by cohort and overall.  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
6.8.5. Clinical Laboratory Evaluation
Laboratory data (including abnormal laboratory data) will be listed by cycle for all 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.


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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.
If available, 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. A QT-concentration analysis of 
change from baseline in QTcF versus serum concentration may be performed, if deemed 
appropriate. 
Lilly will review ECG data and monitor cardiac events/deaths during the course of the study.  
6.9.
Pharmacokinetic Analyses
The sampling schedule for drawing blood samples for LY2510924 and Durvalumab for 
determination of  LY2510924 and Durvalumab concentrations is provided in Attachment 4 of the 
protocol. Serum concentrations of Durvalumab prior to infusion (Cmin) and post-end of infusion 
will be summarized using descriptive statistics Pharmacokinetic parameters for LY2510924 will 
be computed by standard noncompartmental methods using Phoenix™ WinNonlin® or 
equivalent program on a computer that meets or exceeds the minimum system requirements for 
this program. The primary parameters for analysis will be area under the concentration-time 
curve (AUC) of LY2510924.  Other noncompartmental parameters, such as time of half-life 
(t1/2), apparent clearance (CL/F), and apparent volume of distribution (V/F) may be reported.  
Population PK analyses for LY2510924 may be conducted using a population PK approach as 
deemed necessary by Global PK/PD management. Planned PK analyses are specified in separate 
standalone NCA and popPK/PD analysis plans as appropriate. The version of any software used 
for the analysis will be documented and the program will meet the Lilly requirements of software 
validation.  It is possible that other equivalent pharmacokinetic/graphing/scripting software 
programs may be utilized if appropriate, warranted, and approved by Global PK/PD management 
for generating PK and PK/PD tables, figures, and listings. Upon completion of quality control 
and quality review procedures, all documentation will be collected and filed in a Lilly-approved 
repository. All PK and PK/PD analysis, and creation of table, figures, and listings will be the 


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responsibility of Lilly Global PK/PD & Pharmacometrics group based on applicable functional 
Standard Operating Procedures and software approved by this group’s management.
6.10. Biomarker Analyses 
Exploratory biomarkers will be summarized and assessed for correlations with clinical outcomes.  
Biomarker relationships by tumor type, changes in biomarker levels at baseline and over time, 
and differences among dose levels or exposure will be explored as possible.
6.11. Pharmacokinetic/Pharmacodynamic Analyses
The relationship between LY2510924 exposure and selected efficacy, safety outcomes, and 
biomarkers may be explored if relevant.
6.12. Immunogenecity Analyses
Immunogenicity incidence will be tabulated, and correlation to MEDI4736, activity, and safety 
will be assessed, as appropriate, respectively.  The measures that will be analyzed include 
baseline presence and level of ADA, treatment-emergent ADA, levels of neutralizing ADA, and 
incidence and levels of ADA related to IRRs.
6.13. Efficacy Analyses
Tumor response data will be tabulated by cohorts. Particularly, the antitumor effect will be 
summarized by the objective response rate (ORR) and disease control rate (DCR) by cohort and 
overall.  Mean, median, range, and exact 95% confidence intervals (CI) will be provided.  
Reported lesion measurement data, including sum of target lesions, change and/or percent 
change from baseline sum and smallest sum (nadir) 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), time to response (TTR),
duration of response (DoR) and overall survival (OS) will be listed and summarized.  For all 
time-to-event variables, the Kaplan-Meier method (Kaplan and Meier 1958) will be used to 
estimate the survival curves, medians with 95% CI, and survival rates at various time points if 
applicable.  For Phase 1b, time-to-event variables will be summarized by different cohorts.
6.13.1. Efficacy Analysis Variables (RECIST v.1.1)
Definition of efficacy analysis variables are listed alphabetically.
Disease Control Rate is defined as the proportion of treated patients achieving a best overall 
response of complete response (CR), partial response (PR), or stable disease (SD) per RECIST 
v.1.1. Patients who do not have any postbaseline tumor response assessments for any reason are 
considered non-responders and are included in the denominator when calculating the response 
rate.
Note. Best overall response is the best response recorded from the start of treatment until 
disease progression, in the order of CR, PR, SD, PD, and NE.


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Duration of Response is defined from the date of first documented CR or PR that is 
subsequently confirmed (responder) to the date of objective progression or the date of death due 
to any cause, whichever is earlier.  If a responder is not known to have died or have objective 
progression, then the patient will be censored at the date of last evaluable tumor assessment.
Objective response rate is defined as the proportion of treated patients achieving a best overall 
response of PR or CR per RECIST v.1.1. Patients who do not have any postbaseline tumor 
response assessments for any reason are considered non-evaluable and are included in the 
denominator when calculating the response rate.
Overall survival is defined as time from the date of first treatment to the date of death from any 
cause. For each patient who is not known to have died as of the data-inclusion cut-off date for a 
particular analysis, OS will be censored for that analysis at the date of last contact prior to the 
data-inclusion cut-off date (contacts considered in the determination of last contact date include 
AE date, lesion assessment date, visit date, and last known alive date).
Progression-free survival is defined as the time from the date of first treatment until the date of 
radiographic documentation of progression (as defined by RECIST v. 1.1) based on investigator 
assessment or the date of death due to any cause, whichever is earlier.
Time-to-response is the time from the date of first study treatment until the first evidence of a 
confirmed CR or PR.
Table CXAD.6.2 lists rules for determining date of progression or censor for PFS.  The 
censoring is taken in the following order:

If a patient does not have a baseline disease assessment, then the PFS time will be 
censored at the treatment starting date, regardless of whether or not objective progressive 
disease (PD) or death has been observed for the patient; otherwise,

If a patient is not known to have died or have investigator-assessed PD as of the 
data-inclusion cut-off date for the analysis, the PFS time will be censored at the date of 
last postbaseline adequate radiological tumor assessment, or at the date of first treatment 
if the patient does not have any postbaseline adequate radiological assessment.
Note. If there are multiple dates associated with one radiological tumor assessment, the 
assessment date will be set to the first date when the overall response is PD and the last date 
otherwise. A radiological tumor assessment is considered adequate if its response is among CR, 
PR, SD, or PD.
PFS (day) = Date of progression / censor – date of first treatment + 1


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Table CXAD.6.2.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival
Rule
Situation
Date of Progression or Censor
Outcome
1
No baseline tumor assessments
Date of first treatment
Censored
2
No postbaseline assessments and no death
Date of first treatment
Censored
3
No documented progression and no death 
(with a postbaseline tumor assessment)
Date of last adequate tumor assessment
Censored
4
Patient lost to follow-up (or withdrew 
consent from study participation) before 
documented progression or death
Date of last adequate tumor assessment
Censored
5
Documented progression
Date of documented progression
If a tumor assessment was done on multiple 
days, use the earliest date for that visit.
Progressed
6
Death without documented progression
Date of death
Progressed
7
Documented progression or death after 
missing ≥2 consecutive postbaseline tumor 
assessments
Date of last adequate tumor assessment 
before missed assessments or date of first 
treatment , whichever is later
Censored
Note: Progression-free survival and associated outcome is determined by the earliest of the dates above, if more 
than 1 situation applies.
6.13.2. Efficacy Analysis Variables (RECIST v1.1 with confirmatory 
scan for disease progression)
For Study CXAD, RECIST v1.1 with confirmatory scan for disease progression (denote it as 
RECISTc for simplicity) will be adapted to account for the unique tumor response characteristics 
seen with treatment of immuno-oncology therapy.  RECISTc will be applied as detailed in the 
study protocol, and the resulting data will be included in the clinical database.
Objective response rate (RECISTc) is defined as the proportion of treated patients achieving a 
best overall response of PR or CR per RECISTc. Particularly, the best overall response by 
RECISTc (denoted as ORRc) closely related to confirmed response by RECIST v1.1.  ORRc 
further captures responses after unconfirmed PD and it does not require confirmation.  For 
example:

If the best response by RECIST is CR, then the best response by RECISTc
is CR.

If the best response by RECIST is PR, SD, or PD, the best response by 
RECISTc is the best response over the initial assessment (prior to PD by 
RECISTc) and the confirmation stage.
Overall, the best response by RECISTc should be the same or better than the best response by 
RECIST criteria.  In addition, patients who do not have any postbaseline tumor response 


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assessments for any reason are considered non-evaluable and will be included in the denominator 
when calculating the response rate.
PFSc:  The date from the treatment started date to the time of confirmed PD (PDc) assessed by 
RECISTc.

If the initial PD is confirmed at the very next scan (consecutive PD) then 
the date of PDc is the initial PD date by RECIST v1.1.

If the initial PD is unconfirmed at the very next scan (non-consecutive
PD), then the date of PDc is the date of second PD.
Duration of response by RECISTc:  The duration of response is defined from the date 
measurement criteria for CR or PR (whichever is first recorded) are first met to the date of PDc
or the date of death due to any cause, in the absence of an observed PDc.
Graphic Example:
Scenario 1:  The initial PD is confirmed at the next scan (consecutive PD).  The efficacy 
variables by RECISTc and RECIST are the same.
                                                   Best response by RECISTc        PD by RECISTc         
BL          1st Dose              PR                  PR                          PD                         PD                                                    Death
                                                  Best response by RECIST        PD by RECIST         
Scenario 2:  The initial PD is not confirmed at the next scan (non-consecutive PD).  The efficacy 
variables by RECISTc and RECIST are different.
                                                                                        PFS by RECISTc
           
                                                  Duration of Response by RECISTc
                                                                           Best response by RECISTc                PD by RECISTc
BL          1st Dose           PR                PR                          PD                         CR                                  PD                        Death
                                                  Best response by RECIST        PD by RECIST         
                                                           
                                           Duration of Response by RECIST
                      
                    PFS by RECIST


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In addition, the best response after initial PD may be listed.  Other efficacy analysis based on 
RECIST and/or RECISTc may be performed for exploratory analysis (e.g., in patients who had 
baseline and at least one post-baseline scan).
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
Data will be reviewed on a cohort-by-cohort basis during Phase 1a of the study, until the MTD is 
determined. The purpose of these cohort-by-cohort reviews is to evaluate the safety 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 in consultation with collaborator
(AstraZeneca) will make the determination regarding dose escalation based upon their review of 
the safety and tolerability data as described in this protocol.  
Safety and/or PK data will be reviewed during the study if needed for dose escalation,
modifications to the dose escalation strategy or other design elements.
Once MTD is determined for Phase 1a, an interim analysis including safety and PK will be 
performed prior to opening Phase 1b.
In Phase 1b, if a DLT-equivalent toxicity occurs in one third or more of patients during Cycle 1 
(with a minimum of 6 patients enrolled, unless two events occur prior to 6 patients being 
enrolled), a data review will be performed to determine whether to continue at the current 
LY2510924 dose or whether the dose of LY2510924 should be reduced.
In Phase 1b, a safety review may occur for each expansion arm approximately 2 mont hs after 
approximately 8 of the planned patients start study therapy. 
If an unplanned interim analysis is deemed necessary, the sponsor will determine if it is
necessary to amend the protocol.
Any interim analyses may be combined if they are expected to occur within approximately a 
month, and interim analyses may also be combined with the ongoing trial-level safety review or 
annual safety review for annual safety update reporting.
The final analysis and evaluation of the primary objective and the secondary objectives will be 
performed approximately 6 months after the last patient of each expansion arm starts study 
therapy, and the final analysis may be conducted separately for each expansion arm. A clinical 


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study report might be created before the last patient visit.  In this case, all data until the data-
cutoff date will be used for the analysis of safety, efficacy, PK and PD biomarkers.  
6.16. Annual Report Analyses
The following analyses are needed as requested for annual reporting purposes.
Clinical Investigator brochure:

Summary and Listing of SAE

Summary and Listing of Deaths

Summary and Listing 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
Other analyses may be requested if deemed necessary.
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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
Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

Adverse event reporting is consistent with other document disclosures for example, the 
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
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). 
Eur J Cancer. 2009;45(2) 228-247.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
1958;53:457-481.
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.


Leo Document ID = a0e9a3df-ea7b-42cb-8cf1-819e1f6f705a
Approver: 
Approval Date & Time: 02-Jun-2016 20:00:19 GMT
Signature meaning: Approved
PPD