Clinical trial NCT02518113
Conditions: T-cell Acute Lymphoblastic Leukemia T-cell Lymphoblastic Lymphoma
Sponsor: Eli Lilly and Company
Start date: 2015-10-01; Completion date: 2018-01-15
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the safety of the study drug known as LY3039478 in combination with dexamethasone in participants with T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma (T-ALL/T-LBL).

Detailed description:

Arms: arm 1: Part A: 50 mg LY3039478 administered orally three times per week (TIW) and 24 mg dexamethasone administered orally on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression.

75 mg LY3039478 administered orally three times per week (TIW) and 24 mg dexamethasone administered orally on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression.

100 mg LY3039478 administered orally three times per week (TIW) and 24 mg dexamethasone administered orally on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression.

125 mg LY3039478 administered orally three times per week (TIW) and 24 mg dexamethasone administered orally on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression. arm 2: Part B: LY3039478 administered orally TIW at escalating doses and dexamethasone administered orally twice a day (BID) on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression.

There were no participants enrolled to Part B of the study. arm 3: LY3039478 administered orally TIW and dexamethasone administered orally BID on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression.

There were no participants enrolled to Phase 2 of the study. arm 4: Placebo administered orally TIW and dexamethasone administered orally BID on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression.

There were no participants enrolled to Phase 2 of the study.
Interventions: intervention 1: LY3039478 intervention 2: Dexamethasone intervention 3: Placebo
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered orally

Protocol documents:
Prot_000.pdf: 
Protocol I6F-MC-JJCB (a)  
 
A Phase 1b/Randomized Phase 2 Study to Evaluate LY3039478 in Combination with 
Dexamethasone in T-ALL/T-LBL Patients 
 
NCT02518113 
Approved Date: 04-Jun-2015 


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1.
Protocol I6F-MC-JJCB(a)
A Phase 1b/Randomized Phase 2 Study to Evaluate 
LY3039478 in Combination with Dexamethasone in 
T-ALL/T-LBL Patients
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 
LY3039478, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.  This document and its associated attachments are 
subject to United States Freedom of Information Act Exemption 4.
LY3039478
A Phase 1b/randomized Phase 2 study to evaluate LY3039478 in combination with 
dexamethasone in patients with T-ALL/T-LBL.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 04-Jun-2015 GMT


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2.
Synopsis
Clinical Protocol Synopsis:  Study I6F-MC-JJCB(a)
Name of Investigational Product:  LY3039478
Title of Study: A Phase 1b/Randomized Phase 2 Study to Evaluate LY3039478 in Combination with 
Dexamethasone in T-ALL/T-LBL Patients
Number of Planned Patients:  86 to 92 total patients
Entered:
Enrolled/Randomized:
Phase 1: Part A 13 to 16 patients; Part B 13 to 16 patients
Phase 2: 60 patients
Phase of Development: 1b / 2
Length of Study:  approximately 60 months
Planned first patient visit:  May 2015
Planned last patient visit, excluding the continued access:  May 2020
Planned interim analysis:  At end of Phase 1 and during Phase 2, every 12 months and once 30 patients are 
randomized and have completed the CR determination.
Objectives:  
The primary objective is as follows:

Phase 1:  to determine the recommended dose of LY3039478 in combination with dexamethasone in adult 
patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic 
lymphoma (T-LBL) (Part A) and pediatric patients (Part B)

Phase 2: to determine if the overall remission rate (ORR) (CR plus CR with incomplete blood count 
recovery [CRi]) in adult patients with relapsed/refractory T-ALL/T-LBL treated with LY3039478 in 
combination with dexamethasone exceeds that of those patients treated with placebo in combination with 
dexamethasone 
The secondary objectives are as follows:

Phase 1:
o
to characterize the safety and toxicity profile of LY3039478 in combination with dexamethasone 
as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v 4.0
o
to assess the pharmacokinetic (PK) parameters of LY3039478 in combination with 
dexamethasone therapy
o
to document efficacy based on Cheson criteria for leukemia and modified response criteria for 
malignant lymphoma
o
to evaluate gene mutation (eg, NOTCH-1/FBXW7/RAS/PTEN) status with efficacy

Phase 2: 
o
to compare the ORR plus partial remission (PR) and PR alone for both arms
o
to assess the remission rate for patients receiving LY3039478 in combination with dexamethasone 
after failure of placebo in combination with dexamethasone
o
to assess duration of remission (DoR) (= CR and Cri and PR)
o
to assess relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS)
o
to compare the safety and toxicity profile of LY3039478 in combination with dexamethasone to 
dexamethasone and placebo as assessed by NCI CTCAE v 4.0
o
to assess the pharmacokinetic (PK) parameters of LY3039478 and dexamethasone in combination 
therapy
o
to assess patient quality of life using the Functional Assessment of Cancer Therapy-Leukemia
(FACT-Leu)
o
to evaluate gene mutation (eg, NOTCH-1/FBXW7/RAS/PTEN) status with efficacy


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The exploratory objectives are as follows:

to assess clinical utility of the NICD immunohistochemistry (IHC) assay as a potential companion 
diagnostic for LY3039478

to evaluate biomarkers in tumor tissue, blood, plasma, and cerebrospinal fluid (CSF), which may include, 
but not be limited to, NICD enzyme-linked immunosorbent assay (ELISA) (or an alternative validated 
method), gene expression, relevant to the study disease or safety, efficacy, and mechanism of action of 
LY3039478 and dexamethasone

to explore pharmacodynamic (PD) effects of LY3039478 on biomarkers indicative of Notch activity

to evaluate the CSF exposure of LY3039478
Study Design:  Study I6F-MC-JJCB is a multicenter study consisting of a nonrandomized, open-label, 
dose-escalation Phase 1 study followed by a randomized, double-blind, Phase 2 study in patients with relapsed or 
refractory T-ALL/T-LBL.  The Phase 1 portion of the study will consist of 2 different patient populations, an adult 
(Part A) and a pediatric (Part B), and will define the recommended dose of LY3039478 in combination with 
dexamethasone in each of these populations.  The decision to proceed with the pediatric dose exploration (Part B) 
will be made after safety analysis of the adult cohort. The randomized Phase 2 study will be a double-blinded, 
multicenter evaluation to determine if the ORR (CR and CRi) rate in adult patients with relapsed/refractory 
T-ALL/T-LBL treated with LY3039478 in combination with dexamethasone exceeds that of those patients treated 
with placebo in combination with dexamethasone. 
Diagnosis and Main Criteria for Inclusion and Exclusions:  Patients must have T-ALL or T-LBL. T-ALL is 
defined ≥25% of blasts in the bone marrow and expression of at least 2 of the following cell surface antigens:  
CD1a, CD2, CD3 (surface or cytoplasmic), CD4, CD5, CD7, and/or CD8.  If the only T cell markers present are 
CD4 and CD7, the leukemia cells must also lack the myeloid markers CD33 and/or CD13.  Patients with initial 
refractory disease should have received at least 2 multi-agent chemotherapy induction regimens. Patients in first or 
second relapse must have been refractory to at least 1 multi-agent chemotherapy reinduction regimen.  They must 
have had at least 60 days between prior hematopoietic stem cell transplant and first dose of study drug, have 
adequate performance status and organ function, be ≥16 years old for the adult cohort (Phase 1, Part A) and 2 to 
<16 years old for the pediatric cohort (Phase 1, Part B), and have a life expectancy of 2 months.  
Patients may be excluded if they are currently enrolled in another ongoing clinical trial with investigational 
products, have recently discontinued (within less than 2 weeks) prior anticancer therapy, have a serious concomitant 
illness, have an uncontrolled or active infection <7 days prior to administration of study drug, have current or 
recurrent (within 3 months) gastrointestinal disease, have conditions requiring chronic systemic glucocorticoid use, 
have active graft versus host disease, have active leukemic involvement of the central nervous system, or have a 
second primary or prior malignancy that would affect the interpretation of study results.  
Test Product, Dosage, and Mode of Administration:  LY3039478, dose range 25 to 200 mg, given orally as 
capsules 3 times per week during a 28-day cycle.  
Placebo will be given orally as capsules 3 times per week during a 28-day cycle.  
Planned Duration of Treatment:  Patients will receive 2 cycles (28 days each) of LY3039478 unless 1 or more of 
the criteria for discontinuation are fulfilled.  A patient may receive >2 cycles of treatment only if:  1) none of the 
criteria for discontinuation have been fulfilled, and 2) the investigator determines that the patient is experiencing 
clinical benefit from treatment.  
Short-term follow-up period (postdiscontinuation):  30 days.  
Long-term follow-up (postdiscontinuation):  until death.  
Reference Therapy, Dose, and Mode of Administration:  Dexamethasone will be administered at a dose of 24 mg 
on Day 1 through Day 5 every other week to the adult patients and 10 mg/m2 twice a day (BID) to the pediatric 
patients.


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Criteria for Evaluation:
Efficacy:

ORR

CR rate

proportion of patients achieving a CRi

proportion of patients achieving a PR

DoR

OS

RFS

EFS
Safety:  Safety will be evaluated based on recorded adverse events (AEs), physical examinations, vital sign 
measurements, electrocardiograms, and clinical laboratory assessments.  Adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  Adverse events and clinical laboratory values will be 
graded using NCI CTCAE v4.0.
Health Outcomes:  Patient health-related quality of life including physical, social/family, emotional and functional 
well-being will be assessed using the self-administered FACT-Leu questionnaire at the beginning of each visit only 
in the Phase 2 portion of the study.
Pharmacokinetics: Blood and CSF samples will be used to determine the concentrations of LY3039478.  CSF 
concentrations of LY3039478, and plasma concentrations of LY3039478 and dexamethasone will be quantified 
using validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) assays.  The remaining 
plasma samples collected for PK evaluation may be used for exploratory studies to assess the metabolism of 
LY3039478, which may involve sample pooling.
Pharmacodynamics/Tailoring Biomarkers:  Blood, CSF, EDTA plasma, tissue, and bone marrow samples will be 
collected.  Samples will be tested for markers of Notch and related pathway activation including, but not limited to, 
protein expression and activation by IHC and ELISA, and gene expression by quantitative polymerase chain 
reaction (PCR) analysis to evaluate their association with the observed clinical outcomes to LY3039478.
Statistical Methods:
Statistical:
In the Phase 1 portion of the study, approximately 13 to 16 patients will be enrolled into each of the adult (Part A)
and pediatric (Part B) cohorts sequentially and without randomization to dose.  The total sample size per cohort will 
be determined by DLTs.
In the Phase 2 portion of the study, approximately 60 evaluable patients will be randomized to the 2 treatment arms 
in a 2:1 ratio (40 randomized to LY3039478 and dexamethasone and 20 randomized to placebo and 
dexamethasone).
Efficacy analyses will be based on the intention-to-treat (ITT) analysis set.  This population is defined as all patients 
randomized to study treatment.  Patients will be grouped according to dose level cohort or randomized treatment.  A 
secondary analysis of the primary efficacy endpoint based upon the per-protocol set (PPS) of patients may be 
performed if there are significant numbers of patients with major protocol deviations (≥10% of total patient 
population).  The PPS is defined as those patients in the ITT set who are compliant with the study protocol.
Safety analyses will be based on the safety population, defined as all enrolled patients receiving at least 1 dose of 
any study drug.  Patients will be grouped according to treatment received in Cycle 1.
PD and/or tailoring biomarker analyses will be based on the subset of patients from the above populations from 
whom a valid assay result (according to laboratory guideline) has been obtained.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise stated.  All tests of 
interactions will be conducted at a 2-sided alpha level of 0.1, and all confidence intervals (CIs) will be given at a 
2-sided 95% level, unless otherwise stated.  
Efficacy:
No formal efficacy analysis is planned for the Phase 1 portion of this trial.  However, any response data will be 
listed and tabulated.  In the Phase 2 portion, the primary efficacy endpoint of ORR (CR plus CRi) and its exact 95% 


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CI will be estimated for each treatment arm.  The proportion in each treatment arm will be compared using Fisher’s 
exact test.  All randomized patients, according to the ITT principle, will be included in the analysis of this endpoint.  
The secondary efficacy endpoints of proportion of patients achieving an ORR plus PR, and PR, and their exact 95% 
CIs will be estimated for each treatment arm and compared by 2-sided Chi-squared test or Fisher’s exact test 
between 2 arms.  For the secondary efficacy endpoints OS, RFS, and EFS, the Kaplan-Meier method will be used to 
estimate the survival curves as well as survival rates at various prespecified time points (12 months for OS, 6 and 
12 months for RFS and EFS) for each treatment arm. The secondary efficacy endpoint DoR is subject to competing 
risk of death without relapse; therefore, the cumulative incidence of relapse will be used.  In the calculation, patients 
who did not have the event will be considered right-censored observations.  All randomized patients, according to 
the ITT principle, will be included in the analysis of these endpoints.  The comparison of the survival curves 
between treatment groups will be conducted by a log-rank test.
Safety:  Safety analyses will include listings and/or summaries of the following:

adverse events (AEs) and treatment-emergent adverse events (TEAEs),

drug exposure,

dose adjustments,

laboratory measures,

reasons for death, and

hospitalizations and transfusions.
Health Outcomes: FACT-Leu results will be summarized descriptively by cycle, including number of completed 
questionnaires, scores for each scale and subscale, and changes from baseline.
Pharmacokinetics: PK analyses will be conducted on patients who receive at least 1 dose of the study drug and have
samples collected.  PK parameter estimates for LY3039478 and dexamethasone, where possible, will be calculated 
by standard noncompartmental methods of analysis.
Pharmacodynamics/Tailoring Biomarkers: Biomarker data from all patients undergoing biomarker assessments will 
be analyzed using descriptive statistics.
Interim Analyses:  An interim analysis including safety, PK, and PD data will be conducted prior to proceeding to 
the Phase 2 portion of the study.  All relevant data will be reviewed to confirm the estimation of the MTD.  The 
decision to proceed to Phase 2 will be made following discussions between the investigators and Lilly clinical 
research personnel and documented in writing.  In the Phase 2 portion, safety interim analyses are planned every 
12 months, and at the planned futility interim analysis, when response data from 30 patients has been obtained. 
There are no prespecified rules for stopping the trial due to safety concerns.  The assessment committee members 
will review unblinded safety data at each interim analysis to determine whether there are sufficient safety concerns 
to justify the termination of study treatment and/or enrollment.
One futility interim analysis is planned in Phase 2 once 30 patients are randomized and have completed the CR 
status determination.  The assessment committee may recommend stopping the trial for futility if the observed ORR 
(CR plus CRi) rate difference is <0.05 for the treatment arm compared to the control arm.


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3.
Table of Contents
A Phase 1b/Randomized Phase 2 Study to Evaluate 
LY3039478 in Combination with Dexamethasone in 
T-ALL/T-LBL Patients
Section
Page
1.
Protocol I6F-MC-JJCB(a) A Phase 1b/Randomized Phase 2 Study to 
Evaluate LY3039478 in Combination with Dexamethasone in 
T-ALL/T-LBL Patients .......................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................6
4.
Abbreviations and Definitions...........................................................................................12
5.
Introduction ......................................................................................................................18
5.1.
Rationale and Justification for the Study ......................................................................18
5.1.1.
T-Cell Acute Lymphoblastic Leukemia/T-Cell 
Lymphoblastic Lymphoma...................................................................................18
5.1.2.
Notch Signaling and LY3039478 .........................................................................19
5.1.3.
Mechanism of Action and Nonclinical Activity....................................................20
5.1.4.
Nonclinical Pharmacokinetics/Pharmacodynamics...............................................21
5.1.5.
LY3039478 Nonclinical Toxicity.........................................................................22
5.1.6.
Clinical Experience with LY3039478...................................................................23
5.2.
Rationale for Selection of Dose/Schedule and Design Discussion.................................24
5.3.
Rationale for Amendment (a).......................................................................................25
6.
Objectives.........................................................................................................................26
6.1.
Primary Objective ........................................................................................................26
6.2.
Secondary Objectives...................................................................................................26
6.3.
Exploratory Objectives.................................................................................................27
7.
Study Population...............................................................................................................28
7.1.
Inclusion Criteria..........................................................................................................28
7.2.
Exclusion Criteria ........................................................................................................29
7.3.
Discontinuations ..........................................................................................................31
7.3.1.
Discontinuation of Patients...................................................................................31
7.3.2.
Discontinuation of Study Sites .............................................................................31
7.3.3.
Discontinuation of the Study................................................................................32
8.
Investigational Plan...........................................................................................................33
8.1.
Summary of Study Design............................................................................................33
8.2.
Discussion of Design and Control ................................................................................35


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8.3.
Study Periods, Study Completion, and End of Trial......................................................36
8.3.1.
Continued Access Period......................................................................................36
9.
Treatment..........................................................................................................................38
9.1.
Materials and Supplies .................................................................................................38
9.2.
Treatments Administered .............................................................................................38
9.2.1.
Dose-Escalation Phase .........................................................................................40
9.2.2.
Dose-Limiting Toxicity Determination and Maximum 
Tolerated Dose Definition....................................................................................42
9.3.
Method of Assignment to Treatment ............................................................................43
9.3.1.
Phase 1.................................................................................................................43
9.3.2.
Phase 2.................................................................................................................43
9.4.
Dose Adjustments and Delays......................................................................................44
9.4.1.
Dose Adjustments for LY3039478 within a Cycle................................................44
9.4.2.
Dose Adjustments for LY3039478 between Cycles..............................................44
9.4.3.
Dose Adjustments – Dexamethasone....................................................................45
9.5.
Blinding .......................................................................................................................45
9.5.1.
Emergency Unblinding ........................................................................................45
9.5.2.
Inadvertent Unblinding ........................................................................................45
9.6.
Concomitant Therapy...................................................................................................46
9.7.
Treatment Compliance .................................................................................................47
9.7.1.
Evaluable Patients Phase 1 Parts A and B.............................................................48
9.7.2.
Evaluable Patients Phase 2 ...................................................................................48
10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements...................................................................................................................49
10.1. Efficacy Measures........................................................................................................49
10.1.1.
Study Assessments...............................................................................................49
10.1.1.1.
Pretreatment (Baseline)...................................................................................49
10.1.1.2.
During Study Treatment .................................................................................49
10.1.1.3.
Posttreatment Discontinuation Follow-Up ......................................................50
10.1.2.
Primary Efficacy Measure....................................................................................50
10.1.3.
Secondary Efficacy Measures...............................................................................52
10.1.3.1.
T-ALL............................................................................................................52
10.1.3.2.
T-LBL............................................................................................................53
10.2. Health Outcome/Quality of Life Measures ...................................................................54
10.2.1.
Patient-Reported Outcomes..................................................................................54
10.2.2.
Resource Utilization.............................................................................................55
10.3. Safety Evaluations........................................................................................................55


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10.3.1.
Adverse Events ....................................................................................................55
10.3.1.1.
Serious Adverse Events ..................................................................................56
10.3.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................58
10.3.2.
Electrocardiograms ..............................................................................................58
10.3.3.
Safety Monitoring ................................................................................................58
10.3.4.
Complaint Handling.............................................................................................59
10.4. Sample Collection and Testing.....................................................................................59
10.4.1.
Samples for Study Qualification and Health Monitoring.......................................60
10.4.2.
Samples for Pharmacodynamics and/or Biomarkers .............................................60
10.4.3.
Samples for Drug Concentration Measurements 
Pharmacokinetics .................................................................................................61
11.
Data Quality Assurance.....................................................................................................63
11.1. Data Capture System....................................................................................................63
12.
Sample Size and Statistical Methods .................................................................................64
12.1. Determination of Sample Size ......................................................................................64
12.2. Statistical and Analytical Plans.....................................................................................64
12.2.1.
General Considerations ........................................................................................64
12.2.2.
Patient Disposition...............................................................................................65
12.2.3.
Patient Characteristics..........................................................................................65
12.2.4.
Concomitant Therapy...........................................................................................65
12.2.5.
Postdiscontinuation Therapy ................................................................................66
12.2.6.
Treatment Compliance .........................................................................................66
12.2.7.
Primary Outcome and Methodology.....................................................................66
12.2.8.
Other Analyses of Efficacy ..................................................................................66
12.2.9.
Pharmacokinetic Analyses....................................................................................67
12.2.10. Pharmacodynamics and Tailoring Analyses..........................................................68
12.2.11. Health Outcome/Quality of Life Analyses............................................................68
12.2.12. Safety Analyses....................................................................................................68
12.2.13. Subgroup Analyses ..............................................................................................69
12.2.14. Interim Analyses..................................................................................................69
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................71
13.1. Informed Consent.........................................................................................................71
13.2. Ethical Review.............................................................................................................71
13.3. Regulatory Considerations ...........................................................................................71
13.3.1.
Protocol Signatures ..............................................................................................72
13.3.2.
Final Report Signature .........................................................................................72
14.
References ........................................................................................................................73


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List of Tables
Table
Page
Table JJCB.9.1.
Treatment Regimens/Dosing Schedule ...................................................39
Table JJCB.9.2.
Proposed LY3039478 Dose-Escalation Scheme for the Adult 
Cohort ....................................................................................................41
Table JJCB.10.1.
Treatment Failure in T-LBL ...................................................................54
Table JJCB.10.2.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........55


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List of Figures
Figure
Page
Figure JJCB.8.1.
Illustration of study design......................................................................35


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List of Attachments
Attachment
Page
Attachment 1.
Protocol I6F-MC-JJCB Study Schedule..................................................78
Attachment 2.
Protocol I6F-MC-JJCB Clinical Laboratory Tests...................................90
Attachment 3.
Protocol I6F-MC-JJCB Pharmacokinetic, Pharmacodynamic, CSF 
and ECG Sampling Schedule..................................................................92
Attachment 4.
Protocol I6F-MC-JJCB Hepatic Monitoring Tests for Treatment-
Emergent Abnormality ...........................................................................96
Attachment 5.
Protocol I6F-MC-JJCB Eastern Cooperative Oncology Group, and 
Lansky Performance Status.....................................................................97
Attachment 6.
Protocol I6F-MC-JJCB Creatinine Clearance and Serum Creatinine 
Formulas ..............................................................................................100
Attachment 7.
Protocol I6F-MC-JJCB FACT-Leu (Version 4) Questionnaire..............102
Attachment 8.
Protocol JJCB Protocol Amendment I6F-MC-JJCB(a) Summary
A Phase 1b/Randomized Phase 2 Study to Evaluate LY3039478 in 
Combination with Dexamethasone in T-ALL/T-LBL Patients ..............103


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4.
Abbreviations and Definitions
Term
Definition
AE
adverse event
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALL
acute lymphoblastic leukemia
ALT
alanine aminotransferase
assent
Agreement from a child or other individual who is not legally capable of providing 
consent, but who can understand the circumstances and risks involved in participating 
in a study (required by some institutional review boards [IRBs]). 
AST
aspartate aminotransferase
AUC
area under the plasma drug concentration versus time curve
AUC(0-∞)
area under the concentration-time curve from time zero to infinity
AUC[0-tlast]
area under the plasma concentration-time curve from time zero to last measurable 
plasma concentration
AUCτ
area under the concentration-time curve over 1 dosing interval at steady state
audit
A systematic and independent examination of the trial-related activities and documents 
to determine whether the evaluated trial-related activities were conducted, and the data 
were recorded, analyzed, and accurately reported according to the protocol, applicable 
standard operating procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s).
BID
twice per day
blinding/masking
A procedure in which 1 or more parties to the trial are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.  
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received.
BSA
body surface area
CI
confidence interval


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CLL
chronic lymphocytic leukemia
Cmax
maximum observed concentration
CNS
central nervous system
collection database
A computer database where clinical trial data are entered and validated.
companion diagnostic
An in vitro diagnostic device (assay or test) that provides information that is essential 
for the safe and effective use of a corresponding therapeutic product
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
continued access 
period
The period between study completion and end of trial during which patients on study 
therapy who continue to experience clinical benefit may continue to receive study 
therapy until 1 of the criteria for discontinuation is met. 
CR
complete remission
CrCl
creatinine clearance
CRF/eCRF
case report form/electronic case report form
Sometimes referred to as clinical report form:  A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the protocol.
CRi
complete remission with incomplete blood count recovery
CRP
clinical research physician
Individual responsible for the medical conduct of the study.  Responsibilities of the 
CRP may be performed by a physician, clinical research scientist, global safety 
physician, or other medical officer.
CSF
cerebrospinal fluid
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCSI
Development Core Safety Information (of Investigator’s Brochure)
DDI
drug-drug interaction
DLET
dose-limiting equivalent toxicity
DLT
dose-limiting toxicity


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DoR
duration of remission
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDTA
ethylenediaminetetraacetic acid
EFS
event-free survival
ELISA
enzyme-linked immunosorbent assay
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.
Enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB/IRB
ethical review board/institutional review board
A board or committee (institutional, regional, or national) composed of medical and 
nonmedical members whose responsibility is to verify that the safety, welfare, and 
human rights of the patients participating in a clinical trial are protected.
ESA
erythropoiesis-stimulating agent
F
oral absorption
FACT-Leu
Functional Assessment of Cancer Therapy-Leukemia
FHD
first-in-human dose
GCP
good clinical practice
G-CSF
granulocyte colony-stimulating factor
GI
gastrointestinal
GnRH
gonadotropin-releasing hormone
GSI
γ-secretase inhibitors
HD
heterodimerization domain
hERG
human ether-à-go-go-related gene
HNSTD
highest non–severely toxic dose
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration
ICF
informed consent form


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ICH
International Conference on Harmonisation
IHC
immunohistochemistry
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 interim analysis is an analysis of clinical trial data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product (IP)
A pharmaceutical form of an active ingredient substance or placebo being tested, or 
used as a reference, in a clinical trial.  Investigational product (IP) 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 trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
ITT
intention-to-treat
The principle that asserts that the effect of a treatment policy can be best assessed by 
evaluating on the basis of the intention to treat a patient (that is, the planned treatment 
regimen) rather than the actual treatment given.  It has the consequence that patients 
allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.
IVTI
in vivo target inhibition
IWG
International Working Group
IWRS
interactive web-response system
LBL
lymphoblastic lymphoma
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.
MedDRA
Medical Dictionary for Regulatory Activities
MRD
minimal residual disease
MRI
magnetic resonance imaging


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MTD
maximum tolerated dose
N1ICD
NOTCH-1 intracellular domain
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NICD
Notch intracellular domain
NOAEL
no-observed-adverse-effect level
ORR
overall remission rate
OS
overall survival
patient
a study participant who has the disease or condition for which the investigational 
product is targeted.
PD
pharmacodynamic(s)
PEST
proline, glutamate, serine, and threonine
PET-CT
positron emission tomography-computed tomography
PK
pharmacokinetic(s)
PPS
per-protocol set
The set of data generated by the subset of patients who sufficiently complied with the 
protocol to ensure that these data would be likely to exhibit the effects of treatment, 
according to the underlying scientific model.
PR
partial remission
PT
preferred term
QTc 
corrected QT interval
randomize
the process of assigning patients to an experimental group on a random basis
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
RFS
relapse-free survival
re-screen
to screen a patient who was previously declared a screen failure for the same study
SAE
serious adverse event
SAP
Statistical Analysis Plan


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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 study.  In this study, 
screening involves invasive or diagnostic procedures and/or tests (for example, 
diagnostic psychological tests, x-rays, blood draws).  For this type of screening, 
informed consent for these screening procedures and/or tests shall be obtained; this 
consent may be separate from obtaining consent for the study.
screen failure
patient who does not meet 1 or more criteria required for participation in a trial
SCT
stem cell transplantation
SD
stable disease
SOC
system organ class
study completion
This study will be considered complete after the final analysis of overall survival is 
performed.
SUSAR
suspected unexpected serious adverse reaction 
t1/2
elimination half-life
T-ALL
T-cell acute lymphoblastic leukemia
TEAE
treatment-emergent adverse event
Any untoward medical occurrence that either occurs or worsens at any time after 
treatment baseline and that does not necessarily have to have a causal relationship with 
this treatment.
TEC50
threshold plasma concentration of the compound required to inhibit cleavage by 50%
TED50
threshold dose concentration of the compound required to inhibit cleavage by 50%
TIW
3 times per week
T-LBL
T-cell lymphoblastic lymphoma
TLS
tumor lysis syndrome
tmax
time of maximal plasma concentration
TPO
third-party organization
ULN
upper limit of normal


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A Phase 1b/Randomized Phase 2 Study to Evaluate 
LY3039478 in Combination with Dexamethasone in 
T-ALL/T-LBL Patients
5.
Introduction
5.1.
Rationale and Justification for the Study
5.1.1. T-Cell Acute Lymphoblastic Leukemia/T-Cell Lymphoblastic 
Lymphoma
Acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) are heterogeneous 
clonal disorders of hematopoiesis characterized by aberrant proliferation and/or mutation of 
hematopoietic progenitor cells (blasts). In T-cell ALL (T-ALL) and T-cell LBL (T-LBL), the 
neoplasm is characterized by malignant expansion of immature lymphoblasts committed to the 
T-cell lineage. T-ALL and T-LBL are widely thought of as the same disease type differing only 
by the amount of involvement in the bone marrow.  Infiltration above 25% is considered T-ALL 
and below 25% is T-LBL (Hoelzer and Gökbuget 2009).  They are a heterogeneous group of 
diseases with regard to immunophenotyping, cytogenetics molecular genetic abnormalities, and 
clinical features including response to therapy.
Although ALL is relatively more common in children, it can also affect adults.  T-ALL and 
T-LBL account for approximately 12% to 15% of childhood and 25% of adult ALL cases. 
Molecular subtypes of T-ALL with Notch mutations are found in about 50% to 60% of children 
and adults with T-ALL (Armstrong and Look 2005; Graux et al. 2006; Hoelzer and Gökbuget 
2009). 
Treatment for T-LBL has moved from traditional lymphoma protocols to treatments designed for 
ALL (Hoelzer and Gökbuget 2009).  Treatment results in newly diagnosed adult patients with 
ALL have improved in the past decade with an increase of complete remission (CR) rates to 
between 85% and 90% and overall survival (OS) rates to between 40% and 50% with the 
developments of intensified and targeted chemotherapies and stem cell transplantation (SCT)
(Gökbuget and Hoelzer 2009). The 5-year overall survival of T-ALL has improved to between 
48% and 56% (Hoelzer et al. 2009; Marks et al. 2009). T-ALL represents one of the most 
favorable subgroups of adult ALL. Mortality rates of T-ALL patients have significantly 
decreased over the last decades because of advances in the treatment of this aggressive subset of 
ALL. The 5-year OS rates are approximately 35% to 40% in adults and 75% to 85% for children 
and adolescents (Goldberg et al. 2003; Demarest et al. 2011). Despite the progress in the 
treatment results of newly diagnosed T-ALL or T-LBL, approximately half of these patients
relapse within the first 2 years or fail to achieve a CR and have an extremely poor prognosis.
Response rates of 50% are achievable among relapsed or refractory T-ALL/T-LBL patients 
treated with high or intermediate doses of cytarabine-based combination therapy, but remissions 
are of short duration. 


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Given the historically poor clinical outcomes for the majority of patients with relapsed 
T-ALL/T-LBL, there is a clear need for new treatment options.  
5.1.2. Notch Signaling and LY3039478
The Notch pathway is a highly conserved signaling system that plays an important role in 
development in several tissues and organs and in tissue homeostasis. Notch mutations are well 
characterized and implicated in hematological malignancies such as T-ALL. Notch signaling is 
activated when the Notch family receptor transmembrane proteins (NOTCH -1 -4) bind to the 
membrane-bound ligands on neighboring cells. Upon ligand binding the Notch receptor 
undergoes a series of proteolytic cleavage steps. The final step results in the release of the Notch 
intracellular domain (NICD). Notch signaling regulates hematopoietic stem cell maintenance 
and plays a critical role in T-cell development (Maillard et al. 2005). An oncogenic role for 
Notch was first reported as the result of a chromosomal translocation occurring in a patient with 
T-cell leukemia (Grabher et al. 2006).  Overexpression of NICD in hematopoietic progenitor 
cells of mice recapitulated this phenomenon, as they developed T-cell leukemia similar to 
humans.  Furthermore, treatment of these cells with the -secretase inhibitor prevented their cell 
growth.  
NOTCH-1 signaling plays a prominent role in the pathogenesis of T-ALL/T-LBL (Aster et al. 
2011; Tosello and Ferrando 2013).  The first identification of activating NOTCH-1 mutations in 
over 60% of T-ALLs (Weng et al. 2004) was subsequently confirmed in other series including 
T-LBL (Park et al. 2009). NOTCH-1 mutations localized in the heterodimerization (HD)
domain found in 20% of T-ALLs result in ligand-independent activation of the receptor, while 
mutations of the proline, glutamate, serine, and threonine (PEST) domain present in 15% of 
T-ALLs cause increased NOTCH-1 intracellular domain (N1ICD) stability and aberrantly 
prolonged NOTCH-1 activation (Weng et al. 2004). Finally, 20% of T-ALL cases show 
activation of NOTCH-1 via mutations in the FBXW7 gene and result in increased N1ICD protein 
stability (Malyukova et al. 2007; O’Neil et al. 2007; Thompson et al. 2007). Mechanistically, 
FBXW7 mutations are related to NOTCH-1 PEST mutations. Notably, in about 25% of T-ALL 
cases HD mutations are associated with PEST or FBXW7 mutations which results in a dual 
NOTCH-1 activation that combines ligand-independent activation and prolonged ICN1 stability 
(Weng et al. 2004).  
Associations between mutation status and outcome have been inconsistent (summarized in Aster 
et al. 2011 and Tosello and Ferrando 2013). While a few series have suggested that NOTCH-1
mutations are associated with worse outcomes, most have shown no association or a trend 
towards more favorable responses.  
As discussed in Tosello and Ferrando (2013), treatment of T-ALL cell lines with γ-secretase 
inhibitors (GSI) resulted in decreased levels of intracellular NOTCH-1, as well as transcriptional 
down regulation of NOTCH-1-target genes in T-ALL (Palomero et al. 2006b). In addition, 
compound E, a specific and highly active GSI, blocked NOTCH-1 signaling and induced cell 
cycle arrest, resulting in decreased proliferation of T-ALL cell lines (Weng et al. 2004; Palomero 
et al. 2006a).  Finally, treatment of mouse models of T-ALL with GSIs resulted in apparent 


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antileukemic effects in vivo (Cullion et al. 2009; Tatarek et al. 2011). Still, to date, only 
1 clinical trial using GSIs in T-ALL has been reported (Deangelo et al. 2006). This Phase 1
study tested MK-0752, an oral GSI developed as monotherapy, in 7 patients with T-ALL. One 
patient with NOTCH-1 mutated T-ALL achieved a 45% reduction in a mediastinal mass after 
28 days of treatment.  Most patients in the study showed dose-limiting on-target gastrointestinal 
(GI) toxicity.
The use of parenteral intermittent dosing schedules has been proposed as a possible approach to 
ameliorate the toxic effects of GSIs. 
The use of GSIs in animal models inhibited NOTCH signaling, reversed glucocorticoid 
resistance in T-ALL, and abrogated gastrointestinal (GI) toxicity (Real and Ferrando 2009; Real 
et al. 2009; Wei et al. 2010; Samon et al. 2012). The synergistic effects of GSI and 
glucocorticoids and the enteroprotective effects of dexamethasone against GSI-induced gut 
toxicity warrant the design of clinical trials testing the safety and efficacy of this drug 
combination in T-ALL (Cullion et al. 2009; Tammam et al. 2009; Wei et al. 2010).
LY3039478 is a novel small molecule that is a potent inhibitor of N1ICD cleavage with a 
half-maximal inhibitory concentration (IC50) of approximately 1 nM in most of the tumor cell 
lines tested.
LY3039478 potently inhibits mutant Notch receptor activity. In a xenograft tumor model, 
LY3039478 inhibited N1ICD cleavage and expression of Notch-regulated genes in the tumor 
microenvironment. The inhibition of Notch cleavage also resulted in the induction of apoptosis 
in a Notch-dependent xenograft model.
LY3039478 as a Notch inhibitor may provide benefits in patients with T-ALL and T-LBL.  
Study I6F-MC-JJCB (JJCB) is a Phase 1b/Phase 2 clinical trial designed to evaluate LY3039478 
in combination with dexamethasone in T-ALL/T-LBL adult and pediatric patients.  
5.1.3. Mechanism of Action and Nonclinical Activity
LY3039478 is a potent Notch inhibitor with an IC50 of ≤1 nM in the majority of cancer cell lines 
tested for its ability to inhibit NOTCH-1 cleavage (Bender et al. 2013). Several different tumor 
cell lines representing solid tumors (n = 10) and leukemia (n = 7) were used to assess the in vitro
activity of LY3039478 for Notch cleavage inhibition in the context of a whole cell.  Cell lines 
representing malignancies of colon, pancreas, ovary, breast, skin, brain, and leukemia, including 
T-ALL and chronic lymphocytic leukemia (CLL), were included in this evaluation.
In order to understand the pharmacokinetic (PK)/pharmacodynamic (PD) relationship and to 
guide the dosing regimen for the efficacy study, key in vivo target inhibition (IVTI) studies 
involving dose response and time course were carried out following a single oral administration 
of LY3039478 in Balb/C mice.  LY3039478 potently inhibits Notch cleavage and downstream 
Notch signaling in lung and skin of Balb/C mice in a dose-dependent manner with a threshold 
dose concentration of the compound required to inhibit cleavage by 50% (TED50) value for 
N1ICD inhibition of 0.8 and 0.9 mg/kg, respectively, and threshold plasma concentration of the 


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compound required to inhibit cleavage by 50% (TEC50) value of 6.2 and 6.6 ng/mL, 
respectively. LY3039478 inhibits Notch signaling as early as 4 hours in A2780 xenograft tumor.
Based on PK properties of the molecule and similar PD effect on N1ICD levels between 3 and 
10 mg/kg from the dose response study, a series of schedule and dose optimization studies were 
conducted. Doses of 7 to 10 mg/kg administered on an intermittent schedule of every other day 
produced optimal efficacy while balancing on-target GI toxicity.  Furthermore, coadministration 
of dexamethasone with LY3039478 significantly decreased body-weight loss and GI toxicity 
without negatively impacting anti-tumor activity of LY3039478.  LY3039478 also inhibited 
NOTCH-1 cleavage and downstream signaling as measured by analysis of Notch-regulated gene 
expression within the tumor microenvironment. Furthermore, dexamethasone did not interfere
with the LY3039478 mediated inhibition of Notch signaling as measured by NICD cleavage and 
gene expression of Notch regulated genes (HeyL, Hey1, and Hes1). These data provide a sound 
scientific justification for combining LY3039478 with dexamethasone in the treatment of cancer 
while reducing GI toxicity.
Additionally, LY3039478 inhibited Notch signaling in the tumor and produced antitumor activity 
in patient-derived human tumor models (EL1989 adenocarcinoma of colon, EL1986 
adenocarcinoma of colon, EL1997 triple negative invasive ductal carcinoma of breast, and 
EL2056 glioblastoma) and cell line-derived xenograft tumors (A2780 ovarian carcinoma, 
U-87 MG glioblastoma, HCT-116 colon carcinoma, SW480 colon carcinoma, and K562 chronic 
myelogenous leukemia).
In T-ALL cell lines, LY3039478 was used to treat CUTLL1 cells (cells harboring a 
chromosomal rearrangement resulting in expression of a N-terminal truncated membrane bound 
form of NOTCH-1) and CCRF-CEM cells (cells harboring an activating mutation in 
heterodimerization domain of NOTCH-1 and a mutation in FBXW7, a negative regulator of 
NOTCH-1). LY3039478 treatment decreased activated NOTCH-1 protein levels in a 
dose-dependent manner with about 75% inhibition at 10 nM and about 90% N1ICD clearance at 
100 nM.  
Four models of patient-derived T-ALL lymphoblasts were treated in vitro with LY3039478. The 
results of these experiments showed a reduction of cell viability in 2 models. 
5.1.4. Nonclinical Pharmacokinetics/Pharmacodynamics
Preliminary nonclinical PK of LY3039478 was characterized in mice, rats, and dogs.  Oral 
absorption (F) was extensive and rapid (F = 65% to 67%; time of maximal plasma concentration 
[tmax] = 0.25 to 0.4 hour).  Elimination half-life (t1/2) of 2 to 6 hours was consistent with desired 
washout between 3 times per week (TIW) doses.  LY3039478 was well distributed into tissues 
(volume of distribution = 1.4 to 4.9 L/kg) with preferential tumor partitioning 
(tumor/plasma = 3.4 to 33) and unbound brain concentrations 22- to 118-fold in excess of the 
Notch IC50.  In 1-month rat and dog toxicokinetic studies (TIW dosing), LY3039478 exposure 
increased in proportion to dose, with no apparent sex differences or time-dependent changes in 
exposure (eg, accumulation).  LY3039478 was extensively cleared by urinary excretion of parent 
compound, and by hydrolysis of the amide bond connecting the azepine ring to the aliphatic side 


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chain.  No drug-drug interaction (DDI) perpetrator potential was identified:  LY3039478 was not 
an inhibitor or inducer of key cytochrome P450s (CYPs) or transporters.  LY3039478 clearance 
mechanisms, urinary excretion of parent and amide hydrolysis, are consistent with low DDI 
potential.
A PK/PD model was developed to relate the LY3039478 plasma concentration to the level of 
in vivo NOTCH-1 cleavage (IVTI) in mouse lung, as a surrogate marker for tumor.  A precursor-
dependent indirect-response model with a rebound was used to describe the relationship between 
plasma concentrations and NOTCH-1 cleavage.  The model identified a maximal inhibition of 
the NOTCH-1 signal of 98%, and the estimated IC50 was 1.8 ng/mL.  The model adequately 
characterized the observed rebound above baseline levels in NOTCH-1 that occurred between 
12 and 24 hours, with a recovery to baseline by 36 to 48 hours.  A tumor-growth kinetics model 
was also developed based on tumor sizes in mice bearing A2780 xenografts.  This model 
supported an understanding of the relationship between LY3039478 exposure and tumor growth 
delay.  
5.1.5. LY3039478 Nonclinical Toxicity
LY3039478 was evaluated in nonclinical toxicology studies of up to 1 month in duration using 
TIW (eg, Monday, Wednesday, and Friday) oral dosing in rats and dogs to characterize the 
toxicity (see compound’s Investigator’s Brochure [IB] for more details).  
Based on results from nonclinical studies, the primary target organ is the GI tract.  The intestinal 
toxicity in rat and dog 1-month toxicology studies was characterized by fecal abnormalities and 
histologic changes described as a mucoid enteropathy with increases in the size and/or number of 
goblet cells within the mucosal epithelial enterocytes.  Mucoid enteropathy is a known target 
mediated toxicity of Notch inhibitors (Milano et al. 2004).  Although the enteropathy contributed 
to the mortality in rats at the highest dose, the intestinal toxicity was almost completely reversed 
following a 3-week reversibility period in the 1-month rat study.
In the 1-month rat toxicology study, mortality was observed on Days 20, 21, and/or 22 in 2 male 
and 2 female main-study rats and in 2 female toxicokinetic rats at 6 mg/kg/dose.  A mucoid 
enteropathy of the small and large intestines characterized by increases in the size and/or number 
of goblet cells within the mucosal epithelial enterocytes was observed at all doses.  This change 
was sometimes accompanied by blunting of villi, subacute/chronic inflammation, and increased 
mucus in the intestinal lumen.  The mucoid enteropathy was considered to be adverse at 
≥3 mg/kg/dose in males and females due to the increased severity (mild to moderate) at these 
dose levels.  Decreased number of ovarian follicles were observed in all female rats 
(≥1 mg/kg/dose) and were considered adverse to fertility but not to the overall health of the 
female rat.  Additional non adverse histology findings included bone growth plate thickening of 
the femur and sternum and single-cell necrosis of epithelia in the pancreas, exorbital lacrimal 
glands, and mandibular salivary glands.  The mucoid enteropathy, decreased ovarian follicles, 
and all other toxicities were reversible or partially reversible following a 3-week recovery period 
in rats.  The maximum tolerated dose (MTD) and highest non-severely toxic dose (HNSTD) was 


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considered to be 3 mg/kg/dose based on mortality observed at the high dose of 6 mg/kg.  
Additional details and findings from this study are presented in the compound’s IB.
No mortality was observed in the 1-month dog toxicity study. Substantial decreases in body 
weight and food consumption occurred early in the study at 0.3 and 1 mg/kg/dose and resulted in 
supplemental food being offered to all dogs at these dose levels.  Clinical signs were limited to 
fecal changes including soft, watery, mucoid, and discolored feces in dogs administered 0.3 and 
1 mg/kg/dose.  Fecal changes at 0.1 mg/kg/dose were less frequent and less severe than at higher 
doses.  These changes were consistent with the dose-dependent mucoid enteropathy that was 
evident histologically in the small and large intestines at all doses and was considered to be 
adverse at ≥0.3 mg/kg/dose based on the presence of concurrent mucosal degeneration/necrosis
at these mid and high doses.  Generalized lymphoid depletion occurred in multiple tissues 
including the thymus, spleen, mesenteric lymph nodes, and/or gut-associated lymphoid tissue.  
Hypercellularity of the bone marrow (femur and sternum) at 1 mg/kg/dose correlated with 
hematology findings including increased total leukocytes, likely associated with inflammation in 
the large and small intestines.  Increased thickness of the hypertrophy zone was also evident in 
cartilage of the rib and sternum at 1 mg/kg/dose, which was similar but more subtle than the 
finding in the rat.  The MTD and HNSTD in this dog study was 1 mg/kg, the highest dose tested.  
Additional details and findings from this study are presented in the compound’s IB.
Thrombocytopenia was identified as a DLT in a few Phase 1 patients (see Section 5.1.6)
however no effects on platelets were noted in the 1-month rat or dog toxicology studies.  
Based on in vitro hERG results, there is no expected risk for QT prolongation by hERG 
inhibition. In the 1-month dog study, no test article-related effects were observed in any of the 
electrocardiogram (ECG) parameters (heart rate, RR interval, PR interval, QRS duration, QT 
interval, and corrected QT [QTc] interval).  No evidence of mutagenicity was observed in a 
bacterial mutagenicity (Ames) assay.  In additional in vitro assays, LY3039478 was classified as 
a nonirritant and demonstrated no phototoxic potential.  
In conclusion, nonclinical toxicology studies in rats and dogs dosed TIW for 1 month have 
characterized the target tissues for toxicity that may be clinically relevant.  Data indicate that the 
intestinal tract is the primary target organ for LY3039478 toxicity.  The mucoid enteropathy and 
all other toxicities were reversible or partially reversible following a 3-week recovery period in 
rats.  The observed human AUC exposure at the previously tested starting dose of 2.5 mg 
(98.4 ng hr/mL) was 7.9-fold and 26.5-fold lower than AUC at the HNSTD in rats and dogs, 
respectively.  Although exposure multiples are <1 at higher clinical doses, the dose-limiting 
enteropathy in nonclinical studies was monitorable and/or reversible.  
5.1.6. Clinical Experience with LY3039478
As of April 2014, validated data from 39 patients in the first-in-human dose (FHD) 
Study I6F-MC-JJCA (JJCA) treated with LY3039478 in doses ranging from 2.5 mg to 60 mg are 
available. As of November 2014, LY3039478 doses of up to 100 mg have been explored. The 
MTD has been determined to be 75 mg.


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Dose-limiting toxicities (DLTs) observed at dose levels of 20 mg, 30 mg, and 60 mg LY3039478 
were thrombocytopenia Grade 4 in 1 patient in each dose group. Dose limiting toxicities at 
100 mg included Grade 3 nausea (not manageable by medical treatment) and Grade 3 asthenia.  
In addition, 1 patient at 100 mg experienced Grade 2 colitis.
The most common adverse events (AEs) (>5% of patients) assessed as possibly related to study 
drug by the investigator included vomiting (41.0%); diarrhea (30.8%); asthenia, nausea, and
hypophosphatemia (28.2%, each); decreased appetite (17.9%); hair color changes (15.4%);
weight decreased (12.8%); thrombocytopenia, mucosal inflammation, alanine aminotransferase 
(ALT) increased, dry skin, and skin fissures (10.3% each); stomatitis and aspartate 
aminotransferase (AST) increased (7.7%, each); eyelash discoloration, dyspepsia, lipase 
increased, and dysgeusia (5.1%, each).
No Grade 5 Common Terminology Criteria for Adverse Events (CTCAE) events that were 
possibly related to study drug were reported.  Grade 4 events possibly related to study drug 
included thrombocytopenia (3 patients, 7.7%) and increased lipase (1 patient, 2.6%).  Grade 3 
events possibly related to study drug included hypophosphatemia (5 patients, 12.8%) and colitis, 
asthenia, weight loss, and anorexia (1 patient each, 2.6%).
More information about the known and expected benefits, risks and reasonably anticipated AEs 
of LY3039478 can be found in the compound’s IB.  Information on AEs expected to be related 
to the investigational product can be found in Section 7 (Development Core Safety Information
[DCSI]) of the IB.  Information on serious adverse events (SAEs) expected in the study 
population independent of drug exposure and assessed by the sponsor in aggregate, periodically 
during the course of the study, can be found in Section 6 (Effects in Humans) of the IB.
5.2.
Rationale for Selection of Dose/Schedule and Design Discussion
The Phase 1 (Part A) portion of Study JJCB will assess escalating doses of LY3039478 when 
administered TIW in combination with 24 mg of dexamethasone given on Days 1 through 5 
every other week. The TIW schedule for LY3039478 was selected based on the nonclinical 
toxicology and PK/PD data modeling and was explored in the FHD study, Study JJCA.  The 
dose range to be explored in JJCB showed a decrease of a-beta as a PD marker in plasma (80%) 
and at least 50% inhibition of Notch target genes HES1, NRARP, and CCND1 in Study JJCA.  
The starting dose of 50 mg is below the MTD of 75 mg defined in Study JJCA as single-agent 
therapy. The administration schedule and fixed dose of 24 mg of dexamethasone have been 
chosen based on the current standard of care treatment of T-ALL/T-LBL. It is hypothesized that 
the combination of LY3039478 with dexamethasone will provide an active therapy option for 
adult patients with relapsed/refractory T-ALL/T-LBL disease.
The Phase 1 (Part B) portion of Study JJCB will assess escalation doses of LY3039478 when 
administered TIW in combination with dexamethasone in pediatric patients age 2 to <16 years. 
The starting dose for LY3039478 will be 80% of the initial dose administered to adults provided 
that no DLT is observed in the initial adult cohort and follows regulatory guidance as common 
practice.  In addition, the administered dose of LY3039478 for pediatric patients will be 
calculated by body surface area (BSA). LY3039478 will be administered TIW. The 


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dexamethasone dose will be 10 mg/m² twice per day (BID) on Days 1 through 5 every other 
week.
The randomized Phase 2 portion of the study will assess LY3039478 at a dose defined in Phase 1 
(Part A) given TIW in combination with dexamethasone versus placebo given TIW in 
combination with dexamethasone.  Dexamethasone will be administered at a fixed dose of 24 mg 
on Days 1 through 5 every other week.
Treatment with corticosteroids, such as dexamethasone, is part of the standard of care regimen 
for patients with ALL and LBL (Estey et al. 2008).  Besides being a therapy against leukemic 
blasts by direct apoptotic effects and overcoming cytotoxic resistance, corticosteroids play a role 
in the supportive therapy of ALL.  Dexamethasone can also provide protection against central 
nervous system (CNS) relapse of ALL.  Even at relapse, most ALL patients retain sensitivity to 
dexamethasone.  Patients with relapsed/refractory ALL progress quickly and require effective 
therapy, yet there is no established standard of care for relapsed T-ALL/T-LBL therapy. This 
study will combine dexamethasone with the active drug, LY3039478, to test efficacy.  In 
addition, dexamethasone in combination with Notch inhibitors overcomes glucocorticoids 
resistance and mitigates GI toxicity.
5.3.
Rationale for Amendment (a)
This study was amended at the request of the Food and Drug Administration (FDA) to clarify the 
criteria for DLTs (Section 9.2.2) and to change the PK sampling.  In addition, CSF sampling was 
simplified based on new data; the CSF sampling has been reduced to one draw. PK analysis for 
dexamethasone during the Phase 1 portion of the study was added and one additional time point 
for determination of plasma concentrations of LY3039478 and dexamethasone was added during 
the Phase 2 portion of the study (Attachment 3).


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LY3039478
6.
Objectives
6.1.
Primary Objective
The primary objective are as follows:

Phase 1:  to determine the recommended dose of LY3039478 in combination with 
dexamethasone in
o
adults patients with relapsed/refractory T-ALL/T-LBL (Part A)
o
pediatric patients (Part B)

Phase 2: to determine if the overall remission rate (ORR) (CR plus CR with incomplete 
blood count recovery [CRi]) in adult patients with relapsed/refractory T-ALL/T-LBL 
treated with LY3039478 in combination with dexamethasone exceeds that of those 
patients treated with placebo in combination with dexamethasone
6.2.
Secondary Objectives
The secondary objectives of the study are as follows:

Phase 1:
o
to characterize the safety and toxicity profile of LY3039478 in combination with 
dexamethasone as assessed by National Cancer Institute (NCI) CTCAE v 4.0
o
to assess the PK parameters of LY3039478 in combination with dexamethasone
therapy
o
to document efficacy based on Cheson criteria for leukemia and malignant 
lymphoma
o
to evaluate gene mutation (eg, NOTCH1/FBXW7/RAS/PTEN) status with 
efficacy

Phase 2: 
o
to compare the ORR plus partial remission (PR) and PR alone for both arms
o
to assess the remission rate for patients receiving LY3039478 in combination with 
dexamethasone after failure of placebo in combination with dexamethasone
o
to assess duration of remission (DoR) = (CR, CRi, and PR)
o
to assess relapse-free survival (RFS), event-free survival (EFS), and OS
o
to compare the safety and toxicity profile of LY3039478 in combination with 
dexamethasone to dexamethasone and placebo as assessed by NCI CTCAE v 4.0
o
to assess the PK parameters of LY3039478 and dexamethasone in combination 
therapy
o
to assess patient quality of life using the Functional Assessment of Cancer 
Therapy-Leukemia (FACT-Leu)
o
to evaluate gene mutation (eg, NOTCH-1/FBXW7/RAS/PTEN) status with 
efficacy


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LY3039478
6.3.
Exploratory Objectives
The exploratory objectives of the study are as follows:

to assess clinical utility of the NICD immunohistochemistry (IHC) assay as a potential 
companion diagnostic for LY3039478

to evaluate biomarkers in tumor tissue, blood, plasma and cerebrospinal fluid (CSF), 
which may include, but not be limited to, NICD enzyme-linked immunosorbent assay 
(ELISA) (or an alternative validated method), gene expression, relevant to the study 
disease or safety, efficacy, and mechanism of action of LY3039478 and dexamethasone

to explore PD effects of LY3039478 on biomarkers indicative of Notch activity

to evaluate the CSF exposure of LY3039478


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LY3039478
7.
Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened.  Individuals may be re-screened up to 2 times.  Each time re-screening is performed, 
the individual must sign a new informed consent form (ICF) and will be assigned a new 
identification number.  Note that repeating laboratory tests during the 28-day screening period 
does not constitute rescreening.
Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as 
protocol waivers or exemptions) is not permitted.
7.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria 
during screening prior to first dose of study drug.  
[1]
Have acute T-cell lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic 
lymphoma (T-LBL).  
T-ALL is defined by ≥25% of blasts in the bone marrow and expression of at 
least 2 of the following cell surface antigens:

CD1a, CD2, CD3 (surface or cytoplasmic) CD4, CD5, CD7, and/or
CD8.
If the only T-cell markers present are CD4 and CD7, the leukemia cells must 
also lack the myeloid markers CD33 and/or CD13.
[2]
T-ALL or T-LBL patients with relapsed/refractory disease. Patients with 
initial refractory disease should have received at least 2 multi-agent 
chemotherapy induction regimens. Patients in first or second relapse must 
have been refractory to at least 1 multi-agent chemotherapy reinduction 
regimen.
[3]
Have had at least 60 days between prior hematopoietic SCT and first dose of 
study drug.
[4]
Have a performance status of 0 to 2 on the Eastern Cooperative Oncology 
Group (ECOG) scale (see Attachment 5) for adults.
[5]
Lansky score >50% for patients <16 years old.
[6]
Have adequate organ function:

hepatic: bilirubin 1.5 × the upper limit of normal (ULN) and ALT and 
AST 3 × ULN. For patients with liver involvement, ALT and AST 5 × 
ULN

renal: calculated creatinine clearance ≥45 mL/min or a serum creatinine based on 
age/gender (Attachment 6)
[7]
Are at least:


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LY3039478

Adult Phase 1 Part A and Phase 2: ≥16 years old at the time of screening.

Pediatric Phase 1 Part B: 2 to <16 years old.
[8a] Men and women with reproductive potential:  Must agree to use a reliable 
method of birth control during the study and for 3 months following the last 
dose of study drug(s) or country requirements, whichever is longer.
[8b] Females with childbearing potential:  Have had a negative serum pregnancy 
test ≤7 days before the first dose of study drug and also must not be 
breastfeeding.
[9]
Have an estimated life expectancy of at least 2 months and in the judgment of 
the investigator, will be able to complete at least 2 cycles of treatment.
[10] Have given written informed consent/assent prior to any study-specific 
procedures.
All patients and/or their parents or legally authorized representatives must 
sign a written ICF.  Assent, when appropriate, will be obtained according 
to institutional guidelines.
[11] Are able to swallow capsules and tablets.
7.2.
Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[12] Are currently enrolled in a clinical trial involving an investigational product or 
nonapproved use of a drug or device (other than the study drug/device used in 
this study), or concurrently enrolled in any other type of medical research 
judged not to be scientifically or medically compatible with this study.
[13] Have discontinued prior anticancer therapy less than 2 weeks prior to starting 
therapy or 5 half-lives (whichever is longer) with the following exceptions:  

glucocorticoids administered as antileukemic treatment should be 
discontinued at least 5 days prior to starting therapy

mercaptopurine may be dosed up to 5 days prior to first dose of 
LY3039478

Vinca alkaloids may be dosed up to 7 days prior to first dose of 
LY3039478

intrathecal chemotherapy may be dosed up to 7 days prior to first dose 
of LY3039478


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LY3039478

At the discretion of the investigator, hormone-sensitive prostate cancer 
patients who are in remission and stable on gonadotropin-releasing 
hormone (GnRH) agonist therapy and breast cancer patients who are 
stable on antiestrogen therapy (for example, an aromatase inhibitor) may 
have that treatment continued while they are enrolled in this study.
[14] Have previously completed or withdrawn from this study or any other study 
investigating LY3039478 or other Notch inhibitors.  (This exclusion criterion 
does not apply to patients who are re-screened prior to 
enrollment/randomization.)
[15] Have a serious concomitant systemic disorder that, in the opinion of the 
investigator, would compromise the patient’s ability to adhere to the protocol.
[16] Have evidence of uncontrolled, active infection <7 days prior to 
administration of study medication.
[17] Have current or recent (within 3 months of study drug administration) GI
disease with chronic or intermittent diarrhea, or disorders that increase the risk 
of diarrhea, such as inflammatory bowel disease. Nonchronic conditions 
(eg, infectious diarrhea) that are completely resolved for at least 1 week prior 
to starting study treatment are not exclusionary.
[18] Have conditions requiring chronic systemic (not inhaled) glucocorticoid use, 
such as autoimmune disease or severe asthma. Low doses of corticosteroids 
are permitted.
[19] Have active (symptomatic or requiring current medical treatment) graft versus 
host disease.
[20] Have active leukemic involvement of the CNS as shown by spinal fluid 
cytology or imaging.  A lumbar puncture is not required unless CNS
involvement is clinically suspected.  Patients with signs or symptoms of 
leukemic meningitis or a history of leukemic meningitis must have a blast-free 
cerebrospinal fluid within 14 days of the first day of study treatment.
[21] Have a second primary malignancy or prior malignancy that, in the judgment 
of the investigator and following consultation with 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, as judged by the Lilly clinical research physician 
(CRP), are eligible for this study.  The Lilly CRP will approve enrollment of 
patients with prior malignancies in remission before these patients are 
enrolled.


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LY3039478
7.3.
Discontinuations
7.3.1. Discontinuation of Patients
The criteria for enrollment must be followed explicitly.  If a patient who did not meet enrollment 
criteria and was inadvertently enrolled is identified, either by the Sponsor or investigator, a 
discussion must occur between the Lilly CRP and the investigator to determine if the patient may 
continue in the study.  The investigator must obtain documented approval from the Lilly CRP to 
allow the inadvertently enrolled patient to continue in the study with or without treatment with 
study drug.  In addition, patients will be discontinued from the study drug 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 decision
o
the investigator decides that the patient should be discontinued from the study or 
study drugs
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study drug occurs prior to introduction of the new agent

patient decision
o
the patient or the patient’s designee (for example, parents or legal guardian) 
requests to be withdrawn from the study or study drug(s)

sponsor decision
o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and good clinical practice

the patient is significantly noncompliant with study procedures and/or treatment

unacceptable toxicity

treatment failure in T-LBL or PD in T-ALL patients as described in Sections 10.1.3.1
and 10.1.3.2.
The reason for and date of discontinuation will be collected for all patients.  All patients who 
received study drug will have procedures performed as shown in the Study Schedule 
(Attachment 1).
7.3.2. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges it necessary for medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP).


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7.3.3. Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, ethical, 
or other reasons consistent with applicable laws, regulations, and GCP.


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8.
Investigational Plan
8.1.
Summary of Study Design
Study JJCB is a multicenter study consisting of a nonrandomized, open-label, dose-escalation
Phase 1 study followed by a randomized, double-blind, Phase 2 study in patients with relapsed or 
refractory T-ALL/T-LBL. The Phase 1 portion of the study will consist of 2 different patient 
populations, an adult (Part A) and a pediatric (Part B), and will define the recommended dose of 
LY3039478 in combination with dexamethasone in each of these populations. The randomized 
Phase 2 study will be a double-blinded, multicenter evaluation to determine if the CR and CRi 
(CR with incomplete blood count recovery) rate in adult patients with relapsed/refractory
T-ALL/T-LBL treated with LY3039478 in combination with dexamethasone exceeds that of 
those patients treated with placebo in combination with dexamethasone. Figure JJCB.8.1
illustrates the study design.
Eligible adult patients will receive LY3039478 administered orally TIW and dexamethasone 
administered 24 mg orally Days 1 to 5 every other week. In Part B (pediatric patients),
dexamethasone is administered at 10 mg/m2 BID, orally, Days 1 through 5 every other week.  A 
cycle is defined as 28 days of treatment (4 weeks).
The Phase 1 portion will start with the adult cohort (Part A). The decision to proceed with the 
pediatric dose exploration (Part B) will be made after safety analysis of the adult cohort.
The dose escalation, described in Section 9.2.1, will be guided primarily by safety assessments 
from Days 1 through 28 of Cycle 1 for patients in all cohorts.  Dose escalation will occur until 
the MTD (defined in Section 9.2.2) is determined. Patients will be enrolled in Part A with the 
first dose level of 50 mg LY3039478, TIW.  Table JJCB.9.2 outlines the proposed 
dose-escalation scheme.  Dose levels will be determined based on the review of the safety, PK, 
and PD data from the previous doses.  Additional dose levels (to a maximum of 200 mg TIW) 
may be explored if necessary.  No dose escalation will occur beyond MTD.  In Parts A and B, 
the sample size is estimated to be approximately 13 to 16 patients in each part depending on the 
relationship between exposure and toxicity as well as the relationship between exposure and 
pharmacological effects.
After the last patient on Part A has completed Cycle 1 and the recommended dose for the Phase 2 
portion is determined, the randomized, Phase 2 portion will begin following an interim review of 
the data as outlined in Section 12.2.14.  The patient population in the Phase 2 portion of the 
study will be identical to the patient population assessed in Part A.
In the Phase 2 portion, 60 patients will be randomized in a 2:1 ratio to receive either LY3039478
in combination with dexamethasone administered 24 mg orally on Days 1 to 5 every other week 
or placebo in combination with dexamethasone administered 24 mg orally on Days 1 to 5 every
other week.  Placebo or LY3039478 will be administered orally TIW at the recommended dose 
from Part A.  Patients will receive treatment until progression or meeting discontinuation criteria 
(Section 7.3).


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Patients discontinuing the study for treatment failure as defined in Section 7.3.1 will be 
unblinded after discontinuation.  A crossover to LY3039478 in combination with dexamethasone 
will be allowed for patients who were receiving placebo in combination with dexamethasone.
A futility interim analysis will be performed in the Phase 2 portion of the study when 30 patients 
have completed the CR status determination.  The analysis will assess the safety profile, verify 
that the chosen regimen is clinically feasible, and determine if the futility criteria have been met.  
See Section 12.2.14 for additional information on this futility interim analysis.
An internal assessment committee consisting of (at minimum) a Lilly Medical Director, a Lilly 
CRP not associated with the study, a PK scientist, and a statistician will examine the interim 
results and make recommendations about the trial.
The total sample size for this study is estimated to be approximately 86 to 92 patients.
There is no fixed duration of treatment; patients will remain on study until they fulfill 1 of the 
criteria for study discontinuation (Section 7.3).  Refer to Attachment 1 for the Study Schedule.


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LY3039478
Abbreviation: MTD = maximum tolerated dose.
Figure JJCB.8.1.
Illustration of study design.
8.2.
Discussion of Design and Control
A randomized, controlled design is being used in the Phase 2 portion of the study.  
Randomization minimizes systematic bias in the selection and assignment of patients to study 
therapy and provides justification for inferential statistical methods to be used on data from this 
study.  Using an appropriate concurrent control arm enables direct statistical estimation of 
benefits and harms due to study therapy and minimizes bias in the assessment and interpretation 
of observed treatment effects. To further reduce the potential for bias and improve the power of 
the analyses, patients will be stratified for differences in factors thought to be associated with 
clinical outcomes.
Investigational treatment administration in this study is double-blind.  Patients, study personnel 
at investigational sites, and study personnel at Lilly do not have immediate access to treatment 
assignments for any patients.  This design feature minimizes potential bias due to knowledge of 
treatment assignments during the study.


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8.3.
Study Periods, Study Completion, and End of Trial
Terms used to describe the periods during the study are defined below:

baseline:  begins when the ICF is signed and ends at the first study treatment (or at 
discontinuation, if no treatment is given)

study period:  begins at the first study treatment and ends at study completion.  The 
study period does not include the continued access period.
o
study treatment period:  begins at the first study treatment and ends when the 
patient and the investigator agree that the patient will no longer continue study 
treatment.  The date of this agreement is to be reported on the case report form 
(CRF) as the Date of Discontinuation from study treatment..
o
postdiscontinuation follow-up period:  begins the day after the patient and the 
investigator agree that the patient will no longer continue study treatment.

short-term follow-up: begins the day after the patient and the 
investigator agree that the patient will no longer continue study 
treatment and lasts approximately 30 days.

long-term follow-up: begins the day after short-term follow-up is 
completed and continues until the patient’s death or overall study 
completion.

continued access period:  begins after study completion and ends at the end of trial.  
During the continued access period, patients on study therapy who continue to experience 
clinical benefit may continue to receive study therapy until 1 of the criteria for 
discontinuation is met.  The continued access period includes continued access follow-up.
o
continued access follow-up:  begins 1 day after the patient and the 
investigator agree that the patient will no longer continue treatment in the 
extension period and lasts approximately 30 ± 6 days

study completion: begins following the final analysis/evaluation of OS, as determined 
by Lilly.  Investigators will continue to follow the Study Schedule for all patients until 
notified by Lilly that study completion has occurred.  

end of trial: occurs after study completion and after the last patient has discontinued 
study treatment and completed continued access period follow-up (if applicable).
Upon determination of treatment failure or study completion, investigators and patients may be 
unblinded to study treatment assignment.  Patients with relapsed or refractory disease who were 
receiving placebo in combination with dexamethasone may crossover to LY3039478 in 
combination with dexamethasone and follow the “study period” treatment schedule.
8.3.1. Continued Access Period
The continued access period will apply to this study only if at least 1 patient is still on 
LY3039478 when study completion occurs.
Patients receiving LY3039478 and experiencing ongoing clinical benefit and no undue risks may 
continue to receive LY3039478 in the continued access period until 1 of the criteria for 


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LY3039478
discontinuation is met (Section 7.3).  Lilly will notify investigators when the continued access 
period begins.  
Patients  who are in short-term follow-up when the continued access period begins will continue 
in short term follow-up until the [30-day] short-term follow-up visit is completed.  Long-term 
follow-up does not apply.
Patients who are in long term follow-up when the continued access period begins will be 
discontinued from long-term follow-up.
During the continued access period, all AEs, SAEs, and LY3039478 exposure will be reported 
on the CRF.  Serious adverse events will also be reported to Lilly Global Patient Safety (see 
Section 10.3.1).  In the event that an SAE occurs, Lilly may request additional information (such 
as local laboratory results, concomitant medications, and hospitalizations) in order to evaluate 
the reported SAE. 
Investigators will perform any other standard procedures and tests needed to treat and evaluate 
patients; however, the choice and timing of the tests will be at the investigator’s discretion.  Lilly 
will not routinely collect the results of these assessments.


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9.
Treatment
9.1.
Materials and Supplies
All clinical trial materials will be labeled according to the country’s regulatory requirements. 
LY3039478 will be supplied as 25- and 50-mg capsules in bottles for oral consumption for adult 
patients and 10-mg capsules in bottles for oral consumption for pediatric patients.  LY3039478 
capsules should be stored at room temperature within the temperature range stated on the label.  
Investigators should instruct patients or parents to store the capsules at home in the original 
container and to keep out of the reach of children.  Capsules should not be opened, crushed, or 
dissolved.
Placebo will be supplied as capsules in bottles (consisting of inactive ingredients) for oral 
administration. Packaging, storage information, and instructions will match LY3039478.  
Dexamethasone will be supplied as an oral tablet in several potencies including a 4-, 6-, or 8-mg 
dose size or as an oral solution in several potencies including 0.5 mg per 5 mL or 2 mg per 5 mL
for pediatric patients.  It should be used and stored in accordance with the package insert or as 
indicated on the label.
9.2.
Treatments Administered
The following treatments will be administered in this study:  
Phase 1: 
Part A – Adults:  

LY3039478 dosed according to the dose-escalation scheme, oral TIW, Table JJCB.9.2

dexamethasone: 24 mg, oral, Days 1 through 5 every other week
Part B – Pediatric:

The starting dose of LY3039478 will be determined by the adult portion of the study and 
will be 80% of the dose administered to adults and calculated on a BSA, oral TIW, dose 
escalation following similar scheme for adults (Table JJCB.9.2).  Doses calculated based 
on BSA will be rounded to the nearest 10-mg capsule.

dexamethasone: 10 mg/m2 BID, oral, Days 1 through 5 every other week
Phase 2: 

LY3039478 or placebo: at or below the MTD defined from Phase 1, Part A, oral TIW

dexamethasone:  24 mg, oral, Days 1 through 5 every other week
Table JJCB.9.1 shows the treatment regimens.


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LY3039478
Table JJCB.9.1.
Treatment Regimens/Dosing Schedule
Regimen
Period/Cycle
Dose 
Phase 1 Part A 
LY3039478
Treatment/28-day cycle
Escalating doses TIW PO
(see Table 9.2)
Dexamethasone
Treatment/28-day cycle
24 mg Days 1-5 PO
every other week
Phase 1 Part B
LY3039478
Treatment/28-day cycle
Escalating doses (mg/m2)
TIW PO
(80% dose from Part A)
Dexamethasone
Treatment/28-day cycle
10 mg/m2 BID Days 1-5 
PO
every other week
Phase 2
LY3039478 or Placebo
Treatment/28-day cycle
At or below MTD dose 
TIW PO
Dexamethasone
Treatment/28-day cycle
24 mg Days 1-5 PO
every other week
Abbreviations:  BID = twice per day; PO = orally; TIW = 3 times per week.  
LY3039478 or placebo will be administered orally TIW during both the dose-escalation phase 
and the Phase 2 following 1 of these schedules (decision at investigator’s discretion):

Monday, Wednesday, and Friday every week, for a 28-day cycle

Tuesday, Thursday, and Saturday every week, for a 28-day cycle

Wednesday, Friday, and Sunday every week, for a 28-day cycle

Thursday, Saturday, and Monday every week, for a 28-day cycle
LY3039478 or placebo will be taken once per day on days of administration prior to a meal 
(recommendation is within 30 minutes) on an empty stomach.  During all cycles, study drug 
should be taken at approximately the same time on the dosing days. If a patient misses or vomits 
a dose, that dose should be omitted. 
Dexamethasone will be taken approximately 30 minutes after LY3039478 or placebo and 
together with a meal. Pediatric patients (Part B) will take dexamethasone BID approximately 
12 hours apart.  
The patient, caregiver, or clinic personnel will record time and amount of each dose in the patient 
diary on days of PK assessment (Attachment 3) during Cycle 1 and Cycle 2, and study monitors 
will cross-reference clinic records at the site to verify accuracy. For cycles 3 and beyond first 
and last dose date and amount of both drugs for each individual cycle will be documented.
Clinic personnel will instruct patients to pay particularly close attention to record this 
information accurately.  
For Cycle 2 and beyond, a delay of ≤7 days in the start of a cycle (Dose 1) for justifiable reasons 
(for example, inclement weather, holidays, or weekends) other than toxicity will be permitted 
and does not constitute a protocol violation.  


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For Cycle 2 and beyond, a delay of ≤21 days in the start of a cycle (Dose 1) to allow for recovery 
from toxicity will be permitted and does not constitute a protocol violation (refer to 
Section 9.4.2).  
The investigator or his/her designee is responsible for the following:  

explaining the correct use of the drugs and planned duration of each individual’s 
treatment to the patient/site personnel/legal representative

verifying that instructions are followed properly

maintaining accurate records of study drug dispensing and collection

returning all unused medication to Lilly or its designee at the end of the study
In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose clinical trial materials.  
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be assessed.  
9.2.1. Dose-Escalation Phase
Dose escalation will be driven by safety using a modified 3+3 scheme, with incorporation of 
model-based dose escalation (Neuenschwander et al. 2008) to assist in estimation of DLT rate at 
recommended dose level. 
A model-based method that incorporates prior expectations about the dose-toxicity curve and 
controls for over-dosing probability will be applied to the data at the end of each cohort, which 
will provide quantitative guidance to the investigators and Lilly CRP to help determine the next 
dose level. Prior expectations about the dose-toxicity curve will be based on observed DLT rates 
in Study JJCA. After incorporation of observed DLT rates in this study, the posterior probability 
of a DLT at each dose level will be categorized to 4 bands:  

under-dosing: the probability of a DLT at a given dose level in (0, 0.20)

targeted toxicity: the probability of a DLT at a given dose level in (0.20, 0.35)

excessive toxicity: the probability of a DLT at a given dose level in (0.35, 0.60)

unacceptable toxicity: the probability of a DLT at a given dose level in (0.60, 1.00)
The model aims to recommend a dose which maximizes the probability of targeted toxicity, 
while controlling the probability of excessive or unacceptable toxicity to less than 25%. The
maximum increment of escalation will be no more than 100%.  The exact increment will be 
determined by the investigators and Lilly CRP and may be less than the model prediction or 
<100%.  
Each dose level will have a minimum of 3 patients enrolled concurrently to it. If 1 patient 
experiences a DLT, then additional patients can be enrolled to that cohort provided the observed 
DLT rate dose does not exceed 33%.  


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Additional patients may be enrolled at a specific dose level to characterize PK/PD, provide that 
dose level does not exceed the MTD
In case more than 3 patients have been consented concurrently, the additional patients may be 
treated. The decision about which dose level the patient will be treated at will be made after 
discussion between the CRP/study team and the investigators.  The decision will be documented.
Once the MTD has been identified, a discussion between the sponsor and investigators may 
occur in order to treat additional patients at intermediate doses below the MTD.  
Safety data, in particular AEs, will be the primary criteria to allow for the dose escalation.  The 
dose will be escalated following assessment of toxicity using the standard scoring system, 
CTCAE v 4.0, established by the NCI. Any AEs related to LY3039478 and/or dexamethasone 
will be considered as toxicities.  
If available at the time of the dose-escalation decision, PK (eg, maximum observed concentration 
[Cmax], AUC, and apparent systemic clearance) and PD results will be used as 
secondary/supporting data for dose escalation. No dose escalation can occur without prior 
discussion and agreement between the investigator and the Lilly CRP.  The decision will be 
documented in writing.  Intrapatient dose escalations are not permitted.  
Based on the ongoing safety reviews, modifications to the dose-escalation strategy or other 
design elements may be made via protocol amendment to ensure patient safety.  
Table JJCB.9.2 shows the proposed dose levels for LY3039478 in combination with 
dexamethasone for the adult cohort. The starting dose level of 50 mg of LY3039478 was
defined from Study JJCA and data will be evaluated on an ongoing basis until the MTD is 
determined.  If the starting dose exceeds the MTD, a LY3039478 dose level (-1) may be 
explored.  It should be noted that although an example escalation table is shown in 
Table JJCB.9.2, alternate doses may be selected.  Intermediate dose levels will be explored if 
deemed necessary after discussion between the sponsor and investigators and taking into account 
patient safety and PK/PD information.
Table JJCB.9.2.
Proposed LY3039478 Dose-Escalation Scheme for the Adult Cohort
Dose Level
LY3039478
Dose (mg)
Dexamethasone 
Dose (mg)
-1a
25
24
1
50
24
2
75
24
a
Dose level -1 to be used only in the event of dose-limiting toxicities experienced in dose level 1 necessitating a 
dose de-escalation.
The starting dose for pediatric cohort will be defined upon safety assessment of adult cohort. 
The starting dose will be 80% of total adult dose. Pediatric patients will be dosed based on BSA. 
Dose escalation will follow similar scheme to adult cohort.  


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By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
MTD is determined, as defined below.
9.2.2. Dose-Limiting Toxicity Determination and Maximum Tolerated 
Dose Definition
Disease-related myelosuppression is typical in the setting of T-ALL/T-LBL.  Therefore, 
myelosuppression will not be included in the definition of a DLT, unless it fits the criteria 
outlined below.  
A DLT is an AE observed during the first 28-day cycle (when patients receive 
LY3039478 and dexamethasone) that is determined by the investigator to be at least
possibly related to LY3039478 according to CTCAE v 4.0 and fulfills any of the 
following criteria:  

CTCAE Grade 3 nonhematological toxicity.  Exceptions will be made for:
o
Grade 3 nausea, vomiting, or constipation that lasts less than 72 hours and that 
can be controlled with treatment
o
Grade 3 electrolyte disturbance that can be controlled with treatment and 
persists less than 5 days
o
Grade 3 hyperglycemia or Grade 4 hyperglycemia without ketoacidosis during 
and after the end of dexamethasone treatment unless it is not controlled by 
oral medication or insulin before the start of the next dexamethasone round
o
Grade 3 arterial hypertension during and after the end of dexamethasone 
treatment unless it is not controlled by oral medication before the start of the 
next dexamethasone round
o
tumor lysis syndrome (TLS): patients who demonstrate a clinical syndrome 
consistent with TLS and have transient (<7 days) and manageable Grade 3 
abnormalities in serum electrolytes, renal function and/or chemistries (ie, uric 
acid, potassium, phosphorus, calcium, creatinine, blood urea nitrogen, etc.)
o
Grade 3 diarrhea for <5 days and unless it cannot be controlled with standard 
treatment
o
transient (<7 days) Grade 3 elevations of ALT and/or AST, that are not 
accompanied by a Grade 2 bilirubin increase are considered an exception to the 
DLT criteria, unless there is a clear alternative cause (eg, worsening biliary 
obstruction) if agreed by the study investigator and Lilly CRP

any other significant toxicity deemed by the primary investigator and Lilly clinical 
research personnel to be dose limiting (eg, any toxicity that is possibly related to the 
study medication that requires the withdrawal of the patient from the study during 
Cycle 1)
A dose-limiting equivalent toxicity (DLET) is defined as an AE occurring between Day 1 and 
Day 28 of any cycle (other than Cycle 1) for a patient enrolled in the Phase 1 portion or in any 
cycle (including Cycle 1) for a patient enrolled in the Phase 2 portion that would have met the 
criteria for DLT if it had occurred during Cycle 1 for a patient enrolled in the Phase 1 portion.  


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MTD is defined as the highest explored dose level for which the probability of DLT does not 
exceed 33%. For the recommended Phase 2 dose, the rate and nature of AEs observed beyond 
the first cycle of treatment will be considered.  
9.3.
Method of Assignment to Treatment
9.3.1. Phase 1
Patients who enter the study during the Phase 1 portion will be assigned to receive LY3039478 
and dexamethasone. Prior to enrollment into the study, an eligibility check must be conducted 
(for every patient) between the investigational site and the Lilly clinical research personnel, to 
confirm that the patient meets all enrollment criteria.  Upon confirmation of eligibility, the 
sponsor will confirm the dose, cohort, and identification number assignment for each patient.  No 
dose escalations (ie, to the next cohort) can occur without prior discussion and agreement with 
the responsible Lilly CRP.
9.3.2. Phase 2
Patients who enter the study during the Phase 2 portion will be randomized to receive either 
LY3039478 in combination with dexamethasone or placebo in combination with dexamethasone.  
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS).  
A dynamic allocation method, introduced by Pocock and Simon (1975) and extended for unequal 
treatment group sizes by Han et al. (2009), will be adopted to balance patient assignment 
between treatment arms, using a probability factor of 0.9, based on the following factors: 

age 30 years versus >30 years

T-ALL phenotype versus T-LBL, considered as 6 factors, representing the following 
5 phenotypes of T-ALL:
TdT+, variable for all of the following: CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD34
o
Pro-T-ALL: cCD3+, CD7+, CD1a-, CD2-, CD4-, CD8-, CD34+/-
o
Pre-T-ALL: cCD3+, CD7+, CD1a-, CD2+, CD4-, CD8-, CD34+/-
o
Cortical T-ALL: cCD3+, CD7+, CD1a+, CD2+, CD4+, CD8+, CD34-
o
Medullary T-ALL: cCD3+, sCD3+, CD7+, CD1a-, CD2+, CD4+or CD8+, 
CD34-
o
ETP T-ALL: Lack of CD1a and CD8 expression, weak CD5 expression with less 
than 75% positive blasts, and expression of 1 or more of the following myeloid or 
stem cell markers on at least 25% of lymphoblasts: CD117, CD34, HLA-DR, 
CD13, CD33, CD11b, and/or CD65

response to last therapy: refractory/relapse within 1 year of last therapy vs. >1 year
The randomization parameter P will be set to 0.9 to maximize the benefit of the allocation 
procedure, whilst keeping treatment assignments unpredictable.


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The IWRS will be used to assign bottles containing double-blind study drug to each patient. Site 
personnel will confirm that they have located the correct bottles by entering a confirmation 
number found on the bottles into the IWRS.
9.4.
Dose Adjustments and Delays
9.4.1. Dose Adjustments for LY3039478 within a Cycle
No dose adjustments of LY3039478 or placebo will be allowed within a cycle.  If a patient 
treated at a given dose level experiences a DLT or a DLET (as defined in Section 9.2.2), then 
treatment will be suspended for that patient for the duration of the current cycle.  If a toxicity 
does not meet the criteria for a DLT in Cycle 1 of Phase 1 (or a DLET in Cycle 2 and beyond in 
Phase 1 or any cycle in Phase 2) but nonetheless requires omission of dose(s) for tolerability, 
then dosing may resume at the same dose after the toxicity resolves to baseline; however, the 
dose(s) omitted for tolerability during a cycle will not be replaced.  
9.4.2. Dose Adjustments for LY3039478 between Cycles
Before the start of each cycle, nonhematological toxicities (except alopecia and fatigue) must 
resolve to baseline.  The start of LY3039478 may be delayed up to 21 days to allow sufficient 
time for recovery.  Patients experiencing non-transient Grade 4 nonhematological toxicity or not 
recovering from toxicity within 21 days should be discontinued from the study.
The dose of LY3039478 should be reduced to the dose level administered in the previous cohort 
for all subsequent cycles of therapy if the investigator determines that it is in the best interest of 
the patient or if the patient experienced at least 1 of the following events:

DLT (in Cycle 1 for patients in Phase 1)

DLET (in Cycle 2 or beyond for patients in Phase 1, or in any cycle for patients in 
Phase 2)

omission of more than 7 doses of LY3039478 in a single cycle for tolerability
For patients requiring a dose reduction, re-escalation to the original dose level is not permitted.  
A second dose reduction is allowed only for patients treated at adult dose level ≥75 mg or 
pediatric equivalent (dose may be reduced to 25 mg or pediatric equivalent). Dose reduction by 
more than 2 dose levels is not permitted; patients requiring dose reduction by more than 2 dose 
levels should be discontinued from the study.  
If a patient experiences a DLET at the second reduced dose level, then the patient will be 
discontinued from the study.  If a patient requires omission of more than 3 doses for tolerability 
at the reduced dose levels, then treatment may continue if the investigator determines that the 
patient is receiving clinical benefit.  
In the Phase 2 portion of the study, investigators will treat all patients as if the patient is 
receiving active study drug, LY3039478, and will adjust doses accordingly.  


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9.4.3. Dose Adjustments – Dexamethasone
Dose adjustments for dexamethasone will be performed in case of toxicities that can’t be 
controlled with appropriate treatment.
Toxicities and dose adjustments should be managed following available or institutional 
guidelines.
9.5.
Blinding
The Phase 1b portion of this study is open-label whereas the Phase 2 portion of this study is 
double-blind.  
To preserve the blinding of the study, a minimum number of sponsor personnel will see the 
treatment assignments before the study is complete.  
Upon determination of relapsed/refractory disease or study completion, investigators and patients 
may be unblinded to study treatment assignment.
Phase 2 patients who discontinue the study due to relapse/refractory disease or treatment failure 
(Section 7.3.1) may be unblinded and cross over to treatment with LY3039478 in combination 
with dexamethasone if they had been randomized to receive placebo in combination with 
dexamethasone initially.
For this study, the following roles will be permitted to access unblinded data: all members of the 
assessment committee, plus unblinded statisticians and analysts, data scientists and PK/PD 
scientist. Access to unblinded data/documents will be controlled by restricting access to the 
data/documents in Lilly’s data and statistical warehouse. Any changes to this unblinding plan 
may be described in a protocol amendment, the Statistical Analysis Plan (SAP), and/or a separate 
unblinding plan document.  Interim analyses for safety, futility will be conducted, using 
unblinded data, under the guidance of an assessment committee.  See Section 12.2.14 for further 
details.
9.5.1. Emergency Unblinding
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly CRP prior to unblinding 
a patient’s treatment assignment unless this could delay emergency treatment of the patient.  If a 
patient’s treatment assignment is unblinded, Lilly must be notified immediately.
9.5.2. Inadvertent Unblinding
Every effort will be made to blind both the patient and the investigator to the identity of the 
treatment, but the inadvertent unblinding of a patient may occur.  A double-blind study design is 
known to be imperfect in the oncolytic setting because the potential for individual unblinding 
exists due to treatment-related signs and symptoms.  If an investigator, site personnel performing 
assessments, or patient is unblinded, the unblinding will not be sufficient cause (in and of itself) 


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for that patient to be discontinued from study therapy or excluded from any safety or efficacy 
analyses.
Additionally, there may be ethical reasons to have the patient remain on the study treatment.  For 
patients to continue on study treatment in the event of unblinding, the investigator must obtain 
specific approval from a Lilly CRP for the patient to continue in the study.
9.6.
Concomitant Therapy
Appropriate documentation of all forms of premedications, supportive care, and concomitant 
medications must be captured at each visit in the CRF.  Concomitant medications and supportive 
care therapies must also be documented at the time of discontinuation and at the 30-day 
short-term follow-up visit.
No other chemotherapy, other anticancer therapy, immunotherapy, hormonal cancer therapy
(except therapy of hormone-sensitive prostate cancer patients who are stable on GnRH agonist 
therapy and breast cancer patients who are stable on antiestrogen therapy [eg, an aromatase 
inhibitor]), radiation, surgery for cancer, or experimental medications, including herbal 
supplements intended to treat the cancer, will be permitted while patients are on study treatment.  
The need for any form of radiotherapy (including palliative) will be cause for early 
discontinuation from the study.  In addition, any disease relapse requiring other forms of specific 
antitumor therapy will also necessitate early discontinuation from the study.
Prophylactic intrathecal therapy is allowed for patients with high risk of CNS disease as long as 
spinal fluid is negative for blasts and no other evidence of active CNS disease.
Patients should receive full supportive care, if necessary.  Supportive care is given with the intent 
to maximize quality of life.  Those therapies considered acceptable include, but are not limited to
control of infections, treatment of TLS, management of aspariginase toxicity, management of
steroid side effects, use of transfusions, use of granulocyte colony-stimulating factor (G-CSF), 
use of antiemetics, nutritional support, and treatment of pain.  Patients will receive supportive 
care as judged by their treating physician.  If it is unclear whether a therapy should be regarded 
as supportive care, the investigator should consult the Lilly CRP.  The use of any supportive care 
therapy should be reported on the CRFs.
The protocol does not permit the routine use of colony-stimulating factors or erythropoiesis-
stimulating agents (ESAs) during treatment.  The protocol does not allow the use of products that 
stimulate thrombopoiesis.  Erythropoietic therapy may be considered for treatment of 
chemotherapy-induced anemia for patients with hemoglobin 10 g/dL after the patients has been 
counseled about the risks and benefits of ESA use (Smith et al. 2006; Rizzo et al. 2008).
Because recommendations on the use of ESAs are rapidly evolving, investigators should 
frequently refer to the National Comprehensive Cancer Network (NCCN), American Society of 
Clinical Oncology, American Society of Hematology, and/or Centers for Medicare and Medicaid 
Services websites for the latest guidelines or follow local guidelines.


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In the event of diarrhea, the following supportive measures are allowed:  hydration, octreotide, 
and antidiarrheals, including opioids.
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or severe 
(Grade 3 or 4) neutropenia, broad-spectrum antibiotics must be prescribed taking into account 
the local prevalence of infection agents and their probable resistance.  Patients with severe 
diarrhea or any diarrhea associated with severe nausea and vomiting should be hospitalized for 
supportive care including antiemetics, intravenous hydration and correction of electrolyte 
imbalances.  Events that require a patient to be hospitalized are considered SAEs (see 
Section 10.3.1.1).
Patients experiencing febrile neutropenia, especially with diarrhea or dyspnea, should be 
managed in a hospital setting according to standard procedures, with the urgent initiation of 
intravenous antibiotic therapy.  
The use of allopurinol should be considered as an adjunct to appropriate use of hydration in 
prophylaxis of TLS.  Evaluation of hydration status and changes in kidney function, serum 
electrolytes, and uric acid levels may assist in both prophylaxis for and management of acute 
renal function changes and TLS.  When there is concern about the level of disease burden and 
effects of potential rapid cytoreduction, or if the patient has high baseline uric acid levels, 
prophylaxis for TLS with allopurinol or another therapeutic substitute may be considered.  When 
used for prophylaxis, allopurinol should be administered orally once daily starting at a minimum 
the day before the first study drug dose.  Allopurinol may be discontinued or dose adjusted 
during study treatment at the investigator’s discretion, for example, based on renal function.  If 
allopurinol is contraindicated, investigators may consider the use of an appropriate therapeutic 
substitute.
9.7.
Treatment Compliance
Patient compliance with study medication will be assessed at each visit.  Compliance will be 
assessed by direct questioning, counting returned capsules. Furthermore, the patient or caregiver
will have to complete a diary for Cycles 1 and 2 at time points related to the PK sample schedule 
as described in Attachment 3. In addition, any Day 1 dosing date in Cycles >2 have to be 
documented.  
The patient must take 75% of the intended doses to be deemed compliant with study drug 
administration.  Similarly, a patient will be considered significantly noncompliant if he or she is 
judged by the investigator to have intentionally or repeatedly taken more than the prescribed 
amount of medication. Any missed doses during a cycle will be omitted and not replaced.  In the 
event of a missed dose, a patient should resume and continue dosing, beginning with the next 
scheduled dose.
Potential discontinuation of a patient due to study drug noncompliance will be discussed between 
the investigator and the Lilly CRP before the final determination is made to discontinue the 
patient.  If a patient is discontinued due to study drug noncompliance, the patient may be 
replaced.


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9.7.1. Evaluable Patients Phase 1 Parts A and B
Patients who withdraw from the study before receiving study drug(s) will be replaced and will 
not be included in the safety or efficacy assessments.  Safety analyses will be conducted on all 
patients who have received at least 1 dose of any study drug, regardless of whether they are 
deemed evaluable for the assessment of a dose level.
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 to ensure adequate PK data, unless 
accrual to that cohort has stopped due to a DLT.  Patients who are evaluable for PK are defined 
as patients who have a sufficient number of PK samples to evaluate PK parameters after at least 
1 dose of LY3039478. 
Patients who are discontinued from the study before completing Cycle 1 will be deemed 
nonevaluable for assessment of a dose level, unless they experience a DLT prior to withdrawal. 
If patients are noncompliant during Cycle 1 due to reasons other than drug-related toxicity, they 
will be considered nonevaluable.
Nonevaluable patients will 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.
9.7.2. Evaluable Patients Phase 2
In the Phase 2 portion of the study, patients will be considered evaluable after randomization as 
per definition of the intent-to-treat analysis set (Section 12.2.1).


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10. Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and
Appropriateness of Measurements
Written informed consent must be obtained prior to any study-specific pretreatment evaluations. 
Study procedures related to efficacy, safety, health outcome/quality of life measures, sample 
collection and testing assessments and their timing are described in the sections below and 
shown in the Study Schedule (Attachment 1).
10.1. Efficacy Measures 
10.1.1. Study Assessments
10.1.1.1. Pretreatment (Baseline)
For T-ALL patients, a bone marrow biopsy and/or aspirate will be obtained to locally assess 
bone marrow cellularity and to determine the percentage of leukemic blasts within 2 weeks and 
no less than 1 day before the first dose of study drugs. The results of this bone marrow biopsy 
and/or aspirate will serve as the baseline assessment for efficacy; therefore, the results will not be 
required to be received before study drug administration. In addition, a computed tomography 
(CT) or magnetic resonance imaging (MRI) of the thorax and abdomen (including the pelvis)
will be performed within 4 weeks and no less than 1 day before the first dose of study drug.
For T-LBL patients, baseline tumor measurements will be performed within 4 weeks and no less 
than 1 day before the first dose of study drugs. Positron emission tomography-computed 
tomography (PET-CT) is the preferred method of measurement for FDG-avid lymphomas.  A
CT, including spiral CT, or MRI of the thorax and abdomen is indicated for non-avid histologies. 
For all patients with suspected CNS involvement, a lumbar puncture will be performed within 
14 days before the first dose of study drugs. For patients with neurological signs or symptoms at 
diagnosis, a CT/MRI of the brain and/or affected spinal cord is required within 4 weeks before 
the first dose of study drugs.
For patients continuing treatment after study completion, efficacy assessments (frequency and 
type of assessments) will be at the discretion of the investigator and based on the standard of 
care.  
10.1.1.2. During Study Treatment 
For T-ALL patients, during the treatment phase of the study, blood samples will be obtained to 
monitor disease burden weekly according to the Study Schedule (Attachment 1) during Cycle 1 
and biweekly thereafter.  Additionally, a bone marrow core biopsy and/or aspirate sample will be 
obtained on Day 28 (-3 days) of Cycle 1.  If the morphologic result does not provide a clear 
response and it is clinically indicated by the investigator, a second bone marrow examination
should be repeated 1 week later. For T-ALL and where clinically indicated, the CT/MRI will be 
repeated on Day 28 (-3 days) of Cycle 1. A response (CR or PR) must be confirmed no less than 


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28 days from the first evidence of response by bone marrow core biopsy and CT/MRI as
indicated. If 2 consecutive bone marrow assessments demonstrate no tumor with adequate 
cellularity, bone marrow assessments will be discontinued unless there is evidence of relapse. In 
case of CR by CT/MRI on 2 assessments no less than 28 days apart the interval between 
assessments may be increased to every 2 months. 
In T-LBL patients, the method of assessment used at baseline must be used consistently for 
tumor assessment and will be repeated every other cycle starting on Day 28 (-3 days) of Cycle 2.
For T-LBL patients followed by CT/MRI, response (CR or PR) must be confirmed no less than 
28 days from the first evidence of response.  Thereafter, a responding patient will be followed 
every other cycle until objective progression is observed.
10.1.1.3. Posttreatment Discontinuation Follow-Up
Postdiscontinuation follow-up during the study period will be conducted as described in the 
Study Schedule (Attachment 1). 
For T-ALL patients who are in remission, blood samples should be obtained every 1-3 months. 
After relapse, no blood sample analysis is required. The patient will be followed approximately 
every 90 days (14 days) until the patient’s death or overall study completion. Bone marrow 
assessment will be performed at time of treatment discontinuation or in the 30 Day follow-up 
period only if not assessed in the prior 8 weeks. 
For T-LBL patients who discontinue study treatment without objectively measured progressive 
disease, the investigative sites will continue to monitor patients and periodically evaluate tumor 
response approximately every 8 weeks by the same method used at baseline and throughout the 
study until the patient has objective disease progression, or until the final analysis of OS is 
performed.  After the patient has objective disease progression, radiologic tests are no longer 
required and the patient will be followed approximately every 90 days (14 days) until the 
patient’s death or overall study completion.
Response (CR or PR) should be confirmed before the initiation of additional anticancer therapy. 
However, initiation of new therapy should not be delayed solely to confirm response.
After the primary/final analysis of OS, efficacy assessments (frequency and type of assessments) 
will be at the discretion of the investigator, based on the standard of care.
Lilly will continue to collect survival data on all patients but may reduce data collection for other 
efficacy data.  Lilly will notify investigators when this reduced data collection can begin.
10.1.2. Primary Efficacy Measure
For T-ALL patients, assessment of efficacy will be consistent with NCCN guidelines for ALL 
and Cheson criteria (Cheson et al. 2003).  The primary endpoints are defined as follow. 
A CR is defined as <5% blasts in an aspirate sample with marrow spicules and with a count of at 
least 200 nucleated cells, along with peripheral blood levels including platelets ≥100 × 109/L and 
absolute neutrophil count (ANC) ≥1 × 109/L and without circulating blasts.


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A CRi is defined as fulfilling all criteria for CR except for residual neutropenia (<1000/µL) or 
thrombocytopenia (<100,000/µL).  The proportion of patients achieving a CRi is defined as the 
total number of patients achieving a CRi divided by the total number of patients randomized in 
that arm.
All previous extramedullary manifestations of disease must be absent (eg, lymphadenopathy, 
splenomegaly, skin or gum infiltration, testicular masses, CNS involvement). The CR rate is 
estimated as the total number of patients achieving a CR divided by the total number of patients 
randomized in that arm.
The ORR (CR and CRi) is the sum of patients achieving a CR and a CRi divided by the total 
number of patients randomized in that arm.  
The Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007) will be used to 
assess the efficacy of LY3039478 in T-LBL patients followed by CT scan or MRI.
For patients with T-LBL followed by CT/MRI, the criteria for CR is similar to T-ALL and 
requires the disappearance of all measurable disease, signs, symptoms, and biochemical changes 
related to the tumor. 
For T-LBL patients assessed by PET-CT, the criteria for CR is as follows: complete metabolic 
response with the lymph nodes or extralymphatic sites having a score or 1, 2, or 3 with or
without a residual mass on the 5-point assessment scale with high physiologic uptake or with 
activation within spleen or marrow (eg, with chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal mediastinum and/or liver. In this circumstance, 
complete metabolic response may be inferred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the tissue has high physiologic uptake.  There can 
be no new lesions and no evidence of FDG-avid disease in the bone marrow.
The PET-CT 5-point assessment scale is as follows: 1, no uptake above background; 2, uptake 
≤mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake 
markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to 
lymphoma (Cheson et al. 2014).
The first assessment of response for T-LBL patients will be performed on Day 28 (3 days) of 
Cycle 2.  A second assessment must be performed ≥28 days after the first evidence of response
(this is only required for patients being followed by CT scan/MRI).  Two consecutive objective 
status determinations of CR before progression are required for a best response of CR by CT 
scan/MRI.  
Best response will be derived to encompass all tumor assessments from baseline until the earliest 
objective progression or start of new anticancer therapy.  Any responses observed after objective 
progression or the start of new anticancer therapy are excluded from the determination of best 
response.
The date of first documented objective disease progression must be recorded on the CRF even if 
it occurs after the patient has started a new therapy.


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Lilly or its designee will collect and store all tumor measurement images on all enrolled patients 
throughout the study.  An independent review of imaging scans will be performed by Lilly or its 
designee.
Minimal residual disease (MRD) will be used to confirm CR/CRi.  MRD in T-ALL is defined by 
the continued presence of leukemic cells below the level of detection by usual methods.  Patients 
who achieved a CR by morphologic assessment alone could still have leukemic cells in the bone 
marrow.  Flow cytometry will be used to assess MRD in bone marrow. The minimal limit of 
assay sensitivity (to declare MRD negativity) should be <1 × 10-4 (<0.01%).  MRD are 
recommended at the end of the initial induction and additional time points as clinically indicated 
(Bruggeman et al. 2010).  Molecular techniques may be used if necessary.
10.1.3. Secondary Efficacy Measures
The following secondary efficacy measures will be assessed:
Remission rate after failure of placebo plus dexamethasone will be calculated for those patients 
that cross-over in the Phase 2 part of the trial and receive LY3039478 plus dexamethasone. 
OS is defined for all patients in the trial, and measured from the date of study enrollment to the 
date of death from any cause. OS duration is measured from the date of randomization to the 
date of death from any cause in the Phase 2 portion of the study.  For each patient who is not 
known to have died as of the data-inclusion cutoff date for a particular analysis, OS will be 
censored for that analysis at the date of last contact prior to the data inclusion cutoff date 
(contacts considered in the determination of last contact date include AE date, lesion assessment 
date, visit date, and last known alive date).
10.1.3.1. T-ALL
For T-ALL: PR rate is defined as a decrease of at least 50% in blast count on the bone marrow 
aspirate; PR requires all of the hematologic values for a CR but with a decrease of at least 50% 
in the percentage of blasts to 5% to 25% in the bone marrow aspirate.  The proportion of patients 
achieving a PR is defined as the total number of patients achieving a PR divided by the total 
number of patients randomized in that arm.
DoR (CR and CRi) is measured from the date of CR or CRi by blood count recovery and bone 
marrow examination, until the date of relapse.  It is measured until the date T-ALL relapse is 
detected.  For patients who die without report of relapse, DoR is censored on the date of death, 
regardless of cause.  For a patient with no report of relapse or death by the end of the follow-up 
data collection, observation is censored at the date of last contact prior to the data inclusion 
cutoff date.
Relapse-free survival (RFS) is defined as the timeframe before the reappearance of unequivocal 
leukemia blast cells in the blood or the bone marrow (>5%), in the CNS (positive cytospin 
examination of CSF) or in any other extramedullary site after a CR.
RFS is defined only for patients who achieve CR, and is measured from the date of attaining the 
leukemia-free state (as defined in Section 10.1.2) until the date of T-ALL relapse or death from 


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any cause, whichever occurs first.  For a patient who is not known to have relapsed or died by 
the end of study follow-up, observation of RFS is censored at the date of last contact prior to the 
data inclusion cutoff date.
Event-free survival (EFS) is defined for all patients and measured from the date of entry on 
study.  It is measured until treatment failure, relapse from CR, or death from any cause, 
whichever occurs first.  For a patient with none of these events before the end of study 
follow-up, observation of EFS is censored at the date of last contact prior to the data inclusion 
cutoff date.  If the patient does not achieve a CR, EFS is defined as the point of treatment failure 
or death, whichever comes first.  
Refractory disease for T-ALL is defined as failure to achieve CR.
Relapsed disease for T-ALL is defined as the reappearance of the blast in the blood or bone 
marrow (>5%) or any extramedullary site after achievement of a CR.
Treatment failure for T-ALL is defined by progressive disease, which is an increase of at least 
25% in the absolute number of circulating or bone marrow blasts or development of 
extramedullary disease.  For T-ALL patients with preexisting mediastinal disease, progressive 
disease is defined by a greater than 25% increase in the sum of the product of the greatest 
perpendicular diameters (SDP) of the mediastinal enlargement.
10.1.3.2. T-LBL
For T-LBL followed by CT scan/MRI: PR is defined as a reduction of ≥50% in the sum of the 
products of the perpendicular diameters of all measurable lesions compared with pretreatment 
measurements.  No new lesions will appear, and no existing lesions will enlarge.  Stable disease 
(SD) is defined as a <50% reduction and no more than a 25% increase in the sum of the products 
of 2 perpendicular diameters of all measured lesions, and the appearance of no new lesions
(Cheson et al. 2007).
Two consecutive determinations of PR before progression, but not qualifying for a CR, are 
required for a best response of PR for T-LBL patients being followed by CT.  Best response of 
SD is defined as disease that does not meet the criteria for CR, PR, or progressive disease.
For T-LBL followed by PET-CT scan, the criteria for PR is as follows:  partial metabolic 
response and a score of 4 or 5 with reduced uptake compared with baseline and residual masses 
of any size in the lymph nodes or extralymphatic sites.  There can be no new lesions and residual 
uptake higher than uptake in normal marrow but reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy allowed).  If there are persistent focal 
changes in the marrow in the context of a nodal response, consideration should be given to 
further evaluation with MRI or biopsy or an interval scan (Cheson et al. 2014).
DoR for T-LBL is measured from the time when criteria for response (ie, CR or PR) are met, 
until the first documentation of relapse or progression.  For patients who die without report of 
relapse, DoR is censored on the date of death, regardless of cause.  For a patient with no report of 
relapse or death by the end of the follow-up data collection, observation is censored at the date of 
last contact prior to the data inclusion cutoff date.


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RFS for T-LBL is measured from the time of occurrence of a disease-free state or attainment of a 
CR to disease recurrence or death as a result of lymphoma or acute toxicity of treatment.  For a 
patient who is not known to have relapsed or died by the end of study follow-up, observation of 
RFS is censored at the date of last contact prior to the data inclusion cutoff date.
Event-free survival (EFS) is defined for all patients and measured from the date of entry on 
study.  It is measured until treatment failure, relapse from CR, or death from any cause, 
whichever occurs first.  For a patient with none of these events before the end of study 
follow-up, observation of EFS is censored at the date of last contact prior to the data inclusion 
cutoff date.  If the patient does not achieve a CR, EFS is defined as the point of treatment failure 
or death, whichever comes first.
Treatment failure for T-LBL is defined in Table JJCB.10.1.
Table JJCB.10.1.
Treatment Failure in T-LBL
PET-CT Based Response
CT/MRI-Based Response
Relapsed disease or 
progressive disease

Progressive metabolic disease

Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or

New FDG-avid foci consistent 
with lymphoma at interim or end-
of-treatment assessment
An individual node/lesion must be abnormal 
with: 

LDi >1.5 cm and 

Increase by ≥50% from PPD nadir and 

An increase in LDi or SDi from nadir 0.5 cm 
for lesions ≤2 cm 

1 cm for lesions >2 cm
In the setting of splenomegaly, the splenic length 
must increase by >50% of the extent of its prior 
increase beyond baseline (eg, a 15-cm spleen 
must increase to >16 cm).  If no prior 
splenomegaly, must increase by at least 2 cm 
from baseline
Abbreviations: CT = computed tomography; FDG = fluorodeoxyglucose; LDi = longest diameter; MRI = magnetic 
resonance imaging; PET-CT = positron emission tomography-computed tomography; PPD = perpendicular 
diameter; SDi = shortest diameter.
10.2. Health Outcome/Quality of Life Measures 
10.2.1. Patient-Reported Outcomes
Patient health-related quality of life will be measured in the Phase 2 portion of this study using 
the FACT-Leu, which includes a leukemia-specific module intended to be appropriate for 
patients with various leukemias (Cella et al. 2012).  Attachment 7 contains a reference to the 
website where this questionnaire may be downloaded.  The FACT-Leu includes the 27-item 
cancer-specific Functional Assessment of Cancer Therapy-Leukemia-General (FACT-G) that 
assesses physical, social/family, emotional and functional well-being plus a 17-item subscale that 
assesses additional concerns specific to leukemia.  This self-administered questionnaire will be 
completed by the patient at the beginning of visits (prior to other study procedures, unless there 


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are patient safety concerns) as described in the Study Schedule (Attachment 1) for patients where 
the questionnaire has been translated into a language in which the patient is fluent.  Scoring will 
be in accordance with the guidelines suggested by the developers.  
10.2.2. Resource Utilization
Investigators will be asked to document the use of best supportive care measures, concomitant 
medications, transfusions, and disease/adverse event-related hospitalization days.  Such 
assessments are to be taken throughout the Phase 2 portion of the study, through the 30-day 
short-term follow-up, and during the postdiscontinuation follow-up visit.
10.3. Safety Evaluations
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study, or that caused the patient to discontinue 
before completing the study.  The patient should be followed until the event is resolved or 
explained.  Frequency of follow-up evaluation is left to the discretion of the investigator.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  
Table JJCB.10.2 presents a summary of AE and SAE collection with regard to the type of events 
to be reported during each period of the study.  
Table JJCB.10.2.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to Be Reported
Baseline (pretreatment)
Preexisting conditions
All AEs
SAEs related to protocol procedures
Study treatment period
All AEs and SAEs 
30-day short-term posttreatment discontinuation 
follow-up 
All AEs and SAEs 
Long-term posttreatment discontinuation 
follow-up 
All SAEs related to protocol procedures or study drug
Continued access period and follow up
All AEs and SAEs
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
10.3.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical event 
associated with the use of a drug in humans, whether or not it is considered related to that drug.  
However, leukemia-related hematologic effects should not be reported as AEs.  Because Grade 3 
or 4 myelosuppression (leukopenia, neutropenia, thrombocytopenia, and anemia) is expected in 


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the setting of relapsed T-ALL, these cytopenias will not be considered AEs for the purpose of 
this study, unless the investigator classifies them as AEs based on clinical circumstances.
Lack of drug effect is not an AE in clinical trials, because the purpose of the clinical trial is to 
establish drug effect.
Any clinically significant findings from ECGs, laboratory values, vital sign measurements, other
procedures, and so on that result in a diagnosis should be reported to Lilly or its designee.
Cases of pregnancy that occur during maternal or paternal exposures to study drug should be 
reported.  Data on fetal outcome and breastfeeding are collected for regulatory reporting and 
drug safety evaluation.
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the ICF is signed, site personnel will record the occurrence and nature of any AEs and any 
change in the preexisting condition(s).  All AEs related to protocol procedures are reported to 
Lilly or its designee.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure and study drug via CRF, electronic data entry or 
other designated data transmission methods.
Patients will be evaluated for AEs at each visit and will be instructed to call their physician to 
report any AEs between visits.
The NCI CTCAE v4.0 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms.  For AEs without 
matching terminology within the NCI CTCAE v 4.0 criteria, the investigator will be responsible 
for selecting the appropriate system organ class (SOC) and assessing severity grade based on the 
intensity of the event. 
In addition to collecting the AE verbatim and the CTCAE severity grade, AE verbatim text will 
also be mapped by Lilly or its designee to corresponding terminology within the Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via CRF, electronic data entry or designated 
data transmission methods the circumstances and data leading to any such dosage reduction or 
discontinuation of treatment.
10.3.1.1. Serious Adverse Events
An SAE is any adverse event from this study that results in 1 of the following outcomes:

death

a life-threatening experience (ie, immediate risk of dying)

persistent or significant disability/incapacity


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
initial or prolonged inpatient hospitalization

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
SAE collection begins after the patient has signed informed consent and has received study drug.  
If a patient experiences an SAE after signing informed consent, but prior to receiving study drug, 
the event will not be reported as serious unless the investigator feels the event may have been 
caused by a protocol procedure.
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
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 study site personnel contact Lilly or 
its designee by telephone regarding an SAE, study site personnel must also immediately provide
official notification on study-specific SAE forms.
This 24-hour notification requirement refers to the initial SAE information and all follow-up 
SAE information.
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
Planned hospitalizations or procedures for 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 (eg, for the 
administration of study therapy or other protocol-required procedure) should not be considered 
SAEs.
SAEs due to disease relapse or progression, including death, should not be reported unless the 
investigator deems them to be possibly related to the study drug.
If an investigator becomes aware of an SAE occurring after the patient’s participation in the trial 
has ended, and the investigator believes that the SAE is related to a protocol procedure, 
LY3039478 or dexamethasone, the investigator should report the SAE to the sponsor, and the 
SAE 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 Section 6.2.1.2.4.


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10.3.1.2. Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the DCSI of the IB and that the investigator identifies as related to the investigational product
or study procedure.  United States 21 CFR 312.32, European Union Clinical Trial Directive 
2001/20/EC and the associated detailed guidances or national regulatory requirements in 
participating countries require reporting of SUSARs.  Lilly has procedures that will be followed 
for the recording and expedited reporting of SUSARs that are consistent with global regulations 
and associated detailed guidances.
10.3.2. Electrocardiograms
For each patient, 12-lead digital ECGs will be collected as replicates (usually triplicates) 
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. 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 when needed to ensure high quality 
records. 
ECGs will initially 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.
After enrollment, if a clinically significant increase in the QT/QTc interval from baseline or 
other clinically significant quantitative or qualitative change from baseline is identified, the 
patient will be assessed by the investigator for symptoms (eg, palpitations, near syncope, 
syncope) and 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.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control (eg, demographics and study 
details) then store the ECGs in a database.  At a future time, the stored ECG data may be 
overread at the central ECG laboratory for further evaluation of machine-read measurements or 
to meet regulatory requirements.
10.3.3. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CRP
will, as is appropriate, consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical scientist, and review:

trends in safety data


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
laboratory analytes 

AEs
If a patient experiences elevated ALT >5× ULN and elevated total bilirubin >2× ULN, clinical 
and laboratory monitoring should be initiated by the investigator. For patients entering the study 
with ALT >2× ULN, monitoring should be triggered at ALT >2× baseline.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities. To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP regarding collection of specific recommended 
clinical information and follow-up laboratory tests. See Attachment 4.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the assessment committee (an advisory group for this study 
formed to protect the integrity of data; refer to Section 12.2.14) can conduct additional analyses 
of the safety data.
10.3.4. Complaint Handling
Lilly collects product complaints on study drugs used in clinical trials in order to ensure the 
safety of study participants, monitor quality, and to facilitate process and product improvements.
Complaints related to unblinded comparator drugs or concomitant drugs are reported directly to 
the manufacturers of those drugs/devices in accordance with the package insert.
For blinded studies, all product complaints associated with material packaged, labeled, and 
released by Lilly or its designee will be reported.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

submit the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.4. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study and whether these will 
be performed at a central or local laboratory.  
A deviation from the cerebrospinal fluid (CSF) and PK sampling schedule will not be considered 
a protocol violation.


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10.4.1. Samples for Study Qualification and Health Monitoring
Blood, urine, CSF, bone marrow, and tissue samples will be collected to determine whether 
patients meet inclusion/exclusion criteria, to monitor patient health, and to characterize the 
malignancy.  
From T-ALL patient a bone marrow biopsy will be taken by core needle biopsy. A small amount 
of archived paraffin tissue block and bone marrow previously obtained will be requested from 
T-LBL patients. A small amount of archived lymph node tissue or slides with unstained tumor 
sections are required. For both T-ALL and T-LBL patients, due diligence should be used to 
make sure that tumor and/or bone marrow specimen (not a normal adjacent or a tumor margin
sample) are provided.  Pathology notes accompanying archival tissue may also be requested.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.4.2. Samples for Pharmacodynamics and/or Biomarkers
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.  
Collection of samples for exploratory biomarker research is also part of this study.  Blood, CSF, 
EDTA plasma, tissue, and bone marrow samples will be collected. 
Required samples for biomarker research to be collected from all patients in this study are the 
following: 

whole blood

EDTA plasma

archived bone marrow aspirate/biopsy samples from T-ALL patients

on study bone marrow aspirate/biopsy samples from T-ALL patients

archived tumor tissue from T-LBL patients
Optional samples for biomarker research that should be collected from patients in the study 
where possible are the following:

on study pretreatment and posttreatment tumor tissue from T-LBL patients

tumor tissue at time of disease progression or if deemed necessary by the investigator

CSF (adult patients in Phase 1 only)


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Samples will be tested for markers of Notch and related pathway activation including, but not 
limited to, protein expression and activation by immunohistochemistry and ELISA, and gene 
expression by quantitative polymerase chain reaction (PCR) analysis to evaluate their association 
with the observed clinical outcomes to LY3039478, as well as circulating A-beta peptides.  
Samples will also be tested for miRNA and transcriptome expression.
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 LY3039478.  These investigations may be limited to a focused 
candidate gene study or, if appropriate, wider analysis of multiple genes and/or regions 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.
Other samples may be used for research to develop methods, assays, and/or companion 
diagnostics related to T-ALL, Notch gene, and Notch gene pathway and related pathways.
Bone marrow or tissue biopsy will be taken by core needle biopsy and/or surgical biopsy.  
A small amount of archived bone marrow/tissue or slides with unstained tumor sections are 
required for biomarker research.  
Additionally, the optional tumor biopsies from T-LBL patients will be analyzed at laboratories 
using assays designated by the sponsor.  Sample handling and shipment to the central laboratory 
will occur per instructions given to the study site.
The samples will be coded with the patient number and stored for up to a maximum 15 years 
after the last patient visit for the study at a facility selected by the sponsor.  The samples and any 
data generated from them can only be linked back to the patient by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the study drug.
Samples will be destroyed according to a process consistent with local regulation.
10.4.3. Samples for Drug Concentration Measurements 
Pharmacokinetics 
PK samples will be collected as specified in the Pharmacokinetic Sampling Schedule 
(Attachment 3). 
Venous blood samples of approximately 3 mL each will be collected to determine the plasma 
concentrations of LY3039478 and dexamethasone. Separate blood samples are not required for 
LY3039478 and dexamethasone. After harvesting the plasma, samples will be divided into 2 
approximately equal portions by site personnel, one for the determination of plasma 
concentrations of LY3039478, and the other for the determination of plasma concentrations of 
dexamethasone.  Instructions for the collection and handling of blood samples will be provided 
by the sponsor.  A maximum of 5 blood samples may be drawn at additional time points during 


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the study if warranted and agreed upon between both the investigator and Lilly. CSF samples 
will be used to determine the concentrations of LY3039478.  
CSF concentrations of LY3039478, and plasma concentrations of LY3039478 and 
dexamethasone will be quantified using validated liquid chromatography-mass spectrometry / 
mass spectrometry (LC-MS/MS) assays. All bioanalytical samples will be stored in the United 
States. The remaining plasma samples collected for PK evaluation may be used for exploratory 
studies to assess the metabolism of LY3039478, which may involve sample pooling. These 
samples may be retained for a maximum of 2 years following the last patient visit for the study.


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11. Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor 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 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 Lilly, applicable regulatory agencies, and applicable ERBs with direct 
access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this trial.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
CRF data 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
the Lilly data warehouse, using standard Lilly file transfer processes.
Data managed by a central vendor, such as laboratory test data or ECG data, will be stored 
electronically in the central vendor’s database system.  Laboratory data will be transferred from 
the central vendor to the Lilly generic labs system.
Any data for which the paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect patient-
reported outcome measures (eg, a rating scale), a daily dosing schedule, or an event diary.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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12. Sample Size and Statistical Methods
12.1. Determination of Sample Size
Approximately 86 to 92 patients will be enrolled in this multicenter study.
In the Phase 1 portion of the study, the primary objective is to determine the MTD and the 
recommended dose for Phase 2.  Approximately 13 to 16 patients will be enrolled into the adult 
(Part A), and approximately 13 to 16 patients will be enrolled in the pediatric (Part B) cohorts 
sequentially and without randomization to dose.  The total sample size per cohort will be 
determined by DLTs.
In the Phase 2 portion of the study, the primary objective of this study is to compare the ORR 
(CR plus CRi) rate between LY3039478 administered with dexamethasone and placebo 
administered with dexamethasone, in adult patients with relapsed/refractory T-ALL/T-LBL.
Approximately 60 evaluable patients will be randomized to the 2 treatment arms in a 2:1 ratio
(40 randomized to LY3039478 and dexamethasone and 20 randomized to placebo and 
dexamethasone).  
Assuming the ORR for the LY3039478 and dexamethasone arm is 40% and the ORR of the
placebo and dexamethasone is 5%, the sample size of 60 evaluable patients will give 
approximately 82% statistical power to detect the difference, using a 2-sided Fisher’s test at the 
significance level of 0.05, with 1 futility interim once the 30th enrolled patient completes the 
remission status determination (Section 12.2.14).  
Primary analysis for ORR will be conducted once the last patient enrolled has completed 
3 cycles of treatment, discontinued treatment, started new anticancer therapy or met 
criteria for objective progression. Patients who are randomized and do not achieve a CR
or CRi will be considered as nonresponders in the primary analysis for ORR. 
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Lilly.
Efficacy analyses will be based on the intention-to-treat (ITT) analysis set.  This population is 
defined as all patients randomized to study treatment.  Patients will be grouped according to dose 
level cohort or randomized treatment. Sensitivity analyses may be conducted (if applicable) 
excluding patients that are randomized but do not receive treatment, and by actual treatment 
received. 
A secondary analysis of the primary efficacy endpoint based upon the per-protocol set (PPS) of 
patients may be performed if there are significant numbers of patients with major protocol 
deviations (10% of total patient population).  The PPS is defined as those patients in the ITT set 
who are compliant with the study protocol.  Major deviations from the protocol for purposes of 
this analysis will be detailed in the Statistical Analysis Plan.


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Safety analyses will be based on the safety population, defined as all enrolled patients receiving 
at least 1 dose of any study drug.  Patients will be grouped according to treatment received in 
Cycle 1.
PD and/or tailoring biomarker analyses will be based on the subset of patients from the above 
populations from whom a valid assay result (according to laboratory guideline) has been 
obtained.  
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.  All tests of interactions will be conducted at a 2-sided alpha level of 0.1, and all CIs will 
be given at a 2-sided 95% level, unless otherwise stated.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  
Before unblinding of the aggregate database, minor modifications or clarifications to the data 
analysis methods may be described and justified in the statistical analysis plan.
Any other 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.  
The assumptions for each statistical method will be evaluated.  If there is violation of 
assumptions, alternative statistical methods may be used.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
12.2.2. Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients completing the study, or discontinuing (overall and by 
reason for discontinuation).  A summary of all important protocol deviations will be provided.
12.2.3. Patient Characteristics
Patient demographics including age, sex, screening height and weight, and screening body mass 
index will be reported using descriptive statistics. 
Baseline disease characteristics will be summarized by presenting frequency counts and 
percentages including initial diagnosis (T-ALL or T-LBL), T-ALL subtypes, ECOG performance 
status, disease status at study entry (refractory or relapse), Notch and FBWX7 mutational status, 
duration of first remission, number of prior courses of induction therapy, extramedullary disease, 
and history of CNS leukemia. Other patient characteristics will be summarized as deemed 
appropriate.
12.2.4. Concomitant Therapy
Concomitant medications will be summarized for the safety population. 


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12.2.5. Postdiscontinuation Therapy
The numbers and percentages of patients reporting postdiscontinuation therapies will be 
provided overall, by type of therapy (surgery, radiotherapy, systemic therapy, or stem cell 
transplant), and by drug name.  
In the Phase 2 portion, numbers and percentages of patients randomized to placebo and 
dexamethasone who following treatment discontinuation receive LY3039478 and 
dexamethasone with be included in summaries of postdiscontinuation therapies.
12.2.6. Treatment Compliance
The number of dose omissions, reductions, delays, and cycles received and the dose intensity 
will be summarized for all treated patients per treatment arm.  Summarized data will be provided 
for the period prior to first CR, the period following first CR, and the total treatment period.
Treatment compliance information for study drug will be collected through pill counts at each 
visit and the number of tablets taken relative to the number expected to be taken will be 
summarized.
12.2.7. Primary Outcome and Methodology
In the Phase 1 portion, the primary outcome of interest is determining the MTD and 
recommended dose for Phase 2. 
In the Phase 2 portion, the primary efficacy endpoint of ORR (CR plus CRi) rate and its exact 
95% confidence interval (CI) will be estimated for each treatment arm.  The proportion in each 
treatment arm will be compared using Fisher’s exact test.  All randomized patients, according to 
the ITT principle, will be included in the analysis of this endpoint.
Sensitivity analyses of the primary outcome measure will include a re-randomization test. 
12.2.8. Other Analyses of Efficacy
No formal efficacy analysis is planned for the Phase 1 portion of this trial.  However, any 
response data will be listed and tabulated.  
In Phase 2, the following secondary efficacy parameters will be summarized for each treatment 
arm:

Proportion of patients achieving a ORR or PR

Proportion of patients achieving a CR, CRi, and PR

OS

RFS

EFS

DoR
The secondary efficacy endpoints of proportion of patients achieving ORR plus PR, and PR, and 
their exact 95% CIs will be estimated for each treatment arm and compared by 2-sided 
Chi-squared test or Fisher’s exact test between 2 arms. A Fisher’s exact test will be chosen over 


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a Chi-squared test if in the 2x2 table, any of the expected cell counts are less than 5, or any cell 
has zero counts.  
For the secondary efficacy endpoints OS, RFS, and EFS, the Kaplan-Meier method (Kaplan and 
Meier 1958) will be used to estimate the survival curves as well as survival rates at various 
prespecified time points (12 months for OS, 6 and 12 months for RFS and EFS) for each 
treatment arm. 
The secondary efficacy endpoint DoR is subject to competing risk of death without relapse; 
therefore, the cumulative incidence of relapse (Gray 1988; Pepe and Mori 1993; Gooley et al. 
2001) will be used.  In the calculation, patients who did not have the event will be considered 
right-censored observations.  All randomized patients, according to the ITT principle, will be
included in the analysis of these endpoints.  
The comparison of the survival curves between treatment groups will be conducted by a log-rank 
test.  Exploratory analyses for the comparison of the survival curves between treatment groups 
may be conducted by a stratified log-rank test with some of the following stratification variables: 
initial diagnosis (T-ALL phenotype, T-LBL), response to last therapy (refractory or relapsed), 
age, number of prior therapies (≤2, >2), NOTCH-1/FBXW7/RAS/PTEN status.  
The Cox proportional hazard model (Cox 1972) with treatment as a factor will be used to 
estimate the hazard ratio and corresponding 95% CI with Wald’s test p-value after adjusting for 
the following potential predictive/prognostic variables:  initial diagnosis (T-ALL phenotype, 
T-LBL), response to last therapy (refractory or relapsed), age, number of prior therapies (≤2, >2),
NOTCH-1/FBXW7/RAS/PTEN status.
All randomized patients, according to the ITT principle, will be included in the analysis of these 
endpoints.
For the analysis of time-to-event endpoints, a sensitivity analysis censoring the event time at the 
date of SCT will be completed to evaluate the potential impact from imbalance in patients 
receiving transplantation between the study arms.
No missing data will be imputed.  
Efficacy data (CR, CRi, PR, and ORR) for patients receiving patients receiving LY3039478 in 
combination with dexamethasone after failure of placebo in combination with dexamethasone
will be tabulated, and further exploratory analyses of efficacy data conducted as warranted.
Additional exploratory analyses may be performed as deemed appropriate.
12.2.9. Pharmacokinetic Analyses
PK analyses will be conducted on patients who receive at least 1 dose of the study drug and have
samples collected.  PK parameter estimates for plasma LY3039478 and dexamethasone, where 
possible, will be calculated by standard noncompartmental methods of analysis. The primary 
parameters for analysis will be Cmax, area under the plasma concentration-time curve from time 
zero to last measurable plasma concentration (AUC[0-tlast]), area under the concentration-time 


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curve from time zero to infinity or over 1 dosing interval at steady state (AUC[0-∞] or AUCτ).
Other noncompartmental parameters, such as t1/2, apparent clearance (CL/F), and apparent 
volume of distribution (V/F) may be reported. CSF LY3039478 concentrations will be 
summarized. Additional exploratory analyses will be performed if warranted by data and other 
validated PK software programs (for example, NONMEM) may be used if appropriate and 
approved by Global Pharmacokinetics management. The version of any software used for the 
analysis will be documented and the program will meet the Lilly requirements of software 
validation.
The PK data will be combined, and analyses may be conducted to determine a relationship
between exposure and PD effect (eg, Aβ), data permitting. This model may be used to help 
reassess the dose cohort escalation as the study progresses. If deemed necessary, PK/PD 
modeling may be employed to evaluate variability in exposure, pharmacologic effects, and safety
parameters.  
12.2.10.
Pharmacodynamics and Tailoring Analyses
Biomarker data from all patients undergoing biomarker assessments will be analyzed using 
descriptive statistics. Further exploratory analyses will be detailed in the SAP.
12.2.11.
Health Outcome/Quality of Life Analyses 
FACT-Leu results will be summarized descriptively by cycle and for postdiscontinuation visits, 
including number of completed questionnaires, compliance rates, reasons for noncompliance,
scores for each scale and subscale, and changes from baseline.  Resource utilization with be 
summarized descriptively by cycle.
12.2.12.
Safety Analyses
All safety summaries and analyses will be based upon the safety population as defined in 
Section 12.2.1.  An additional treatment group will be included in analyses representing safety 
data for patients receiving LY3039478 in combination with dexamethasone after failure of 
placebo in combination with dexamethasone.
Overall exposure to study drug, the numbers of patients completing each cycle, and the dose 
intensity will be summarized using descriptive statistics.  The number of patients with any dose 
adjustment will be presented for entire treatment period as well as for each cycle.  The number of 
patients with dose reductions, dose delays, or dose omissions will also be summarized, as will 
the reasons for dose adjustments. 
An overall summary of AEs will be provided for AEs deemed by the investigator to be possibly 
related to study medication, and repeated for events regardless of study drug causality.  Incidence 
rates of these events will be compared between treatment arms using Fisher’s exact test. 
A treatment-emergent AE (TEAE) is defined as an event that first occurred or worsened in 
severity after baseline.  


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The number of evaluable patients who experienced a TEAE, SAE, AE related to study drug, 
died, or discontinued from the study due to an AE will be summarized by treatment.
CTCAE v4.0 (or higher) will be used to report AEs by CTCAE terms.
Laboratory and nonlaboratory CTCAEs will be summarized by CTCAE term and maximum 
CTCAE grade, including the total for maximum Grade 3 and 4.  These summaries will be 
provided for events regardless of study drug causality, and repeated for events deemed by the 
investigator to be possibly related to study medication.
MedDRA v16.1 (or higher) will be used when reporting AEs by MedDRA terms.  The MedDRA 
lower level term will be used in the treatment-emergent computation.  TEAEs will be 
summarized by SOC and by decreasing frequency of preferred term (PT) within SOC.
Reasons for death will be summarized separately for on-therapy and within 30 days of last dose 
of study drug/last visit.  Serious adverse events will be summarized by PT. 
Hospitalizations and transfusions during the study treatment period or during the 30-day short-
term follow-up period will be summarized by treatment group.
12.2.13.
Subgroup Analyses
Exploratory subgroup analyses of efficacy endpoints will be performed for stratification or 
potential prognostic variables (for example, NOTCH-1/FBXW7/RAS/PTEN status, age [≤30, 
>30 years], initial diagnosis [T-ALL phenotype, T-LBL], ECOG status [0 or 1 vs 2], response to 
last therapy [refractory or relapsed], number of prior therapies [≤2, >2]).
Other subgroup analyses may be performed as deemed appropriate.
12.2.14.
Interim Analyses
The Phase 1 portion is a nonrandomized, open-label study, and no interim analyses are planned 
until the end of Phase 1.  Patient safety will be assessed prior to each dose escalation to ensure 
nothing precludes administration of larger doses to future study patients. In addition to 
reviewing AEs and laboratory measurements, PK and PD profiles (if available) of LY3039478
will be reviewed per cohort.  Based on these interim results, modifications (for example, 
reductions in dose increment) to the dose-escalation strategy or other design elements may be 
made to ensure patient safety.  The study investigators and the Lilly CRP will make the 
determination regarding dose escalation based on their review of the safety/tolerability data and 
the PK/PD data from the previous cohorts.  An interim analysis including safety, PK, and PD 
data will be conducted prior to proceeding to the Phase 2 portion of the study.  All relevant data 
will be reviewed to confirm the estimation of the MTD.  The decision to proceed to Phase 2 will 
be made following discussions between the investigators and Lilly clinical research personnel 
and documented in writing.
In the Phase 2 portion, safety interim analyses are planned every 12 months, and at the planned 
futility interim analysis, when response data from 30 randomized patients have been obtained.
There are no prespecified rules for stopping the trial due to safety concerns.  The assessment 


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committee members will review unblinded safety data at each interim analysis to determine 
whether there are sufficient safety concerns to justify the termination of study treatment and/or 
enrollment.
One futility interim analysis is planned in Phase 2 once 30 patients are randomized and have 
completed the CR status determination. The assessment committee may recommend stopping 
the trial for futility if the observed ORR (CR plus CRi) rate difference is <0.05 for the treatment 
arm compared to the control arm.  Simulations have been conducted in order to understand the 
operating characteristics of the futility rule and the impact on statistical power is considered 
minimal. It is not planned to stop the trial early for efficacy, thus there are no adjustments for 
multiplicity. 
A limited number of preidentified individuals may gain access to the limited unblinded data, as 
specified in the unblinding plan, prior to the interim or final database lock, in order to initiate the 
final population PK/PD model development processes for interim or final analyses.  Information 
that may unblind the study during the analyses will not be reported to study sites or blinded study 
team until the study has been unblinded.
Only the assessment committee is authorized to evaluate unblinded interim efficacy and safety 
analyses.  Study sites will receive information about interim results ONLY if they need to know 
for the safety of their patients.
Unblinding details are specified in the blinding section of the protocol (Section 9.5).  If changes 
to the unblinding plan occurred after protocol approval, they may be described in either a 
protocol amendment, the unblinding plan section of the SAP, or in separate unblinding plan 
document.


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13. Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study, and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICF 
prior to the performance of any protocol procedures and prior to the administration of study drug.
A legal representative must give informed consent for a child to participate in this study.  In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if capable.
As used in this protocol, the term “informed consent” includes all consent and assent given by 
patients or their legal representatives.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at the investigative sites.  
All ICFs must be compliant with the International Conference on Harmonisation (ICH) guideline 
on Good Clinical Practice (GCP).
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative sites. 
The ERB should include or consult with experts who are knowledgeable in pediatric ethical, 
clinical, and psychosocial issues.
The study site’s ERBs should be provided with the following:

the current IB or package labeling and updates during the course of the study

the ICF

the assent form

relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:


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
consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 

the ICH GCP Guideline (E6)

the ICH Guideline, Clinical Investigation of Medicinal Products in the Pediatric 
Population (E11)

applicable laws and regulations
The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of Lilly will be assigned to a TPO.
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other trial-related data.
Physicians with a specialty in hematology, hemato-oncology, or pediatric hematology will 
participate as investigators in this clinical trial.
13.3.1. 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.
13.3.2. Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
The investigator with the most enrolled patients will serve as the clinical study report 
coordinating investigator.  If this investigator is unable to fulfill this function, another 
investigator will be chosen by Lilly to serve as the clinical study report coordinating investigator.
The Lilly responsible medical officer and statistician will sign/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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Majumder PK. Down-regulation of the Notch pathway mediated by a gamma-secretase 
inhibitor induces anti-tumour effects in mouse models of T-cell leukaemia. Br J Pharmacol.
2009;158(5):1183-1195.
Tatarek J, Cullion K, Ashworth T, Gerstein R, Aster J, Kelliher MA. Notch-1 inhibition targets 
the leukemia-initiating cells in a Tal1/Lmo2 mouse model of T-ALL. Blood.
2011;118(6):1579–1590.
Thompson BJ, Buonamici S, Sulis ML, Palomero T, Vilimas T, Basso G, Ferrando A, Aifantis I.
The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med.
2007;204(8):1825-1835.
Tosello V, Ferrando AA. The NOTCH signaling pathway: role in the pathogenesis of T-cell 
acute lymphoblastic leukemia and implication for therapy. Ther Adv Hematol. 
2013;4(3):199-210.


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Wei P, Walls M, Qiu M, Ding R, Denlinger R, Wong A, Tsaparikos K, Jani JP, Hosea N, Sands 
M, Randolph S, Smeal T. Evaluation of selective gamma-secretase inhibitor PF-03084014 for 
its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol 
Cancer Ther. 2010;9(6):1618-1628.
Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizarry C, Blacklow 
SC, Look AT, Aster JC. Activating mutations of NOTCH-1 in human T cell acute 
lymphoblastic leukemia. Science. 2004;306(5694):269-271.


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Attachment 1.Protocol I6F-MC-JJCB Study Schedule
Study Schedule, Protocol I6F-MC-JJCB:  Phase 1 and Phase 2 Baseline Assessments
Relative Day 
Prior to Day 1 of Cycle 1
28
14
7
Notes
Study Entry
Informed consent 
X
Informed consent must be signed prior to performing any 
protocol procedure.
Inclusion/exclusion 
evaluation
X
Comprehensive medical 
history
X
Physical 
Exam
Physical exam
X
Including testicular exam for males
Height/weight
X
Vital signs 
X
Temperature, blood pressure, pulse rate
Lansky Performance Status
X
For Phase 1 pediatric patients <16 years
ECOG Performance Status
X
For adults in Phase 1 and Phase 2
Lab and Diagnostic Tests
Electrocardiogram (ECG)
X
Central ECG required
Echocardiography
X
Echocardiography or another acceptable alternative 
method to determine ejection fraction such as MUGA scan  
Hematology 
X
Manual differentiation
Serum chemistry
X
Includes:  hsCRP, immunoglobins IgA, IgG, IgM
Coagulation 
X
Prothrombin time (PT/INR), partial thromboplastin time 
(PTT), fibrinogen, d-dimer, antithrombin (AT)
HTLV
X
Urinalysis
X
Serum pregnancy test
X
to be performed on women of child-bearing potential
Archived bone marrow 
samples 
X
For T-ALL patients only. For example, bone marrow 
biopsies/clot sections/slides >28 days. Lack of sample 
will not be considered a protocol deviation.
Archived tumor tissue or 
tumor biopsy
X
For T-LBL patients only >28 days prior enrollment 
Immunological 
phenotyping  
X
Peripheral blood and bone marrow
Lymphocyte panel according Attachment 2
Expression analysis
X
Peripheral blood 
Disease/Tumor Assessment 
CT/MRI of head 
X
Only if neurological symptoms are present, to detect 
meningeal disease, chloromas, or CNS symptoms
CT/MRI thorax and 
abdomen
X
For T-ALL patients or T-LBL patients followed by 
CT/MRI
PET-CT
X
For T-LBL patients with FDG-avid lymphomas
Lumbar puncture
X
Only if CNS involvement is suspected – see exclusion. 
criterion 20 
Bone marrow biopsy
and/or aspirate
X
For T-ALL patients only. With approval from Lilly this 
sample may be obtained earlier than 14 days.  
Tumor biopsya
X
For T-LBL patients 
CTCAE grading 
(Preexisting conditions)
X
To be reported only after study eligibility is confirmed
Concomitant medications
X
FACT-Leu
X
Phase 2 Only 


I6F-MC-JJCB(a) Clinical Protocol
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LY3039478
Abbreviations: CNS = central nervous system; CT = computed tomography; CTCAE = Common Terminology 
Criteria for Adverse Events; ECOG = Eastern Cooperative Oncology Group; FACT-Leu = Functional 
Assessment of Cancer Therapy-Leukemia; hsCRP = high-sensitivity C-reactive protein; HTLV= Human T-cell 
leukemia virus type 1; INR = international normalized ratio; MRI = magnetic resonance imaging; MUGA = 
multi-gated acquisition scan; PET-CT = positron emission tomography-computed tomography; T-ALL = T-cell 
acute lymphoblastic leukemia; T-LBL = T-cell lymphoblastic lymphoma.
a
For patients with T-LBL, a prestudy treatment tumor biopsy/sample is required from tumors that can be biopsied 
at acceptable clinical risk in the judgment of the investigator.  T-LBL patients without accessible tumor for 
biopsy are eligible.


LY3039478
I6F-MC-JJCB(a) Clinical Protocol
Page 80
Study Schedule, Protocol I6F-MC-JJCB:  Phase 1 
Cycle 1
Week 1
Week 2
Week 3
Week 4
Study Procedures
Day
1
Day
2
Day
3
Day 
4
Day 
5
Day
8
Day
9
Day 
10
Day
11
Day
12
Day
15
Day
16
Day
17
Day
18
Day
19
Day
22
Day 
23
Day
24
Day
25
Day
26
LY3039478 therapy
a
X
X
X
X
X
X
X
X
X
X
X
X
Dexamethasone
X
X
X
X
X
X
X
X
X
X
Physical exam
X
X
X
X
Vital signs 
(temperature, pulse rate, 
blood pressure)
X
X
X
X
Weight
X
ECOG Performance 
Status for ≥16 years 
X
X
X
X
Lansky Performance 
Status for <16 years
X
X
X
X
CTCAE version 4.0 
grading
X
X
X
X
Concomitant 
medications
X
X
X
X
CT/MRI thorax and at 
least upper abdomen for 
T-ALL patientsb
X
Central ECG
c
X
Hematology
d
X
X
X
X
Serum chemistry
d
X
X
X
X
ECG chemistry
c, d
X
Coagulationd
X
X
X
X
Blood PK samplingc
X
X
Tumor biopsy (T-LBL), 
optionale
X
Bone marrow biopsy 
and/or aspiratef
X


LY3039478
I6F-MC-JJCB(a) Clinical Protocol
Page 81
Cycle 1
Week 1
Week 2
Week 3
Week 4
Study Procedures
Day
1
Day
2
Day
3
Day 
4
Day 
5
Day
8
Day
9
Day 
10
Day
11
Day
12
Day
15
Day
16
Day
17
Day
18
Day
19
Day
22
Day 
23
Day
24
Day
25
Day
26
Blood PD biomarkers (A 
beta)
c
X
Blood PD biomarkersc
X
X
Lumbar puncture for 
T-ALLc optional
X
Pharmacogenetics 
sample (anytime)
X
Abbreviations:  CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Group; MRI = magnetic resonance imaging; PD = pharmacodynamic; PK = pharmacokinetic; T-ALL = T-cell acute lymphoblastic leukemia; T-
LBL = T-cell lymphoblastic lymphoma.
a
LY3039478 is to be administered 3 days per week through each 28-day cycle.  If assessments associated with a dose cannot be performed, the assessments 
may be performed either with the previous dose (if known in advance) or the next dose. 
b
Per protocol Section 10.1.1.  To be done for only those patients who had lesions at the their baseline assessment.
c
For complete details, see Attachment 3.
d
For central versus local labs refer to Attachment 2.
e
Predose any time <28 days prior start of study drug and per protocol Section 10.4.2 postdose as clinically determined by investigator
f
Per protocol Section 10.1.1


LY3039478
I6F-MC-JJCB(a) Clinical Protocol
Page 82
Study Schedule, Protocol I6F-MC-JJCB:  Phase 1 Cycle 2
Cycle 2- n
Week 1
Week 2
Week 3
Week 4
Study Procedures
Day
1
Day
2
Day
3
Day 
4
Day 
5
Day
8
Day
9
Day 
10
Day
11
Day
12
Day
15
Day
16
Day
17
Day
18
Day
19
Day
22
Day
23
Day
24
Day
25
Day
26
LY3039478 therapy
a
X
X
X
X
X
X
X
X
X
X
X
X
Dexamethasone
X
X
X
X
X
X
X
X
X
X
Physical exam
X
X
Vital signs 
(temperature, pulse rate, 
blood pressure,)
X
X
Weight
X
ECOG Performance 
Status ≥16 years
X
X
Lansky Performance 
Status <16 years
X
X
CTCAE version 4.0 
grading
X
X
Concomitant medications
X
X
CT/MRI thorax and at 
least upper abdomen for 
T-ALL patientsb or 
T-LBL patients followed 
by CT/MRI
X
PET-CT for T-LBL 
patients
X
Central ECG
c
X
Hematology
d
X
X
Serum chemistry
d
X
X
ECG chemistry
c,d
X
Coagulationd
X
X
Blood PK samplec
X
Tumor biopsy (T-LBL),
optionale
X


LY3039478
I6F-MC-JJCB(a) Clinical Protocol
Page 83
Cycle 2- n
Week 1
Week 2
Week 3
Week 4
Study Procedures
Day
1
Day
2
Day
3
Day 
4
Day 
5
Day
8
Day
9
Day 
10
Day
11
Day
12
Day
15
Day
16
Day
17
Day
18
Day
19
Day
22
Day
23
Day
24
Day
25
Day
26
Bone marrow biopsy
and/or aspiratef
X
X
Blood PD biomarkersc
X
Abbreviations:  CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Group; MRI = magnetic resonance imaging; PD = pharmacodynamic; PET-CT = positron emission tomography-computed tomography; PK = 
pharmacokinetic; T-ALL = T-cell acute lymphoblastic leukemia; T-LBL = T-cell lymphoblastic lymphoma.
a
LY3039478 is to be administered 3 days per week through each 28-day cycle.  If assessments associated with a dose cannot be performed, the assessments 
may be performed either with the previous dose (if known in advance) or the next dose. 
b
Per protocol Section 10.1.1.  To be done for only those patients who had lesions at the their baseline assessment.
c
For complete details, see Attachment 3.
d
For central versus local laboratories refer to Attachment 2.
e
Predose any time <28 days prior start of study drug and per protocol Section 10.4.2 postdose as clinically determined by investigator.
f
For confirmation of CR and when clinically indicated by investigator; per protocol Section 10.1.1.


LY3039478
I6F-MC-JJCB(a) Clinical Protocol
Page 84
Study Schedule, Protocol I6F-MC-JJCB:  Phase 2
Cycle 1
Week 1
Week 2
Week 3
Week 4
Study Procedures
Day
1
Day
2
Day
3
Day 
4
Day 
5
Day
8
Day
9
Day 
10
Day
11
Day
12
Day
15
Day
16
Day
17
Day
18
Day
19
Day
22
Day
23
Day
24
Day
25
Day
26
LY3039478 therapy
a or 
Placebo
X
X
X
X
X
X
X
X
X
X
X
X
Dexamethasone 
X
X
X
X
X
X
X
X
X
X
Physical exam
X
X
Vital signs 
(temperature, pulse rate, 
blood pressure)
X
X
Weight
X
ECOG Performance 
Status
X
X
CTCAE version 4.0 
grading
X
X
Concomitant medications
X
X
CT/MRI thorax and at 
least upper abdomen for 
T-ALL patientsb
X
Central ECG
c
X
Hematology
d
X
X
Serum chemistry
d
X
X
ECG chemistryc,d
X
Coagulationd
X
X
Blood PK samplingc
X
X
Tumor biopsy, T-LBL 
optionale
X
Bone marrow biopsy 
and/or aspiratef
X
FACT-Leu
X
Resource utilization
X


LY3039478
I6F-MC-JJCB(a) Clinical Protocol
Page 85
Cycle 1
Week 1
Week 2
Week 3
Week 4
Study Procedures
Day
1
Day
2
Day
3
Day 
4
Day 
5
Day
8
Day
9
Day 
10
Day
11
Day
12
Day
15
Day
16
Day
17
Day
18
Day
19
Day
22
Day
23
Day
24
Day
25
Day
26
Blood PD biomarkersc
X
Pharmacogentics sample 
(anytime)
X
Abbreviations:  CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Group; FACT-Leu = Functional Assessment of Cancer Therapy-Leukemia; MRI = magnetic resonance imaging; PD = pharmacodynamic; PK = 
pharmacokinetic; T-ALL = T-cell acute lymphoblastic leukemia; T-LBL = T-cell lymphoblastic lymphoma.
a
LY3039478 is to be administered 3 days per week through each 28-day cycle.  If assessments associated with a dose cannot be performed, the assessments 
may be performed either with the previous dose (if known in advance) or the next dose. 
b
Per protocol Section 10.1.1.  To be done for only those patients who had lesions at the their baseline assessment.
c
For complete details, see Attachment 3.
d
For central versus local labs refer to Attachment 2.
e
Optional biopsy postdose, or at time of progression, or as clinically determined by investigator.
f
Per protocol Section 10.1.1.


LY3039478
I6F-MC-JJCB(a) Clinical Protocol
Page 86
Cycle 2- n
Week 1
Week 2
Week 3
Week 4
Study Procedures
Day
1
Day
2
Day
3
Day 
4
Day 
5
Day
8
Day
9
Day 
10
Day
11
Day
12
Day
15
Day
16
Day
17
Day
18
Day
19
Day
22
Day
23
Day
24
Day
25
Day
26
LY3039478 therapya or 
placebo
X
X
X
X
X
X
X
X
X
X
X
X
Dexamethasone 
X
X
X
X
X
X
X
X
X
X
Physical exam
X
X
Vital signs 
(temperature, pulse rate, 
blood pressure)
X
X
Weight
X
ECOG Performance Status
X
X
CTCAE version 4.0 
Grading
X
X
Concomitant medications
X
X
CT/MRI thorax and at least 
upper abdomen for T-ALL 
patientsb or T-LBL patients 
followed by CT/MRI
X
PET-CT for T-LBL 
patients
X
Central ECGc
X
Hematologyd
X
X
Serum chemistryd
X
X
ECG chemistryc,d
X
Coagulationd
X
X
Blood PK samplec
X
Tumor biopsy, (T-LBL),
optionale
X
Bone marrow biopsy
and/or aspiratef
X
FACT-Leu
X
Resource utilization
X


LY3039478
I6F-MC-JJCB(a) Clinical Protocol
Page 87
Abbreviations:  CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Group; FACT-Leu = Functional Assessment of Cancer Therapy-Leukemia; MRI = magnetic resonance imaging; PD = pharmacodynamic; 
PET-CT = positron emission tomography-computed tomography; PK = pharmacokinetic; T-ALL = T-cell acute lymphoblastic leukemia; T-LBL = T-cell 
lymphoblastic lymphoma.
a
LY3039478 is to be administered 3 days per week through each 28-day cycle.  If assessments associated with a dose cannot be performed, the assessments 
may be performed either with the previous dose (if known in advance) or the next dose. 
b
Per protocol Section 10.1.1.  To be done for only those patients who had lesions at the their baseline assessment.
c
For complete details, see Attachment 3.
d
For central versus local labs refer to Attachment 2.
e
Optional biopsy postdose, or at time of progression, or as clinically determined by investigator.
f
For confirmation of CR and when clinically indicated by investigator (timing as clinically indicated); per protocol Section 10.1.1.


I6F-MC-JJCB(a) Clinical Protocol
Page 88
LY3039478
Study Schedule, Protocol I6F-MC-JJCB:  Phase 1 and 2 Follow-up Visits
Initial 
Follow-up 
Visita
801
Long-Term 
Follow-up 
Visitsb
8XX
Notes
Physical Exam
Physical exam
X
Weight
X
Vital signs 
X
Temperature, blood pressure, pulse rate
Performance status
X
Hematology with 
manual differentialc
X
X
For T-ALL patients who are in remission, CBC and 
platelets should be obtained every 1-3 months for 
the first 2 years and then every 3-6 months.
Coagulationc
X
Serum chemistryc
X
CTCAE grading 
X
X
Concomitant 
medications
X
FACT-Leu
X
X 
Phase 2 only and patients in remission
Resource utilization
X
X
Phase 2 only and patients in remission
Efficacy Measures
Patient survival 
status
X
X
Remission status
X
X
CT/MRI as clinically indiacated every 2 -4 months
For T-LBL patients followed by CT/MRI every 2 to 
4 month as clinically indicated.
For T-LBL patients followed by PET-CT only as 
clinically indicated.
Abbreviations:  CBC = complete blood count; CT = computed tomography; CTCAE = Common Terminology 
Criteria for Adverse Events; FACT-Leu = Functional Assessment of Cancer Therapy-Leukemia; MRI = 
magnetic resonance imaging; PET = positron emission tomography; 
T-ALL = T-cell acute lymphoblastic leukemia; T-LBL = T-cell lymphoblastic lymphoma.  
a
Initial follow-up assessments occur approximately 30 days following the end of treatment.
b
Long-term follow-up assessments occur approximately every 60 days following the end of the initial follow-up.  
Note that follow up for patient AEs does not follow this schedule and is at the discretion of the investigator.
c
For central versus local labs refer to Attachment 2.


LY3039478
I6F-MC-JJCB(a) Clinical Protocol
Page 89
Study Schedule, Protocol I6F-MC-JJCB: Continued Access  
Note:  Efficacy assessments will be done at the investigator’s discretion based on the standard of care.
Continued Access Period Only Visit 501-5XX
Continued Access 
Follow-upa
Week 1
Week 2
Week 3
Week 4         
Visit 901
Study 
Procedures
Day 1 Day 2 Day 3Day 4 Day 5 Day 
8 
Day 
10
Day
12
Day 15 Day 16Day 17 Day 18 Day 19 Day 
22
Day 
24
Day
26
LY3039478 
therapy
X
X
X
X
X
X
X
X
X
X
X
X
Dexamethasone
X
X
X
X
X
X
X
X
X
X
Physical exam
X
X
Vital signs 
(temperature, 
pulse rate, blood 
pressure)
X
X
CTCAE version 
4.0 grading
X
X
Hematologyb
X
Serum 
chemistryb
X
Abbreviations:  ECOG = eastern cooperative oncology group; CTCAE = Common Terminology Criteria for Adverse Events
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 30 days ± 6 days.
b
For central versus local labs refer to Attachment 2.


I6F-MC-JJCB(a) Clinical Protocol
Page 90
LY3039478
Attachment 2.Protocol I6F-MC-JJCB Clinical Laboratory 
Tests
Clinical Laboratory Tests
Hematologya,b with manual differentiation:
Clinical Chemistrya,b:
Serum Concentrations of:
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Phosphorus
Mean cell volume (MCV)
Magnesium
Mean cell hemoglobin concentration (MCHC)
Chloride
Leukocytes (WBC)
Total bilirubin
Neutrophils, segmented
Direct bilirubin
Neutrophils, bands
Alkaline phosphatase
Lymphocytes
Alanine aminotransferase (ALT)
Monocytes
Aspartate aminotransferase (AST)
Eosinophils
Lactate dehydrogenase (LDH)
Basophils
Gamma-glutamyl (GGT)
Metamyelocytes
Blood urea nitrogen (BUN) or blood urea
Myelocytes
Creatinine
Promyelocytes
Uric acid
Blasts
Calcium
Atypical lymphocytes
Glucose, random
Platelets
Albumin
Nucleated RBCs (NRBC)/100 WBC
Total protein
Reticulocytes
Lipase
Urinalysisa,c:
Other:
Specific gravity
Immunoglobulins G, A, and M (IgG, IgA, IgM)b,c
pH
High-sensitivity C-reactive protein (hsCRP)b,d
Protein
HTLVb,c
Glucose
Ketones 
Pregnancy Test (females only)a,c
Blood
Urine leukocyte esterase
Cerebrospinal Fluida
Leukocytes (WBC)
Immunophenotyping Lymphocyte panel in 
peripheral blood and bone marrowa:  
Lymphoblasts
TdT, CD1a, CD2/3/4/5/7/8/11b/13/33/34/65/117, 
cCD3, HLA-DR, % of lymphoblasts in bone marrow
ECG Chemistry
b
Lipasee
Coagulationb:
Thyroid stimulating hormone (TSH)
D-dimer
Tri-iodothyronine (T3)
PTT
Thyroxine (T4)
PT/INR
Albumine
Fibrinogen
Glucose, randome
Antithrombin
Calciume


I6F-MC-JJCB(a) Clinical Protocol
Page 91
LY3039478
Sodiume
Bone Marrowa,b,f with manual differentiation:
Potassiume
Aspirate
Phosphoruse
Core biopsy
Magnesiume
Serum creatininee
Abbreviations:  CBC= complete blood count; ECG = electrocardiogram; HTLV= Human T-cell leukemia virus 
type 1; M/E= myeloid/erythroid; PT/INR = international normalized ratio of prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cells; WBC = white blood cells.
a
Local or investigator-designated laboratory. 
b
Assayed by Lilly-designated laboratory.
c
Performed at baseline only.
d
To be performed with each chemistry panel.
e
Test not performed if both chemistry and ECG chemistry required at same time point.  See Attachment 3.
f
Including Lilly-designated laboratory assessment of minimal residual disease (MRD) to confirm remission 
status.


I6F-MC-JJCB(a) Clinical Protocol
Page 92
LY3039478
Attachment 3.Protocol I6F-MC-JJCB Pharmacokinetic,
Pharmacodynamic, CSF and ECG Sampling Schedule


LY3039478
I6F-MC-JJCB(a) Clinical Protocol
Page 93
PK, PD, CSF, and ECG Sampling Schedule – Phase 1– Part A (Adult Patients)
PK 
Sample 
Number
Cycle
Day
PK Sampling 
Time for 
LY3039478a
PK Sampling Time 
for Dexamethasonea
CSF Sampling 
Time for 
LY3039478b
PD 
Sampling 
Time for 
Aβ(1-x)]c
PD Sampling Time for 
NICD and Gene 
Expression 
Analysisd,e.f
ECG 
and ECG 
Chemistry
1
1
1
Predose 
Predose
Predose
Predose
Predose
2
1
1
1-2h
1-2h
1-2h
3
1
1
3-4h
3-4h
3-4h
3-4h
4
1
1
6-8h
6-8h
6-8h
6-8h
5
1
1
24-30h
24-30h
24-30h
24-30h
6
1
8
Predose 
Predose
7
1
8
1-2h
1-4h
8
1
8
3-4h
9
1
8
6-8h
6-8h
10
1
8
24-30h
11
2
1
Predose
Predose
Abbreviation:  CSF = cerebrospinal fluid; ECG = electrocardiogram; NICD = Notch intracellular domain; PD = pharmacodynamic; PK = pharmacokinetic.
a
Samples of approximately 3 mL of whole blood will be collected for measurement of LY3039478 and dexamethasone on Cycle 1 Day 1 only. On other days, 
2 mL of whole blood will be collected for measurement of LY3039478.
b
Optional and only for Phase 1 adult patients.
c
Samples of approximately 3 mL of whole blood will be collected.
d
For the NICD ELISA, approximately 8 mL of whole blood will be collected in sodium citrate CPT tubes.
e
For the gene expression analysis, approximately 2.5 mL of whole blood will be collected.
f
NICD collection will be performed at select sites only.
Note:  Collection of PD samples, where similar intervals are presented, should be collected the same time as PK samples. Collection of CSF sample should be at 
the same time as either the 1-2h or 3-4h plasma PK sample.


LY3039478
I6F-MC-JJCB(a) Clinical Protocol
Page 94
PK, PD, and ECG Sampling Schedule – Phase 1- Part B (Pediatric Patients)
PK 
Sample 
Number
Cycle
Day
PK Sampling Time for 
LY3039478a
PK Sampling Time 
for Dexamethasonea
PD Sampling Time 
for NICD and Gene 
Expression 
Analysisb
ECG 
and ECG 
Chemistry
1
1
1
Predose 
Predose
Predose
Predose
2
1
1
1-3h
1-3h
1-3h
3
1
1
6-8h
6-8h
6-8h
6-8 h
4
1
8
Predose
Predose
Predose
5
1
8
1-3h
3h
Abbreviation:  ECG = electrocardiogram; NICD = Notch intracellular domain; PD = pharmacodynamic; PK = pharmacokinetic.
a
Samples of approximately 2 mL of whole blood will be collected for measurement of LY3039478 and dexamethasone (where assayed).
b
NICD collection will be performed at select sites only.
Note:  Collection of PD samples, where similar intervals are presented, should be collected the same time as PK samples.  


LY3039478
I6F-MC-JJCB(a) Clinical Protocol
Page 95
PK, PD, and ECG Sampling Schedule – Phase 2 (Approximately 30 Patients)
PK Sample 
Number
Cycle
Day
PK Sampling Time for 
LY3039478/
Placebob
PK Sampling Time for 
Dexamethasoneb
PD Sampling Time for NICD 
and Gene Expressionc
ECGa
and ECG 
Chemistry
1
1
1
Predose 
Predose 
Predose
Predose
2
1
1
1-3h
1-3h
1-3h
3
1
1
6-8h
6-8h
6-8h
4
1
15
Predose
Predose 
5
1
15
1-3h
1-3h
6
1
15
6-8h
6-8h
7
2
1
Predose
Predose
Abbreviation:  ECG = electrocardiogram; NICD = Notch intracellular domain; PD = pharmacodynamic; PK = pharmacokinetic.
a
ECG required for all patients.
B Samples of approximately 3 mL of whole blood will be collected for measurement of LY3039478 and dexamethasone in Cycle 1 only. On other days, 2 mL 
of whole blood will be collected for measurement of LY3039478.
c
NICD collection will be performed at select sites only.
Note:  Collection of PD samples, where similar intervals are presented, should be collected the same time as PK samples.  


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Attachment 4.Protocol I6F-MC-JJCB Hepatic Monitoring 
Tests for Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow up with patients in consultation with the Lilly clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmentedb
Lymphocytes
Hepatic Serologiesa,c
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
CPK 
Anti-smooth muscle antibodya
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; INR = international normalized ratio; RBC = red blood cells; WBC = white 
blood cells.
a
Assayed by Lilly-designated laboratory.
b
Neutrophils reported by automated differential hematology instruments include both segmented and band forms.  
Whenever 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.
c
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Attachment 5.Protocol I6F-MC-JJCB Eastern Cooperative 
Oncology Group, and Lansky Performance Status
ECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance 
without restriction.
1
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work.
2
Ambulatory and capable of all selfcare but unable to 
carry out any work activities. Up and about more than 
50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair 
more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare.  
Totally confined to bed or chair.
5
Dead.  
Source:  Oken et al. 1982.


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Lansky Performance Status
Play-Performance Scale for Children
Directions for Clinicians
The play-performance scale for children is designed to provide a standardized measure 
of the performance status of the child with cancer.
Appropriate for use with children:

With any type of malignancy

Aged 1 to 16 years

Inpatients and outpatients

In active treatment and long-term follow-up
Procedures
The play-performance scale is:

Rated by parent according to directions on form

Rated on the basis of the past week

To be readministered to assess change over time or following treatment


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Parent Form
Child’s name:
Date of birth: _____/_____/____
                       mo     day       yr
Your name:
Relationship
Mother:
____
Father:
____
Other:
____
Today’s Date: _____________
Directions for parents: On this form is a series of descriptions.  Each description has a number 
beside it. Think about your child’s play and activity over the past week.  Think about both 
good days and bad days.  Average out this period.  Now read the descriptions and pick the one 
that best describes your child’s play during the past week.  Circle the number beside that one
description.
100
-
Fully active, normal
90
-
Minor restrictions in physically strenuous activity
80
-
Active, but tires more quickly
70
-
Both greater restriction of, and less time spent in, active play
60
-
Up and around, but minimal active play; keeps busy with quieter activities
50
-
Gets dressed, but lies around much of the day; no active play; able to participate in 
all quiet play and activities
40
-
Mostly in bed; participates in quiet activities
30
-
In bed; needs assistance, even for quiet play
20
-
Often sleeping; play entirely limited to very passive activities
10
-
No play; does not get out of bed
0
-
Unresponsive


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Attachment 6.Protocol I6F-MC-JJCB Creatinine Clearance
and Serum Creatinine Formulas
For adult patients (≥16 Years) Note:  This formula is to be used for calculating creatinine 
clearance (CrCl) from local laboratory results only.  
For serum creatinine 
concentration in mg/dL:
CrCl =
(mL/min) 
(140 – agea) (wt)    0.85 (if female), or 1.0 (if male)
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(mL/min)
(140 – agea) (wt)  0.85 (if female), or 1.0 (if male)
0.81 serum creatinine (mol/L)
a age in years, weight (wt) in kilograms.
Reference:  Cockcroft and Gault 1976.
-OR-
GFR(mL/min/1.73m2= 170 x [PCr]-0.999 x [age]-0.176
x [0.762 if patient is female] x [1.18 if patient is black]
x [SUN]-0.17 x [Alb]+0.318
GFR = glomerular filtration rate; PCr = plasma creatinine, mg/dL; SUN = serum urea nitrogen, mg/dL; Alb = serum 
albumin, g/dL
Source:  Murray and Ratain 2003.


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Note:  This formula is to be used for calculating creatinine clearance from local laboratory 
results only. For Pediatric Patients (patients < 16 years of age)
CrCl mL/min =
(k * Ht)
Crserum
Patient
K
Infant (LBW <1 year)
0.33
Infant (term <1 year)
0.45
Child or adolescent girl
0.55
Adolescent boy
0.70
Notes:  Height is measured in cm.  Serum creatinine is measured in mg/dL.  Measured creatinine should be in steady 
state. 
Abbreviations:  CrCl = creatinine clearance; Crserum = serum creatinine; Ht = height; LBW = low birth weight.
Source:  Schwartz et al. 1987.
Serum creatinine formula based on age/gender 
Age
Maximum Serum
Creatinine (mg/dL)
Male
Female
1 to <2 years
0.6
0.6
2 to <6 years
0.8
0.8
6 to <10 years
1.0
1.0
10 to <13 years
1.2
1.2
13 to <16 years
1.5
1.4
≥16 years
1.7
1.4
The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR (Schwartz 
et al. 1987) utilizing child length and stature data published by the Centers for Disease Control and Prevention 
(CDC).


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Attachment 7.Protocol I6F-MC-JJCB FACT-Leu (Version 4) 
Questionnaire
The FACT-Leu is one in a family of questionnaires available through FACIT and is available to 
download at the following website:
www.facit.org/FACITOrg/Questionaires


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Attachment 8.
Protocol JJCB Protocol Amendment 
I6F-MC-JJCB(a) Summary
A Phase 1b/Randomized Phase 2 Study to Evaluate 
LY3039478 in Combination with Dexamethasone in 
T-ALL/T-LBL Patients
Overview
Protocol I6F-MC-JJCB, a Phase 1b/Randomized Phase 2 Study to Evaluate LY3039478 in 
Combination with Dexamethasone in T-ALL/T-LBL patients has been amended.  The new 
protocol is indicated by amendment (a) and will be used to conduct the study in place of any 
preceding version of the protocol.
This study was amended at the request of the Food and Drug Administration (FDA) to clarify the 
criteria for DLTs (Section 9.2.2) and to change the PK sampling. In addition, CSF sampling was 
simplified based on new data; the CSF sampling has been reduced to one draw.  PK analysis for 
dexamethasone during the Phase 1 portion of the study was added and one additional time point 
for the determination of plasma concentrations of LY3039478 and dexamethasone was added 
during the Phase 2 portion of the study (Attachment 3).
All appropriate section headings have been changed to designate the updated protocol number 
and other minor editorial changes and formatting corrections were made, but are not necessarily 
documented below.


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
The numbering system used for inclusion and exclusion criteria provides a unique number for 
each criterion and allows for efficiency in data collection.
In case an amendment to the protocol adds a criterion, that criterion will receive the next 
available number, regardless of whether it is an inclusion or exclusion criterion.


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2. Synopsis
Clinical Protocol Synopsis:  Study I6F-MC-JJCB(a)
Name of Investigational Product:  LY3039478
Title of Study: A Phase 1b/Randomized Phase 2 Study to Evaluate LY3039478 in Combination with 
Dexamethasone in T-ALL/T-LBL Patients
Number of Planned Patients:  86 to 92 total patients
Entered:
Enrolled/Randomized:  
Phase 1: Part A 13 to 16 patients; Part B 13 to 16 patients
Phase 2:  60 patients
Phase of Development: 1b / 2
Length of Study:  approximately 60 months
Planned first patient visit:  May 2015
Planned last patient visit, excluding the continued access:  May 2020
Planned interim analysis:  At end of Phase 1 and during Phase 2, every 12 months and once 30 patients are 
randomized and have completed the CR determination.
Objectives:  
The primary objective is as follows:

Phase 1:  to determine the recommended dose of LY3039478 in combination with dexamethasone in adult 
patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic 
lymphoma (T-LBL) (Part A) and pediatric patients (Part B)

Phase 2: to determine if the overall remission rate (ORR) (CR plus CR with incomplete blood count 
recovery [CRi]) in adult patients with relapsed/refractory T-ALL/T-LBL treated with LY3039478 in 
combination with dexamethasone exceeds that of those patients treated with placebo in combination with 
dexamethasone 
The secondary objectives are as follows:

Phase 1:
o
to characterize the safety and toxicity profile of LY3039478 in combination with dexamethasone 
as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v 4.0
o
to assess the pharmacokinetic (PK) parameters of LY3039478 in combination with 
dexamethasone therapy
o
to document efficacy based on Cheson criteria for leukemia and modified response criteria for 
malignant lymphoma
o
to evaluate gene mutation (eg, NOTCH-1/FBXW7/RAS/PTEN) status with efficacy

Phase 2: 
o
to compare the ORR plus partial remission (PR) and PR alone for both arms
o
to assess the remission rate for patients receiving LY3039478 in combination with dexamethasone 
after failure of placebo in combination with dexamethasone
o
to assess duration of remission (DoR) (= CR and Cri and PR)
o
to assess relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS)
o
to compare the safety and toxicity profile of LY3039478 in combination with dexamethasone to 
dexamethasone and placebo as assessed by NCI CTCAE v 4.0
o
to assess the pharmacokinetic (PK) parameters of LY3039478 and dexamethasone in combination 
therapy
o
to assess patient quality of life using the Functional Assessment of Cancer Therapy-Leukemia
(FACT-Leu)
o
to evaluate gene mutation (eg, NOTCH-1/FBXW7/RAS/PTEN) status with efficacy


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The exploratory objectives are as follows:

to assess clinical utility of the NICD immunohistochemistry (IHC) assay as a potential companion 
diagnostic for LY3039478

to evaluate biomarkers in tumor tissue, blood, plasma, and cerebrospinal fluid (CSF), which may include, 
but not be limited to, NICD enzyme-linked immunosorbent assay (ELISA) (or an alternative validated 
method), gene expression, relevant to the study disease or safety, efficacy, and mechanism of action of 
LY3039478 and dexamethasone

to explore pharmacodynamic (PD) effects of LY3039478 on biomarkers indicative of Notch activity

to evaluate the CSF PK exposure of LY3039478
Study Design:  Study I6F-MC-JJCB is a multicenter study consisting of a nonrandomized, open-label, 
dose-escalation Phase 1 study followed by a randomized, double-blind, Phase 2 study in patients with relapsed or 
refractory T-ALL/T-LBL.  The Phase 1 portion of the study will consist of 2 different patient populations, an adult 
(Part A) and a pediatric (Part B), and will define the recommended dose of LY3039478 in combination with 
dexamethasone in each of these populations.  The decision to proceed with the pediatric dose exploration (Part B) 
will be made after safety analysis of the adult cohort. The randomized Phase 2 study will be a double-blinded, 
multicenter evaluation to determine if the ORR (CR and CRi) rate in adult patients with relapsed/refractory 
T-ALL/T-LBL treated with LY3039478 in combination with dexamethasone exceeds that of those patients treated 
with placebo in combination with dexamethasone. 
Diagnosis and Main Criteria for Inclusion and Exclusions:  Patients must have T-ALL or T-LBL.  T-ALL is 
defined ≥25% of blasts in the bone marrow and expression of at least 2 of the following cell surface antigens:  
CD1a, CD2, CD3 (surface or cytoplasmic), CD4, CD5, CD7, and/or CD8.  If the only T cell markers present are 
CD4 and CD7, the leukemia cells must also lack the myeloid markers CD33 and/or CD13.  Patients with initial 
refractory disease should have received at least 2 multi-agent chemotherapy induction regimens. Patients in first or 
second relapse must have been refractory to at least 1 multi-agent chemotherapy reinduction regimen.  They must 
have had at least 60 days between prior hematopoietic stem cell transplant and first dose of study drug, have 
adequate performance status and organ function, be ≥16 years old for the adult cohort (Phase 1, Part A) and 2 to 
<16 years old for the pediatric cohort (Phase 1, Part B), and have a life expectancy of 2 months.  
Patients may be excluded if they are currently enrolled in another ongoing clinical trial with investigational 
products, have recently discontinued (within less than 2 weeks) prior anticancer therapy, have a serious concomitant 
illness, have an uncontrolled or active infection <7 days prior to administration of study drug, have current or 
recurrent (within 3 months) gastrointestinal disease, have conditions requiring chronic systemic glucocorticoid use, 
have active graft versus host disease, have active leukemic involvement of the central nervous system, or have a 
second primary or prior malignancy that would affect the interpretation of study results.  
Test Product, Dosage, and Mode of Administration:  LY3039478, dose range 25 to 200 mg, given orally as 
capsules 3 times per week during a 28-day cycle.  
Placebo will be given orally as capsules 3 times per week during a 28-day cycle.  
Planned Duration of Treatment:  Patients will receive 2 cycles (28 days each) of LY3039478 unless 1 or more of 
the criteria for discontinuation are fulfilled.  A patient may receive >2 cycles of treatment only if:  1) none of the 
criteria for discontinuation have been fulfilled, and 2) the investigator determines that the patient is experiencing 
clinical benefit from treatment.  
Short-term follow-up period (postdiscontinuation):  30 days.  
Long-term follow-up (postdiscontinuation):  until death.  
Reference Therapy, Dose, and Mode of Administration:  Dexamethasone will be administered at a dose of 24 mg 
on Day 1 through Day 5 every other week to the adult patients and 10 mg/m2 twice a day (BID) to the pediatric 
patients. 


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Criteria for Evaluation:
Efficacy:

ORR

CR rate

proportion of patients achieving a CRi

proportion of patients achieving a PR

DoR

OS

RFS

EFS
Safety:  Safety will be evaluated based on recorded adverse events (AEs), physical examinations, vital sign 
measurements, electrocardiograms, and clinical laboratory assessments.  Adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  Adverse events and clinical laboratory values will be 
graded using NCI CTCAE v4.0.
Health Outcomes:  Patient health-related quality of life including physical, social/family, emotional and functional 
well-being will be assessed using the self-administered FACT-Leu questionnaire at the beginning of each visit only 
in the Phase 2 portion of the study.
Pharmacokinetics: Blood and CSF samples will be used to determine the concentrations of LY3039478.  Plasma 
and CSF concentrations of LY3039478, and plasma concentrations of LY3039478 and dexamethasone will be 
quantified using validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) assays.  The 
remaining plasma samples collected for PK evaluation may be used for exploratory studies to assess the metabolism 
of LY3039478, which may involve sample pooling.
Pharmacodynamics/Tailoring Biomarkers:  Blood, CSF, EDTA plasma, tissue, and bone marrow samples will be 
collected.  Samples will be tested for markers of Notch and related pathway activation including, but not limited to, 
protein expression and activation by IHC and ELISA, and gene expression by quantitative polymerase chain 
reaction (PCR) analysis to evaluate their association with the observed clinical outcomes to LY3039478.
Statistical Methods:
Statistical:
In the Phase 1 portion of the study, approximately 13 to 16 patients will be enrolled into each of the adult (Part A) 
and pediatric (Part B) cohorts sequentially and without randomization to dose.  The total sample size per cohort will 
be determined by DLTs.
In the Phase 2 portion of the study, approximately 60 evaluable patients will be randomized to the 2 treatment arms 
in a 2:1 ratio (40 randomized to LY3039478 and dexamethasone and 20 randomized to placebo and 
dexamethasone).
Efficacy analyses will be based on the intention-to-treat (ITT) analysis set.  This population is defined as all patients 
randomized to study treatment.  Patients will be grouped according to dose level cohort or randomized treatment.  A 
secondary analysis of the primary efficacy endpoint based upon the per-protocol set (PPS) of patients may be 
performed if there are significant numbers of patients with major protocol deviations (≥10% of total patient 
population).  The PPS is defined as those patients in the ITT set who are compliant with the study protocol.
Safety analyses will be based on the safety population, defined as all enrolled patients receiving at least 1 dose of 
any study drug.  Patients will be grouped according to treatment received in Cycle 1.
PD and/or tailoring biomarker analyses will be based on the subset of patients from the above populations from 
whom a valid assay result (according to laboratory guideline) has been obtained.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise stated.  All tests of 
interactions will be conducted at a 2-sided alpha level of 0.1, and all confidence intervals (CIs) will be given at a 
2-sided 95% level, unless otherwise stated.  
Efficacy:
No formal efficacy analysis is planned for the Phase 1 portion of this trial.  However, any response data will be 
listed and tabulated.  In the Phase 2 portion, the primary efficacy endpoint of ORR (CR plus CRi) and its exact 95% 


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LY3039478
CI will be estimated for each treatment arm.  The proportion in each treatment arm will be compared using Fisher’s 
exact test.  All randomized patients, according to the ITT principle, will be included in the analysis of this endpoint.  
The secondary efficacy endpoints of proportion of patients achieving an ORR plus PR, and PR, and their exact 95% 
CIs will be estimated for each treatment arm and compared by 2-sided Chi-squared test or Fisher’s exact test 
between 2 arms.  For the secondary efficacy endpoints OS, RFS, and EFS, the Kaplan-Meier method will be used to 
estimate the survival curves as well as survival rates at various prespecified time points (12 months for OS, 6 and 
12 months for RFS and EFS) for each treatment arm.  The secondary efficacy endpoint DoR is subject to competing 
risk of death without relapse; therefore, the cumulative incidence of relapse will be used.  In the calculation, patients 
who did not have the event will be considered right-censored observations.  All randomized patients, according to 
the ITT principle, will be included in the analysis of these endpoints.  The comparison of the survival curves 
between treatment groups will be conducted by a log-rank test.
Safety:  Safety analyses will include listings and/or summaries of the following:

adverse events (AEs) and treatment-emergent adverse events (TEAEs),

drug exposure,

dose adjustments,

laboratory measures,

reasons for death, and

hospitalizations and transfusions.
Health Outcomes: FACT-Leu results will be summarized descriptively by cycle, including number of completed 
questionnaires, scores for each scale and subscale, and changes from baseline.
Pharmacokinetics:  PK analyses will be conducted on patients who receive at least 1 dose of the study drug and have
samples collected.  PK parameter estimates for LY3039478 and dexamethasone, where possible, will be calculated 
by standard noncompartmental methods of analysis.
Pharmacodynamics/Tailoring Biomarkers: Biomarker data from all patients undergoing biomarker assessments will 
be analyzed using descriptive statistics.
Interim Analyses:  An interim analysis including safety, PK, and PD data will be conducted prior to proceeding to 
the Phase 2 portion of the study.  All relevant data will be reviewed to confirm the estimation of the MTD.  The 
decision to proceed to Phase 2 will be made following discussions between the investigators and Lilly clinical 
research personnel and documented in writing.  In the Phase 2 portion, safety interim analyses are planned every 
12 months, and at the planned futility interim analysis, when response data from 30 patients has been obtained. 
There are no prespecified rules for stopping the trial due to safety concerns.  The assessment committee members 
will review unblinded safety data at each interim analysis to determine whether there are sufficient safety concerns 
to justify the termination of study treatment and/or enrollment.
One futility interim analysis is planned in Phase 2 once 30 patients are randomized and have completed the CR 
status determination.  The assessment committee may recommend stopping the trial for futility if the observed ORR 
(CR plus CRi) rate difference is <0.05 for the treatment arm compared to the control arm.
5.3
Rationale for Amendment (a)
This study was amended at the request of the Food and Drug Administration (FDA) to clarify the 
criteria for DLTs (Section 9.2.2), to change the PK sampling, and simplify the CSF sampling.  
The CSF sampling has been reduced to one draw and PK samples will be split into 2 
approximately equal portions:  one for the determination of plasma concentrations of 
LY3039478 and the other for the determination of plasma concentrations of dexamethasone.  
One additional PK sample is being added to the Phase 2 portion of the study during Cycle 1 at 
Day 15 during the 6-8 hour post-dose range (Attachment 3).


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6.3 Exploratory Objectives
The exploratory objectives of the study are as follows:

to assess clinical utility of the NICD immunohistochemistry (IHC) assay as a potential 
companion diagnostic for LY3039478

to evaluate biomarkers in tumor tissue, blood, plasma and cerebrospinal fluid (CSF), 
which may include, but not be limited to, NICD enzyme-linked immunosorbent assay 
(ELISA) (or an alternative validated method), gene expression, relevant to the study 
disease or safety, efficacy, and mechanism of action of LY3039478 and dexamethasone

to explore PD effects of LY3039478 on biomarkers indicative of Notch activity

to evaluate the CSF PK exposure of LY3039478
9.2.2
Dose-Limiting Toxicity Determination and Maximum Tolerated Dose Definition
A DLT is an AE observed during the first 28-day cycle (when patients receive 
LY3039478 and dexamethasone) that is determined by the investigator to be at least
possibly related to LY3039478 according to CTCAE v 4.0 and fulfills any of the 
following criteria:  

CTCAE Grade 3 nonhematological toxicity.  Exceptions will be made for:
o
Grade 3 nausea, vomiting, or constipation that lasts less than 72 hours and that can be 
controlled with treatment
o
Grade 3 electrolyte disturbance that can be controlled with treatment and persists less 
than 5 days
o
Grade 3 hyperglycemia or Grade 4 hyperglycemia without ketoacidosis during and 
after the end of dexamethasone treatment unless it is not controlled by oral 
medication or insulin before the start of the next dexamethasone round
o
Grade 3 arterial hypertension during and after the end of dexamethasone treatment 
unless it is not controlled by oral medication before the start of the next 
dexamethasone round
o
tumor lysis syndrome (TLS):  patients who demonstrate a clinical syndrome 
consistent with TLS and have transient (<7 days) and manageable Grade 3 
abnormalities in serum electrolytes, renal function and/or chemistries (ie, uric acid, 
potassium, phosphorus, calcium, creatinine, blood urea nitrogen, etc.)
o
CTCAE Grade 3 diarrhea for <5 days and unless it cannot be controlled with standard 
treatment
o
transient (<7 days) Grade 3 elevations of ALT and/or AST, that are not accompanied 
by a Grade 2 bilirubin increase are considered an exception to the DLT criteria, 
unless there is a clear alternative cause (eg, worsening biliary obstruction) if agreed 
by the study investigator and Lilly CRP
o
hyperglycemia during and after the end of dexamethasone treatment unless it is not 
controlled by oral medication or insulin before the start of the next dexamethasone 
round
o
arterial hypertension during and after the end of dexamethasone treatment unless it is 
not controlled by oral medication before the start of the next dexamethasone round


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LY3039478

any other significant toxicity deemed by the primary investigator and Lilly clinical 
research personnel to be dose limiting (eg, any toxicity that is possibly related to the 
study medication that requires the withdrawal of the patient from the study during 
Cycle 1)
10.4.3. Samples for Drug Concentration Measurements Pharmacokinetics 
PK samples will be collected as specified in the Pharmacokinetic Sampling Schedule 
(Attachment 3).  
Blood and CSF Venous blood samples of approximately 3 mL each will be used collected to 
determine the plasma concentrations of LY3039478 and dexamethasone.  Separate blood 
samples are not required for LY3039478 and dexamethasone.  After harvesting the plasma, 
samples will be divided into 2 approximately equal portions by site personnel, one for the 
determination of plasma concentrations of LY3039478, and the other for the determination of 
plasma concentrations of dexamethasone.  Instructions for the collection and handling of blood 
samples will be provided by the sponsor.  A maximum of 5 blood samples may be drawn at 
additional time points during the study if warranted and agreed upon between both the 
investigator and Lilly. CSF samples will be used to determine the concentrations of LY3039478.  
Plasma and CSF concentrations of LY3039478, and plasma concentrations of LY3039478 and 
dexamethasone will be quantified using validated liquid chromatography-mass spectrometry / 
mass spectrometry (LC-MS/MS) assays.  All bioanalytical samples will be stored in the United 
States.  The remaining plasma samples collected for PK evaluation may be used for exploratory 
studies to assess the metabolism of LY3039478, which may involve sample pooling.  These 
samples may be retained for a maximum of 2 years following the last patient visit for the study.
12.1 Determination of Sample Size
…
Primary analysis for ORR will be conducted once the last patient enrolled has completed 
3 cycles of treatment, discontinued treatment, started new anticancer therapy or met criteria for 
objective progression.  Patients who are randomized and do not achieve a CR or CRi will be 
considered as nonresponders in the primary analysis for ORR.
12.2.8 Other Analyses of Efficacy
No formal efficacy analysis is planned for the Phase 1 portion of this trial.  However, any 
response data will be listed and tabulated.  
In Phase 2, the following secondary efficacy parameters will be summarized for each treatment 
arm:

Proportion of patients achieving a ORR or PR

Proportion of patients achieving a CR, CRi, and PR

OS


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
RFS

EFS

DoR
…
The Cox proportional hazard model (Cox 1972) with treatment as a factor will be used to 
estimate the hazard ratio and corresponding 90 95% CI with Wald’s test p-value after adjusting 
for the following potential predictive/prognostic variables:  initial diagnosis (T-ALL phenotype, 
T LBL), response to last therapy (refractory or relapsed), age, number of prior therapies (≤2, >2), 
NOTCH-1/FBXW7/RAS/PTEN status.
…
12.2.9 Pharmacokinetic Analyses
PK analyses will be conducted on patients who receive at least 1 dose of the study drug and 
have samples collected.  PK parameter estimates for plasma and CSF LY3039478 and 
plasma dexamethasone, where possible, will be calculated by standard noncompartmental 
methods of analysis.  The primary parameters for analysis will be Cmax, area under the 
plasma concentration-time curve from time zero to last measurable plasma concentration 
(AUC[0-tlast]), area under the concentration-time curve from time zero to infinity or over 
1 dosing interval at steady state (AUC[0-∞] or AUCτ).  Other noncompartmental 
parameters, such as t1/2, apparent clearance (CL/F), and apparent volume of distribution 
(V/F) may be reported.  CSF LY3039478 concentrations will be summarized.  Additional 
exploratory analyses will be performed if warranted by data and other validated PK software 
programs (for example, NONMEM) may be used if appropriate and approved by Global 
Pharmacokinetics management.  The version of any software used for the analysis will be 
documented and the program will meet the Lilly requirements of software validation.
…


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PK, PD, CSF and ECG Sampling Schedule – Phase 1– Part A (Adult Patients)
PK 
Sample 
Number
Cycle
Day
PK Sampling 
Time for 
LY3039478a
PK Sampling time 
for dexamethasone
CSF Sampling 
Time for 
LY3039478b
PD Sampling 
Time for 
Aβ(1-x)]c
PD Sampling time for 
NICD and Gene 
expression 
Analysisd,e,f
ECG 
and ECG 
Chemistry
1
1
1
Predose 
Predose
Predose
Predose
Predose
2
1
1
1-2h
1-2h
1-2h
3
1
1
3-4h
3-4h
3-4h
3-4h
4
1
1
6-8h
6-8h
6-8h
6-8h
5
1
1
24-30h
24-30h
24-30h
24-30h
6
1
8
Predose 
Predose
Predose
7
1
8
1-2h
1-4h
8
1
8
3-4h
3-4h
9
1
8
6-8h
6-8h
6-8h
10
1
8
24-30h
24-30h
11
2
1
Predose
Predose
Abbreviation:  CSF = cerebrospinal fluid; ECG = electrocardiogram; NICD = Notch intracellular domain; PD = pharmacodynamic; PK = pharmacokinetic.
a
Samples of approximately 2 3 mL of whole blood will be collected for measurement of LY3039478 and dexamethasone on Cycle 1 Day 1 only.  On other 
days, 2mL of whole blood will be collected for measurement of LY3039478.
b
Optional and only for Phase 1 adult patients.
c
Samples of approximately 3 mL of whole blood will be collected.
d
For the NICD ELISA, approximately 8 mL of whole blood will be collected in sodium citrate CPT tubes.
e
For the gene expression analysis, approximately 2.5 mL of whole blood will be collected.
f
NICD collection will be performed at select sites only.
Note:  Collection of PD samples, where similar intervals are presented, should be collected the same time as PK samples.  Collection of CSF sample should be at 
the same time as either the 1-2h or 3-4h plasma PK sample.


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PK, PD, and ECG Sampling Schedule – Phase 1- Part B (Pediatric Patients)
PK 
Sample 
Number
Cycle
Day
PK Sampling Time 
for LY3039478a
PK Sampling time 
for dexamethasone
PD Sampling time 
for NICD and 
Gene expression 
Analysisb
ECG 
and ECG 
Chemistry
1
1
1
Predose 
Predose
Predose
Predose
2
1
1
1-3h
1-3h
1-3h
3
1
1
6-8h
6-8h
6-8h
6-8
4
1
8
Predose
Predose
Predose
5
1
8
1-3h
3h
Abbreviation:  ECG = electrocardiogram; NICD = Notch intracellular domain; PD = pharmacodynamic; PK = pharmacokinetic.
a
Samples of approximately 2 mL of whole blood will be collected for measurement of LY3039478 and dexamethasone (where assayed).
b
NICD collection will be performed at select sites only.
Note:  Collection of PD samples, where similar intervals are presented, should be collected the same time as PK samples.  


LY3039478
I6F-MC-JJCB(a) Clinical Protocol
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PK, PD, and ECG Sampling Schedule – Phase 2 (Approximately 30 Patients)
PK Sample 
Number
Cycle
Day
PK Sampling Time for 
LY3039478/
placebo
PK Sampling Time for 
Dexamethasoneb
PD Sampling time for NICD 
and Gene expressionc
ECGa
and ECG 
Chemistry
1
1
1
Predose 
Predose 
Predose
Predose
2
1
1
1-3h
1-3h
1-3h
3
1
1
6-8h
6-8h
6-8h
4
1
15
Predose
Predose 
5
1
15
1-3h
1-3h
6
21
15
Predose 6-8h
6-8h
Predose
7
2
1
Predose
Predose
Abbreviation:  ECG = electrocardiogram; NICD = Notch intracellular domain; PD = pharmacodynamic; PK = pharmacokinetic.
a
ECG required for all patients.
b
Samples of approximately 3 mL of whole blood will be collected for measurement of LY3039478 and dexamethasone in Cycle 1 only. On other days, 2mL of 
whole blood will be collected for measurement of LY3039478.
c
NICD collection will be performed at select sites only.
Note:  Collection of PD samples, where similar intervals are presented, should be collected the same time as PK samples.  


Leo Document ID = 725edb8f-ca88-4917-8a65-8c94f90d25ac
Approver: 
Approval Date & Time: 28-May-2015 09:43:49 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 04-Jun-2015 19:35:46 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan I6F-MC-JJCB (a)  
 
A Phase 1b/Randomized Phase 2 Study to Evaluate LY3039478 in Combination with 
Dexamethasone in T-ALL/T-LBL Patients 
 
NCT02518113 
Approved Date: 17-Jun-2015 


I6F-MC-JJCB Statistical Analysis Plan Version 1
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1.
Statistical Analysis Plan
I6F-MC-JJCB A Phase 1b/Randomized Phase 2 Study to 
Evaluate LY3039478 in Combination with Dexamethasone 
in T-ALL/T-LBL Patients
Confidential Information
The information contained in this Statistical Analysis Plan (SAP) is confidential and the 
information contained within it may not be reproduced or otherwise disseminated without 
the approval of Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachments or appendices are subject to United States Freedom of Information Act 
Exemption 4.
LY3039478, T-ALL/T-LBL
A randomized Phase 1b/2 study to evaluate LY3039478 in combination with 
dexamethasone in patients with T-ALL/T-LBL.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I6F-MC-JJCB
Phase 2
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 17-Jun-2015 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan  I6F-MC-JJCB A Phase 1b/Randomized 
Phase 2 Study to Evaluate LY3039478 in Combination with 
Dexamethasone in T-ALL/T-LBL Patients..........................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................8
4.1.
Primary Objective ..........................................................................................................8
4.2.
Secondary Objectives.....................................................................................................8
4.3.
Exploratory Objectives...................................................................................................9
5.
Study Design.....................................................................................................................10
5.1.
Summary of Study Design............................................................................................10
5.2.
Determination of Sample Size ......................................................................................12
5.3.
Method of Assignment to Treatment ............................................................................13
5.3.1.
Phase 1.................................................................................................................13
5.3.2.
Phase 2.................................................................................................................13
6.
A Priori Statistical Methods ..............................................................................................15
6.1.
General Considerations ................................................................................................15
6.2.
Adjustments for Covariates ..........................................................................................17
6.3.
Handling of Dropouts or Missing Data.........................................................................17
6.4.
Multicenter Studies ......................................................................................................17
6.5.
Multiple Comparisons/Multiplicity...............................................................................17
6.6.
Analysis Set Definitions...............................................................................................17
6.7.
Patient Disposition .......................................................................................................18
6.8.
Patient Characteristics ..................................................................................................18
6.9.
Treatment Compliance .................................................................................................19
6.10. Concomitant Therapy...................................................................................................20
6.11. Efficacy Analyses ........................................................................................................20
6.11.1.
Primary Outcome and Methodology.....................................................................23
6.11.2.
Additional Analyses of the Primary Outcome.......................................................23
6.11.3.
Secondary Efficacy Analyses ...............................................................................23
6.11.4.
Sensitivity Analyses.............................................................................................24
6.12. Health Outcomes/Quality-of-Life Analyses..................................................................25
6.12.1.
Patient-Reported Outcomes..................................................................................25
6.12.2.
Resource Utilization.............................................................................................25
6.13. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................26


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6.13.1.
Pharmacodynamics and Tailoring Analyses..........................................................26
6.14. Safety Analyses............................................................................................................26
6.14.1.
Extent of Exposure...............................................................................................27
6.14.2.
Adverse Events ....................................................................................................27
6.14.2.1.
Dose Limiting Toxicity...................................................................................28
6.14.3.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................28
6.14.4.
Clinical Laboratory Evaluation.............................................................................29
6.14.5.
Vital Signs and Other Physical Findings...............................................................29
6.14.6.
Electrocardiograms ..............................................................................................29
6.15. Subgroup Analyses.......................................................................................................30
6.16. Protocol Violations.......................................................................................................30
6.17. Interim Analyses and Data Monitoring.........................................................................31
6.18. Annual Report Analyses...............................................................................................32
6.19. Clinical Trial Registry Analyses...................................................................................32
7.
References ........................................................................................................................34
8.
Appendices .......................................................................................................................35
FACIT Administration and Scoring Guidelines..............................................................36
Scoring the FACT-G: ....................................................................................................36


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Table of Contents
Table
Page
Table JJCB.6.1. Data Definitions and Rules ............................................................................16


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Table of Contents
Figure
Page
Figure JJCB.5.1. Illustration of study design.............................................................................12


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Table of Contents
Appendix
Page
Appendix 1.
FACT-Leukemia Scoring Guidelines.............................................................36


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


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4.
Study Objectives
4.1.
Primary Objective
The primary objective are as follows:

Phase 1:  to determine the recommended dose of LY3039478 in combination with 
dexamethasone in 
o
adults patients with relapsed/refractory T-ALL/T-LBL (Part A)
o
pediatric patients (Part B)

Phase 2:  to determine if the overall remission rate (ORR) (CR plus CR with incomplete 
blood count recovery [CRi]) in adult patients with relapsed/refractory T-ALL/T-LBL 
treated with LY3039478 in combination with dexamethasone exceeds that of those 
patients treated with placebo in combination with dexamethasone
4.2.
Secondary Objectives
The secondary objectives of the study are as follows:

Phase 1:
o
to characterize the safety and toxicity profile of LY3039478 in combination with 
dexamethasone as assessed by National Cancer Institute (NCI) CTCAE v 4.0
o
to assess the PK parameters of LY3039478 in combination with dexamethasone 
therapy
o
to document efficacy based on Cheson criteria for leukemia and malignant 
lymphoma 
o
to evaluate gene mutation (eg, NOTCH1/FBXW7/RAS/PTEN) status with 
efficacy

Phase 2:  
o
to compare the ORR plus partial remission (PR) and PR alone for both arms
o
to assess the remission rate for patients receiving LY3039478 in combination with 
dexamethasone after failure of placebo in combination with dexamethasone
o
to assess duration of remission (DoR) = (CR, CRi, and PR)
o
to assess relapse-free survival (RFS), event-free survival (EFS), and OS
o
to compare the safety and toxicity profile of LY3039478 in combination with 
dexamethasone to dexamethasone and placebo as assessed by NCI CTCAE v 4.0
o
to assess the PK parameters of LY3039478 and dexamethasone in combination 
therapy
o
to assess patient quality of life using the Functional Assessment of Cancer 
Therapy-Leukemia (FACT-Leu)
o
to evaluate gene mutation (eg, NOTCH-1/FBXW7/RAS/PTEN) status with 
efficacy


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4.3.
Exploratory Objectives 
The exploratory objectives of the study are as follows:

to assess clinical utility of the NICD immunohistochemistry (IHC) assay as a potential 
companion diagnostic for LY3039478

to evaluate biomarkers in tumor tissue, blood, plasma and cerebrospinal fluid (CSF), 
which may include, but not be limited to, NICD enzyme-linked immunosorbent assay 
(ELISA) (or an alternative validated method), gene expression, relevant to the study 
disease or safety, efficacy, and mechanism of action of LY3039478 and dexamethasone

to explore PD effects of LY3039478 on biomarkers indicative of Notch activity

to evaluate the CSF PK of LY3039478


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5.
Study Design 
5.1.
Summary of Study Design
Study JJCB is a multicenter study consisting of a nonrandomized, open-label, dose-escalation 
Phase 1 study followed by a randomized, double-blind, Phase 2 study in patients with relapsed or 
refractory T-ALL/T-LBL.  The Phase 1 portion of the study will consist of 2 different patient 
populations, an adult (Part A) and a pediatric (Part B), and will define the recommended dose of 
LY3039478 in combination with dexamethasone in each of these populations.  The randomized 
Phase 2 study will be a double-blinded, multicenter evaluation to determine if the CR and CRi 
(CR with incomplete blood count recovery) rate in adult patients with relapsed/refractory 
T-ALL/T-LBL treated with LY3039478 in combination with dexamethasone exceeds that of 
those patients treated with placebo in combination with dexamethasone.  Figure JJCB.5.1
illustrates the study design.
Eligible adult patients will receive LY3039478 administered orally TIW(3 times per week) and 
dexamethasone administered 24 mg orally Days 1 to 5 every other week.  In Part B (pediatric 
patients), dexamethasone is administered at 10 mg/m2 BID, orally, Days 1 through 5 every other 
week.  A cycle is defined as 28 days of treatment (4 weeks).
The Phase 1 portion will start with the adult cohort (Part A).  The decision to proceed with the 
pediatric dose exploration (Part B) will be made after safety analysis of the adult cohort.
The dose escalation will be guided primarily by safety assessments from Days 1 through 28 of 
Cycle 1 for patients in all cohorts.  Dose escalation will occur until the MTD is determined.  
Patients will be enrolled in Part A with the first dose level of 50 mg LY3039478, TIW.  Dose 
levels will be determined based on the review of the safety, PK, and PD data from the previous 
doses.  Additional dose levels (to a maximum of 200 mg TIW) may be explored if necessary.  No 
dose escalation will occur beyond MTD.  In Parts A and B, the sample size is estimated to be 
approximately 13 to 16 patients in each part depending on the relationship between exposure and 
toxicity as well as the relationship between exposure and pharmacological effects.
After the last patient on Part A has completed Cycle 1 and the recommended dose for the Phase 2 
portion is determined, the randomized, Phase 2 portion will begin following an interim review of 
the data.  The patient population in the Phase 2 portion of the study will be identical to the 
patient population assessed in Part A.
In the Phase 2 portion, 60 patients will be randomized in a 2:1 ratio to receive either LY3039478 
in combination with dexamethasone administered 24 mg orally on Days 1 to 5 every other week 
or placebo in combination with dexamethasone administered 24 mg orally on Days 1 to 5 every 
other week.  Placebo or LY3039478 will be administered orally TIW at the recommended dose 
from Part A.  Patients will receive treatment until progression or meeting discontinuation criteria 
as outlined in the protocol.


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Patients discontinuing the study for treatment failure will be unblinded after discontinuation.  A 
crossover to LY3039478 in combination with dexamethasone will be allowed for patients who 
were receiving placebo in combination with dexamethasone.
A futility interim analysis will be performed in the Phase 2 portion of the study when 30 patients 
have completed the CR status determination.  The analysis will assess the safety profile, verify 
that the chosen regimen is clinically feasible, and determine if the futility criteria have been met.  
An internal assessment committee consisting of (at minimum) a Lilly Medical Director, a Lilly 
CRP not associated with the study, a PK scientist, and a statistician will examine the interim 
results and make recommendations about the trial.
The total sample size for this study is estimated to be approximately 86 to 92 patients.
There is no fixed duration of treatment; patients will remain on study until they fulfill 1 of the 
criteria for study discontinuation.  


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Abbreviation: MTD = maximum tolerated dose.
Figure JJCB.5.1.
Illustration of study design.
5.2.
Determination of Sample Size
Approximately 86 to 92 patients will be enrolled in this multicenter study.
In the Phase 1 portion of the study, the primary objective is to determine the MTD and the 
recommended dose for Phase 2.  Approximately 13 to 16 patients will be enrolled into the adult 
(Part A), and approximately 13 to 16 patients will be enrolled in the pediatric (Part B) cohorts 
sequentially and without randomization to dose.  The total sample size per cohort will be 
determined by DLTs.
In the Phase 2 portion of the study, the primary objective of this study is to compare the ORR
(CR plus CRi) rate between LY3039478 administered with dexamethasone and placebo 
administered with dexamethasone, in adult patients with relapsed/refractory T-ALL/T-LBL.  
Approximately 60 evaluable patients will be randomized to the 2 treatment arms in a 2:1 ratio 
(40 randomized to LY3039478 and dexamethasone and 20 randomized to placebo and 
dexamethasone).  


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Assuming the ORR for the LY3039478 and dexamethasone arm is 40% and the ORR of the 
placebo and dexamethasone is 5%, the sample size of 60 evaluable patients will give 
approximately 82% statistical power to detect the difference, using a 2-sided Fisher’s test at the 
significance level of 0.05, with 1 futility interim once the 30th enrolled patient completes the 
remission status determination.  
Patients who are randomized and do not achieve a CR or CRi will be considered as 
nonresponders in the primary analysis for ORR. 
5.3.
Method of Assignment to Treatment
5.3.1. Phase 1
Patients who enter the study during the Phase 1 portion will be assigned to receive LY3039478
and dexamethasone.  Prior to enrollment into the study, an eligibility check must be conducted 
(for every patient) between the investigational site and the Lilly clinical research personnel, to 
confirm that the patient meets all enrollment criteria.  Upon confirmation of eligibility, the 
sponsor will confirm the dose, cohort, and identification number assignment for each patient.  No 
dose escalations (that is, to the next cohort) can occur without prior discussion and agreement 
with the responsible Lilly CRP/CRS.
5.3.2. Phase 2
Patients who enter the study during the Phase 2 portion will be randomized to receive either 
LY3039478 in combination with dexamethasone or placebo in combination with dexamethasone.  
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS).  
A dynamic allocation method, introduced by Pocock and Simon (1975) and extended for unequal 
treatment group sizes by Han et al. (2009), will be adopted to balance patient assignment 
between treatment arms, using a probability factor of 0.9, based on the following factors:  

age 30 years versus >30 years

T-ALL phenotype versus T-LBL, considered as 6 factors, representing the following  
5 phenotypes of T-ALL:
TdT+, variable for all of the following:  CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD34
o
Pro-T-ALL:  cCD3+, CD7+, CD1a-, CD2-, CD4-, CD8-, CD34+/-
o
Pre-T-ALL:  cCD3+, CD7+, CD1a-, CD2+, CD4-, CD8-, CD34+/-
o
Cortical T-ALL:  cCD3+, CD7+, CD1a+, CD2+, CD4+, CD8+, CD34-
o
Medullary T-ALL:  cCD3+, sCD3+, CD7+, CD1a-, CD2+, CD4+or CD8+, 
CD34-
o
ETP T-ALL:  Lack of CD1a and CD8 expression, weak CD5 expression with less 
than 75% positive blasts, and expression of 1 or more of the following myeloid or 
stem cell markers on at least 25% of lymphoblasts:  CD117, CD34, HLA-DR, 
CD13, CD33, CD11b, and/or CD65


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
response to last therapy:  refractory/relapse within 1 year of last therapy vs. >1 year
The randomization parameter P will be set to 0.9 to maximize the benefit of the allocation 
procedure, whilst keeping treatment assignments unpredictable.


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6.
A Priori Statistical Methods
6.1.
General Considerations
Phase 1 Part A, Phase 1 Part B and Phase 2 study parts will be reported in separate TFLs.
Results of descriptive analyses and estimates from inferential analyses will be presented by
dose level cohort (phase 1) or by treatment (phase 2). In the phase 2 study part, an additional 
group will be included in primary efficacy and safety TFLs to represent data for patients 
receiving LY3039478 in combination with dexamethasone after failure of placebo in 
combination with dexamethasone.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.  All tests of interactions will be conducted at a 2-sided alpha level of 0.1, and all CIs will 
be given at a 2-sided 95% level, unless otherwise stated.
The assumptions for each statistical method will be evaluated.  If there is violation of 
assumptions, alternative statistical methods may be used.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
For continuous variables, summary statistics will include number of patients,
mean, median, standard deviation, minimum, and maximum. Categorical endpoints will be
summarized using number of patients, frequency, and percentages. Any missing longitudinal
data will not be imputed, rather estimated from an appropriate random mixed effects model.
Transformations will be applied where assumptions behind any analysis are better satisfied by
data being transformed onto an alternative scale. All results from any of these analyses will be
back transformed to the original scale. Alternatively, nonparametric methods will be applied.


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Table JJCB.6.1.
Data Definitions and Rules
Term
Definitions or Rule
Entered
Patients who have signed the informed consent document directly.
Screen failures
Patients who have signed informed consent, do not meet eligibility
criteria and are not randomized.
Randomized/ Enrolled
Patients who have been assigned to study treatment and but may have 
not received any study treatment (LY3039478, LY3039478-
matched placebo, or Dexamethasone).
Patients on therapy
Patients who have been randomized/enrolled to study treatment and 
have received at least 1 dose of study treatment (LY3039478, 
LY3039478-matched placebo, or Dexamethasone).
Study day
If assessment is on or after date of first LY3039478/ LY3039478-
matched placebo dose then
(date of assessment) – (date of first study treatment dose) + 1
If assessment precedes first treatment dose then
(date of assessment) – (date of first study treatment dose)
There is no study day 0. Study day 1 is the date of first dose and study
day -1 is the day before the first dose.
Cycle day
If assessment is on or after date of first LY3039478/ LY3039478-
matched placebo dose then
(date of assessment) – (date of first study treatment dose in cycle) + 1
If assessment precedes first treatment dose then
(date of assessment) – (date of first study treatment dose in cycle)
There is no cycle day 0. Cycle day 1 is the date of first dose in the cycle
and cycle day -1 is the day before the first dose.
Baseline
For change from baseline analysis, baseline value is defined as the last
reported measure on or before the first dose date (or discontinuation, if 
no treatment is given). 
Study treatment period
Time from treatment start to when the patient and the investigator agree 
that the patient will no longer continue study treatment.  The date of 
this agreement is to be reported on the case report form (CRF) as the 
Date of Discontinuation from study treatment.
Post-discontinuation –
short-term follow-up
The short term follow-up period begins 1 day after discontinuation of 
study treatment and lasts approximately 30 days (Visit 801).
Post-discontinuation –
long-term follow-up
The long-term follow-up period begins 1 day after the short-term 
follow-up period (Visit 801) is completed and continues until patient’s 
death or overall study completion
Continued access 
follow up
The continued access follow up period begins 1 day after the patient 
and investigator determine that the patient will no longer continue 
treatment in the continued access period and lasts approximately 30 
days.


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6.2.
Adjustments for Covariates
Additional analyses may be performed on efficacy measures to adjust for factors that may affect 
survival or disease progression.
All of the patient characteristics listed in Section 6.8 will be considered.
6.3.
Handling of Dropouts or Missing Data
Patients who are randomized and do not achieve a CR or CRi will be considered as 
nonresponders in the primary analysis for ORR.  
The primary method for handling missing time-to-event data will be censoring.
Partial dates will be imputed, with missing day imputed as 15, and missing month and day 
imputed as 1-July.
6.4.
Multicenter Studies
This is a multicenter study. Data collected will be analysed as a whole. Exploratory analyses by 
individual study sites or country may be conducted as warranted. 
6.5.
Multiple Comparisons/Multiplicity
No adjustment for multiplicity is planned for this study. The primary analysis in phase 2 will 
compare the ORR for LY3039478 plus dexamethasone and placebo plus dexamethasone. 
It is not planned to stop the trial early for efficacy, thus there are no adjustments for multiplicity
6.6.
Analysis Set Definitions
Efficacy analyses will be based on the intention-to-treat (ITT) analysis set.  This population is 
defined as all patients randomized to study treatment.  
Patients will be grouped according to dose level cohort (phase 1) or randomized treatment (phase 
2). Sensitivity analyses may be conducted (if applicable) excluding patients that are randomized 
but do not receive treatment, and by actual treatment received.  
A secondary analysis of the primary efficacy endpoint in phase 2 based upon the per-protocol 
set (PPS) of patients may be performed if there are significant numbers of patients with major 
protocol deviations (10% of total patient population).  The PPS is defined as those patients in 
the ITT set who are compliant with the study protocol.  The following criteria will be used in the 
determination of the PPS

Inclusion/Exclusion criteria not met which may impact efficacy conclusions: Protocol 
inclusion criteria [1], [2], [3], [4], [5] and protocol exclusion criteria [13], [19], [20], [21].

Study drug non-compliance as defined in Section 6.10.

Received incorrect treatment that affects efficacy analysis

Received prohibited medications whilst on study treatment, including other 
chemotherapy, other anticancer therapy, immunotherapy, hormonal cancer therapy 


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(except therapy of hormone-sensitive prostate cancer patients who are stable on GnRH 
agonist therapy and breast cancer patients who are stable on antiestrogen therapy (eg, an 
aromatase inhibitor), radiation, surgery for cancer, or experimental medications.  
Safety analyses will be based on the safety analysis set, defined as all enrolled patients receiving 
at least 1 dose of any study drug.  Patients will be grouped according to actual treatment 
received.
PD and/or tailoring biomarker analyses will be based on the subset of patients from the above 
populations from whom a valid assay result (according to laboratory guideline) has been 
obtained.  
6.7.
Patient Disposition
A detailed description of patient disposition will be provided.  It will include a summary of the 
number and percentage of patients entered into the study, enrolled in the study, and treated as 
well as number and percentage of patients completing the study, or discontinuing (overall and by 
reason for discontinuation).  
All entered patients will be accounted for in this summary of disposition. Screen failures and 
patients who died or discontinued before treatment begins will be specified. 
A listing of primary reasons for both study treatment and study discontinuation will also be 
provided according to each randomized treatment arm.
A summary of all important protocol deviations will be provided.
A listing of patients who discontinued due to AE or death from treatment and study itself will 
also be provided with additional information on cause of death and the AE associated with 
discontinuation. 
6.8.
Patient Characteristics
Patient demographics including age, sex, screening height, weight and body mass index, race, 
ethnicity, patient habits (caffeine/alcohol use) and country will be reported using descriptive 
statistics.  
Baseline disease characteristics will be summarized by cohort (phase 1a, phase 1b) or 
randomized treatment arm (phase 2). Continuous variables will be summarized by median and 
range, and compared amongst treatment arms by ANOVA. Categorical variables will be 
summarized by frequency counts and compared amongst treatment arms by Fishers exact test.
Statistical comparisons will be provided in phase 2 where data warrant only. The following 
disease characteristics will be summarized: 

Sex

Age

Diagnosis: T-ALL and T-LBL, with T-ALL additionally split by subtype:
TdT+, variable for all of the following:  CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD34


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o
Pro-T-ALL:  cCD3+, CD7+, CD1a-, CD2-, CD4-, CD8-, CD34+/-
o
Pre-T-ALL:  cCD3+, CD7+, CD1a-, CD2+, CD4-, CD8-, CD34+/-
o
Cortical T-ALL:  cCD3+, CD7+, CD1a+, CD2+, CD4+, CD8+, CD34-
o
Medullary T-ALL:  cCD3+, sCD3+, CD7+, CD1a-, CD2+, CD4+or CD8+, 
CD34-
o
ETP T-ALL:  Lack of CD1a and CD8 expression, weak CD5 expression with less 
than 75% positive blasts, and expression of 1 or more of the following myeloid or 
stem cell markers on at least 25% of lymphoblasts:  CD117, CD34, HLA-DR, 
CD13, CD33, CD11b, and/or CD65

ECOG status at randomization, or Lanksky status for Phase 1 Part B (pediatrics)

Disease status: Refractory or relapsed, with relapse additionally split by: first relapse, 
second relapse, relapse after SCT

Notch and/or FBWX7 mutational status: Yes, no [See Trinquand et al, 2013 for further 
details]

RAS and/or PTEN abnormalities: Yes, no [See Trinquand et al, 2013 for further details]

Extramedullary disease: Yes, no

History of CNS leukemia: Yes, no

Time since initial diagnosis

Duration of first remission

Response to last therapy:  refractory, or relapsed with duration of remission  <1 year, 1-2 
years, 2-5 years, >5 years

Number of prior courses of induction therapy (1, 2, 3, ≥4)

Country
Other patient characteristics will be summarized as deemed appropriate.
Prior therapies and procedures e.g. stem cell transplant will be listed. 
6.9.
Treatment Compliance
Treatment compliance information for study drug will be collected through pill counts at each 
visit and the number of tablets taken relative to the number expected to be taken will be 
summarized.
The patient must take 75% of the intended doses to be deemed compliant with study drug 
administration. Similarly, a patient will be considered significantly noncompliant if he or she is 
judged by the investigator to have intentionally or repeatedly taken more than the prescribed 
amount of medication.  
Percent compliance is calculated from dispensed and returned capsules as: 
100 x (total amount of drug taken (mg) / total amount of drug prescribed (mg))
Total amount of drug prescribed is the sum of products of dosing intervals and the expected dose 
for each interval. Total dose prescribed should take into consideration any dose adjustment(s)
before treatment discontinuation date. Treatment compliance will be summarized for
LY3039478 and Dexamethosone separately by randomized treatment, cycle, and overall.


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6.10. 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 listings will include 
both the term reported in CRF and the WHO dictionary term and if  concomitant medication use 
is due to adverse event (AE), the associated AE will also be listed. A separate listing of 
transfusions will be created. 
Anti-cancer systemic therapy, radiotherapy and surgery that occurs post discontinuation of
study treatment is captured separately from concomitant medication as the existence of such
therapies can lead to censoring of time to event endpoints. Patients that received post 
discontinuation therapies will be listed by treatment arms.
6.11. Efficacy Analyses
Efficacy analyses will be conducted on the ITT analysis set, with patients grouped according to 
randomized treatment. 
The following are definitions of the primary and secondary efficacy endpoints:
Primary Endpoint:
Overall Response Rate (ORR) is defined as the proportion of patients who achieved a best 
overall response of either complete remission (CR) or incomplete remission (CRi). The ORR 
(CR and CRi) is the sum of patients achieving a CR or a CRi divided by the total number of 
patients randomized in that arm.
Secondary Endpoints:

Partial Response (PR) is defined as the proportion of patients who achieved a best overall 
response of partial remission (PR), out of the total number of patients randomized in that 
arm. 

Complete Remission (CR) is defined as the proportion of patients who achieved a best 
overall response of complete remission (CR), out of the total number of patients randomized 
in that arm. 

ORR and PR is defined as the proportion of patients who achieved a best overall response of 
either complete remission (CR), incomplete remission (CRi) or partial remission (PR), out of 
the total number of patients randomized in that arm. 
All of the above endpoints (ORR, PR, CR, ORR and PR) will also be calculated for those 
patients that cross-over in the Phase 2 part of the trial and receive LY3039478 plus 
dexamethasone after failure of placebo plus dexamethasone.  

Overall Survival (OS) is defined for all patients in the trial, and measured from the date of 
study enrollment to the date of death from any cause.  OS duration is measured from the date 
of randomization to the date of death from any cause in the Phase 2 portion of the study.  For 
each patient who is not known to have died as of the data-inclusion cutoff date for a 
particular analysis, OS will be censored for that analysis at the date of last contact prior to the 


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data inclusion cutoff date (contacts considered in the determination of last contact date 
include AE date, lesion assessment date, visit date, and last known alive date).  

Relapse Free Survival (RFS) is defined only for patients who achieve CR/CRi. 
For T-ALL, RFS is measured from the date of attaining the leukemia-free state until the date 
of T-ALL relapse or death from any cause, whichever occurs first. Relapsed disease for T-
ALL is defined as the reappearance of the blast in the blood or bone marrow (>5%) or any 
extramedullary site after achievement of a CR. 
For T-LBL, RFS is measured from the time of occurrence of a disease-free state or 
attainment of a CR to disease recurrence or death as a result of lymphoma or acute toxicity of 
treatment. 
For a patient who is not known to have relapsed or died by the end of study follow-up, 
observation of RFS is censored at the date of last contact prior to the data inclusion cutoff, at 
which an adequate assessment was completed, i.e. blood or bone marrow samples, CT-MRI 
or PET assessment.

Event Free Survival (EFS) is defined for all patients and measured from the date of entry on 
study.  It is measured until treatment failure, relapse from CR, or death from any cause, 
whichever occurs first.  
For T-ALL, treatment failure is defined by progressive disease, which is an increase of at 
least 25% in the absolute number of circulating or bone marrow blasts or development of 
extramedullary disease. For T-ALL patients with preexisting mediastinal disease, progressive 
disease is defined by a greater than 25% increase in the sum of the product of the greatest 
perpendicular diameters (SDP) of the mediastinal enlargement.   
For T-LBL, treatment failure is defined as relapsed or progressive disease in protocol Table 
JJCB.10.1.   
For a patient with none of these events before the end of study follow-up, observation of EFS 
is censored at the date of last contact prior to the data inclusion cutoff date, at which an 
adequate assessment was completed i.e. blood or bone marrow samples, CT-MRI or PET 
assessment.  If the patient does not achieve a CR, EFS is defined as the point of treatment 
failure or death, whichever comes first.  
Censoring Rules for EFS and RFS
If there are multiple dates associated with one assessment, in order to determine date of 
progressive or relapsed disease, the assessment date will be set to the first date when the overall 
response is PD or relapsed disease and the last date otherwise.  An EFS or RFS determination is 
considered adequate if the response is CR, CRi, SD, PD, Relapsed Disease or Refractory.


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Table JJCB.6.2 lists censoring rules which will be applied in sensitivity analysis (SA) 
definitions. 
Table JJCB.6.2.
Censoring Rules Sensitivity Analysis Definitions
Sensitivity 
Analysis 
Definition #
Situation
Date of Progression or Censor
Censored / 
Progressed 
SA 1
Patient receives stem cell 
transplant before relapse, 
progression or death
Date of stem cell transplant
Censored
SA 2
Relapsed disease, progressive 
disease or death after ≥ 2 
missed assessments, including 
blood/bone marrow samples, 
CT/MRI or PET assessments.
Date of last post baseline assessment 
before missed assessments or 
Date of randomization (for EFS) or 
disease-free state (for RFS) if no other 
assessment in between
Censored
SA 3
Patient dose not have adequate 
baseline assessment (bone 
marrow biopsy/aspirate or 
PET-CT, or CT-MRI)
Date of randomization for EFS analysis
Patient not eligible for RFS analysis
Censored
SA 4
Patient is lost to follow-up 
without relapsed or progressive
disease
Date of next scheduled post baseline 
adequate assessment at or after 
becoming lost to follow-up 
Progressed
SA 5
Patient is lost to follow-up 
without relapsed or progressive 
disease
Date of next scheduled post baseline 
adequate assessment at or after 
becoming lost to follow-up
Progressed for the 
treatment arm and 
censored for the 
control arm

Duration of Response (DoR) DoR for T-ALL is measured from the date of CR, CRi or PR
by blood count recovery and bone marrow examination, until the date of relapse.  DoR for T-
LBL is measured from the time when criteria for response (ie, CR or PR) are met, until the 
first documentation of relapse or progression. For patients who die without report of relapse, 
DoR is censored on the date of death, regardless of cause.  For a patient with no report of 
relapse or death by the end of the follow-up data collection, observation is censored at the 
date of last contact prior to the data inclusion cutoff date.


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6.11.1. Primary Outcome and Methodology
In the Phase 1 portion, the primary outcome of interest is determining the MTD and 
recommended dose for Phase 2. Efficacy data will be tabulated and listed, no formal hypothesis 
testing is planned. 
In the Phase 2 portion, the primary efficacy endpoint of ORR (CR plus CRi) rate and its 
exact 95% confidence interval (CI) will be estimated for each treatment arm.  The 
proportion in each treatment arm will be compared using Fisher’s exact test.  Primary 
analysis will utilize the ITT analysis set.
Best response will be derived to encompass all tumor assessments from baseline until the 
earliest objective progression or start of new anticancer therapy. Primary analysis for 
ORR will be conducted once all enrolled patients have completed 3 cycles of treatment, 
discontinued treatment, started new anticancer therapy or met criteria for objective 
progression. Patients who are randomized and do not achieve a CR or CRi will be 
considered as nonresponders in the primary analysis for ORR.
6.11.2. Additional Analyses of the Primary Outcome
Sensitivity analyses of the primary outcome measure will include a re-randomization test. The 
observed responses and randomization stratification covariates will be considered as a set of 
fixed values, and the treatment assignment then re-randomized using the same allocation 
mechanism from the trial. Approximately 5000 re-randomizations will be performed and the 
resulting p-values evaluated by:

Comparing the observed difference in proportion of ORR with the re-randomized treatment 
differences

Comparing the observed Fisher’s test p-value for the comparison of treatments with the re-
randomized treatment comparison. 
6.11.3. Secondary Efficacy Analyses
Response Endpoints
The secondary efficacy endpoints of ORR and PR, PR and CR, and their exact 95% CIs will be 
estimated for each treatment arm and compared by 2-sided Chi-squared test or Fisher’s exact test
between 2 arms.  A Fisher’s exact test will be chosen over a Chi-squared test if in the 2x2 table, 
any of the expected cell counts are less than 5, or any cell has zero counts. 
Efficacy data (CR, CRi, PR, and ORR) for patients receiving LY3039478 in combination with 
dexamethasone after failure of placebo in combination with dexamethasone will be tabulated, 
and further exploratory analyses of efficacy data conducted as warranted.
Time to Event Endpoints
For the secondary efficacy endpoints OS, RFS, and EFS, the Kaplan-Meier method (Kaplan and 
Meier 1958) will be used to estimate the survival curves as well as survival rates at various 


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prespecified time points (12 months for OS, 6 and 12 months for RFS and EFS) for each 
treatment arm.  
The secondary efficacy endpoint DoR is subject to competing risk of death without relapse; 
therefore, the cumulative incidence of relapse (Gray 1988; Pepe and Mori 1993; Gooley et al. 
2001) will be used.  In the calculation, patients who did not have the event will be considered 
right-censored observations.  
The comparison of the survival curves between treatment groups will be conducted by a log-rank 
test.  Exploratory analyses for the comparison of the survival curves between treatment groups 
may additionally be conducted by a stratified log-rank test with some of the following 
stratification variables:  initial diagnosis (T-ALL phenotype, T-LBL), response to last therapy 
(refractory or relapsed), age, number of prior therapies (≤2, >2), NOTCH-1/FBXW7/RAS/PTEN 
status.  
The Cox proportional hazard model (Cox 1972) with treatment as a factor will be used to 
estimate the hazard ratio and corresponding 95% CI with Wald’s test p-value after adjusting for 
the following potential predictive/prognostic variables:  initial diagnosis (T-ALL phenotype, 
T-LBL), response to last therapy (refractory or relapsed), age, number of prior therapies (≤2, >2), 
NOTCH-1/FBXW7/RAS/PTEN status.
The unadjusted impact of patient baseline disease characteristics listed in Section 6.8 on OS and 
EFS will be explored using Cox proportional hazard models (Cox 1972) with the baseline 
characteristic as a factor (continuous variables split at median) and the hazard ratio and 
corresponding 95% CI plotted on a forest plot. Any characteristics found to be significant 
prognostic markers for EFS or OR may be included as  additional covariates in COX 
proportional hazard model analyses to compare treatment arms. 
6.11.4. Sensitivity Analyses
For the analysis of time-to-event endpoints EFS and RFS, sensitivity analysis definitions as 
described in table JJCB.6.2 will be completed for the log-rank test. Such analyses will only be 
conducted if the primary analysis of such endpoints warrants sensitivity analysis to evaluate 
whether and to what extent the conclusion would be affected under the different censoring rules. 
For the analysis of OS, sensitivity analysis definition SA1 as described in Table JJCB.6.2 will 
also be completed. Further analyses may explore OS adjusting for patients which received 
LY3039478 plus dexamethasone following treatment failure of placebo plus dexamethasone, if 
warranted. 
Additionally, analyses may be conducted (if applicable) excluding patients that are randomized 
but do not receive treatment, and by actual treatment received.  


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6.12. Health Outcomes/Quality-of-Life Analyses 
6.12.1. Patient-Reported Outcomes
The FACT-Leu includes the 27-item cancer-specific Functional Assessment of Cancer Therapy-
Leukemia-General (FACT-G) that assesses physical, social/family, emotional and functional 
well-being plus a 17-item subscale that assesses additional concerns specific to leukemia. 
Methods for handling missing data, reverse scoring and other scoring guidelines are provided in 
Appendix 1.
FACT-Leu results will be summarized descriptively by cycle and for postdiscontinuation visits, 
including number of completed questionnaires, compliance rates, reasons for noncompliance, 
scores for each scale, subscale and total scores, and changes from baseline. 
Each of the 5 subscales, plus the Leukaemia trial outcome index, FACT-G total score and 
FACT-Leukaemia total score will be analysed by mixed effect model repeated measures. The
model will include randomized treatment, cycle and the interaction of randomized treatment and 
cycle as fixed effects, with baseline and the interaction of baseline and cycle as a covariate. An 
unstructured variance covariance matrix will be used, provided data permit. Otherwise the 
following variance covariance structures will be tested and that with the best fit according to AIC 
selected: compound symmetry, heterogeneous Toeplitz, first-order autoregressive combined with 
random patient effect, heterogeneous autoregressive, or heterogeneous compound symmetry.  
The Kenward-Roger method will be used to estimate denominator degrees of freedom.  Least 
square means and treatment comparisons with corresponding 95% confidence intervals (CIs) for 
each cycle will be presented in tabular and graphical displays. 
6.12.2. Resource Utilization
Investigators will be asked to document the use of best supportive care measures, concomitant 
medications, transfusions, and disease/adverse event-related hospitalization days.  Such 
assessments are to be taken throughout the Phase 2 portion of the study, through the 30-day 
short-term follow-up, and during the postdiscontinuation follow-up visit.
The proportion of patients receiving concomitant medications for supportive care, and each type 
of WHO drug name will be summarized by randomized treatment and cycle, including overall 
cycles, and compared using fishers exact test. Further exploratory analyses may be conducted if 
warranted, for example the mean number of doses for medications administered to at least 10% 
of phase 2 patients.
The proportion of patients receiving transfusions will be summarized by randomized treatment 
and cycle, including overall cycles, and compared between treatment arms using a fishers exact
test. Further analyses adjusting for covariates may be conducted if warranted. 
The number of hospitalization days, and number of platelet and RBC transfusions, will be 
summarized descriptively by randomized treatment and cycle. 


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6.13. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods 
The Lilly pharmacokineticist will be responsible for PK and PK/PD analysis. 
PK analyses will be conducted on patients who receive at least 1 dose of the study drug and have 
samples collected.  PK parameter estimates for plasma and CSF LY3039478 and plasma 
dexamethasone, where possible, will be calculated by standard noncompartmental methods of 
analysis.  The primary parameters for analysis will be Cmax, area under the plasma 
concentration-time curve from time zero to last measurable plasma concentration (AUC[0-tlast]), 
area under the concentration-time curve from time zero to infinity or over 1 dosing interval at 
steady state (AUC[0-∞] or AUCτ). Other noncompartmental parameters, such as t1/2, apparent 
clearance (CL/F), and apparent volume of distribution (V/F) may be reported. Additional 
exploratory analyses will be performed if warranted by data and other validated PK software 
programs (for example, NONMEM) may be used if appropriate and approved by Global 
Pharmacokinetics management. The version of any software used for the analysis will be 
documented and the program will meet the Lilly requirements of software validation.
The PK data will be combined, and analyses may be conducted to determine a relationship
between exposure and PD effect (eg, Aβ), data permitting. This model may be used to help 
reassess the dose cohort escalation as the study progresses. If deemed necessary, PK/PD 
modeling may be employed to evaluate variability in exposure, pharmacologic effects, and safety 
parameters.  
6.13.1. Pharmacodynamics and Tailoring Analyses
Biomarker data from all patients undergoing biomarker assessments will be analyzed using 
descriptive statistics.  Biomarkers (including NICD and gene expression) will be explored at 
baseline for prognostic value in ORR, EFS or OS outcome, and for potential predictive value in 
an efficacious response to treatment.
ORR will be summarized by gene mutation status (eg, NOTCH-1/FBXW7/RAS/PTEN) and 
presented in tabular and graphical displays. Interaction effect between the gene mutation statuses
may be further analyzed as warranted. 
Further exploratory analyses of pharmacodynamic markers will be conducted as warranted.
6.14. Safety Analyses
All safety summaries and analyses will be based upon the safety population that includes patients 
that have received at least one dose of study drug. Safety analyses will be conducted according to 
actual treatment received. Data collected for patients receiving LY3039478 plus Dexamethosone 
following treatment failure of placebo plus dexamethasone included as an additional treatment 
group in TFLs. 
Safety data will be listed and summarized with patient counts and percentages in each treatment
arm. Details of the analyses are described in the following sections.


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6.14.1. Extent of Exposure
The number of dose omissions, reductions, delays, and cycles received and the dose intensity 
will be summarized for all treated patients per treatment arm.  Summarized data will be provided 
for the period prior to first CR, the period following first CR, and the total treatment period.
Percent dose intensity is calculated as:
100 x (actual cumulative dose taken (mg) / planned cumulative dose (mg))
Note that planned dose is the same as actual dose if there is no dose modification or cycle delays. 
Reasons for dose adjustments will also be summarized, and if the reason for dose modification is 
due to AE, the associated AE will be provided. 
6.14.2. Adverse Events
A listing of all adverse events by patient will be presented. This listing will include patient 
number, adverse event (actual term and preferred term), event start and end dates, CTCAE grade, 
relationship to study drug/procedure, seriousness, and outcome. A listing of SAE will be 
produced using the similar format.
An overall summary will be provided for AEs. The number and percent of evaluable patients will 
be summarized by treatment for each category below. The summary will provide counts for all 
AEs, and AEs possibly related to study treatment.

Patients with at least one TEAE

Patients with at least one grade 3 or 4 TEAE

Patients with at least one SAE

Patients who discontinued due to AE

Patients who discontinued due to SAE

Patients who died due to AE on study treatment

Patients who died due to AE within 30 days of discontinuation from study treatment
Treatment-emergent adverse events (TEAE) are defined as follows:

Any event that first occurred or worsened in severity after baseline, based on the
MedDRA LLT term and CTCAE severity grade. This means that any episode of the same 
AE with the same grade as at baseline that starts after the first dose of study treatment 
will not be defined as treatment emergent, even if now considered possibly drug related.

Or any PEC (emerged prior to informed consent) or any AE (emerged after signed 
informed consent) that were still present prior to first dose but has increased in severity 
(CTCAE grade) following the start of treatment, regardless of causality.
As per Lilly’s standard operating procedures, all “probably related,” “possibly related,” or “does 
not know” AEs and SAEs will be defined as related to study drug.


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MedDRA v16.1 (or higher) will be used when reporting AEs by MedDRA terms.  TEAEs will be 
summarized by SOC and by decreasing frequency of preferred term (PT) within SOC.
TEAEs will be summarized by CTCAE grade, including the total for maximum Grade 3 and 4, 
and Grade 3, 4 and 5. These summaries will be provided for events regardless of study drug 
causality, and repeated for events deemed by the investigator to be possibly related to study 
medication.
Laboratory parameter abnormalities will be summarized by CTCAE grade.
6.14.2.1. Dose Limiting Toxicity
Dose limiting toxicities (DLT) will be listed for all patients on therapy in Phase 1. DLT-
equivalent toxicities will also be listed for all patients on therapy in Phase 1 and Phase 2.
In Phase 1 of the study, dose escalation will be driven by safety using a modified 3+3 scheme, 
with incorporation of model-based dose escalation (Neuenschwander et al. 2008) to assist in 
estimation of DLT rate at recommended dose level.  
A model-based method that incorporates prior expectations about the dose-toxicity curve and 
controls for over-dosing probability will be applied to the data at the end of each cohort, which 
will provide quantitative guidance to the investigators and Lilly CRP to help determine the next 
dose level.  Prior expectations about the dose-toxicity curve will be based on observed DLT rates 
in Study JJCA.  After incorporation of observed DLT rates in this study, the posterior probability 
of a DLT at each dose level will be categorized to 4 bands:  

under-dosing:  the probability of a DLT at a given dose level in (0, 0.20)

targeted toxicity:  the probability of a DLT at a given dose level in (0.20, 0.35)

excessive toxicity:  the probability of a DLT at a given dose level in (0.35, 0.60)

unacceptable toxicity:  the probability of a DLT at a given dose level in (0.60, 1.00)
The model aims to recommend a dose which maximizes the probability of targeted toxicity, 
while controlling the probability of excessive or unacceptable toxicity to less than 25%.  The 
maximum increment of escalation will be no more than 100%.  The exact increment will be 
determined by the investigators and Lilly CRP and may be less than the model prediction or 
<100%.  
Further details on the derivation of a prior for DLT rate and simulations on the dose escalation 
model are provided in a separate simulation plan document. 
6.14.3. Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events
All deaths in this study, including the reasons for death, will be listed by treatment. The reasons 
for death will be also summarized separately for on-therapy, within 30 days of last dose of study 
drug and during the long term follow-up periods. 


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6.14.4. Clinical Laboratory Evaluation
Listings of all laboratory results will be provided (using SI units [International System of Units], 
when available) by treatment, for hematology, chemistry, urinalysis, ECG chemistry, immune 
phenotype, coagulation, CSF and bone marrow. Normal reference ranges, percent of the result 
outside of range (result divided by lower limit if result is less than lower limit; result divided by 
higher limit if result is greater than higher limit) and percent change from baseline will also be 
included. Seected laboratory parameters may be plotted by time. 
Laboratory analytes below/above quantifiable levels (data in the database recorded as “<x” and 
“>x) will be reported as such in listings, and imputed to the lower or upper limit of quantification 
in any summarise or analyses. 
Neutrophils, platelets, lympthocytes, monocytes, eosinophils, basophils, RBC, WBC, Nucleated 
RBCs (NRBC)/100 WBC blasts and other laboratory parameters of interest to disease status will 
be plotted by time. Data will be log transformed and the logged ratio to baseline analysed by 
mixed effect model repeated measures with treatment, cycle, and the interaction of treatment and 
cycle as fixed effects, with baseline and the interaction of baseline and cycle as a covariate. An 
unstructured variance covariance matrix will be used, data permitting. Otherwise, the following 
variance covariance structures will be tested and that with the best fit according to AIC selected: 
compound symmetry, heterogeneous Toeplitz, first-order autoregressive combined with random 
patient effect, heterogeneous autoregressive, or heterogeneous compound symmetry.  The 
Kenward-Roger method will be used to estimate denominator degrees of freedom.  Geometric
means and treatment comparisons with corresponding 95% confidence intervals (CIs) for each 
cycle will be presented in tabular and graphical displays. 
A waterfall plot will be provided for minimum percentage bone marrow blasts by treatment arm, 
coloured by gene mutation status.
A calculated CTCAE grade using CTCAE v4.0 (or higher) will be provided for all laboratory 
results which can be used independently of clinical judgment to determine a CTCAE severity 
grade. 
6.14.5. Vital Signs and Other Physical Findings
Vital signs measurements including height, weight, temperature, blood pressure and post-
baseline ECOG or Lanksy performance status will be listed by treatment arm.
6.14.6. Electrocardiograms
Electrocardiogram (ECG) assessment of normality and clinical significance will be listed by 
treatment group.  Myocardial information and quantitative results including PR, QRS, QTcB 
(Bazett’s correction), QTcF (Fridericia’s correction) and RR intervals will provided in patient 
listings for absolute and change from baseline. In addition, summaries of outlying corrected QT 
intervals (QTc, QTcB and QTcF) will be provided by treatment. Outlying intervals include 
absolute values > 450, >480 and >500 msec and change from baseline >30 and >60 msec.


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Further exploratory analyses may be conducted as warranted.
6.15. Subgroup Analyses
Exploratory subgroup analyses of efficacy endpoints will be performed for stratification or 
potential prognostic variables as listed in Section 6.8. Other subgroup analyses may be 
performed as deemed appropriate.
6.16. Protocol Violations
Protocol violations will be identified based on information recorded on the investigator log and 
through statistical programming of the data. A list of data dependent protocol violations in 
general and specific to this study is as follows: 
General:

Inclusion/Exclusion criteria not met which may impact efficacy conclusions: Protocol 
inclusion criteria [1], [2], [3], [4], [5] and protocol exclusion criteria [13], [19], [20], [21].

Study drug non-compliance as defined in Section 6.10.

Received incorrect treatment that affects efficacy analysis

Received prohibited medications whilst on study treatment, including other chemotherapy, 
other anticancer therapy, immunotherapy, hormonal cancer therapy (except therapy of 
hormone-sensitive prostate cancer patients who are stable on GnRH agonist therapy and 
breast cancer patients who are stable on antiestrogen therapy (eg, an aromatase inhibitor), 
radiation, surgery for cancer, or experimental medications.  

Informed consent violations

If patient with “entry criteria not met” is marked at screening but patient moves on to cycle 1
Study specific:

For Cycle 2 and beyond, a delay of >7 days in the start of a cycle (Dose 1) for any reason 
other than recovery from toxicity, or a delay of >21 days in the start of a cycle (Dose 1) for 
any reason. 

Failure to obtain bone marrow biopsy and/or aspirate samples, or tumor biopsy (T-LBL 
patients) (at screening only)

Crossover to LY3039478 plus dexamethosone without documented treatment failure on 
placebo plus dexamethasone.

Failure to perform safety procedures or missing safety measurements per requirements in 
Study Schedule (Attachment 1 in Protocol)

Hematology/chemistry

ECG
Note: only collections “not done” are considered significant protocol violations.


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This list of these protocol violations may be included in a patient listing, and patients with 
missing safety assessments will identified from a tabular display of individual patient assessment 
according to study schedule.  These data dependent protocol violations, together with the data 
from the investigator log will be summarized to include only important protocol violations for 
the final study report. 
6.17. Interim Analyses and Data Monitoring 
Phase 1: The Phase 1 portion is a nonrandomized, open-label study, and no interim analyses are 
planned until the end of Phase 1.  Patient safety will be assessed prior to each dose escalation to 
ensure nothing precludes administration of larger doses to future study patients.  In addition to 
reviewing AEs and laboratory measurements, PK and PD profiles (if available) of LY3039478 
will be reviewed per cohort.  Based on these interim results, modifications (for example, 
reductions in dose increment) to the dose-escalation strategy or other design elements may be 
made to ensure patient safety.  The study investigators and the Lilly CRP will make the 
determination regarding dose escalation based on their review of the safety/tolerability data and 
the PK/PD data from the previous cohorts.  An interim analysis including safety, PK, and PD 
data will be conducted prior to proceeding to the Phase 2 portion of the study.  All relevant data 
will be reviewed to confirm the estimation of the MTD.  The decision to proceed to Phase 2 will 
be made following discussions between the investigators and Lilly clinical research personnel 
and documented in writing.
Phase 2: An Assessment Committee will be established prior to the inclusion of the first patient 
in the phase 2 portion of the trial. The AC will review unblinded interim analyses of safety and 
efficacy data. Information that may unblind the study during the analyses will not be reported to 
study sites or blinded study team until the study has been unblinded.
In the Phase 2 portion, safety interim analyses are planned every 12 months, and at the planned 
futility interim analysis, when response data from 30 randomized patients have been obtained.  
There are no prespecified rules for stopping the trial due to safety concerns.  The assessment 
committee members will review unblinded safety data at each interim analysis to determine 
whether there are sufficient safety concerns to justify the termination of study treatment and/or 
enrollment.
One futility interim analysis is planned in Phase 2 once 30 patients are randomized and have 
completed the CR status determination. PK and/or PD data, if available, will also be reviewed at 
this interim analysis. Given the small sample size per treatment arm at the interim analysis: n=10 
for the placebo plus dexamethasone (control) arm, and n=20 for the LY3039478 plus 
dexamethasone (test) arm, and the low anticipated ORR for the control arm (<=5%) in this study, 
no formal inferential analysis is planned at the interim analysis. The AC may recommend to stop 
the study for futility if the observed improvement in response rates is less than 5%. For example, 
if the control arm has 1 response in 10 patients (10%), the test arm would need to observe at least 
3 responses in 20 patients (15%) to warrant continuing the study. This decision criterion is 


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provided to the AC for guidance only. Any recommendation to stop for futility will be based on 
AC review of all available safety and efficacy data in addition to ORR rate.   
Simulations have been conducted in order to understand the operating characteristics of the 
futility rule and the impact on statistical power is considered minimal.  It is not planned to stop 
the trial early for efficacy, thus there are no adjustments for multiplicity.  
Only the assessment committee is authorized to evaluate unblinded interim efficacy and safety 
analyses.  Study sites will receive information about interim results ONLY if they need to know 
for the safety of their patients.
6.18. Annual Report Analyses
The following reports are needed for the DSUR: 
1. Estimated cumulative subject exposure
2. Cumulative exposure to investigational drug, by demographic characteristics for ongoing 
unblinded clinical trials and completed clinical trials
3. Exposure information for ongoing clinical trials and clinical trials that completed during 
the reporting period
4. Listing of subjects who died during the DSUR period
5. Discontinuations due to adverse event during the DSUR Period. 
For guidance on creation of these reports, see the DSUR collaboration site 
(http://lillynetcollaboration.global.lilly.com/sites/GMRS_GPS/Surv/dsur/default.aspx?PageView
=Shared)
6.19. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) and EudraCT requirements.  
Analyses provided for the CTR requirements include the following:
Summary of adverse events, provided as a dataset which will be converted to an XML file.   
Both Serious Adverse Events and ‘Other’ Adverse Events are summarized: by treatment 
group, by MedDRA preferred term.

An adverse event is considered ‘Serious’ whether or not it is a treatment emergent 
adverse event (TEAE).

An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment group, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.


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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).

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 
Analyses provided for the EudraCT requirements include the following:

Summary of adverse events, provided as a dataset which will be converted to an XML 
file, in accordance with EudraCT requirements.

Categorical breakdown of age across the entire study, represented planned and actual 
number of patients for the following age groups: infants and toddlers (28 days-23 
months), children (2-11 years), adolescents (12-17 years), adults (18-64 years, 65-84 
years and 85 years and over).   
For the purpose of CTR/ EudraCT reporting, patients who have died, or are still in the study 
but off treatment, at primary DBL will be considered a completer. Those that withdrew 
consent for all procedures, including follow-up, or were lost to follow up, will be considered 
as early discontinuers. Patients who remain on treatment will be counted as continuing 
treatment.


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7.
References 
Gooley TA, Leisenring W, Crowley J, Storer BE. Why Kaplan-Meier fails and cumulative index 
succeeds when estimating failure probabilities in the presence of competing risks. In: Crowley 
J, Hoering A, Ankerst D, editors. Handbook of Statistics in Clinical Oncology. New York: 
Marcel Dekker; 2001:p 513-524.
Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Amer Stat Assoc. 
1958;53(282):457-481.
Trinquand A et al. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk 
classification or adult t-cell acute lymphoblastic leukemia: A group for research in adult acute 
lymphoblastic leukemia study. Journal of Clinical Oncology. 2013; 31:4333-4342.


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8.
Appendices 


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Appendix 1.
FACT-Leukemia Scoring Guidelines
The following information has been downloaded from http://www.facit.org/FACITOrg/Questionnaires
FACIT Administration and Scoring Guidelines
Scoring the FACT-G:
The FACT-G scoring guide identifies those items that must be reversed before being added to obtain 
subscale totals.  Negatively stated items are reversed by subtracting the response from “4”.  After 
reversing proper items, all subscale items are summed to a total, which is the subscale score.  For all 
FACIT scales and symptom indices, the higher the score the better the QOL.
Handling missing items.  If there are missing items, subscale scores can be prorated.  This is done by 
multiplying the sum of the subscale by the number of items in the subscale, then dividing by the number 
of items actually answered.  This can be done on the scoring guide or by using the formula below:
Prorated subscale score = [Sum of item scores] x [N of items in subscale][N of items answered]
When there are missing data, prorating by subscale in this way is acceptable as long as more than 50% of 
the items were answered (e.g., a minimum of 4 of 7 items, 4 of 6 items, etc).  The total score is then 
calculated as the sum of the un-weighted subscale scores.  The FACT scale is considered to be an 
acceptable indicator of patient quality of life as long as overall item response rate is greater than 80% 
(e.g., at least 22 of 27 FACT-G items completed).  This is not to be confused with individual subscale 
item response rate, which allows a subscale score to be prorated for missing items if greater than 50% of 
items are answered. In addition, a total score should only be calculated if ALL of the component 
subscales have valid scores.  
Scoring the Specific Scales & Symptom Indices:
For the "Additional Concerns" subscale (e.g., cancer-specific questions) and the symptom indices, the 
procedure for scoring is the same as described above for the FACT-G. Again, over 50% of the items (e.g., 
5 of 9 items, 7 of 12 items) must be completed in order to consider each subscale score valid.  
Deriving a Total Score: 
The total score for the specific FACIT scales is the sum of the FACT-G (the first 4 subscales common to 
almost all scales) plus the "Additional Concerns" subscale. The symptom indices do not include the 
FACT-G in the total score. By following this scoring guide and transcribing the FACT-G score, the two 
totals can be summed to derive the TOTAL FACT/FACIT SCORE. 


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FACT-Leukemia Scoring Guidelines (Version 4) 
Instructions:*
1. Record answers in "item response" column. If missing, mark with an X
   
2. Perform reversals as indicated, and sum individual items to obtain a score.
3. Multiply the sum of the item scores by the number of items in the subscale, then divide by the  
    number of items answered.  This produces the subscale score.
4. Add subscale scores to derive total scores (TOI, FACT-G & FACT-Leukemia). 
5. The higher the score, the better the QOL.
Subscale
  Item Code    Reverse item?       Item response        
Item Score
PHYSICAL
GP1
4
-
________
=________
WELL-BEING
GP2
4
-
________
=________
   (PWB)
GP3
4
-
________
=________
      
GP4
4
-
________
=________
      
GP5
4
-
________
=________
      
GP6
4
-
________
=________
      
GP7
4
-
________
=________
              Sum individual item scores: ________  
                      Multiply by 7: ________
             Divide by number of items answered: ________=PWB subscale 
SOCIAL/FAMILY
GS1
0
+
________
=________
WELL-BEING
GS2
0
+
________
=________
    (SWB)
GS3
0
+
________
=________
      
GS4
0
+
________
=________
      
GS5
0
+
________
=________
   
GS6
0
+
________
=________
      
GS7
0
+
________
=________
Score range: 0-28
Score range: 0-28


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             Sum individual item scores: ________  
                     Multiply by 7: ________
            Divide by number of items answered: ________=SWB subscale 
EMOTIONAL
GE1
4
-
________
=________
WELL-BEING
GE2
0
+
________
=________
    (EWB)
GE3
4
-
________
=________
      
GE4
4
-
________
=________
     
GE5
4
-
________
=________
GE6
4
-
________
=________
             Sum individual item scores: ________  
                     Multiply by 6: ________
            Divide by number of items answered: ________=EWB subscale 
FUNCTIONAL  
GF1
0
+
________
=________
WELL-BEING 
GF2
0
+
________
=________
     (FWB)
GF3
0
+
________
=________
      
GF4
0
+
________
=________
      
GF5
0
+
________
=________
      
GF6
0
+
________
=________
      
GF7
0
+
________
=________
             Sum individual item scores: ________  
                     Multiply by 7: ________
            Divide by number of items answered: ________=FWB subscale 
Score range: 0-24
Score range: 0-28


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Subscale
         Item Code       Reverse item?            Item response        
Item Score
LEUKEMIA
BRM3
4
-
________
=________
SUBSCALE
P2
4
-
________
=________
   (LEUS)
BRM2
4
-
________
=________
        
ES3
4
-
________
=________
        
LEU1
4
-
________
=________
        
TH1
4
-
________
=________
        
TH2
4
-
________
=________
        
HI12
4
-
________
=________
        
BMT6
4
-
________
=________
        
C2
4
-
________
=________
        
C6
0
+
________
=________
        
An7
0
+
________
=________
        
N3
4
-
________
=________
        
LEU5
4
-
________
=________
        
LEU6
4
-
________
=________
        
BRM9
4
-
________
=________
LEU7
4
-
________
=________
              Sum individual item scores:________  
                   Multiply by 17: ________
            Divide by number of items answered: ________=LEU Subscale 
To derive a FACT-Leukemia Trial Outcome Index (TOI):
  __________ + __________ + __________ =________=FACT-Leukemia 
TOI
  (PWB score)   (FWB score)   (LeuS score)  
Score range: 0-68
Score range: 0-124


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To Derive a FACT-G total score:
        __________ + __________ + __________ + __________=________=FACT-G Total 
score
        (PWB score)    (SWB score)   (EWB score)  (FWB score)
To Derive a FACT-Leukemia total score:
              _________ + __________ + __________ + __________ + __________ =________=FACT-Leukemia 
Total 
             (PWB score)  (SWB score)   (EWB score)   (FWB score)    (LeuS score)                    score
Score range: 0-108
Score range: 0-176