Clinical trial NCT02450539
Conditions: Non-Small Cell Lung Cancer Stage IV
Keywords: patient reported outcomes (PRO) patient focused outcomes (PFO) biomarkers CDK 4 and 6
Sponsor: Eli Lilly and Company
Start date: 2015-08-06; Completion date: 2020-07-29
Enrollment: 159 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the effectiveness of the study drug known as abemaciclib versus docetaxel in participants with stage IV squamous non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.

Detailed description:

Arms: arm 1: 200 milligram (mg) abemaciclib given orally every 12 hours (Q12H) on days 1 to 21 of each 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. arm 2: 75 milligram per meter squared (mg/m²) docetaxel given intravenously (IV) on day 1 of each 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
Interventions: intervention 1: Abemaciclib intervention 2: Docetaxel
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered IV

Protocol documents:
Prot_002.pdf: 
Protocol I3Y-MC-JPBX (b) 
 
A Randomized Phase 2 Study of Abemaciclib (LY2835219) versus Docetaxel in Patients with 
Stage IV Squamous Non-Small Cell Lung Cancer Previously Treated with Platinum-Based 
Chemotherapy 
 
NCT02450539 
 
Approval Date: 12-Feb-2020 


I 3 Y-M C -J P B X ( b) Cli ni c al Pr ot o c ol
P a g e 1
L Y 2 8 3 5 2 1 9
1. Pr ot o c ol I 3 Y-M C -J P B X ( b)
A R a n d o mi z e d P h a s e 2 St u d y  of Ab e m a ci cli b ( L Y 2 8 3 5 2 1 9) 
v er s u s D o c et a x el i n P ati e nt s wit h St a g e I V S q u a m o u s 
N o n -S m all C ell L u n g C a n c er Pr e vi o u sl y  Tr e at e d wit h 
Pl ati n u m - Ba s e d C h e m ot h er a p y
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s pr ot o c ol i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
a b e m a ci cli b ( L Y2 8 3 5 2 1 9 ), u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt 
wit h Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.  T hi s d o c u m e nt a n d it s a s s o ci at e d 
att a c h m e nt s ar e s u bj e ct t o U nit e d St at e s Fr e e d o m of I nf or m ati o n A ct E x e m pti o n 4.
A b e m a ci cli b ( L Y2 8 3 5 2 1 9 )
St u d y J P B X i s a m ulti c e nt er, r a n d o mi z e d, o p e n -l a b el, p ar all el, c o m p ar at or-c o ntr oll e d, 
P h a s e 2 tri al i n St a g e I V s q u a m o u s n o n -s m all c ell l u n g c a n c er p ati e nt s w h o h a v e 
pr o gr e s s e d aft er pl ati n u m -b a s e d c h e m ot h er a p y, e v al u ati n g s e c o n d -li n e tr e at m e nt wit h 
a b e m a ci cli b v er s u s d o c et a x el.
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol A p pr o v e d b y Lill y : 2 7 M ar c h 2 0 1 5
A m e n d m e nt ( a) A p pr o v e d b y Lill y: 0 8 F e br u ar y 2 0 1 9
A m e n d m e nt ( b) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n d at e pr o vi d e d b el o w.
A p pr o v al D at e: 1 2- F e b- 2 0 2 0 G M T


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2. Synopsis
Study Rationale
Patients with metastatic non-small cell lung cancer (NSCLC) with squamous histology have a 
poor overall survival compared to NSCLC patients with adenocarcinoma histology.  Squamous 
cancer cells are correlated with a loss of p16INK4a methylation and an absence of Kirsten rat 
sarcoma (KRAS) mutations.  The p16INK4A-cyclin D-cyclin-dependent kinases 4 and 6 (CDK 4 
and 6) - retinoblastoma pathway is frequently dysregulated in NSCLC, including squamous 
histology, and therefore represents an attractive therapeutic target (Zhou et al. 2001).  
Abemaciclib is a potent and selective small molecule inhibitor of CDK4 and 6 that has shown 
acceptable safety/tolerability as well as evidence of clinical activity in multiple tumor types.
The Phase 2 Study I3Y-MC-JPBX (JPBX) will evaluate the clinical activity of abemaciclib 
versus docetaxel therapy with respect to investigator-assessed progression-free survival (PFS) in 
patients with Stage IV squamous cell carcinoma NSCLC who have relapsed after prior 
platinum-based therapy for advanced disease.
Clinical Protocol Synopsis:  Study I3Y-MC-JPBX
Name of Investigational Product:  Abemaciclib (LY2835219)
Title of Study:  A Randomized Phase 2 Study of Abemaciclib (LY2835219) versus Docetaxel in Patients with 
Stage IV Squamous Non-Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy
Number of Planned Patients: 150
Entered:  195
Enrolled/Randomized:  150
Completed:  150
Phase of Development: 2
Length of Study:  Approximately 21 months
Planned first patient visit:  June 2015
Planned last patient visit:  February 2017
Objectives:  The primary objective of this study is to compare  treatment with abemaciclib versus docetaxel 
therapy with respect to investigator-assessed progression-free survival (PFS) in patients with Stage IV squamous 
cell carcinoma NSCLC who have relapsed after prior platinum-based therapy for advanced disease.
The secondary objectives of the study are:

To evaluate the pharmacokinetic (PK) parameters including abemaciclib and its active metabolites

To compare treatment of abemaciclib versus docetaxel with respect to the following:
  •  Overall survival (OS)
  •  Overall response rate (ORR) [complete response (CR) + partial response (PR)]
  •  Disease control rate (DCR) [CR + PR + stable disease]
  •  Time to worsening of Performance Status (PS)
  •  The safety and tolerability using the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0
  •  Change from baseline in patient-reported outcomes including:  1) the MD Anderson Symptom Inventory 
Lung Cancer (MDASI-LC) questionnaire pain and disease-related symptoms scores; and 2) the EuroQol 
Group’s EQ-5D-5L questionnaire index score, derived from the 5-item descriptive system, and visual 
analog scale (VAS) self-rated health score.


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The exploratory objectives are:

To explore potential biomarkers related to the cell cycle pathway components, abemaciclib, and/or the 
pathogenesis of lung cancer, and their associations with clinical outcomes

To explore the relationship between abemaciclib exposure and response

To explore if change in tumor size is associated with PFS and OS
Study Design:  Study I3Y-MC-JPBX is a multicenter, randomized, open-label, parallel, comparator-controlled, 
Phase 2 trial in Stage IV squamous NSCLC patients who have progressed after platinum-based chemotherapy,
evaluating treatment with abemaciclib versus docetaxel. The study will enroll approximately 150 patients in 
2:1 randomization (100 patients in abemaciclib and 50 patients in docetaxel).  Patients will be stratified at 
randomization according to the following: Eastern Cooperative Oncology Group (ECOG) PS (0 vs. 1); number 
of prior therapies (received only platinum-based therapy vs. platinum-based therapy plus immune checkpoint 
inhibitor); and time since the initiation of first-line therapy (≤9 vs. >9 months).
Diagnosis and Main Criteria for Inclusion and Exclusions: Patients are eligible to be included in the study if 
they meet following criteria: [1] have confirmed diagnosis of Stage IV NSCLC disease of predominantly 
squamous histology; [2] availability of adequate formalin-fixed paraffin-embedded tumor-derived material 
(tumor blocks or slides); [3] have progressed during or after one and only one prior first-line platinum-based 
chemotherapy regimen with or without maintenance therapy for advanced/metastatic disease; [4] have a PS of 0 
to 1 on the ECOG scale; [5] have the presence of measurable disease as defined by Response Evaluation Criteria 
In Solid Tumors (RECIST) Version 1.1; [6] have discontinued all previous treatments for cancer (including 
chemotherapy, radiotherapy, immunotherapy, and endocrine therapy) prior to receiving study drug, and 
recovered from the acute effects of therapy; [7] have adequate organ function; [8] are ≥18 years of age; [9] have 
agreed contraception methods; [10] have an estimated life expectancy of at least 12 weeks and in the judgment of 
the investigator will be able to complete at least 2 cycles of treatment; [11] have given written informed consent 
prior to any study-specific procedures; [12] are reliable and willing to make themselves available for the duration 
of the study and are willing to follow study procedures; and [13] are able to swallow capsules or tablets.
Patients will be excluded from the study if they meet any of the following criteria: [14] are currently receiving an 
investigational drug in a clinical trial or participating in any other type of medical research judged not to be 
scientifically or medically compatible with this study; [15] have known or suspected allergy to docetaxel or any 
of its components; [16] have received treatment with a drug that has not received regulatory approval for any 
indication; [17] have received prior treatment with any CDK 4 and 6 inhibitor; [18] have had major surgery 
(excluding biopsy) < 28 days of the initial dose of study drug and/or have not recovered from the acute effects of 
the surgery; [19] have a personal history of any of the following conditions: syncope of either unexplained or 
cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest; [20] have 
serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in 
this study; [21] have a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the 
cervix), unless in complete remission with no therapy; [22] have the presence of unstable central nervous system 
metastasis; [23] have active bacterial, fungal, and/or known viral infection; or [24] are female, pregnant and 
lactating women; unwilling to use medically effective birth control method.
Test Product, Dosage, and Mode of Administration:  Abemaciclib 200 mg orally every 12 hours on Days 1 to 
21 of a 21-day cycle
Reference Therapy, Dose, and Mode of Administration:  Docetaxel 75 mg/m2 intravenous infusion on Day 1 
of a 21-day cycle
Planned Duration of Treatment:
Treatment period: until disease progression or unacceptable toxicity occurs (or both)
Short-term follow-up (postdiscontinuation):  30 days
Long-term follow-up (postdiscontinuation):  until death


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Criteria for Evaluation:
Efficacy:

Efficacy assessments include imaging studies/tumor assessments, according to RECIST v. 1.1, 
performed every 6 weeks, and survival.

PFS

OS

Overall Response Rate

DCR

Time to worsening ECOG PS
Safety:

Safety will be evaluated based on recorded adverse events (AEs), physical examinations, vital sign 
measurements, and clinical laboratory assessments.  Adverse events and clinical lab values will be 
coded using NCI CTCAE Version 4.0.
Health Outcomes:

Health outcomes will be assessed using standardized instruments, MDASI-LC and EQ-5D-5L.  
Investigators will report resource utilization such as concomitant medications, transfusions, radiation 
therapy, surgery, and treatment-related hospitalization days.
Pharmacokinetics:

The plasma concentrations of abemaciclib and its metabolites LSN2839567 and LSN3106726 will be 
measured for patients receiving abemaciclib.  Covariate effects (such as age, weight, sex, and plasma 
protein levels) on the PK parameters of abemaciclib in plasma will also be investigated.
Biomarkers:

Whole blood, plasma, and tissue samples will be tested for biomarkers relevant to the cell cycle 
pathway, abemaciclib, docetaxel, and/or the pathogenesis of lung cancer and to correlate these markers 
to clinical outcomes.


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Statistical Methods:
Statistical:  This study will enroll approximately 150 patients in 2:1 randomization (100 patients in abemaciclib 
and 50 patients in docetaxel).  The primary PFS analysis will be performed after 120 PFS events are observed. 
Historical information will be incorporated into the control arm during the primary analysis by using a Bayesian 
approach. Assuming a hazard ratio (HR) of 0.64, with 150 patients and the proposed Bayesian design, power of 
90.5% was estimated by simulation. Under a frequentist design, this sample size yields roughly 75% power with 
1-sided type I error of 0.05. If the true median PFS for the docetaxel arm is 3 months, the HR of 0.64 amounts to 
an approximately 1.7-month improvement in median PFS for the abemaciclib arm under an additional 
assumption of exponential survival distribution.
Efficacy: Efficacy analyses will be based on the intention-to-treat (ITT) analysis set.  This population is defined 
as all patients randomized to study treatment.  The primary method of analysis for comparing PFS between the 
treatment arms will use a Bayesian exponential-likelihood model with a hierarchical random-effects distribution 
on treatment effects.  In addition to the primary analysis of PFS, the following analysis will be conducted based 
on observed PFS data: 1) A stratified log-rank test (stratified using the same factors as the randomization 
scheme) will be used to compare the PFS distribution between treatment groups. 2) The Kaplan-Meier method  
will be used to estimate the PFS curve for each treatment group. 3) The Cox proportional hazard model will be 
used to estimate treatment HR and corresponding 95% confidence interval.
Safety:  All safety summaries and analyses will be based upon the Safety Population as defined as all enrolled 
patients receiving at least 1 dose of any study drug. Overall exposure to study drug, the numbers of patients 
completing each cycle, and the dose intensity will be summarized using descriptive statistics. An overall 
summary of AEs will be provided for AEs deemed by the investigator to be possibly related to study drug, and 
repeated for events regardless of study drug causality.  Incidence rates of these events will be compared between 
treatment arms using Chi-square test.
Health Outcomes:  The MDASI-LC will be summarized for each assessment period.  EQ-5D 5L responses for 
each item will be summarized by frequency and corresponding percentages.  Descriptive statistics for the index 
and VAS will be calculated.
Pharmacokinetics:  Mean population PK parameters for abemaciclib in plasma (clearance, exposure, volume of 
distribution, and half-lives) and inter-individual PK variability will be computed using nonlinear mixed effect 
modeling (NONMEM).
Pharmacodynamics: Pharmacodynamic (PD) data (such as neutrophil, lymphocytes, or platelets counts in blood, 
etc.) collected in this study may be analyzed by means of NONMEM and connected to the population PK model 
in a PK/PD model.
Biomarkers:  Correlative analyses will be performed to investigate the associations between biomarkers and 
clinical outcomes.


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3. Table of Contents
A Randomized Phase 2 Study of Abemaciclib (LY2835219) 
versus Docetaxel in Patients with Stage IV Squamous 
Non-Small Cell Lung Cancer Previously Treated with 
Platinum-Based Chemotherapy
Section
Page
1.
Protocol I3Y-MC-JPBX(b)  A Randomized Phase 2 Study of 
Abemaciclib (LY2835219) versus Docetaxel in Patients with Stage 
IV Squamous Non-Small Cell Lung Cancer Previously Treated with 
Platinum-Based Chemotherapy ...........................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................6
4.
Abbreviations and Definitions...........................................................................................13
5.
Introduction ......................................................................................................................19
5.1.
Lung Cancer.................................................................................................................19
5.1.1.
Second-Line Treatment Options...........................................................................19
5.1.2.
Squamous NSCLC ...............................................................................................21
5.2.
Study Rationale............................................................................................................21
5.3.
Rationale for Amendment (a).......................................................................................22
5.4.
Rationale for Amendment (b).......................................................................................23
6.
Objectives.........................................................................................................................24
6.1.
Primary Objective ........................................................................................................24
6.2.
Secondary Objectives...................................................................................................24
6.3.
Exploratory Objectives.................................................................................................24
7.
Study Population...............................................................................................................25
7.1.
Inclusion Criteria..........................................................................................................25
7.2.
Exclusion Criteria ........................................................................................................27
7.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................28
7.3.
Discontinuation............................................................................................................29
7.3.1.
Discontinuation of Inadvertently Enrolled Patients...............................................29
7.3.2.
Discontinuation of Study Drug.............................................................................29
7.3.3.
Discontinuation from the Study............................................................................30
7.3.4.
Discontinuation of Study Sites .............................................................................30
7.3.5.
Discontinuation of the Study................................................................................30
8.
Investigational Plan...........................................................................................................31
8.1.
Summary of Study Design............................................................................................31


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8.2.
Study Design................................................................................................................31
8.2.1.
Study Completion and End of Trial......................................................................32
8.2.2.
Continued Access Period......................................................................................33
8.3.
Discussion of Design and Control ................................................................................34
9.
Treatment..........................................................................................................................35
9.1.
Treatments Administered .............................................................................................35
9.1.1.
Docetaxel.............................................................................................................36
9.2.
Materials and Supplies .................................................................................................36
9.3.
Method of Assignment to Treatment ............................................................................36
9.4.
Selection and Timing of Doses.....................................................................................36
9.4.1.
Dose Rationale for Abemaciclib from Study JPBA ..............................................37
9.4.2.
Special Treatment Considerations ........................................................................38
9.4.2.1.
Dose Adjustments and Delays ........................................................................38
9.4.2.1.1.
Abemaciclib Dose Adjustments ................................................................40
9.4.2.1.2.
Abemaciclib Dose Delays and Omission...................................................40
9.4.2.1.2.1.
Hematologic Toxicity..........................................................................40
9.4.2.1.2.2.
Nonhematologic Toxicity....................................................................41
9.4.2.1.2.3.
Diarrhea..............................................................................................42
9.4.2.1.2.4.
Hepatic Toxicity .................................................................................42
9.4.2.1.2.5.
Interstitial Lung Disease/Pneumonitis .................................................42
9.4.2.1.3.
Docetaxel..................................................................................................42
9.4.2.1.3.1.
Docetaxel Hypersensitivity Reactions .................................................43
9.4.2.1.3.2.
Docetaxel Hematologic Toxicity.........................................................44
9.4.2.1.3.3.
Docetaxel Fluid Retention...................................................................44
9.4.2.1.3.4.
Docetaxel Cutaneous Reaction............................................................44
9.5.
Blinding .......................................................................................................................44
9.6.
Concomitant Therapy...................................................................................................44
9.6.1.
Premedication Prior to Infusion of Docetaxel.......................................................45
9.6.2.
Supportive Care ...................................................................................................45
9.6.2.1.
Palliative Radiotherapy...................................................................................46
9.6.2.2.
Supportive Management for Diarrhea .............................................................46
9.6.2.3.
Granulocyte-Colony Stimulating Factors........................................................46
9.6.2.4.
Therapy for Febrile Neutropenia.....................................................................46
9.6.2.5.
Bisphosphonates and RANK-L Targeted Agents ............................................46
9.6.2.6.
Other Study Conditions: Surgery (or Equally Considered 
Procedure) During Study Treatment Phase......................................................47
9.6.2.7.
Antiemetic Agents..........................................................................................47
9.6.2.8.
Analgesic Agents............................................................................................47


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9.6.2.9.
Appetite Stimulants ........................................................................................47
9.7.
Treatment Compliance .................................................................................................47
9.8.
Patient Diaries..............................................................................................................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.
Efficacy Assessments at Baseline and during Study 
Treatment.............................................................................................................49
10.1.2.
Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up ............................................................................49
10.1.3.
Primary Efficacy Measure....................................................................................50
10.1.4.
Secondary Efficacy Measures...............................................................................50
10.1.5.
Exploratory Efficacy Measures ............................................................................51
10.2. Health Outcome/Quality of Life Measures ...................................................................51
10.2.1.
Patient-Reported Outcomes..................................................................................51
10.2.1.1.
MDASI-LC ....................................................................................................52
10.2.2.
Resource Utilization.............................................................................................53
10.3. Safety Evaluations........................................................................................................53
10.3.1.
Adverse Events ....................................................................................................54
10.3.1.1.
Serious Adverse Events ..................................................................................56
10.3.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................57
10.3.2.
Other Safety Measures .........................................................................................57
10.3.2.1.
Electrocardiograms.........................................................................................57
10.3.3.
Safety Monitoring ................................................................................................58
10.3.3.1.
Special Hepatic Safety Data Collection...........................................................58
10.3.3.2.
Renal Function ...............................................................................................58
10.3.3.3.
Venous Thromboembolic Events (VTEs)........................................................59
10.3.3.4.
Interstitial Lung Disease/Pneumonitis.............................................................59
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 Biomarkers .......................................................................................60
10.4.2.1.
Archived Tumor Tissue ..................................................................................60
10.4.2.2.
Whole Blood Samples for Pharmacogenetic Evaluations ................................61
10.4.2.3.
Plasma Samples for Exploratory Biomarker Evaluations.................................61
10.4.3.
Samples for Drug Concentration Measurements 
Pharmacokinetics - Abemaciclib Only..................................................................62
10.5. Appropriateness of Measurements................................................................................62


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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
12.2.4.1.
Postdiscontinuation Therapy...........................................................................65
12.2.5.
Treatment Compliance .........................................................................................65
12.2.6.
Primary Outcome and Methodology.....................................................................66
12.2.7.
Analyses of Efficacy ............................................................................................67
12.2.8.
Pharmacokinetic and Pharmacodynamic Analyses ...............................................67
12.2.9.
Biomarker Analysis..............................................................................................68
12.2.10. Health Outcome/Quality of Life Analyses............................................................68
12.2.10.1. MDASI-LC ....................................................................................................68
12.2.10.2. Health State Utility.........................................................................................68
12.2.10.3. Use of Pain Medications.................................................................................69
12.2.11. Safety Analyses....................................................................................................69
12.2.12. Subgroup Analyses ..............................................................................................70
12.2.13. Interim Analyses..................................................................................................70
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.
Investigator Information.......................................................................................72
13.3.2.
Protocol Signatures ..............................................................................................72
13.3.3.
Final Report Signature .........................................................................................72
14.
References ........................................................................................................................73


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List of Tables
Table
Page
Table JPBX.9.1.
Treatment Regimens/Dosing Schedule ...................................................35
Table JPBX.9.2.
Toxicity Dose Adjustments and Delays of Abemaciclib for 
Study JPBX............................................................................................38
Table JPBX.9.3.
Dose Adjustments of Abemaciclib for Study JPBX ................................40
Table JPBX.9.4.
General Dose Delays of Abemaciclib for Study JPBX............................40
Table JPBX.10.1.
Secondary Efficacy Endpoints................................................................50
Table JPBX.10.2.
Adverse Event and Serious Adverse Event Reporting Guidelines ...........54
Table JPBX.12.1.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival.......................................................................66
Table JPBX.12.2.
World Health Organization Pain Scale....................................................69


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List of Figures
Figure
Page
Figure JPBX.8.1.
Illustration of study design......................................................................31
Figure JPBX.8.2.
Study period and continued access diagram. ...........................................33


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List of Attachments
Attachment
Page
Protocol JPBX Study Schedule...............................................................77
Protocol JPBX Clinical Laboratory Tests................................................85
Protocol JPBX Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ...........................................................................................86
Protocol JPBX ECOG Performance Status .............................................87
Protocol JPBX Creatinine Clearance Formula.........................................88
Protocol JPBX Details of Statistical Progression-Free Survival 
Model and Simulation Result..................................................................89
Protocol JPBX RECIST Criteria 1.1 .......................................................92
Protocol JPBX Pharmacokinetic and ECG  Sampling Schedule ..............99
Protocol JPBX Sampling Summary ......................................................100
Protocol JPBX Inducers and Strong Inhibitors of CYP3A.....................101
Protocol JPBX CTCAE 4.03 Definitions for Diarrhea and 
Interstitial Lung Disease .......................................................................102
Protocol JPBX Amendment(b) Summary A Randomized Phase 2 
Study of Abemaciclib (LY2835219) versus Docetaxel in Patients 
with Stage IV Squamous Non-Small Cell Lung Cancer Previously 
Treated with Platinum-Based Chemotherapy ........................................104


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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.
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
assent
Agreement from a child or other individual who is not legally capable of providing 
consent, but who can understand the circumstances and risks involved in participating 
in a study (required by some institutional review boards [IRBs]).
AST
aspartate aminotransferase
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).
BAC
Bayesian Augmented Control
BSC
best supportive care
CDK
p16INK4A-cyclin D-cyclin-dependent kinases
CI
confidence interval
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


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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 
[investigational product[s] or study treatment] who continue to experience clinical 
benefit and no undue risks may continue to receive [investigational product[s] or study 
treatment] until one of the criteria for discontinuation is met. 
CR
complete response
CrCl
creatinine clearance
CRF/eCRF
case report form/electronic case report form
Sometimes referred to as clinical report form:  A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the protocol.
CRP
clinical research physician
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.
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DCR
disease control rate
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
epidermal growth factor receptor
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last patient.


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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.
EQ-5D-5L
EuroQol 5 Dimension 5 Level
ERB
ethical 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.
FFPE
formalin-fixed paraffin-embedded
GCP
good clinical practice
G-CSF
granulocyte-colony stimulating factor
HIV
human immunodeficiency virus
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
ILD
interstitial lung disease
IND
Investigational New Drug application
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


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investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
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.
IUD
intrauterine device
IV
intravenous
IWRS
interactive web-response system
KRAS
Kirsten rat sarcoma
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.
LLT
Lower Level Term
MATE
multidrug and toxin extrusion protein
MDASI-LC
MD Anderson Symptom Inventory – Lung Cancer
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NONMEM
nonlinear mixed effect modeling
NSCLC
non-small cell lung cancer
ORR
overall response rate


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OS
overall survival
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PD
progressive disease
PET
positron emission tomography
PK
pharmacokinetic
PK/PD
Pharmacokinetic/pharmacodynamic
PFS
progression-free survival
PO
orally
PR
partial response
PRO
patient-reported outcome
PS
performance status
PT
Preferred Term
Q12H
every 12 hours
QoL
quality of life
QTc
corrected QT interval
RANK-L
nuclear factor kappa B ligand
randomize
the process of assigning patients to an experimental group on a random basis
Rb
retinoblastoma
RECIST
Response Evaluation Criteria in Solid Tumors
reporting database
A point-in-time copy of the collection database.  The final reporting database is used to 
produce the analyses and output reports for interim or final analyses of data.
re-screen
to screen a patient who was previously declared a screen failure for the same study
SAE
serious adverse event


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SAP
Statistical Analysis Plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  In this study, 
screening involves invasive or diagnostic procedures and/or tests (for example, 
diagnostic psychological tests, x-rays, blood draws).  Informed consent for these 
screening procedures and/or tests shall be obtained.
screen failure
patient who does not meet one or more criteria required for participation in a trial
SD
stable disease
SmPC
Summary of Product Characteristics
SOC
System Organ Class
Study completion
This study will be considered complete after the final analysis of overall survival is 
performed.
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin
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.
TKI
tyrosine kinase inhibitor
ULN
upper limits of normal
US
United States
VAS
visual analog scale
VTE
venous thromboembolic event


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A Randomized Phase 2 Study of Abemaciclib (LY2835219) 
versus Docetaxel in Patients with Stage IV Squamous 
Non-Small Cell Lung Cancer Previously Treated with 
Platinum-Based Chemotherapy
5. Introduction
5.1.
Lung Cancer
Lung cancer is the most common cancer worldwide, with an estimated 1.6 million new cases per 
year, and the leading cause of cancer-related mortality with an estimated 1.4 million 
cancer-related deaths per year (Bray et al. 2012; Bunn 2012). The majority of lung cancer cases 
(approximately 85%) consist of non-small cell lung cancer (NSCLC), with 65% to 75% of cases 
presenting as Stage III or Stage IV (SEER 1975-2006; Ihde 1992; Shepherd et al. 1993; Walling 
1994).  Lung cancer can further be classified into histology subtypes: nonsquamous carcinoma,
which includes adenocarcinoma that accounts for approximately 40% of NSCLCs, large cell 
carcinoma, and other cell types; and squamous (30%) (McKeage et al. 2010; Piperdi et al. 2014). 
Important differences exist between major subtypes of NSCLC that have prognostic and 
predictive value of differential response rate, overall survival (OS), or toxicity profile. Clinical 
studies have demonstrated that patients with squamous histology have poorer outcomes, with a 
1-year survival rate of approximately 14.6% (Simon 2014).
Patients with good performance status (PS) are first generally given platinum-based 
chemotherapy (Bülzebruck et al. 1992), which is associated with longer survival, improved
quality of life (QoL), disease-related symptoms, and PS (Cullen et al. 1988; Socinski et al. 2003; 
Stinchcombe and Socinski 2009).  However, even with treatment, the majority of patients 
relapse, with a median time to progression of 3 to 6 months after initiating chemotherapy 
(Schiller et al. 2002; Sandler et al. 2006; Stinchcombe and Socinski 2009). Recent clinical trials 
suggest that approximately 40% to 50% of patients are eligible for second-line chemotherapy 
(Socinski et al. 2002; Sandler et al. 2006).
Currently approved second-line standard of care treatments for NSCLC consist of monotherapy 
with pemetrexed, erlotinib, or docetaxel (Hanna et al. 2004; Shepherd et al. 2005). Second-line 
treatment outcomes remain poor, with an overall response rate (ORR) of less than 10% and 
median OS of 7 to 9 months (Garon et al. 2014). Ramucirumab was recently approved in the 
United States (US) for treatment of NSCLC in combination with docetaxel in patients that have 
relapsed after initial platinum-based therapy.  Those with squamous histology have challenges 
for treatment options because of the lack of driver mutations associated with response to 
approved agents (Garon et al. 2014).
5.1.1. Second-Line Treatment Options
Pemetrexed: Pemetrexed is indicated as single-agent second-line treatment chemotherapy for 
locally advanced or metastatic nonsquamous NSCLC (Alimta, US package insert, 2013). In an 
open-label randomized Phase 3 study of pemetrexed versus docetaxel in patients that have 


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relapsed after first-line platinum-based therapy, pemetrexed demonstrated similar efficacy to 
docetaxel in respect to median survival (8.3 vs. 7.9 months) and progression-free survival (PFS)
(2.9 vs. 2.9 months) (Hanna et al. 2004).  A retrospective analysis of NSCLC subtypes 
demonstrated that patients with squamous cell histology demonstrated a median OS of 
6.2 months with pemetrexed compared to 7.4 months for docetaxel (Scagliotti et al. 2009).
EGFR TKIs
Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is 
indicated for the treatment of patients with locally advanced or metastatic NSCLC after failure of 
at least 1 prior chemotherapy regimen (Tarceva US package insert, 2010).  In the BR.21 study, a 
double blind, placebo-controlled trial, erlotinib was evaluated in NSCLC patients that had failed 
first-line or second-line chemotherapy treatments. The median PFS was 2.2 months in the 
erlotinib arm compared to 1.8 months in the placebo group (adjusted hazard ratio [HR]; 0.61; 
95% confidence interval [CI]: 0.51, 0.74; p<0.001).  The erlotinib group had a median OS of 
6.7 months compared to 4.7 months for the control group (HR 0.70; 95% CI: 0.58, 0.85; 
p<0.001) (Shepherd et al. 2005).
Geftinib, another first-generation EGFR TKI, has been registered for advanced NSCLC for any 
line in patients with tumors expressing activating EFGR-mutation. In the ISEL trial, geftinib 
failed to show improved survival in chemotherapy-refractory patients compared to placebo; 
however, survival was significantly improved in the subset of Asian origin population (Thatcher
et al. 2005; Carnio et al 2014). In the INTEREST study comparing geftinib to docetaxel, the trial 
met its primary endpoint of non-inferiority for survival with a mean OS of 8.0 month compared 
to 7.9 months in the docetaxel arm (Thatcher et al. 2005; Manegold 2014).
Docetaxel:  Docetaxel is approved for the treatment of patients with locally advanced or 
metastatic NSCLC after failure of prior platinum-based chemotherapy. In the TAX 317 study, 
docetaxel 75 mg/m2 administered every 3 weeks demonstrated significant median survival 
compared to best supportive care (BSC) (7.0 vs. 4.6 months, respectively) (Shepherd et al. 2000). 
Time to progression was noted to be 12.4 weeks in the docetaxel arm compared to 7 weeks in the 
BSC arm (Docetaxel label). In the TAILOR study in EGFR wild-type patients after first-line
platinum doublet, erlotinib had a median OS and PFS of 5.4 and 2.4 months, respectively. 
Docetaxel has a medium OS of 8.2 months and median PFS of 2.9 months (Garassino et al. 
2013).
Ramucirumab:  In the REVEL study, NSCLC patients were randomized to either docetaxel 
plus ramucirumab or docetaxel monotherapy after receiving first-line platinum based therapy. A 
total of 1253 patients were randomized, with 628 assigned to ramucirumab plus docetaxel and 
625 patients assigned to placebo plus docetaxel, with the squamous population being 157 and 
171, respectively. In all subtypes, the median survival was 10.5 months for those receiving 
ramucirumab plus docetaxel compared to 9.1 months in the control group. A subgroup analysis 
of patients with squamous histology showed a longer survival for those receiving ramucirumab 
compared to the control arm (9.5 months vs. 8.2 months). Median PFS was 4.5 months for the 
ramucirumab group compared to 3.0 months for the control group (Garon et al. 2014).


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Immunotherapy
Nivolumab, a fully human IgG4 immune checkpoint inhibitor antibody, was recently approved in 
the US for treatment of patients with advanced (metastatic) squamous NSCLC who have 
progressed after a platinum-based chemotherapy. Nivolumab works by inhibiting the cellular 
pathway known as PD-L1 protein on cells that blocks the body’s immune system from attacking 
cancerous cells. In the CheckMate 017 study, 272 patients received either nivolumab
(135 patients) or docetaxel (137 patients). The interim analysis showed a median OS of 
9.2 months and 6 months (HR 0.59; 95% CI: 0.44, 0.79; p=0.00025) with nivolumab and 
docetaxel, respectively. In a Phase 2, single-arm study (CheckMate 063), 117 patients with 
squamous NSCLC received nivolumab after progressing with a platinum-based therapy and at 
least one additional systemic regimen (Rizvi et al. 2015). The overall median PFS was 
1.9 months (95% CI: 1.8, 3.2) and the median overall survival was 8.2 months (95% CI: 6.1, 
10.9) (Rizvi et al. 2015).
5.1.2. Squamous NSCLC
Squamous histology has a worse OS rate compared to those with adenocarcinoma histology 
(Al-Farsi and Ellis 2014). Additionally, molecular profiles differ between these 2 histology 
types in respect to mutations of EGFR or V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
(KRAS) genes. EGFR mutations, translocations of anaplastic lymphoma kinase (ALK), and 
mutations in KRAS have been reported largely in adenocarcinoma (nonsquamous) histology 
subtype (Simon 2014). Squamous cancer cells rarely have mutations in EGFR or ALK fusions, 
and are correlated with a loss of p16INK4a methylation and an absence of KRAS mutations (Zhou 
et al. 2001).  Alterations in other receptor tyrosine kinases, such as fibroblast growth factor 
receptor 1 (20% squamous NSCLC), discoidin domain receptor (4% squamous NSCLC), and 
TP53 (80% squamous NSCLC), are affected by somatic mutations, and inactivation of CDKN2A 
and RB1 pathways (79%) have been identified (Shtivelman et al. 2014). Additionally, the 
16INK4A-cyclin D-cyclin-dependent kinases 4 and 6 (CDK 4 and 6) - retinoblastoma pathway is 
frequently dysregulated in NSCLC, including squamous histology, and therefore represents an 
attractive therapeutic target (Zhou et al. 2001).
5.2.
Study Rationale
During the cell cycle, the G1 restriction point controls entry into S phase and is essential for 
maintaining control of cell division (Sherr 1996; Ortega et al. 2002).  CDK 4 and 6 participates 
in a complex with D-type cyclins to initiate the transition through the G1 restriction point. 
Cyclin-dependent kinase inhibitors p15INK4b and p16INK4a, the retinoblastoma tumor suppressor 
protein, and cyclin D family members are among the major regulatory genes of the G1/S 
transition.  Overexpression of cyclin D1, abnormal RB1 pathway functioning, and mutated or 
aberrant p16INK4a have been reported in lung cancer (Zhou et al. 2001).
The CDK 4 and 6 - cyclinD complex regulates the G1 restriction point through phosphorylation 
of the retinoblastoma (Rb) tumor suppressor protein.  Alterations in this pathway occur 
frequently in a broad spectrum of human cancers and involve: 1) loss of cyclin-dependent kinase 
inhibitors by mutation or epigenetic silencing, 2) mutation/overexpression of either CDK 4 and 6 


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or cyclin D, or 3) inactivation of Rb.  With the possible exception of those tumors with complete 
inactivation of Rb, which functions downstream of the CDK 4 and 6 - cyclinD complex, all these 
cancers are potentially sensitive to pharmacologic inhibition of CDK 4 and 6.  From a 
therapeutic standpoint, the goal of inhibiting CDK 4 and 6 with a small molecule inhibitor is to 
prevent cell cycle progression through the G1 restriction point, thus arresting tumor growth.
Abemaciclib is a potent and selective small molecule inhibitor of CDK 4 and 6 that has shown 
acceptable safety/tolerability as well as evidence of clinical activity in multiple tumor types. In 
the Phase 1 Study I3Y-MC-JPBA (JPBA), abemaciclib has shown acceptable safety/tolerability, 
as well as evidence of clinical activity in multiple tumor types.  In addition, Study JPBA 
included a NSCLC expansion cohort of 68 patients with any histology subtype that was 
advanced and/or metastatic. Two of the 68 patients (1 nonsquamous KRAS mutant and 1 
squamous) had a partial response (PR). Among the remaining patients, 31 (45.6%) had stable 
disease (SD), 16 (23.5%) had progressive disease (PD), and 19 (27.9%) were not evaluable.
Nine patients were squamous NSCLC.  Within the squamous population, one patient achieved a 
PR. The disease control rate (DCR) [PR+SD] was 55% (5 patients), with 33% (3 patients) 
having a DCR for 24 or more weeks. Clinical activity was noted in both histologies with 
abemaciclib.
Limited treatment options exist for patients with squamous NSCLC compared to those with 
nonsquamous histology, with docetaxel being the standard of care for this patient population in 
the second-line setting. However, docetaxel has modest improvement in PFS (2.9 months) while 
adding significant toxicity in the advanced population. Abemaciclib appears to have single-
agent activity based upon preliminary efficacy data and a safety profile that is manageable and 
amenable to chronic administration.
More information about the known and expected benefits, risks and reasonably anticipated 
adverse events (AEs) of abemaciclib may be found in the Investigator’s Brochure (IB).  
Information on AEs expected to be related to the study drug may be found in Section 7 
(Development Core Safety Information) of the IB.  Information on serious adverse events 
(SAEs) expected in the study population independent of drug exposure and that will be assessed 
by the sponsor in aggregate, periodically during the course of the study, may be found in 
Section 6 (Effects in Humans) of the IB.
More detailed information about the known and expected benefits and risks of docetaxel may be 
found in the following:  Package Insert and Summary of Product Characteristics (SmPC).
5.3.
Rationale for Amendment (a)
Study JPBX protocol was amended to update the dosing guidance for cases of nonhematologic 
toxicity, diarrhea, and ALT increase.  This amendment will harmonize the dosing guidance 
across all clinical trials of abemaciclib in the metastatic setting.  The amendment updated the 
safety language regarding hepatic monitoring, assessment of renal function, and venous 
thromboembolic events (VTEs) for ongoing patients. Minor typographical and formatting edits 
were made throughout the document for clarity and consistency.


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5.4.
Rationale for Amendment (b)
Study JPBX protocol was amended to update the safety monitoring and guidance for interstitial 
lung disease (ILD)/pneumonitis. Changes to the dose adjustment and delay section and 
Table JPBX.9.2 were done to specify dose modifications in response to ILD/pneumonitis events.  
These updates are in alignment with changes made in the development core safety information of 
the IB.
The protocol was updated to bring references to abemaciclib into alignment with the sponsor’s 
standard language.
Section 9.6 (Concomitant Therapy) was updated to align with the current IB.  Additional 
language was added cautioning against concomitant use of abemaciclib and substrates of the 
following:

P-glycoprotein

breast cancer resistance protein

organic cation transporter 2

multidrug and toxin extrusion protein 1 (MATE1), and

MATE2-K
Substrates of these transporters, including metformin, digoxin, and dofetilide, should be 
substituted or avoided.
The Concomitant Therapy (Section 9.6) was also updated to remove cautionary language 
regarding coadministration of narrow therapeutic index CYP substrate drugs. This is based on a
clinical study (Study I3Y-MC-JPCB) which found no meaningful effect of abemaciclib on the 
pharmacokinetics of CYP substrates, namely caffeine [CYP1A2], S-warfarin [CYP2C9], 
midazolam [CYP3A], and dextromethorphan [CYP2D6].  
The list of Inducers and Strong Inhibitors of CYP3A (Attachment 10) was also modified to 
reflect updated guidance.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.


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6. Objectives
6.1.
Primary Objective
The primary objective of this study is to compare treatment with abemaciclib versus docetaxel 
therapy with respect to investigator-assessed PFS in patients with Stage IV squamous cell 
carcinoma NSCLC who have relapsed after prior platinum-based therapy for advanced disease.
6.2.
Secondary Objectives
The secondary objectives of the study are as follows:

To evaluate the pharmacokinetic (PK) parameters including abemaciclib and its 
active metabolites

To compare treatment of abemaciclib versus docetaxel with respect to the following:
  •  Overall survival (OS)
  •  Overall response rate (ORR) [complete response (CR) + partial response 
(PR)]
  •  Disease control rate (DCR) [CR + PR + stable disease (SD)]
  •  Time to worsening of Performance Status (PS)
  •  The safety and tolerability using the National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE version 4.0)
  •  Change from baseline in patient-reported outcomes (PROs), including:  1) the 
MD Anderson Symptom Inventory Lung Cancer (MDASI-LC) questionnaire 
pain and disease-related symptoms scores; and 2) the EuroQol Group’s EQ-
5D-5L questionnaire index score, derived from the 5-item descriptive system,
and visual analog scale (VAS) self-rated health score.
6.3.
Exploratory Objectives

To explore potential biomarkers related to the cell cycle pathway components, 
abemaciclib, and/or the pathogenesis of lung cancer, and their associations with 
clinical outcomes

To explore the relationship between abemaciclib exposure and response

To explore if change in tumor size is associated with PFS and OS


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7. Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Each time re-screening is performed, the individual must sign a new informed 
consent form (ICF) and will be assigned a new identification number.
The following patients may be eligible for rescreening if any of the following circumstances:

Patients who have become eligible to enroll in the study as the result of a protocol
amendment.

Patient status has changed such that the eligibility criterion that caused the patient to 
screen fail would no longer cause the patient to screen fail again.

Patients who complete screening and meet all inclusion and exclusion requirements but 
are unable to be enrolled due to extenuating circumstances (such as severe weather, death 
in family, or child illness).
The investigator should contact the Lilly clinical research physician (CRP) prior to re-screening 
a patient.
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:
[1]
have confirmed diagnosis of Stage IV NSCLC disease predominantly 
squamous histology according to the American Joint Committee on Cancer on 
Cancer Staging Handbook (Edge et al. 2009). Squamous NSCLC diagnosis 
must be confirmed by histology or cytology local pathology report.
[2]
have availability of adequate formalin-fixed paraffin-embedded (FFPE) 
tumor-derived material (tumor blocks or 10 slides minimum) from a core 
needle biopsy or surgery for analysis of biomarkers.  This sample should be 
the most recent available sample containing adequate material. Re-biopsy 
after progression from prior therapy is not required.
[3]
have progressed during or after platinum-based chemotherapy regimen for 
advanced disease

Patients may have received one additional line of therapy only if an 
immune checkpoint inhibitor was administered (for example, nivolumab). 
This prior immunotherapy is allowed and does count as prior therapy. No 
other anticancer agents (for example, chemotherapy, radiotherapy) are 
permitted as prior therapy. 

Patients with recurrent disease after adjuvant or neoadjuvant therapy or 
patients who have received combined chemotherapy and radiation for 
locally advanced disease are eligible, if:


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a.
The patient has progressed within 6 months after completion of 
adjuvant or neoadjuvant platinum-based therapy (adjuvant therapy 
will be considered the patient’s one and only prior first-line, 
platinum-based chemotherapy). The time from completion of the 
last cycle of adjuvant or neoadjuvant therapy to progression must 
be less than 6 months.  For radiotherapy for locally advanced 
disease with curative intent with chemotherapy (platinum-based 
therapy), the time of completion of chemotherapy or radiotherapy,
whichever finishes last, to progression must be less than 6 months 
to count as a line of therapy.

May not have received docetaxel as monotherapy or in combination with 
platinum therapy in first-line setting, or in the neoadjuvant/adjuvant setting
a.
Prior paclitaxel therapy as monotherapy or in combination is 
permitted (for example, single-agent neoadjuvant/adjuvant setting 
or combination in first line).
[4]
have a performance status (PS) of 0 to 1 on the Eastern Cooperative Oncology 
Group (ECOG) scale (see Attachment 4)
[5]
have the presence of measurable disease as defined by the Response 
Evaluation Criteria In Solid Tumors RECIST 1.1 (Eisenhauer et al. 2009, see 
Attachment 7)
[6]
have discontinued all previous treatments for cancer (including chemotherapy, 
radiotherapy, immunotherapy, and endocrine therapy) for at least 21 days for 
myelosuppressive agents; or 14 days for nonmyelosuppressive agents prior to 
receiving study drug, and recovered from the acute effects of therapy 
(treatment-related toxicity resolved to baseline) except for residual alopecia

Radiation therapy:  Prior radiotherapy to chest is permitted if completed 
>3 weeks; and prior radiotherapy to the brain is permitted if completed 
>4 weeks with assessment of stable disease. Patients must have recovered 
from the acute toxic effects of the radiotherapy treatment prior to the first 
dose of study treatment.
[7]
have adequate organ function, including:

hematologic:  absolute neutrophil count (ANC) 1.5 × 109/L, platelets 
100 × 109/L, and hemoglobin 9 g/dL.  Patients may receive erythrocyte 
transfusions to achieve this hemoglobin level at the discretion of the 
investigator.  Initial study drug treatment must not begin earlier than the 
day after the erythrocyte transfusion.

hepatic:  bilirubin 1.5 times the upper limit of normal (ULN) and alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) 3 times
ULN. For patients with hepatic metastases, ALT and AST equaling 
≤5.0 times ULN are acceptable.


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
renal:  Calculated creatinine clearance ≥50 mL/min (per the 
Cockcroft-Gault formula or equivalent, see Attachment 5)
[8]
are ≥ 18 years of age
[9]
have agreed contraception methods as follows
[9a] are a man and agree to use a reliable medically approved method of birth 
control (for example, intrauterine device [IUD], birth control pills, or 
barrier method) and to not donate sperm during the study and for at least 
3 months following the last dose of study drugs(s) or country 
requirements, whichever is longer]
[9b] are women of child-bearing potential who test negative for pregnancy 
within 14 days of start of study treatment and agree to use a reliable 
medically approved method of birth control (for example, IUD, birth 
control pills, or barrier method) during the study and for 3 months 
following the last dose of the study drug(s) or country requirements, 
whichever is longer
[10] have an estimated life expectancy of at least 12 weeks and in the judgment of 
the investigator, will be able to complete at least 2 cycles of treatment
[11] have given written informed consent prior to any study-specific procedures
[12] are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[13] are able to swallow capsules or tablets
7.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[14] are currently receiving treatment in a clinical trial involving an investigational 
product or non-approved 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
[15] have known or suspected allergy to docetaxel or any of its components
[16] have received treatment with a drug that has not received regulatory approval 
for any indication within 14 or 21 days of the initial dose of study drug of 
nonmyelosuppressive or myelosuppressive agent, respectively
[17] have received prior treatment with any CDK 4 and 6 inhibitor (or participated 
in any CDK 4and 6 inhibitor clinical trial for which treatment assignment is 
still blinded)


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[18] have had major surgery (excluding biopsy) < 28 days of the initial dose of 
study drug and/or have not recovered from the acute effects of the surgery
[19] have a personal history within the last 12 months of any of the following 
conditions: syncope of either unexplained or cardiovascular etiology, 
ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest.
[20] have serious preexisting medical conditions that, in the judgment of the 
investigator, would preclude participation in this study (for example, history 
of major surgical resection involving the stomach or small bowel)
[21] have a history of any other cancer (except non-melanoma skin cancer or 
carcinoma in-situ of the cervix), unless in complete remission with no therapy 
for a minimum of 3 years
[22] have the presence of unstable central nervous system (CNS) metastasis:

History of CNS metastasis or stable CNS metastases are allowed (no 
longer requiring active therapy such as steroid medications).  Patients with 
symptoms of CNS involvement or a history of CNS metastasis will have 
brain scan during baseline procedures to document stability. Patients
having prior brain scan within 45 days of starting therapy and without 
symptoms of CNS metastases (stable or unstable) do not need to repeat 
scan at baseline (within 28 days of starting study treatment).

Steroidal treatment (if indicated) should be completed after cranial 
irradiation (whole brain radiation therapy, focal radiation therapy, and 
stereotactic radiosurgery)

Prior radiotherapy to the brain must be completed >4 weeks prior to 
randomization with assessment of stable disease. 

Prior surgical resection should be performed at least 28 days prior to 
randomization.  The patient may have no evidence of Grade ≥1 CNS 
hemorrhage based on pretreatment magnetic resonance imaging (MRI) or 
intravenous (IV) contrast computed tomography (CT) scan (performed 
within 28 days before starting study treatment).
[23] have active bacterial, fungal, and/or known viral infection (for example, 
human immunodeficiency virus [HIV] antibodies, hepatitis B surface antigen, 
or hepatitis C antibodies). Screening for active infections is not required for 
enrollment.
[24] females who are pregnant or lactating
7.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion Criterion [19] is necessary because the effects of abemaciclib on corrected QT (QTc)
prolongation are unknown; these conditions may put the patient at additional risk.


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Exclusion Criterion [22] is necessary because patients with unstable CNS metastasis are not 
likely to receive sufficient study treatment, preventing a full assessment of the agents 
administered in this study.  Exclusion Criterion [24] is necessary because the effects of 
abemaciclib on the developing fetus are unknown.
7.3.
Discontinuation
If a patient withdraws informed consent, he or she must not be contacted unless he or she has 
explicitly provided permission and consent.  Lilly may continue to use previously collected 
medical research data prior to the withdrawal consistent with the original authorization.
7.3.1. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly. If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the sponsor CRP and the investigator to determine whether the patient may continue in the study, 
with or without study drug.  Inadvertently enrolled patients may be maintained in the study and 
on study drug when the Lilly CRP agrees with the investigator that it is medically appropriate for 
that patient. The patient may not continue in the study with or without study drug if the Lilly
CRP does not agree with the investigator’s determination it is medically appropriate for the 
patient to continue. The investigator must obtain documented approval from the Lilly CRP to 
allow the inadvertently enrolled patient to continue in the study with or without study drug.
7.3.2. Discontinuation of Study Drug
Patients will be discontinued from study drug in the following circumstances:

disease progression as defined by RECIST v. 1.1

unacceptable toxicity

the patient has had 2 dose reductions and experiences an AE that would cause a third dose 
reduction

the patient is significantly noncompliant with study procedures and/or treatment

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 
drug for any reason (for example, the patient becomes pregnant)
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, legal guardian) requests to be 
withdrawn from the study or study drug


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
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 (GCP)
The reason for and date of discontinuation will be collected for all patients.  All randomized
patients who discontinue regardless of whether or not they received study drug will have 
procedures performed as shown in the Study Schedule (Attachment 1).
7.3.3. Discontinuation from the Study
Patients will be discontinued from the study in the following circumstances:

the investigator decides that the patient should be discontinued from the study

the patient or the patient’s designee (for example, legal guardian) requests that the 
patient be withdrawn from the study

Lilly stops the study or stops the patient’s participation in the study for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP
7.3.4. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges discontinuation of study site participation necessary for medical, 
safety, regulatory, ethical, or other reasons consistent with applicable laws, regulations, and 
GCP.
7.3.5. Discontinuation of the Study
The study will be discontinued if Lilly judges discontinuation of the study 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
8.2.
Study Design
Study I3Y-MC-JPBX (JPBX) is a multicenter, randomized, open-label, parallel, 
comparator-controlled, Phase 2 trial in Stage IV squamous NSCLC patients who have progressed 
after platinum-based chemotherapy for advanced disease, evaluating treatment with abemaciclib 
versus docetaxel.
Patients will be stratified at randomization according to the following: ECOG PS (0 vs 1); 
number of prior therapies (received only platinum-based therapy vs. platinum-based therapy plus 
immune checkpoint inhibitor); and time since the initiation of first-line therapy (≤9 vs. >9 
months) (Figure JPBX.8.1).
Abbreviations: IV = intravenous; N = number; NSCLC = non-small cell lung cancer; PD = progressive 
disease; PO = orally; Q12H = every 12 hours; R = randomized.
Figure JPBX.8.1.
Illustration of study design.
Database lock for the primary analysis of the PFS endpoint will occur when approximately 
120 investigator-assessed PFS events have been observed. The primary analysis of OS will 
occur 12 months after last patients have been enrolled. This is to ensure adequate survival data 
are available at the time of analysis.  All patients will be followed for survival information until 
death or study completion, whichever comes first.
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 


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treatment.  The date of this agreement is to be reported on the case report form 
(CRF) as the Date of Discontinuation from study treatment.

Postdiscontinuation Follow-Up:  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 (+0 to 7 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 (final OS analysis) and ends at 
the end of trial (last patient visit for the study).  During the continued access period,
patients on study treatment who continue to experience clinical benefit and no undue 
risks may continue to receive study treatment until one of the criteria for discontinuation 
is met.  The continued access period includes continued access follow-up.
o
Continued access follow-up:  begins the 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.
8.2.1. Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete [study
completion]) following the final analysis of OS (12 months after enrollment is complete), 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” refers to the date of the last visit or last scheduled procedure for the last patient
(Figure JPBX.8.2).  The end of trial occurs after study completion and after the last patient has 
discontinued study treatment and completed any applicable continued access follow-up.


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Abbreviation:  OS = overall survival.
Figure JPBX.8.2.
Study period and continued access diagram.
8.2.2. Continued Access Period
Patients receiving treatment with either abemaciclib or docetaxel and experiencing ongoing 
clinical benefit and no undue risks may continue to receive their current treatment in the 
continued access period until one of the criteria for 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 study drug 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.
Continued Access Period


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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.
8.3.
Discussion of Design and Control
A randomized, controlled design is being used in this study.  Randomization minimizes 
systematic bias in the selection and assignment of patients to study treatment and provides 
justification for inferential statistical methods to be used on data from this study. It is expected 
that abemaciclib will produce robust safety data and better efficacy outcomes than the control; 
therefore, a 2:1 randomization has been used in this study. Using an appropriate concurrent 
control arm enables direct statistical estimation of benefits and harms due to study treatment and 
minimizes bias in the assessment and interpretation of observed treatment effects. Patients will 
be stratified for differences in factors thought to be associated with clinical outcomes to further 
reduce the potential for bias and improve the power of the analyses.
A Bayesian augmented control design is being used in this study.  This statistical model enables 
historical data for the concurrent control group to be used analytically in this prospective study, 
which improves (frequentist) operating characteristics compared with standard (frequentist) 
designs (see Attachment 6 for more details).


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9. Treatment
9.1.
Treatments Administered
The following treatments will be administered in this study:

Experimental Arm A:  Abemaciclib 200 mg orally every 12 hours (Q12H) on Days 1 to 
21 of a 21-day cycle

Control (Standard of Care) Arm B:  Docetaxel 75 mg/m2 intravenous (IV) infusion on 
Day 1 of a 21-day cycle.
Table JPBX.9.1 shows the treatment regimens.
Table JPBX.9.1.
Treatment Regimens/Dosing Schedule
Regimen
Period/Cycle
Dose
Abemaciclib
Treatment/21-day cycle
200 mg PO Q12H Days 1 to 21 of each cycle
Docetaxela,b,c
Treatment/21-day cycle
75 mg/m2 IV Day 1 of each cycle
Abbreviations:  IV = intravenous; PO = orally; Q12H = every 12 hours.
a
Patients should be premedicated with corticosteroids such as dexamethasone 16 mg per day (e.g., 8 mg twice a 
day) for 3 days starting 1 day prior to docetaxel administration in order to reduce the incidence and severity of 
fluid retention, as well as the severity of hypersensitivity.  All premedication administered must be adequately 
documented in the electronic case report form(eCRF).
b
Body surface area must be calculated and the docetaxel dose adapted accordingly before each subsequent cycle.
c
Korean and Taiwan sites will administer docetaxel 60 mg/m2 IV Day 1 of each cycle.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the study drug and planned duration of each individual’s 
treatment to the patient, site personnel and/or legal representative,

verifying that instructions are followed properly, 

maintaining accurate records of study drug dispensing and collection, 

and returning all unused medication to Lilly or its designee at the end of the study.
Note: 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.


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9.1.1. Docetaxel
Investigators should consult the manufacturer`s instructions for docetaxel for complete 
prescribing information and follow institutional procedures for the administration of docetaxel.  
Docetaxel will be administered as an IV infusion of 75 mg/m2 over approximately 60 minutes.
For sites in Korea and Taiwan, patients will receive docetaxel at a dose of 60 mg/m2 as an 
approximate 60-minute IV infusion.
9.2.
Materials and Supplies
Abemaciclib will be supplied by Lilly for oral administration.  Abemaciclib should be stored 
according to the temperature range listed on the product label, and should not be opened, 
crushed, or chewed.
Docetaxel is a commercially available product. Docetaxel branded or generic is permitted.
Investigators should consult the manufacturer’s instructions for complete packaging, labeling, 
storage, and stability information.
All study drug provided by Lilly will be labeled according to local country regulatory 
requirements.  Investigators are responsible for instructing patients to store abemaciclib in the 
original package provided and to keep all medication out of the reach of children.
Lilly is not responsible for the supply of any premedication required according to docetaxel 
label.
9.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be randomly assigned to receive either 
abemaciclib or docetaxel during baseline screening at least 4 days prior to planned Cycle 1 Day 1 
to allow premedication for docetaxel to occur per label recommendation.  Randomization will be 
stratified by the following factors:

ECOG PS at baseline (0 vs. 1)

time since initiation of first-line therapy (≤ 9 months vs. > 9 months)

number of prior therapies (received only platinum-based therapy vs. platinum-based 
therapy plus immune checkpoint inhibitor)
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS).
9.4.
Selection and Timing of Doses
A cycle is defined as a planned treatment interval of 21 days (a delay of a cycle due to holidays, 
weekends, bad weather, or other unforeseen circumstances will be permitted up to 7 days and not 
counted as a protocol deviation; refer to Table JPBX.9.4).


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Abemaciclib will be taken orally Q12H (±approximately 2 hours) on Days 1 through 21 of a 
21-day cycle, for a total of 42 doses per cycle.  During all cycles, abemaciclib should be taken at 
approximately the same times each day. On Cycle 1 Day 8, abemaciclib should be taken at 
home at least 4 hours prior to the schedule visit time. If a patient misses or vomits a dose, that 
dose should be omitted. The dose of abemaciclib will be administered in the clinic on Day 1 of 
each cycle.
Docetaxel will be administered IV in the clinic on Day 1 of every cycle.  Body surface area must 
be calculated and the docetaxel dose adapted accordingly before each subsequent cycle.  Applied 
dosages should be no more than 10% above or below calculated ones.  Infusions administered 
within 3 days before or 7 days after the planned 3-week time point due to administrative or 
unforeseen circumstances(for example, weekend) will be considered acceptable and are at the 
discretion of the treating investigator. Patients who require a delay of more than 14 days in 
starting a new cycle of chemotherapy (> 35-day interval between consecutive cycles) should be 
removed from treatment.
A patient may continue to receive study drug until he or she meets 1 or more of the specified 
reasons for discontinuation (as described in Section 7.3).
The first administration of study treatment has to be performed within 28 days of consent and no 
more than 14 days after randomization during baseline.
9.4.1. Dose Rationale for Abemaciclib from Study JPBA
Selection of 200 mg every 12 hours for assessment during Study JPBX is based on safety, 
clinical activity, and PK and pharmacodynamic data from patients with NSCLC enrolled in 
Study JPBA.
Study JPBA is the Phase 1 dose-escalation and tumor cohort-expansion study in advanced cancer 
patients that included a cohort expansion in NSCLC patients. Findings from the Phase 1 
Study JPBA indicate that the abemaciclib single-agent maximum tolerated dose (MTD) of 
200 mg administered orally Q12H demonstrates an acceptable safety profile.
The most 
common treatment-emergent adverse events (TEAEs) possibly related to study drug for patients 
in Study JPBA included diarrhea, nausea, fatigue, neutropenia, vomiting, leukopenia, 
thrombocytopenia, anemia, decreased appetite, and blood creatinine increased. The adverse 
event findings are consistent in those patients in the NSCLC cohort.
Additionally, preliminary analysis of the PK data obtained in Study JPBA for abemaciclib at 
150 and 200 mg Q12H suggests that the dose of 200 mg administered every 12 hours yields 
slightly higher and more consistent steady-state plasma concentration levels for abemaciclib.
In particular, the mean minimum steady-state concentration for abemaciclib is more consistently 
maintained at a value of approximately 200 ng/mL, which represents a threshold value associated 
with more robust and sustained CDK 4 and 6 inhibition and cell cycle arrest, as indicated by the 
decrease in phosphorylated retinoblastoma and topoisomerase II alpha expression measured in 
skin biopsies.


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Collectively, these findings indicate that the MTD of 200 mg orally Q12H demonstrates an 
acceptable safety profile, evidence of target inhibition and cell cycle arrest in skin, and clinical 
activity against NSCLC. The dose of 200 mg administered every 12 hours is therefore 
recommended for further assessment in Study JPBX.
9.4.2. Special Treatment Considerations
9.4.2.1.
Dose Adjustments and Delays
Table JPBX.9.2.
Toxicity Dose Adjustments and Delays of Abemaciclib for 
Study JPBX
Toxicity Type
Dose Adjustment Guidelines
Dose Action
Dose Change
Hematologic Toxicity
Section 9.4.2.1.2.1
Grade 3
Dose MUST be 
suspended until toxicity 
resolves to at least 
Grade 2
Dose MAY be 
reduced by one dose 
level - investigator’s 
discretion.
Hematologic Toxicity 
Section 9.4.2.1.2.1
Recurrent Grade 3
Dose MUST be 
suspended until toxicity 
resolves to at least 
Grade 2
Dose MUST be 
reduced by one dose 
level.
Hematologic Toxicity 
Section 9.4.2.1.2.1
Grade 4
Dose MUST be 
suspended until toxicity 
resolves to at least 
Grade 2
Dose MUST be 
reduced by one dose 
level.
Hematologic toxicity: If 
patient requires 
administration of blood 
cell growth factors
Sections 9.4.2.1.2.1 and 
9.6.2.3
Regardless of severity
(Use of growth factors 
according to ASCO 
Guidelines)
Dose MUST be 
suspended for at least 
48 hours after the last 
dose of blood cell 
growth factors was 
administered and until 
toxicity resolves to at 
least Grade 2.
Dose MUST be 
reduced by one dose 
level unless already 
performed for 
incidence of toxicity 
that lead to the use of 
growth factor.
Nonhematologic Toxicitya
(except diarrhea, ALT 
increased, and 
ILD/Pneumonitis)
Section 9.4.2.1.2.2
Persistent or recurrentb
Grade 2 that does not resolve 
with maximal supportive 
measures within 7 days to 
baseline or Grade 1
Dose MUST be 
suspended until toxicity 
resolves to either 
baseline or Grade 1.
Dose MUST be 
reduced by one dose 
level.
Nonhematologic Toxicity
(except diarrhea, ALT 
increased, and
ILD/Pneumonitis)
Section 9.4.2.1.2.2
Grade 3 or 4
Dose MUST be 
suspended until toxicity 
resolves to either 
baseline or Grade 1.
Dose MUST be 
reduced by one dose 
level.
Diarrhea
Sections 9.4.2.1.2.3 and 
9.6.2.2
Grade 2 that does not resolve 
within 24 hours to at least
Grade 1
Dose MUST be 
suspended until toxicity 
resolves to at least 
Grade 1.
Dose reduction is 
NOT required.


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Toxicity Type
Dose Adjustment Guidelines
Dose Action
Dose Change
Diarrhea
Sections 9.4.2.1.2.3 and 
9.6.2.2
Persistent or recurrentb Grade 
2 that does not resolve with 
maximal supportive measures 
or any Grade of diarrhea that 
requires hospitalization
Dose MUST be 
suspended until toxicity 
resolves to at least 
Grade 1.
Dose MUST be 
reduced by one dose 
level.
Diarrhea
Sections 9.4.2.1.2.3 and 
9.6.2.2
Grade 3 or 4
Dose MUST be 
suspended until toxicity 
resolves to at least 
Grade 1.
Dose MUST be 
reduced by one dose 
level.
ALT Increased 
Sections 9.4.2.1.2.4 and 
10.3.3.1
Persistent or recurrentb Grade
2 (>3.0-5.0×ULN)c, or
Grade 3 (>5.0-20.0×ULN)d
Dose MUST be 
suspended until toxicity 
resolves to baseline or 
Grade 1.
Dose MUST be 
reduced by 1 dose 
level.
ALT Increased 
Sections 9.4.2.1.2.4 and 
10.3.3.1
Grade 4 (>20.0×ULN)
Abemaciclib MUST be 
discontinued.
Abemaciclib MUST
be discontinued.
ALT Increased with 
increased total bilirubin, in 
the absence of cholestasis
Sections 9.4.2.1.2.4 and 
10.3.3.1
Grade 3 increased ALT 
(˃5.0×ULN) with total 
bilirubin >2×ULN
Abemaciclib MUST be 
discontinued.
Abemaciclib MUST
be discontinued.
ILD/Pneumonitis
Sections 9.4.2.1.2.5 and 
10.3.3.4
Grade 2 that persists or recurs 
despite maximal supportive 
measures and does not return 
to baseline or Grade 1 within 7 
days
Dose MUST be 
suspended until toxicity 
resolves to baseline or 
Grade ≤1.
Dose MUST be 
reduced by 1 dose 
level.
ILD/Pneumonitis
Sections 9.4.2.1.2.5 and 
10.3.3.4
Grade 3 or 4
Abemaciclib MUST be 
discontinued.
Abemaciclib MUST
be discontinued.
Abbreviations:  ALT = alanine transaminase; ASCO = American Society of Clinical Oncology; ILD = interstitial lung 
disease; ULN = upper limit of normal.
Note:  MAY = per the investigator’s clinical judgment; MUST = mandatory.
a
Additional guidance for hepatic and renal monitoring is in Sections 10.3.3.1 and 10.3.3.2.
b
Determination of persistent events will be at the discretion of the investigator.  Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).  As a 
general guidance, based on the risk/benefit balance assessment per the investigator, for a patient who experiences 
a new episode of Grade 3 hematological toxicity after more than 8 weeks following the last episode of same 
Grade 3 hematological toxicity, the investigator may consider resuming the patient on the same drug dose should 
the patient satisfy the following conditions:

shows stable hematological counts (Grade ≤2) during that timeframe

has absence of any signs or risk of infection

is benefiting from study treatment
c
Note: the patient who presents with no liver metastases at baseline.
d
Grade 3 ALT increased is a trigger for additional assessments and possibly hepatic monitoring.  See Section
10.3.3.1 for additional guidance for hepatic monitoring.


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9.4.2.1.1. Abemaciclib Dose Adjustments
Dose adjustments as outlined in Table JPBX.9.3 are allowed both within a cycle and between 
cycles. Abemaciclib must be reduced sequentially by one dose level.
For patients requiring dose reduction(s), any re-escalation to a prior dose level is permitted only
after consultation with the Lilly CRP. After re-escalation, subsequent dose adjustments should 
be based on the dose of abemaciclib that the patient is currently receiving.
Table JPBX.9.3.
Dose Adjustments of Abemaciclib for Study JPBX
Dose Adjustment
Oral Dose
Frequency
0
200 mg
Q12H
1
150 mg
Q12H
2
100 mg
Q12H
Abbreviation:  Q12H = every 12 hours.
If a patient receiving the 100-mg Q12H dose of abemaciclib requires a further dose reduction, 
the patient should be discontinued from study treatment.  If a patient who, in the judgment of the 
investigator, is receiving clinical benefit from study therapy and requires further dose reduction 
than what is outlined in Table JPBX.9.3, then the investigator must discuss with the Lilly CRP 
prior to any further dose reduction.
9.4.2.1.2. Abemaciclib Dose Delays and Omission
Table JPBX.9.4.
General Dose Delays of Abemaciclib for Study JPBX
General Dose Delays
Time Permitted for Delay
Delay of a cycle due to holidays, weekends, bad weather, or other 
unforeseen circumstances
7 days
Toxicity-time for recovery to baseline or at least Grade 1 for 
nonhematologic and at least Grade 2 for hematologic toxicity
Up to 14 days
The start of a cycle may be delayed to allow sufficient time for recovery from toxicity possibly 
related to study drug.  Patients not recovering from such toxicity within 14 days beyond the last 
day of the prior cycle will be considered for discontinuation from the study.
9.4.2.1.2.1.
Hematologic Toxicity
Before the start of each cycle, hematologic toxicity possibly related to abemaciclib must resolve 
to either baseline or at least Grade 2.
If a patient experiences Grade 3 hematologic toxicity, then dosing must be suspended (until the
toxicity resolves to either baseline or at least Grade 2) and the dose of abemaciclib may be
reduced by one dose level as outlined in at the discretion of the investigator as outlined in 
Table JPBX.9.3. If the patient experiences a recurrent episode of Grade 3 hematologic toxicity, 


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then dosing must be suspended (until the toxicity resolves to at least Grade 2) and the dose of 
abemaciclib must be reduced by 1 dose level.
If a patient experiences Grade 4 hematologic toxicity possibly related to abemaciclib, then 
dosing must be suspended (until the toxicity resolves to either baseline or at least Grade 2) and 
the dose of abemaciclib must be reduced as outlined in Table JPBX.9.3.
Recurrent toxicity refers to the same event occurring within the next 8 weeks (as measured from 
the stop date of the preceding event).  As a general guidance, based on the risk/benefit balance 
assessment per the investigator, for a patient who experiences a new episode of Grade 3 
hematological toxicity after more than 8 weeks following the last episode of same Grade 3 
hematological toxicity, the investigator may consider resuming the patient on the same drug dose 
should the patient satisfy the following conditions:

The patient showed stable hematological counts (Grade ≤2) during that timeframe

In the absence of any signs or risk of infection 

The patient is benefiting from study treatment
If a patient requires administration of blood cell growth factors, the dose of LY2835219 must be 
suspended for at least 48 hours after the last dose of blood cell growth factors was administered 
and until toxicity resolves to at least Grade 2, then must be reduced by 1 dose level, if a dose 
reduction for the specific event necessitating the use of the growth factors has not already 
occurred.
9.4.2.1.2.2.
Nonhematologic Toxicity
Before the start of each cycle, nonhematologic toxicity (except alopecia and fatigue) possibly 
related to abemaciclib must resolve to either baseline or at least Grade 1.
Refer to Section 9.4.2.1.2.3 for guidance and supportive measures of diarrhea toxicity possibly 
related to abemaciclib, Sections 9.4.2.1.2.4 and 10.3.3.1 for additional hepatic safety and 
monitoring guidance, and Sections 9.4.2.1.2.5 and 10.3.3.4 for ILD/pneumonitis guidance.  If a 
patient experiences ≥Grade 3 nonhematologic toxicity (except diarrhea, refer to 
Section 9.4.2.1.2.3; ALT increased, refer to Sections 9.4.2.1.2.4 and 10.3.3.1; ILD/pneumonitis, 
refer to Sections 9.4.2.1.2.5 and 10.3.3.4) possibly related to abemaciclib, then dosing must be 
suspended (until the toxicity resolves to either baseline or at least Grade 1) and the dose of 
abemaciclib must be reduced as outlined in Table JPBX.9.3.
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea, 
refer to Section 9.4.2.1.2.3; ALT increased, refer to Sections 9.4.2.1.2.4 and 10.3.3.1; 
ILD/pneumonitis, refer to Sections 9.4.2.1.2.5 and 10.3.3.4) possibly related to abemaciclib that 
does not resolve with maximal supportive measures within 7 days to either baseline or Grade 1, 
then dosing must be suspended (until the toxicity resolves to either baseline or at least Grade 1) 
and the dose of abemaciclib must be reduced as outlined in Table JPBX.9.3.


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9.4.2.1.2.3.
Diarrhea
A patient experiencing diarrhea requiring hospitalization (irrespective of grade; that is, requiring 
IV rehydration) or severe diarrhea (Grade 3 or 4; see Section 9.6.2.2 and Attachment 11) must
have study treatment suspended (until the toxicity resolves to either baseline or at least Grade 1) 
and the dose of abemaciclib must be reduced as outlined in Table JPBX.9.3.
If a patient experiences Grade 2 diarrhea that does not resolve with maximal supportive measures 
(refer to Section 9.6.2.2) within 24 hours to at least Grade 1, the study drug must be suspended 
(until the toxicity resolves to at least Grade 1) but abemaciclib dose reduction is not required. 
However, if a patient experiences persistent or recurrent Grade 2 diarrhea that does not resolve 
with maximal supportive measures (refer to Section 9.6.2.2) within 24 hours to at least Grade 1, 
then abemaciclib must be suspended (until the toxicity resolves to at least Grade 1) and the dose 
of abemaciclib must be reduced as outlined in Table JPBX.9.3.
9.4.2.1.2.4.
Hepatic Toxicity
Dose modifications and management for increased ALT are provided in Table JPBX.9.2. For 
persistent or recurrent Grade 2 ALT increased that does not resolve with maximal supportive 
measures within 7 days to baseline or Grade 1, or Grade 3 ALT increased, abemaciclib must be 
suspended until the toxicity has resolved to at least Grade 1 and the dose must be reduced by 1 
dose level. Discontinue abemaciclib for Grade 3 increased ALT (˃5.0 x ULN) with total 
bilirubin (TBL) >2 x ULN, in the absence of cholestasis. For Grade 4 ALT increased, the patient 
must be discontinued from abemaciclib.  Refer to Section 10.3.3.1 for additional hepatic 
monitoring guidance.
9.4.2.1.2.5.
Interstitial Lung Disease/Pneumonitis
Dose modifications and management for ILD/pneumonitis are provided in Table JPBX.9.2. For 
persistent or recurrent Grade 2 ILD/pneumonitis that does not resolve with maximal supportive 
measures within 7 days to baseline or Grade 1, treatment with abemaciclib must be suspended 
until the toxicity resolves to baseline or Grade 1 and the dose must be reduced by 1 dose level.  
For Grade 3 or 4 ILD/pneumonitis, the patient must be discontinued from abemaciclib.  Refer to 
Section 10.3.3.4 for additional ILD/pneumonitis monitoring guidance.
9.4.2.1.3. Docetaxel
Investigators should consult the manufacturer’s instructions for docetaxel for complete 
prescribing information (including warnings, precautions, contraindications, and adverse 
reactions) and follow institutional procedures for the administration of docetaxel.  All 
implemented dose modifications are permanent.  The doses must be modified according to the 
lowest hematology values and the highest degree of nonhematologic toxicities observed at any 
time during the previous cycle.  If a patient develops several different toxic effects and there are 
conflicting recommendations, the dose reduction required for the clinically most severe toxic 
effect must be chosen.
Patients in Korea and Taiwan who receive 60 mg/m2 dose of docetaxel who experience described 
toxicities should have treatment withheld until resolution of the toxicity and then resumed at 
50 mg/m2.  For patients in Korea or Taiwan who were initially dosed at 60 mg/m2 followed by 


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dose reduction to 50 mg/m2, no further dose reduction will occur, and docetaxel treatment will be 
discontinued.  Patients who develop ≥Grade 3 peripheral neuropathy should have docetaxel 
treatment discontinued entirely.  Any Grade 3 or 4 nausea and vomiting should lead to an 
adaptation in the antiemetic therapy and docetaxel dosing should continue at an unchanged 
dosage.  If this approach is not successful, docetaxel should be reduced.
9.4.2.1.3.1.
Docetaxel Hypersensitivity Reactions
Patients should be observed closely for hypersensitivity reactions, especially during the first and 
second infusions.  Severe hypersensitivity reactions characterized by generalized rash/erythema, 
hypotension and/or bronchospasm, or very rarely fatal anaphylaxis have been reported in patients 
premedicated with 3 days of corticosteroids.  Severe hypersensitivity reactions require immediate 
discontinuation of the docetaxel infusion and aggressive therapy.  Patients with a history of 
severe hypersensitivity reactions should not be rechallenged with docetaxel.
Hypersensitivity reactions may occur within a few minutes following initiation of a docetaxel 
infusion.  If minor reactions such as flushing or localized skin reactions occur, interruption of 
therapy is not required.  All patients should be premedicated with corticosteroids prior to the 
initiation of the infusion of docetaxel (see Section 9.6.1).
For mild symptoms:  Complete docetaxel infusion.  Supervise at bedside.  No treatment required.
For moderate symptoms:  Stop docetaxel infusion.  Administer diphenhydramine 25 to 50 mg IV 
and dexamethasone 10 mg IV.  Resume the docetaxel infusion after recovery of symptoms.  If 
symptoms recur, stop the docetaxel infusion and remove patient from docetaxel treatment.
For severe life-threatening symptoms:  Stop docetaxel infusion.  Give IV diphenhydramine and 
dexamethasone as above. Add epinephrine or bronchodilators if indicated.  The patient should 
be removed from docetaxel treatment.
Management of subsequent treatment cycles:  The recommended pretreatment for subsequent 
infusions is 50 mg diphenhydramine IV and 10 mg dexamethasone IV 30 minutes prior to 
docetaxel infusion.  This is in addition to the prescribed oral dexamethasone.
Patients with hypersensitivity reactions to docetaxel are at risk for recurrent reactions.  For 
patients who experience moderate hypersensitivity reactions, the docetaxel should be 
administered over 2 hours for subsequent treatment courses in addition to premedication as noted 
above.  These patients must be informed of the potential risk of recurrent allergic reactions and 
must be carefully monitored.
In cases of late-occurring (for example, appearance within 1 week after treatment) 
hypersensitivity symptoms of a localized or generalized pruritus, symptomatic treatment may be 
given (for example, oral antihistamine).  Additional oral or IV premedication with antihistamine 
may also be given for the next cycle of treatment depending on the intensity of the reaction 
observed.  No dose reductions will be made in any case.


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9.4.2.1.3.2.
Docetaxel Hematologic Toxicity
Neutropenia (<2000 neutrophils/mm3) occurs in almost all patients treated with docetaxel 60 to 
100 mg/m2 and Grade 4 neutropenia (<500 cells/mm3) occurs in 85% of patients given 
100 mg/m2 and 75% of patients given 60 mg/m2.  Frequent monitoring of blood counts is 
therefore essential so that the dose can be adjusted.  Docetaxel should not be administered to 
patients with neutrophils <1500 cells/mm3.
9.4.2.1.3.3.
Docetaxel Fluid Retention
Severe fluid retention has been reported following docetaxel therapy.  It is characterized by 
poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, 
dyspnea at rest, cardiac tamponade, and pronounced abdominal distention (due to ascites).  
Patients should be premedicated with corticosteroids prior to each docetaxel administration to 
reduce the incidence and severity of fluid retention (see Section 9.6.1).  When fluid retention 
occurs, peripheral edema usually starts in the lower extremities and may become generalized 
with a median weight gain of 2 kg.  Patients with preexisting pleural effusions should be closely 
monitored from the first dose of docetaxel for the possible exacerbation of the effusion.
9.4.2.1.3.4.
Docetaxel Cutaneous Reaction
Localized erythema of the extremities with edema followed by desquamation has been observed.  
In case of severe skin toxicity, an adjustment in docetaxel dosage is recommended.
9.5.
Blinding
This is an open-label study.
See Section 12.1 for further details.
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.
Abemaciclib is extensively metabolized through oxidation by cytochrome P450 (CYP) 3A.  In 
clinical drug interaction studies, coadministration of clarithromycin, a strong CYP3A inhibitor, 
increased exposure (area under the concentration-time curve) to abemaciclib by 3.4-fold (Study 
I3Y-MC-JPBE) and coadministration of rifampin, a strong CYP3A inducer, decreased exposure 
to abemaciclib by 95% (Study I3Y-MC-JPBF).  Therefore, grapefruit or grapefruit juice as well 
as inducers and inhibitors of CYP3A should be substituted or avoided if possible (Attachment 
10). Although dexamethasone is a CYP3A4 inducer, use during the study is allowed.  The dose 
of corticosteroids, including dexamethasone, will be captured throughout the study.
Abemaciclib can be coadministered with drugs that are substrates of CYP enzymes.
Abemaciclib and/or its major metabolites inhibit the efflux transporters P-glycoprotein and 
breast cancer resistance protein and renal transporters organic cation transporter 2, MATE1, and 
MATE2-K at clinically relevant concentrations.  Therefore, substrates of these transporters such 


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as metformin and those with a narrow therapeutic index such as digoxin and dofetilide should be 
substituted or avoided if possible.
Docetaxel is a CYP3A4 substrate. Grapefruit juice as well as inducers and strong inhibitors of 
CYP3A4 should be substituted or avoided if possible (Attachment 10).  If systemic 
administration of a CYP3A4 inhibitor cannot be avoided in patients receiving treatment with 
docetaxel injection, consider close monitoring for toxicity and/or docetaxel injection dose 
reduction. The dose of corticosteroids, including dexamethasone, will be captured throughout the 
study.
Dexamethasone is a known CYP3A4 inducer.  Patients receiving docetaxel should be pretreated 
with dexamethasone per label recommendations. All patients may receive supportive therapy 
with dexamethasone, preferably ≤10 days, if clinically indicated. Patients requiring more than 
10 days of dexamethasone therapy will not incur a protocol deviation.
With the exceptions listed in the sections below, no other chemotherapy, experimental 
medications, other anticancer therapy, immunotherapy, hormonal cancer therapy, radiation, 
surgery for cancer, or experimental medications will be permitted while patients are on study 
treatment.
9.6.1. Premedication Prior to Infusion of Docetaxel
Investigators should consult the manufacturer’s instructions for docetaxel for complete 
prescribing information (including warnings, precautions, contraindications, and adverse 
reactions) and follow institutional procedures for the administration of docetaxel.  Patients 
should be premedicated with corticosteroids, such as dexamethasone 16 mg per day (for 
example, 8 mg twice a day) for 3 days starting 1 day prior to docetaxel administration in order to 
reduce the incidence and severity of fluid retention, as well as the severity of hypersensitivity 
reactions.  Additional antiemetic premedication may be employed at the discretion of the 
investigator. All premedication administered must be adequately documented in the electronic 
CRF (eCRF).
9.6.2. Supportive Care
Patients will receive supportive care as judged by their treating physician, if necessary.  
Supportive care measures may include but are not limited to antidiarrheal agents, antiemetic 
agents, opiate and nonopiate analgesic agents, appetite stimulants, and granulocyte and erythroid 
growth factors.  Details of interventions (for example, medications such as sedatives, antibiotics, 
analgesics, antihistamines, steroids, or erythroid-stimulating agents), procedures (for example, 
paracentesis or thoracentesis), or blood products (for example, blood cells, platelets, or fresh 
frozen plasma transfusions) should be recorded on the eCRFs.  If it is unclear whether a therapy 
should be regarded as supportive care, the investigator should consult the Lilly CRP.  Use of any 
supportive care therapy should be reported on the eCRFs.  Guidelines regarding the use of other 
specific supportive care agents are presented below.


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9.6.2.1.
Palliative Radiotherapy
Palliative radiotherapy, unless required due to progressive disease, is permitted during the study.
9.6.2.2.
Supportive Management for Diarrhea
At randomization, patient should receive instructions on the management of diarrhea.  In the 
event of diarrhea (see Attachment 11), supportive measures should be initiated as early as 
possible.  These include the following:

At the first sign of loose stools, the patient should initiate anti-diarrheal therapy (for 
example, loperamide) and notify the investigator/site for further instructions and 
appropriate follow-up.

Patients should also be encouraged to drink fluids (for example, 8 to 10 glasses of clear 
liquids per day).

Site personnel should assess response within 24 hours.

If diarrhea does not resolve with anti-diarrheal therapy within 24 hours to either baseline 
or Grade 1, study drug should be suspended until diarrhea is resolved to baseline or 
Grade 1.

When study drug recommences dosing should be adjusted as outlined in 
Sections 9.4.2.1.1, 9.4.2.1.2, and 9.4.2.1.3.
In severe cases of diarrhea, the measuring of neutrophil counts and body temperature and 
proactive management of diarrhea with antidiarrheal agents should be considered.
If diarrhea is severe (requiring IV rehydration) and/or associated with fever or severe 
neutropenia, broad-spectrum antibiotics such as fluoroquinolones must be prescribed.
Patients with severe diarrhea or any grade of diarrhea associated with severe nausea or vomiting 
should be carefully monitored and given intravenous fluid (IV hydration) and electrolyte 
replacement.
9.6.2.3.
Granulocyte-Colony Stimulating Factors
The use of granulocyte-colony stimulating factor (G-CSF) is permitted during investigational 
therapy at the discretion of the investigator.  G-CSF or similar agents are strongly recommended 
following Grade 3 or 4 neutropenia of duration >5 days or following any incidence of febrile 
neutropenia (ANC <1.0 x 103/µL [1.0 x 109/L] with a single temperature ≥38.3°C or a sustained 
temperature of ≥38.0°C for >1 hour).
9.6.2.4.
Therapy for Febrile Neutropenia
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 IV
antibiotic therapy.  Events that require a patient to be hospitalized are considered SAEs (see 
Section 10.3.1.1).
9.6.2.5.
Bisphosphonates and RANK-L Targeted Agents
Use of bisphosphonates or approved receptor activator of nuclear factor kappa-B ligand 
(RANK-L) targeted agents (for example, denosumab) is permitted during participation in the 


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study.  Patients should if possible begin treatment with bisphosphonates or RANK-L targeted 
agents at least 7 days prior to randomization. Patients who start the study receiving 
bisphosphonates or RANK-L targeted agents should, if possible, avoid switching treatments (for 
example, replacing a bisphosphonate with denosumab) while on study treatment. However, 
patients switching treatments will not incur a protocol deviation.  Patients are not permitted to 
begin treatment with bisphosphonates or RANK-L targeted agents while receiving study 
treatment. After study treatment discontinuation, use of bisphosphonates or RANK-L targeted 
agents is at the discretion of the treating physician.
9.6.2.6.
Other Study Conditions: Surgery (or Equally Considered Procedure) 
During Study Treatment Phase
If any surgery should be required during the study (palliative surgery or medically indicated by 
the investigator), the patient should undergo radiologic evaluation before surgery for 
documentation of disease status.  Elective, nonemergent surgery is strongly discouraged during 
study participation.  The time of study treatment interruption before surgery should be at least 
7 days following the last dose of study treatment.  Patients may resume all study treatment no 
less than 28 days following surgery, provided there has been adequate recovery in the opinion of 
the investigator.  Following surgery, radiological evaluation of disease is required prior to 
resumption of study treatment. The duration of treatment suspension for surgical procedure and 
healing is not considered noncompliance and will not incur a protocol violation.
9.6.2.7.
Antiemetic Agents
The use of antiemetic agents is permitted during this study and at the discretion of the 
investigator.  However, it is recommended to follow the guidelines of the Multinational 
Association of Supportive Care in Cancer and American Society of Clinical Oncology; 
dexamethasone may be sufficient, but 5-HT3 antagonists and NK1 antagonists may be used 
(Kris et al. 2006; Gralla et al. 2010).
9.6.2.8.
Analgesic Agents
The use of analgesic agents is permitted at the discretion of the investigator.
9.6.2.9.
Appetite Stimulants
The use of appetite stimulants is permitted at the discretion of the investigator.  Acceptable 
agents include, but are not limited to, megestrol acetate and dronabinol.
9.7.
Treatment Compliance
Patient compliance with study drug will be assessed at each visit.
Abemaciclib compliance will be assessed by counting returned solid oral dosage units. Study 
medication administration data will be recorded in the patient’s medical record and eCRF.
Patients who are significantly noncompliant will be discontinued from the study.  A patient will 
be considered significantly noncompliant if he or she misses more than 7 or more consecutive 
days of abemaciclib (full doses), or more than 25% cumulative days of abemaciclib (full doses) 
during the study.  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 


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amount of medication. Abemaciclib dose suspensions or delays related to at toxicity may occur 
and will not result in a patient being considered as noncompliant.
Docetaxel will be administered only by trained medical personnel at the investigational sites and 
under the direction of the investigator.  As a result, monitoring of patient compliance is ensured.
Patients who require a delay of more than 14 days in starting a new cycle of docetaxel (> 35-day 
interval between consecutive cycles) should be removed from treatment.
9.8.
Patient Diaries
The study will include patient diaries to provide dosing instructions, help patients with treatment
planning, and track actual doses of study abemaciclib taken by the patient. Information from the
diaries may be used for documenting study treatment compliance as well as dosing time relative
to PK blood draws and electrocardiogram (ECG) collection.


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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. Efficacy Assessments at Baseline and during Study Treatment
Within 28 days before the first dose of study drug, baseline tumor measurements will be 
performed on each patient.  Computed tomography (CT), including spiral CT, scans and MRI
are the preferred methods of measurement. Tumor assessments should include the chest and 
abdominal region.
The CT portion of a positron emission tomography (PET)-CT scan may be used as a method of 
response assessment if the site can document that the CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast). A PET scan alone or as part of a PET-CT may be 
performed for additional analyses but cannot be used to assess response according to RECIST.
The method of assessment used at baseline must be used consistently for tumor assessment and 
will be repeated every other cycle, beginning with Cycle 3 Day 1 (+3 days). If possible, the 
patient should have postbaseline assessments completed before Day 1 of the required cycles for 
reassessments to permit results to be discussed with the patient at the day of the patient visit to 
the clinic. If a cycle is delayed, tumor assessment should be concurrent with Day 1 of the new 
cycle.
For patients continuing treatment after study completion (that is, during the continued access 
period), efficacy assessments (frequency and type of assessments) will be at the discretion of the 
investigator, based on the standard of care.
10.1.2. Efficacy Assessments during the Study Period 
Postdiscontinuation Follow-Up
Postdiscontinuation follow-up during the study period will be conducted as described in the 
Study Schedule (Attachment 1).
For those patients who discontinue study treatment without objectively measured PD, the 
investigative sites will continue to monitor patients and periodically evaluate tumor response 
every 6 weeks by the same method used at baseline and throughout the study until the patient has 
objective disease progression, or study completion.  After the patient has objective disease 


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progression, radiologic tests are no longer required and the patient will be followed up 
approximately every 60 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.
Efficacy assessments (frequency and type of assessments) for patients still on treatment during 
the continued access period 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.
10.1.3. Primary Efficacy Measure
The primary efficacy measure is investigator-assessed PFS as defined as the time from 
randomization until the first evidence of objective progression as defined by RECIST 1.1 
(Eisenhauer et al. 2009) or death from any cause, whichever is earlier.  Patients who have neither 
progressed nor died will be censored at the day of their last radiographic tumor assessment, if 
available, or the date of randomization if no postbaseline radiographic assessment is available. 
The detailed censoring rules are described in Table JPBX.10.1.
The primary PFS analysis will be derived from the local investigator’s tumor assessments.
Lilly or its designee will collect and store all tumor measurement images on all enrolled patients 
throughout the study.  An central review of imaging scans will be performed by Lilly or its 
designee.
10.1.4. Secondary Efficacy Measures
The following secondary efficacy measures (Table JPBX.10.1) will be collected at the times 
shown in the Study Schedule (Attachment 1).
Table JPBX.10.1.
Secondary Efficacy Endpoints
Endpoint
Definition
Overall Survival
The time from the date of study enrollment to the date of death from any cause
Overall Response Rate
The proportion of patients with CR or PR according to RECIST v1.1
Disease Control Rate
The proportion of patients with CR, PR, or SD according to RECIST v1.1
Time to Worsening ECOG 
Performance Status (PS)
The time from the date of randomization to the date of first PS ≥2
Abbreviations:  CR = complete response; PR = partial response; PS = performance status; RECIST = Response 
Evaluation Criteria In Solid Tumors; SD = stable disease.
Overall Survival (OS):  OS duration is measured from the date of randomization of any study 
drug to the date of death from any cause.  For each patient who is not known to have died as of 


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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).
Overall Response Rate:  The overall response rate is the percentage of patients with a best 
response of CR or PR.
Disease Control Rate (DCR):  The DCR is the percentage of patients with a best response of 
CR, PR, or SD.
Time to Worsening ECOG Performance Status:  will be defined as the time from 
randomization to an ECOG PS evaluation of 2 or worse.  Patients with no evaluation of 2 or 
worse will have their time to deterioration of PS censored at the date of the last PS evaluation.
10.1.5. Exploratory Efficacy Measures
Biomarkers: Exploratory analysis using blood and tumor tissues will be done to explore
potential biomarkers related to the mechanism of action of abemaciclib, docetaxel, the cell cycle, 
and/or the pathogenesis of lung cancer to better understand relationships of cellular signaling 
defects, exposure, and response with clinical outcomes.
Change in Tumor Size: Change in tumor size will be measured using target lesion
measurements. This measurement will only be available on patients with measurable disease.
10.2. Health Outcome/Quality of Life Measures
10.2.1. Patient-Reported Outcomes
Patient-reported outcomes will be measured using 2 standardized questionnaires, the MDASI-LC 
and the EQ-5D-5L.  The MDASI-LC questionnaire is a well-developed and validated assessment 
with adequate measurement properties to capture well-known cancer disease- and treatment-
related symptoms and the consequences of these patient experiences.  Inclusion of this 
MDASI-LC is intended to establish the measurement properties of this questionnaire in this 
setting.
Items of particular interest are the patient-rated diarrhea and fatigue; it will be important to 
estimate the effects of these symptoms on the 6 MDASI Interference Items as well as on the 
EQ-5D-5L quality of life measures (that is, the health state utility index and the visual analog 
rating of health status).  Additionally, the inclusion of 8 additional MDASI-LC items to evaluate 
patient-reported effects of brain metastases as well as 3 additional MDASI-LC exploratory items 
will be evaluated for redundancy and validity.  This development work will help to inform the 
patient-reported consequences of treatment and will provide important information to distinguish 
the relative benefits of the evaluated treatments.  Importantly, establishing the validity and 
conceptual framework for this MDASI-LC and EQ-5D-5L set of items will allow us to 
prespecify important constructs in future clinical trials.


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Patient-reported questionnaires should be completed by all patients except when there is no 
available translation for a language in which the patient is fluent or literate.
At each time points identified in the Study Schedule (Attachment 1), a paper copy of the 
questionnaire should be administered to the patient prior to extensive interaction with the site 
staff and study drug administration.
On each measurement occasion and as specified in the Study Schedule (Attachment 1) (that is, 
once during screening, on Day 1 of each cycle, and at the Visit 801 follow-up visit), the patients 
should first complete the MDASI-LC questionnaire. Only after the MDASI-LC is completed 
should the patient complete the EQ-5D-5L questionnaire.
10.2.1.1. MDASI-LC
The MDASI-LC (Mendoza et al. 2011) is a 22-item questionnaire that includes 13 core symptom
items, 6 core interference items, and 3 lung-specific symptom items (coughing, constipation, and 
sore throat).  An additional MDASI page will include 11 exploratory items that are not a 
standard part of the validated MDASI-LC questionnaire.  Advanced lung cancer is a leading 
source of brain metastases, and symptoms related to brain metastases are described by 8 of these 
exploratory items (weakness on 1 side of body, difficulty understanding, difficulty speaking, 
seizures, difficulty concentrating, vision, change in appearance, and irritability).  These 
8 exploratory items are sourced from the brain-specific items included in the validated 
MDASI-Brain Tumor questionnaire.  The remaining 3 exploratory items comprise one additional 
item to further evaluate brain symptoms (headache) and 2 items to evaluate expected 
treatment-related toxicities including diarrhea and changes to the skin (that is, skin changes or 
skin rash).
“Worst pain” in the past 24 hours (MDASI-LC Item 1) and changes in the use of pain medication 
since the last assessment (that is, previous clinic visit) will be separately and jointly assessed as 
described in Section 12.2.10.1.
Responses for the MDASI-LC items are captured through the use of 11-point numeric rating 
scales anchored at 0 (not present or does not interfere) and ranged through 10 (as bad as you can 
imagine or completely interferes).  The MDASI-LC recall period is 24 hours, and typical 
completion time for this instrument is less than 5 to 10 minutes.
10.2.1.2. EQ-5D-5L
The EuroQol 5 Dimension 5 Level (EQ-5D-5L) is a self-reported standardized and validated
measure of health status, and will allow for comparison with other tumor types and disease states 
(Janssen et al. 2008). Responses to the EQ-5D-5L descriptive items (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression) constitute a patient’s profile that is converted
to a single summary index by applying a formula that essentially attaches population-specific 
weights to each 5-dimension response pattern. These index scores represent utilities that are 
applied to survival outcomes as a QoL adjustment important in conducting economic evaluations 
of comparative treatment benefit. Additionally, the EQ-5D-5L also includes a visual analog 
scale (VAS or “thermometer”) used to assess patients’ current health state through use of a 0-100 


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continuous “thermometer” rating scale.
The EQ-5D-5L is designed to be used in conjunction with other patient-reported measures.  
Patients will complete the questionnaire at each specified visit and according to the Study 
Schedule (Attachment 1).
Administration is preferably scheduled after the MDASI-LC, and before extensive contact with 
study personnel or clinicians, which could result in biased patient response.  The recall period is 
“today.”  The EQ-5D-5L is designed for respondent self-completion within a period of only a 
few minutes.
10.2.2. Resource Utilization
Investigators will be asked to report the use of all concomitant medications (in particular, 
analgesics, bisphosphonates, and RANK-L targeted agents), blood product transfusions, 
radiation therapy, surgery, and hospitalization days.
Data on each individual prescription and over-the-counter analgesic medication will be recorded 
on the Concomitant Medication eCRF.  The use of pain medications from the previous visit 
should be reviewed with the patient at each subsequent visit.  Any changes to analgesic use 
based on this information should be recorded on the Concomitant Medication eCRF, and the 
term “any changes” includes new or stopped analgesics.  Data on neurosurgical blocks will be 
recorded on the eCRF. This information should be collected during the study and at the 30-day 
follow-up visit.  Changes in pain medication will be evaluate separately and in conjunction with 
changes in the level of self-reported MDASI-LC pain assessments to avoid confounding of study 
drug treatment effect with the analgesic effect of increased or decreased intensity of 
pain/analgesic medication use.
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 JPBX.10.2 presents a summary of AE and SAE reporting guidelines.  Table JPBX.10.2
also shows which database or system is used to store AE and SAE data.


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Table JPBX.10.2.
Adverse Event and Serious Adverse Event Reporting Guidelines
Period
Types of AEs/SAEs to be Reported
Collection 
Database
Lilly Safety 
System
Baseline (pretreatment)
Preexisting conditions
x
All AEs
x
SAEs related to protocol procedures
x
x
Study treatment period
All AEs 
x
All SAEs
x
x
30-day short-term 
postdiscontinuation follow-up 
All AEs 
x
All SAEs
x
x
Long-term postdiscontinuation 
follow-up 
All SAEs related to protocol 
procedures or study drug
x
x
Continued access period
All AEs
x
All SAEs
x
x
Continued access follow-up
All AEs
x
All SAEs
x
x
After the patient is no longer 
participating in the study (that is, no 
longer receiving study treatment 
and no longer in follow-up)
All SAEs related to protocol 
procedures or study drug that the 
investigator becomes aware of
x
Abbreviations:  AE = adverse event; SAE = serious adverse event.
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.
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 electrocardiograms (ECG; for example, QTc 
prolongation), labs, vital sign measurements, other procedures, and so on that result in a 
diagnosis should be reported to Lilly or its designee.  All non-clinically significant findings must 
be documented in the patient record as not clinically significant and therefore will not be 
documented in the eCRF.


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Cases of pregnancy that occur during maternal or paternal exposures to study drug should be 
reported.  Data on fetal outcome and breast-feeding are collected for regulatory reporting and 
drug safety evaluation.
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the 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.
In addition, the investigator will record all relevant AE/SAE information in the CRF.  
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure or study drug via eCRF.
The investigator will decide whether he or she interprets the observed AEs as related to disease, 
to the study medication, study procedure, or other concomitant treatment or pathologies.  To 
assess the relationship of the AE to study drug or study procedure, the following terminologies 
are defined:

Probably related:  a direct cause and effect relationship between the study treatment and 
the AE is likely

Possibly related:  a cause and effect relationship between the study treatment and the AE 
has not been demonstrated at this time and is not probable, but is also not impossible

Does not know:  the investigator cannot determine

Not related:  without question, the AE is definitely not associated with the study 
treatment
The investigator should classify all “probably related,” “possibly related,” or “does not know” 
AEs and SAEs as related to study drug/study procedure.
Patients will be evaluated for AEs at each visit and will be instructed to call their physician to 
report any AEs between visits.
The National Cancer Institute (NCI)-CTCAE v 4.0 will serve as the reference document for 
choosing appropriate terminology for, and grading the severity of, all AEs and other symptoms.  
For AEs without matching terminology within the NCI-CTCAE v 4.0 criteria, the investigator 
will be responsible for selecting the appropriate system organ class and assessing severity grade 
based on the intensity of the event.
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.


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If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via eCRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment.
10.3.1.1. Serious Adverse Events
An SAE is any adverse event from this study that results in one of the following outcomes:

death

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

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.
Serious adverse event 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 serious adverse event (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 (for 
example, for the administration of study treatment or other protocol-required procedure) should 
not be considered SAEs.


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Serious adverse events due to disease progression, including death, should not be reported unless 
the investigator deems them to be possibly related to the study drug.
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 or study 
drug, 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.
10.3.1.2. Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the Development Core Safety Information in the IB and that the investigator identifies as 
related to the study drug or study procedure.  United States 21 CFR 312.32 and European Union 
Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national regulatory 
requirements in participating countries require the reporting of SUSARs.  Lilly has procedures 
that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulations and associated detailed guidances.
10.3.2. Other Safety Measures
10.3.2.1. Electrocardiograms
For each patient assigned to abemaciclib, a single local 12-lead digital ECGs will be collected 
according to the Study Schedule (Attachment 1 and Attachment 8).  Patients must be supine (or 
reclined as flat as possible) for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed to 
ensure high-quality records.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria 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 present, the 
investigator will assess the patient for symptoms (for example, palpitations, near syncope, 
syncope) and to determine if the patient can continue in the study.  The investigator or qualified 
designee is responsible for determining if any change in patient management is needed and must 
document his/her review of the ECG printed at the time of evaluation.


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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

laboratory analytes 

adverse events
10.3.3.1. Special Hepatic Safety Data Collection
If a study patient experiences elevated ALT ≥5×ULN and elevated total bilirubin (TBL)
≥2×ULN, or ALT >8x ULN for patients with underlying baseline hepatic metastases, liver tests
(Attachment 3), including ALT, AST, TBL, direct bilirubin, gamma glutamyl transferase (GGT), 
and creatine phosphokinase (CPK), should be repeated within 3 to 5 days to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator, based on the 
hepatic monitoring tests (Attachment 3) and in consultation with the Lilly CRP.  Monitoring of 
ALT, AST, and TBL should continue until levels normalize or return to approximate baseline 
levels.  Additional diagnostic testing should be considered to rule out cause of increased liver 
enzymes per the investigator’s discretion.
Hepatic monitoring tests (Attachment 3) should be collected in the event that 1 or more of the 
following conditions is met for the patient during the course of the study:

ALT ≥5×ULN and TBL ≥2×ULN

ALT >8x ULN for patients with underlying hepatic metastasis

discontinuation from study treatment due to a hepatic event or an abnormality of 
liver tests
10.3.3.2. Renal Function
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting cystatin C-calculated glomerular filtration rate.  
Increases in serum creatinine occurred within the first 2 weeks of treatment, remained stable 
through the treatment period, and were reversible upon treatment discontinuation.  If 
deterioration of renal function is suspected, serum creatinine should not be the only measure 
used to assess a patient’s renal function.
Dose adjustment (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function.  If 
deterioration of renal function is suspected per the investigator’s clinical assessment, dose 
alteration should follow the protocol guidance for non-hematological toxicities 
(Table JPBX.9.3).


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10.3.3.3. Venous Thromboembolic Events (VTEs)
In the randomized Phase 3 studies in breast cancer patients who received abemaciclib in 
combination with endocrine therapy, there was a greater number of patients who experienced 
VTEs in the abemaciclib plus endocrine therapy arm than in the placebo plus endocrine therapy 
arm. The majority of the events were non-serious and were treated with low-molecular-weight 
heparin.  Generally, these events did not result in discontinuation of the study treatment. At this 
time, the mechanism underlying the association between abemaciclib and the occurrence of 
VTEs is not known.  For suspected or confirmed VTE (e.g., deep vein thrombosis or pulmonary 
embolism), treatment should occur according to usual clinical practice. In studies with single-
agent abemaciclib use in the mBC population or other tumor types, including NSCLC, no 
increased rates of VTEs were observed as compared to the incidence of VTEs for these particular 
patient populations who were treated with other anticancer agents.  
10.3.3.4. Interstitial Lung Disease/Pneumonitis
Interstitial lung disease/pneumonitis has been identified as an adverse drug reaction for 
abemaciclib. The majority of events observed in clinical trials were Grade 1 or Grade 2 with 
serious cases and fatal events reported. Additional information is available in the IB.
Ask your patients to report any new or worsening pulmonary symptoms such as dyspnea, cough, 
and fever, and investigate and treat as per your local clinical practice (including corticosteroids 
as appropriate). If ILD/pneumonitis is suspected, investigations may include imaging, such as 
high-resolution computed tomography, bronchoalveolar lavage, and biopsy as clinically 
indicated.
Refer to Table JPBX.9.2 for guidance on dose adjustments of abemaciclib for patients with 
ILD/pneumonitis (see Attachment 11 for ILD/pneumonitis CTCAE grades). Discontinue
abemaciclib in cases of severe ILD/pneumonitis.
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 comparator drugs or concomitant drugs are reported directly to the 
manufacturers of those drugs/devices in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.4. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.


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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.
Attachment 9 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study.
10.4.1. Samples for Study Qualification and Health Monitoring
Blood samples will be collected to determine whether patients meet inclusion/exclusion criteria 
and to monitor patient health. Enrollment and treatment decisions may be based upon results of 
tests performed locally.  If local laboratory tests are used for this purpose, then a duplicate 
specimen must be submitted to the central laboratory.  Discrepancies between the local and 
central laboratory that may have an impact on eligibility or treatment decisions will not be 
considered protocol violations.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.4.2. Samples for Biomarkers
Samples for biomarker research to be collected from all patients in this study are the following:

tumor tissue

whole blood

plasma
Analyses may include, but are not limited to, nucleic acid and protein profiles to better 
understand the disease process and to develop predictive biomarkers.  These samples are 
described in the following sections.
10.4.2.1. Archived Tumor Tissue
For patients in the study, a small amount of preserved tumor tissue (either resected whole or 
partial tumor block, or core needle biopsy), previously taken to evaluate the patient’s disease, is 
required to be provided by sites upon patient randomization for biomarker research. Re-biopsy 
after progression from prior therapy is not required.
Available FFPE primary and/or metastatic tumor tissue should be as a block or 10 to 15
unstained slides.  However, if archived tissue is limited, a minimum of 10 slides should be 
submitted to meet the inclusion criteria of the study. Any block submitted will be returned to the 
site.  Any slides will be discarded within 15 years after last patient visit for the trial, unless 
otherwise determined by government or local law.


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In tumor tissue samples, the cell cycle pathway components and markers relevant to lung cancer 
pathogenesis may be evaluated to assess any potential correlation with response to abemaciclib
and/or docetaxel.  Tumor samples may be analyzed to explore potential tumor gene signature(s) 
associated with response or resistance to abemaciclib therapy.  These studies may be analyzed at 
a laboratory designated by the sponsor and may include immunohistochemistry of proteins, copy 
number amplifications, RNA gene-expression profiling, and/or genetic analyses of the tumor 
specimen DNA.  Such analyses may employ targeted or high-throughput sequencing approaches.  
For this purpose, the results of this analysis will be correlated with clinical efficacy data.
10.4.2.2. Whole Blood Samples for Pharmacogenetic Evaluations
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 whole blood sample will be collected for pharmacogenetic 
analysis.
Samples may be genotyped and analysis may be performed to evaluate a genetic association with 
response to abemaciclib.  These investigations may be limited to a focused candidate gene study 
or, if appropriate, genome-wide analysis may be performed to identify regions of the genome 
associated with the variability observed in drug response.  The pharmacogenetic biomarker 
samples will only be used for investigations related to disease and drug or class of drugs under 
study in the context of this clinical program.  They will not be used for broad exploratory 
unspecified disease or population genetic analysis.
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.
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 unless otherwise 
determined by government or local law.
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.
10.4.2.3. Plasma Samples for Exploratory Biomarker Evaluations
Ethylenediamine tetraacetic acid (EDTA)-anticoagulated plasma samples will be collected and 
analysis may be performed on biomarkers that may play a role in the abemaciclib mechanism of 
action.  The evaluation of these samples may involve analysis of DNA, RNA, and proteins 
(including any of these components derived from exosomes) to investigate their association with 
observed clinical outcomes to study drug.  The samples will be coded with the patient number 


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and stored for up to a maximum 15 years.  Details for collecting, processing, and storing the 
samples are similar those provided in Section 10.4.2.2.
10.4.3. Samples for Drug Concentration Measurements 
Pharmacokinetics - Abemaciclib Only
At the visits and times specified in the Pharmacokinetic and Pharmacodynamic Sampling
Schedule (Attachment 8), venous blood samples of approximately 2 mL each will be collected to 
determine the plasma concentrations of abemaciclib and its major metabolites LSN2839567 and
LSN3106726.
Instructions for the collection and handling of blood samples will be provided by the sponsor.  It 
is preferred that the blood samples be obtained from a peripheral location.  Blood samples will 
be allowed from central access devices but a sample drawn from a central catheter of any type 
for PK must take precautions to prevent obtaining a dilute sample.  If multiple samples are 
obtained centrally, the PK sample should be the last specimen drawn to reduce the potential for a 
diluted or improperly drawn sample.  The actual date and time (24-hour clock time) of each 
sampling will be recorded. In addition, the actual date and time of doses proximal to PK 
sampling days will be recorded on the appropriate form, according to the instructions provided.
A maximum of 5 samples may be drawn at additional time points during the study if warranted 
and agreed upon between both the investigator and Lilly.
These samples will be analyzed at a laboratory designated by the sponsor.  Plasma 
concentrations of abemaciclib plus its metabolites LSN2839567and LSN3106726 will be 
assayed using a validated liquid chromatography-tandem mass spectrometry method.
Bioanalytical samples collected to measure investigational product concentration and 
metabolism and/or protein binding will be retained for a maximum of 1 year following last 
patient visit for the study.  The PK samples will be stored at a facility designated by the sponsor.
10.5. Appropriateness of Measurements
Efficacy measurements by radiographic imaging are standard, widely used, generally recognized 
as reliable, accurate, and able to discriminate between effective and ineffective agents.
Safety measurements by laboratory monitoring are standard, widely used, generally recognized 
as reliable, accurate, and able to discriminate between agents with acceptable and unacceptable 
safety profiles.


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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.
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data, will be stored electronically in the central vendor’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
generic 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 PRO 
measures (for example, a rating scale), a daily dosing schedule, or an event diary.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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12.
Sample Size and Statistical Methods
12.1. Determination of Sample Size
The primary objective of this study is to compare abemaciclib versus docetaxel in terms of PFS 
in patients with Stage IV squamous cell carcinoma NSCLC after progression with a 
platinum-based therapy for advanced disease.  The study will enroll approximately 150 patients 
in 2:1 randomization (100 patients in abemaciclib and 50 patients in docetaxel).  The primary
PFS analysis will be performed after 120 PFS events are observed (that is, 20% censoring rate).
Historical information will be incorporated into control arm during the primary analysis by using 
a Bayesian approach. Assuming a hazard ratio (HR) of 0.64, with 150 patients and the proposed 
Bayesian design, power of 90.5% was estimated by simulation. Under a frequentist design, this 
sample size yields roughly 75% power with 1-sided type I error of 0.05.
If the true median PFS for the docetaxel arm is 3 months, the HR of 0.64 amounts to an 
approximately 1.7-month improvement in median PFS for the abemaciclib arm under an 
additional assumption of exponential survival distribution.
Refer to Attachment 6 for more detail on the statistical model and simulations.
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 
randomized treatment.
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.
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.
Any other change to the data analysis methods described in the protocol, and the justification for 
making the change, will be described in the clinical study report.
Additional exploratory analyses of the data will be conducted as deemed appropriate.


I 3 Y-M C -J P B X ( b) Cli ni c al Pr ot o c ol
P a g e 6 5
L Y 2 8 3 5 2 1 9
1 2. 2. 2. P ati e nt Di s p o siti o n
A detaile d descri pti o n o f pati e nt dis p ositio n will be pr o vi de d.  It will  incl u de a s u m mar y  of t he 
n u m ber a n d perce nta ge of patie nts e ntere d i nt o t he st u d y , e nr olle d i n t he st u d y, a n d treate d as 
well as n u m ber a n d perce nta ge of patie nts c o m pleti n g t he st u d y , or disc o nti n ui n g ( o verall a n d by 
reas o n f or disc o nti n uati on).
A s u m mar y  of all i m p orta nt pr ot oc ol de viati ons will be pr o vi de d.
1 2. 2. 3. P ati e nt C h ar a ct eri sti c s
P ati e nt de mo gra p hics , i ncl u di n g a ge, se x, scree ni n g hei g ht a n d wei g ht, a n d scree ni n g b o d y  mass 
i n de x, will be re p orte d usi n g descri pt i ve statistics.
Baseli ne disease c haracterist ics will be s u m marize d b y prese nti n g fre q ue nc y c o u nts a n d 
perce nta ges f or pat h ol o gical dia g n osis ( hist ol o gica l or c y t olo gical), disease sta ge, or
perf or m a nce stat us.
P ati e nt pree xisti n g c o n dit i on, hist ori cal ill ness, a n d prior c he m ot h era p y (i nclu di n g b ot h c y t ot o xic 
a n d tar gete d a ge nts) will be s u m marize d b y treat me nt ar m.
1 2. 2. 4. C o n c o mit a nt T h er a p y
C o nc o mita nt me dicat i ons will be s u m marize d b y treat me nt ar m i n a fre q ue nc y ta ble list i n g t he
t er ms rec or de d o n t he e C R F.
1 2. 2. 4. 1. P o st di s c o nti n u ati o n T h er a p y
T he n u m bers a n d perce nta ges of patie nts re p orti n g p ost disc o nt i n uati on t hera pies will be 
pr o vi de d o verall, b y  t yp e of  t hera p y (s ur ger y, ra di ot hera p y, or s yste mic t hera p y), a n d b y dr u g 
na me.
1 2. 2. 5. Tr e at m e nt C o m pli a n c e
T he n u m ber of d ose o missi o ns, re d ucti o ns, del a ys, t he n u m ber of c ycles recei ve d, a n d d ose 
i nte nsit y will be s u m marize d f or all treate d patie nts per treat me nt ar m.
Treat me nt c o m plia nce i nf or mat i on f or a be macicli b will be c o llecte d t hr o u g h s oli d oral d osa ge 
u nit c o u nts at eac h t u mor assess me nt visit .  T he esti mate of perce nt c o mplia nce will  be gi ve n b y:
Perce nt C o m plia nce =
Act ual  c u m ulati ve d ose ta ke n
E x pecte d c u m ulati ve d ose t o be ta ke n x 1 0 0
T he act ual  c u mulati ve d ose ta ke n will be deter mi ne d base d o n c o u nti n g t he n u m ber of d osa ge 
u nits ret ur ne d at eac h visit a n d s u btracti n g t hat n u m ber fr o m t he n u m ber of d osa ge u nits
di s pe nse d.  T he e x pecte d c u m ulative d ose t o be ta ke n will be deter mi ne d base d o n t he assi g ne d 
d ose a n d ta ki n g i nt o acc o u nt a n y  d ose re d uctio ns or o missi o ns.


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12.2.6. Primary Outcome and Methodology
The primary endpoint of this study is PFS. PFS time is measured from the date of randomization 
to the date of investigator-determined objective progression as defined by RECIST v1.1, or death 
from any cause.  Patients who have neither progressed nor died will be censored at the day of 
their last radiographic tumor assessment (if available) or date of randomization if no post 
initiation (that is, postbaseline) radiographic assessment is available.  The detailed censoring 
rules are described below (Table JPBX.12.1).
The primary method of analysis for comparing PFS between the treatment arms will use a 
Bayesian exponential-likelihood model with a hierarchical random-effects distribution on 
treatment effects. The final model will incorporate historical data from a completed study 
(Garon et al. 2014) to augment the prospective control-arm data. If the Bayesian posterior 
probability of superiority of abemaciclib arm to docetaxel arm (that is, HR <1) exceeds 0.95, 
then it will be concluded that the experimental arm is superior. See Attachment 6 for more 
details. In addition to the primary analysis of PFS, following analysis will be conducted based 
on observed PFS data:

Log-rank test will be used to compare the PFS distribution between treatment groups 
with and without adjustment using the same factors as the randomization scheme.

Kaplan-Meier method (Kaplan and Meier 1958) will be used to estimate the PFS curve 
for each treatment group.

The Cox proportional hazard model (Cox 1972) will be used to estimate the HR and 
corresponding 95% CI with and without stratified by randomization factors.
Table JPBX.12.1.
Rules for Determining Date of Progression or Censor for 
Progression-Free Survival
Situation
Date of Progression or Censor
Outcome
1
No baseline tumor assessments
Date of Randomization
Censored
2
No post baseline assessments and no death
Date of Randomization
Censored
3
No documented progression and no death (with a 
post-baseline tumor assessment)
Date of last adequate tumor 
assessment
Censored
4
Patient lost to follow-up (or withdrew consent 
from study participation) before documented 
progression or death
Date of last adequate tumor 
assessment
Censored
5
Documented progression
Date of documented progression.
If a tumor assessment was done on 
multiple days, use the earliest date for 
that visit.
Progressed
6
Death without documented progression
Date of death
Progressed
7
Death or documented progression after missed ≥2 
consecutively post-baseline tumor assessment 
visits
Date of last adequate tumor 
assessment before missed assessments 
or date of randomization, whichever is 
later
Censored


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12.2.7. Analyses of Efficacy
Secondary efficacy objective for this study include comparison of OS, ORR, DCR, and time to 
worsening of PS.
Kaplan-Meier analysis will be performed on the observed distribution of OS. Parameter
estimates of the OS median and quartiles will be reported for each treatment group. All
parameter estimates will be quoted together with their 95% confidence limits. Overall survival
will be compared between treatment arms using the log-rank test.
The ORR and DCR of each treatment arm will be calculated as defined by RECIST v1.1.  All 
rates will be compared between treatment arms based on a normal approximation for the
difference between the rates.
Exploratory analysis may be performed to investigate associations between change in tumor size 
data and PFS and OS data.
12.2.8. Pharmacokinetic and Pharmacodynamic Analyses
PK analyses will be conducted on all patients who have received at least 1 dose of abemaciclib
and have had samples collected (see Attachment 8).
Mean population PK parameters for abemaciclib in plasma (clearance, exposure, volume of 
distribution, and half-lives) and inter-individual PK variability will be computed using nonlinear 
mixed effect modeling (NONMEM).  The current PK model for abemaciclib, which has been 
developed using plasma concentration data available from the Phase 1 Study JPBA, will be 
updated using the plasma data collected in this study.  Covariate effects (such as age, weight, 
sex, and plasma protein levels) on the PK parameters of abemaciclib in plasma will also be 
investigated.
Pharmacodynamic biomarker samples will be collected as specified in the Study Schedule 
(Attachment 1).  Refer to these attachments (including footnotes) for important information 
about these samples and their collection.  Furthermore, pharmacodynamic data (such as 
neutrophil, lymphocytes, or platelets counts in blood, etc.) collected in this study may also be 
analyzed by means of NONMEM and connected to the population PK model in a 
PK/pharmacodynamic (PK/PD) model.
Pharmacodynamic data from all patients undergoing pharmacodynamic assessments will be 
analyzed.  The pharmacodynamic data will be combined and exploratory analyses will be 
conducted to determine if a relationship exists between plasma concentration and 
pharmacodynamic effect(s) in humans.  Interpatient variability in human pharmacodynamic
response will also be assessed.
The version of software used for the analysis will be documented and will meet the Lilly 
requirements of software validation.


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12.2.9. Biomarker Analysis
Associations between clinical endpoints and biomarkers will be evaluated using data from 
patients who have an evaluable sample for each biomarker of interest, and such evaluation will 
be done on an individual marker basis.
12.2.10.
Health Outcome/Quality of Life Analyses
Patient-reported outcomes are measured through paper versions of the following:

MDASI-LC (includes additional page with 11 exploratory items that will be scored 
separately)

EQ-5D-5L (EuroQol 5-Dimension 5 Level)
The reason and number of missing and incomplete questionnaires/assessments by visit will be 
summarized for each questionnaire and study arm.
12.2.10.1.
MDASI-LC
The MDASI-LC population will include all patients who completed at least 1 baseline 
assessment (that is, a completed baseline or a Cycle 1 MDASI-LC questionnaire completed 
before the administration of any study drug) followed by at least 1 MDASI-LC assessment after 
1 cycle of study drug (for example, a completed MDASI-LC questionnaire at Cycle 2 Day 1 or 
later).
The MDASI-LC will be summarized for each assessment period and scored as described 
(Mendoza et al. 2011).  The first 22 MDASI-LC items will be reported as core symptoms 
(Items 1-13), interference items (Items 14-19), and lung symptoms (Items 20-22).  Eight of the
11 additional exploratory items will be reported as brain tumor symptoms derived from the 
MDASI-BT questionnaire (Items 23-30). The last 3 of the 11 exploratory items include 
1 additional brain symptom (Item 31) and 2 treatment-expected toxicities (Items 32-33); each of 
these 3 items should be separately scored and reported (that is, no summated average is to be 
calculated across these 3 items).
For each patient in the MDASI-LC population (as described above), the maximum change from 
baseline score will be calculated and summarized for MDASI-LC composite scores (that is, 
Core Symptoms, Interference Items, Lung Symptoms with the Core Symptoms, and Brain 
Tumor Symptoms), the “worst pain” item, and separately for each of the last 3 exploratory items 
(Items 31-33).
Further analysis details will be described in the statistical analysis plan (SAP).
12.2.10.2.
Health State Utility
The EQ-5D-5L population will include all patients who completed at least 1 baseline assessment 
(that is, a completed baseline or a Cycle 1 EQ-5D-5L questionnaire completed before the 
administration of any study drug) followed by at least 1 completed EQ-5D-5L assessment after 
1 cycle of study drug (for example, a completed EQ-5D-5L questionnaire at Cycle 2 Day 1 or 
later).


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The EQ-5D-5L data will be scored based on EuroQol recommendations.  The index score is 
calculated from a set of item weights to derive a score of <0 to 1, with 1 representing the best 
health status.  The VAS is scored from 0 (worst imaginable health state) through 100 (best 
imaginable health state) to represent the patient’s self-report for each day.  EQ-5D-5L responses 
for each item will be summarized by frequency and corresponding percentages.  Descriptive 
statistics for the index and VAS will be calculated as described in the SAP.
12.2.10.3.
Use of Pain Medications
Pain medication will be classified into 1 of 6 categories by the sponsor, using an analgesic ladder 
approach with medication category based on a World Health Organization scale outlined in
Table JPBX.12.2.  A therapy category for each cycle will be assigned according to the maximum 
category of analgesic agent(s) recorded in the Concomitant Form for that cycle.  Categories of 
pain medication for each cycle (that is, categories for classification of NSAIDs and opioids and 
other non-opioid analgesics by level of strength to treat levels of pain severity according to 
Anatomical Therapeutic Chemical [ATC] classification code) will be determined based on ATC
classification code as applied to the collected analgesic use data.  Change in categories based on 
the analgesic ladder compared to baseline will be described by arm. Note that it may not be 
possible to distinguish opioids that were given parentally (coded as 4 in Table JPBX.12.2) from 
those that are also available orally and may have therefore been administered by mouth to be 
coded as 2 or 3 in Table JPBX.12.2. Information in the eCRF concerning pain medication may 
help distinguish the parenteral from the oral dosage form.  For example, morphine is available as 
an injectable and is also available orally; here the relatively low parenteral mg strength (for 
example, 10 mg) could help distinguish from a 30- to 60-mg oral dosage form.
Table JPBX.12.2.
World Health Organization Pain Scale
Code
Description
0
No analgesia
1
Aspirin (for pain, not cardiovascular prophylaxis), acetaminophen, nonsteroidal anti-inflammatory drugs
2
Codeine, hydrocodone, pentazocine, oxycodone
3
Oral morphine, hydromorphone, methadone, transdermal fentanyl
4
Parenteral opiates
5
Neurosurgical procedures (blocks)
12.2.11.
Safety Analyses
All safety summaries and analyses will be based upon the Safety Population as defined in 
Section 12.2.1.
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.


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Adverse events will be reported using a unified CTCAE/MedDRA reporting process:

The CTCAE v4.0 term reported by the investigator will be mapped to the MedDRA 
Preferred Term (PT) and System Organ Class (SOC) of the corresponding MedDRA 
Lower Level Term (LLT), unless the reported CTCAE term is ‘Other – specify’.

If the reported CTCAE term is ‘Other – specify’, the MedDRA LLT, PT, and SOC 
mapped from the verbatim AE term will be used.

All listings and summaries will use the PT resulting from this process.
Preexisting conditions are defined as adverse events that begin prior to the first dose of study
drug. A TEAE is defined as an event that first occurred or worsened in severity after baseline.
Comparisons of preexisting conditions to on-treatment events at the LLT level will be used in the
treatment-emergent computation.
An overall summary of AEs will be provided for AEs deemed by the investigator to be possibly 
related to study drug, and repeated for events regardless of study drug causality.  Incidence rates 
of these events will be compared between treatment arms using Chi square test.
The following summaries will be produced by PT within SOC: preexisting conditions, SAEs,
TEAEs, drug-related TEAEs, and procedure-related TEAEs.
The following summaries will be produced by PT within SOC and maximum CTCAE grade:
laboratory-based TEAEs, nonlaboratory-based TEAEs, drug-related laboratory-based TEAEs,
and drug-related nonlaboratory-based TEAEs.
Reasons for death will be summarized separately for on-therapy and within 30 days of treatment 
discontinuation.  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.
12.2.12.
Subgroup Analyses
Subgroup analyses of PFS and OS will be performed for potential predictive and prognostic
subgroup variables.
12.2.13.
Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended.


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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, 
where permitted by local law or regulation, by the patient's 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.
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 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 study site’s ERBs should be provided with the following:

the current IB or package labeling (for example, Package Insert, or SmPC) and updates 
during the course of the study

the ICF

relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:

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 

ICH GCP Guideline (E6)

applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).


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Some of the obligations of Lilly will be assigned to a third-party organization.
An identification code assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting AEs and/or other trial-related data.
13.3.1. Investigator Information
Physicians with a specialty in oncology will participate as investigators in this clinical trial.
13.3.2. Protocol Signatures
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.
13.3.3. Final Report Signature
The clinical study report (CSR) coordinating investigator will sign the final CSR 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. 
Lilly will select an investigator to serve as the CSR coordinating investigator.
The Lilly responsible medical officer and statistician will sign/approve the final CSR 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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Tynan M, Moore M, Kies MS. Phase III trial comparing a defined duration of therapy versus 
continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell 
lung cancer. J Clin Oncol. 2002;20(5):1335-1343.


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Stinchcombe TE, Socinski MA.  Treatment paradigms for advanced stage non-small cell lung 
cancer in the era of multiple lines of therapy. J Thorac Oncol. 2009;4(2):243-250.
Tarceva [US package insert]. Melville, NY: OSI Pharmaceuticals, Inc.; 2010. Available at: 
www.accessdata.fda.gov/drugsatfda_docs/label/2010/021743s14s16lbl.pdf. Accessed 
February 9, 2015.
Thatcher N., Chang A, Parikh P, Rodigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, 
Tan EH, Pemberton K, Archer V, Carroll Kl. Geftinib plus best supportive care in previously 
treated patients with refractory advanced  non-small cell lung cance: results from a ranomised , 
placebo controlled, multicenter study (Iressa Survival Evaluation in Lung cancer). Lancet.
2005;366:1527-1537.
Walling J. Chemotherapy for advanced non-small lung cancer. Respir Med. 1994;88:649-657.
Zhou JX, Niehans GA, Shar A, Rubins JB, Frizelle SP, Kratzke RA. Mechanisms of G1 
checkpoint loss in resected early stage non-small cell lung cancer. Lung Cancer.
2001;32:27-28.


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Protocol JPBX Study Schedule


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Study Schedule, Protocol I3Y-MC-JPBX
Perform procedure as indicated.
Baseline Schedule
Study Period
Baseline
Visit
0
Duration
Up to 28 days
Relative Day
≤28
≤14
Relative to C1D1
Procedure 
Category
Procedure
Comments
Study Entry/ 
Enrollment
Informed Consent Form 
signed
X
Prior to conducting any protocol-specific tests / procedures
Inclusion/Exclusion 
evaluation
X
Medical History
Initial medical 
history/preexisting conditions
X
Historical illnesses
X
Including habits assessment of alcohol and tobacco use
Physical examination 
X
Including height and weight
Physical 
Examination
ECOG performance status
X
Vital signs
X
Includes blood pressure, pulse, respiratory rate, and temperature
Adverse Events Collection/CTCAE Grading
X
Concomitant Medication Notation
X
Note: RANK-L or bisphosphonate agents should be initiated at least 
7 days  prior to randomization to study treatment, if applicable. For 
patients assigned to docetaxel, pretreatment with corticosteroids is 
recommended per label at least 3 days prior to first dose of docetaxel.
Tumor 
Assessment
Radiologic imaging 
according to RECIST 1.1
X
Performed locally.  All patients, CT or MRI scan of the chest and 
abdomen. CT scan is the best currently available and reproducible 
method to measure lesions selected for response assessment; it is 
recommended that CT imaging of the abdomen be performed with IV 
contrast whenever possible.  MRI may be used instead of CT in 
selected instances. Gadolinium-enhanced MRI is preferred if
hypersensitivity to contrast.
Brain MRI
X
Only those patients with symptoms of  CNS involvement or known 
history of CNS metastasis must have brain MRI to confirm status of 
CNS metastases within 28 days of C1D1. The patient may have no 
evidence of Grade ≥1 CNS hemorrhage based on pretreatment MRI .
A prior brain scan within 45 days of C1D1 may be used for baseline 
scan if no symptoms of CNS metastases.
Tumor measurement 
(palpable or visible)
X
Photography of metastatic skin lesions with ruler required, if 
applicable


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Baseline Schedule
Study Period
Baseline
Visit
0
Duration
Up to 28 days
Relative Day
≤28
≤14
Relative to C1D1
Procedure 
Category
Procedure
Comments
Lab/
Diagnostic Tests
Serum Pregnancy Test
X
Local serum pregnancy test is performed on females with child-
bearing potential.
Central hematology
X
Enrollment and treatment decisions may be based upon results of tests 
performed locally. If local laboratory tests are used for this purpose, 
then a duplicate specimen must be submitted to the central laboratory.
Discrepancies between local and central laboratory that may have an 
impact on eligibility or treatment decisions will not be considered 
protocol deviations.
Central Chemistry
X
Enrollment and treatment decisions may be based upon results of tests 
performed locally. If local laboratory tests are used for this purpose, 
then a duplicate specimen must be submitted to the central laboratory. 
Discrepancies between local and central laboratory that may have an 
impact on eligibility or treatment decisions will not be considered 
protocol deviations.
Local ECG
X
Abemaciclib patients will have a single copy baseline ECG. Patients 
must be supine (or reclined as flat as possible) for approximately 5 to 
10 minutes before ECG.
Archived Tumor Tissue
X
Archived Tissue is required for participation in study.  Sample must be
submitted for those patients who have met all inclusion/exclusion 
criteria before randomization can occur. A FFPE archived tumor 
tissue sample or 10-15 unstained slides (sample from block or core 
needle biopsy), cut at 5 microns (minimum of 10 slides) are required 
for randomization.  Due diligence should be used to make sure that 
tumor specimen (not normal adjacent or tumor margins) is provided
Health 
Outcomes
MDASI-LC; EQ-5D-5L
X
Patients complete prior to extensive interaction with site staff.
Treatment 
Assignment
IWRS randomization
X
IWRS should be accessed at least 4 days prior to C1D1 to initiate 
pretreatment with dexamethasone for those patients randomized to 
docetaxel therapy per label recommendations. Archive tissue must be 
submitted before randomization can occur. Patients should begin 
treatment within 14 days of randomization.
Abbreviations:  C1D1 = Cycle 1, Day 1; CNS = central nervous system ; CT = computed tomography; CTCAE = Common Terminology Criteria 
for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ; EQ-5D-5L = EuroQol 5 Dimension 5 Level;
FFPE = formalin-fixed paraffin-embedded; IV = intravenous; IWRS = interactive web-response system; MDASI-LC = MD Anderson Symptom 
Inventory Lung Cancer; MRI = magnetic resonance imaging; RANK-L = nuclear factor kappa B ligand; RECIST = Response Evaluation Criteria 
in Solid Tumors.


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On 
Treatment
Study Period
Study Treatment Period
Cycle/Visit
1
2
3
4-X
Comments
Duration
21 days
21 days
21 days
21 days
A cycle is defined as the planned treatment 
interval of 21 days plus any subsequent delay 
prior to the start of the next cycle. A delay of a 
cycle due to holidays, weekends, bad weather, or 
other unforeseen circumstances will be permitted 
up to 7 days and not counted as a protocol 
deviation.
Relative Day 
within Dosing 
Cycle
1
8
1
8
1
8
1
8
Procedure 
Category
Procedure
Comments
Physical 
Examination
Weight
X
X
X
X
Weight is not required to be repeated on C1D1 if 
weight was collected within 3 days of C1D1 
during baseline procedures.
Vital signs
X
X
X
X
Includes blood pressure, pulse, respiratory rate, 
and temperature
ECOG 
performance 
status
X
X
X
X
Adverse Events 
Collection/CTCAE Grading
X
X
X
X
Concomitant Medication 
Notation
X
X
X
X
Lab/
Diagnostic 
Tests
Central 
hematology
X
X
X
X
X
X
X
X
Sample may be drawn within  72 hours prior to 
treatment on Day 1 of each cycle, and within ±2 
business days at Day 8 of each cycle. If 
baseline sample was drawn within 72 hours of 
C1D1, it does not need to be repeated.  If results 
of the laboratory tests obtained at planned Day 1 
of the next cycle require a delay in the start of 
the subsequent cycle, any repeat laboratory tests 
should be obtained as clinically indicated.  Local 
labs may be drawn for treatment adjustment and 
patient management purposes.
Central 
chemistry
X
X
X
X
X
X
X
X
Sample may be drawn within 72 hours prior to 
treatment on Day 1 of each cycle, and within ±2 
business days at Day 8 of each cycle. If 
baseline sample was drawn within 72 hours of 
C1D1, it does not need to be repeated.  If results 
of the laboratory tests obtained at planned Day 1 
of the next cycle require a delay in the start of 
the subsequent cycle, any repeat laboratory tests 
should be obtained as clinically indicated.  Local 
labs may be drawn for treatment adjustment and 
patient management purposes
Local Serum 
Pregnancy 
Test
X
X
X
X
For those females who are able to bear children, 
repeat pregnancy test should be done prior to 
administration of study treatment.


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On 
Treatment
Study Period
Study Treatment Period
Cycle/Visit
1
2
3
4-X
Duration
21 days
21 days
21 days
21 days
A cycle is defined as the planned treatment 
interval of 21 days plus any subsequent delay 
prior to the start of the next cycle. A delay of a 
cycle due to holidays, weekends, bad weather,
or other unforeseen circumstances will be 
permitted up to 7 days and not counted as a 
protocol deviation.
Relative Day 
within Dosing 
Cycle
1
8
1
8
1
8
1
8
Procedure 
Category
Procedure
Comments
Lab/
Diagnostic 
Tests
Pharmacokinetic 
sampling 
X
X
X
X
X
See ECG and Pharmacokinetic Sampling 
Schedule (Attachment 8) for specific timing. 
No PK is required for patients assigned to 
docetaxel arm.
Pharmacogenetic 
whole blood 
sample
X
Biomarker 
plasma sample
X
X
Draw sample before patient is dosed on C1D1 
and upon arrival at site on C2D1.
Local ECG
(abemaciclib 
patients only)
X
X
For abemaciclib patients only: Single Copy. 
Predose on C1D1-Predose:  C1D8:  Upon 
arrival to site and 3 ± 0.5 h after first ECG 
collected this day: C2D1: Predose. Patients 
must be supine (or reclined as flat as possible) 
for approximately 5 to 10 minutes before ECG.
Tumor 
Assessment
Tumor 
measurement 
(palpable or 
visible)
X
X
Repeat every 6 weeks (every other even cycle) 
until documented progression and within 14 
days of clinical progression. If skin lesions are 
noted, photography should be done with a 
digital camera and measured. Assessments may 
be completed ±3 days of scheduled cycle Day 
1.
Radiologic 
imaging 
according to 
RECIST (CT 
scan/MRI)
X
X
Performed locally. Patients will undergo 
radiographic assessment of disease status every 
6 weeks (± 3 business days), as calculated from 
the first dose of study therapy until there is 
radiographic documentation of PD.
Additionally, imaging should be performed
within 14 days of clinical progression.
Health 
Outcomes
MDASI-LC; 
EQ-5D-5L
X
X
X
X
Patients complete prior to extensive interaction 
with site staff. Questionnaires should be 
administered on C1D1 and then Day 1 of every 
cycle thereafter.
Study 
Treatment 
Abemaciclib
X
X
X
X
Dosed every 12 hours (± 2 hours) orally. The 
patient will receive D1 doses for each cycle in 
the clinic. On C1D8, patient will need to take 
abemaciclib 4 hours prior to schedule visit time
for PK purposes.
Docetaxel
X
X
X
X
Administered on Day 1 of every cycle, 
intravenously. Weight must be obtained prior 
to administration. Patient should be pretreated 
with corticosteroids per label recommendations.
Abbreviations:  C1D1 = Cycle 1, Day 1; C1D8 = Cycle 1, Day 8; C2D1 = Cycle 2, Day 1; CNS = central nervous system; CT = computerized 
tomography ; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; EQ-5D-5L = EuroQol 5 Dimension 5 Level; MDASI-LC = MD Anderson Symptom Inventory Lung Cancer; MRI = magnetic resonance 
imaging; PD = progressive disease; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors.


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Post–
Treatment 
Follow-up 
Period
Study 
Period
Short-term 
Follow-Up
Long-term 
Follow-Up
Visit
801
802-X
Post-Treatment Discontinuation Follow-Up should begin after the last 
dose of study therapy or, if study therapy has been omitted for an 
extended period, the date it is decided that the patient will not restart 
study therapy.
Duration
30 +/-  7 days
Variable
Long-term follow-up begins the day after the short-term post-
discontinuation follow-up visit (v801) is completed and continues until 
the patient’s death, lost to follow-up, or overall study completion. The 
variable period depends on whether disease progression has occurred, 
and tumor assessments are due. Once disease progression has occurred 
visits should occur every 60 days
Relative 
Day
30
Procedure 
Category
Procedure
Comments
Physical 
Examination 
Weight
X
Vital signs
X
Includes blood pressure, pulse, respiratory rate, and temperature
ECOG 
performance 
status
X
Tumor 
Assessment
Tumor 
measurement 
(palpable or 
visible)
X
X
Not required if progressive disease is documented while on treatment or 
at Visit 801. If the patient discontinues treatment and begins treatment 
with another anticancer therapy off study, scans will continue until 
progression or study ends. Reassessment should be repeated 
approximately every 6 weeks following the first dose of treatment until 
disease progression.
Radiologic 
imaging 
according to 
RECIST
X
X
The same method of imaging used at baseline should be used for each 
subsequent assessment.  Not required if PD is documented while on 
treatment or at Visit 801. If the patient discontinues treatment and 
begins treatment with another anticancer therapy off study, scans will 
continue until progression or study ends. During long-term follow-up 
period, repeat scans should performed approximately every 6 weeks 
until disease progression.
Survival information
X
X
Although preferable to collect during a clinic visit, survival information 
may be collected by contacting the patient or family directly (for 
example, via telephone) if no procedures required. This should be 
collected at minimum every 60 days if no other procedures are 
performed. Additional long-term follow-up data collection may include 
post-discontinuation anticancer therapies.
Adverse Events 
Collection/CTCAE Grading
X
X
After Visit 801, only study protocol or drug-related events are reported.
If a patient has an ongoing AE or SAE possibly related to study drug 
(for instance, abnormal electrolytes), the patient should be followed 
until the event is resolved, the event is no longer considered to be drug-
related, the event becomes stable or returns to baseline, a new treatment 
is initiated for the patient, or the patient dies or is lost to follow-up.  
Any subsequent follow-up(s) for AEs will be no more than 30 days ± 5 
days in duration.
Concomitant Medication 
Notation
X


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Post–
Treatment 
Follow-up 
Period
Study 
Period
Short-term 
Follow-Up
Long-term 
Follow-Up
Visit
801
802-X
Post-Treatment Discontinuation Follow-Up should begin after the last 
dose of study therapy or, if study therapy has been omitted for an 
extended period, the date it is decided that the patient will not restart 
study therapy.
Duration
30 +/-  7 days
Variable
Long-term follow-up begins the day after the short-term post-
discontinuation follow-up visit (v801) is completed and continues until 
the patient’s death, lost to follow-up, or overall study completion. The 
variable period depends on whether disease progression has occurred, 
and tumor assessments are due. Once disease progression has occurred 
visits should occur every 60 days
Relative 
Day
30
Procedure 
Category
Procedure
Comments
Lab/
Diagnostic 
Tests
Central 
Hematology
X
Central 
Chemistry
X
Local Serum 
Pregnancy Test
X
For those females who are able to bear children
Plasma 
Biomarker
X
Local ECG
X
Only for patients randomized to abemaciclib
Health 
Outcomes
MDASI-LC, 
EQ-5D-5L
X
Patients complete prior to extensive interaction with site staff.
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EQ-5D-5L = EuroQol 5 Dimension 5 Level; IV = intravenous; MDASI = MD Anderson Symptom Inventory Lung 
Cancer; MRI = magnetic resonance imaging; PD = progressive disease; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid 
Tumors; SAE = serious adverse event.


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Study Schedule for the Continued 
Access Period
Patients on Study 
Treatment
Continued Access 
Period Follow-Up
Comments
Cycle
X
Follow-Upa
Visit
501-5XX
901
Duration 
(days)
21
30(+/- 5 days)
Relative day 
within a cycle
1
Procedure 
Category
Procedure
Lab
Local Serum Pregnancy Test
X
X
For those females with child bearing 
potential. Repeat pregnancy test 
should be done at each cycle prior to 
administration of study treatment.
Adverse Events Collection/CTCAE Gradingb
X
X
Study 
Treatment
Abemaciclibc
X
Only for those that were assigned to 
abemaciclib at randomization will 
continue to receive abemaciclib 
orally every 12 hours until criteria 
for discontinuation is met.
Docetaxeld
X
Patients assigned to docetaxel may 
continue to received docetaxel 
intravenously on Day 1 of every 
cycle until criteria for 
discontinuation is met.
Abbreviations:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; SAE = serious adverse event.
a
The continued access period begins after study completion (that is, after final OS analysis) and ends at the end of trial (that is the last patient 
visit).
b
Data on SAEs that occur before the end of trial will be stored in the collection database and the Lilly Safety System. Only related SAE/AEs 
will be reported while the patient continues to receive treatment.
c
Abemaciclib is to be administered every 12 hours on Days 1 through 21 of each cycle for those that have received abemaciclib treatment on 
study until a criteria for discontinuation is met.
d
Docetaxel is to be administered once every 3 weeks on Day 1 of each cycle for those that have received docetaxel treatment on study until a 
criteria for discontinuation is met.


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Protocol JPBX Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya (except as indicated)
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Potassium
Erythrocyte count (RBC)
Total bilirubin
Mean cell volume (MCV)
Direct bilirubin
Mean cell hemoglobin concentration (MCHC)
Alkaline phosphatase
Leukocytes (WBC)
Alanine aminotransferase (ALT)
Neutrophils, segmented and bands
Aspartate aminotransferase (AST)
Lymphocytes
Blood urea nitrogen (BUN)
Monocytes
Creatinine
Chloride
Eosinophils
Calcium
Basophils
Albumin
Platelets
Total Protein
Glucose (random)
Lactase Dehydrogenase (LDH)
Calculated creatinine clearance ≥50 mL/min (per the 
Cockcroft-Gault formula or equivalent, Attachment 5)
Serum Pregnancy Test (females only)b (local only)
Abbreviations:  RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated (central) laboratory.
b
Assayed by investigator-designated (local) laboratory.


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Protocol JPBX 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, segmented and bands
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
CPK
Anti-smooth muscle antibodya
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Protocol JPBX ECOG Performance Status
Eastern Cooperative Oncology Group (ECOG) Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., 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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Protocol JPBX Creatinine Clearance 
Formula
Note:  This formula is to be used for calculating creatinine clearance (CrCl) from local 
laboratory results only.
For serum creatinine 
concentration in mg/dL:
CrCl =
(mL/min) 
(140 – agea) (wt)    0.85 (if female), or 1.0 (if male)
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(mL/min)
(140 – agea) (wt)  0.85 (if female), or 1.0 (if male)
0.81 serum creatinine (mol/L)
a Age in years, weight (wt) in kilograms.
Reference:  Cockcroft and Gault 1976.


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Protocol JPBX Details of Statistical 
Progression-Free Survival Model and Simulation Result
For this study, we use a Bayesian Augmented Control (BAC) model that allows information 
borrowing from a previous study to augment the data on the control arm in the current study.  
The primary endpoint of this trial is progression-free survival (PFS) time.  PFS is modeled using 
an exponential-likelihood model (constant baseline hazard) as specified below:
where T is the hazard rate for the experimental arm, and is the hazard rate for the current 
control arm.  θT is the log hazard ratio (HR) between the 2 hazard rates.
The model used for incorporating the historical controls is as follows:
where 1 is the hazard rate for the historical control, is as above, and 1 is the log HR between 
the 2 hazard rates.
The following hierarchical model is used,
and we specify priors for the hyperparameters:
We use the relatively uninformative priors of Normal (0, 100) for the normally distributed 
parameters. For the Inverse Gamma prior for 2, we chose a distribution with mean of 0.1 and 
with equivalent weight of 0.03 to enable borrowing of approximately 40 patients from historical 
data when true control hazard rate is consistent with historical control hazard rate, that is, 2 
Inverse Gamma(0.015, 0.00015). This is consistent with the prior opinion that the standard 
deviation of the log(HR) of the assumed population of historical studies relative to current 
control arm is 0.1.
The mathematical details to assess the amount of borrowing are as follows:  since the mean (μ) 
and variance (σ2) of the hazard rate (λ) are αβ and αβ2, respectively, then the quantity (μ/σ)2
reproduces α.  We can compute α for each trial and mean α across each simulated scenario.  
These simulations are performed across a grid of “true” values for λ under the case of 


I 3 Y-M C -J P B X ( b) Cli ni c al Pr ot o c ol
P a g e 9 0
L Y 2 8 3 5 2 1 9
“ b orr o wi n g” a n d “ n o b orr o wi n g,” w here t he “ n o b orr o wi n g” case is ac hie ve d b y si m ulat i n g 
u n der a l ar ge valu e f or t he mea n of τ.  T he differe nce bet wee n t he mea n α’s f or eac h tr ue λ o n 
t he grid pr o vi des a n esti mate of t he e q ui vale nt n u m ber of e ve nts attri b uta ble t o b orr o wi n g.  T his 
val ue is pl otte d a gai nst tr ue la m b da t o s h o w h o w m uc h b orr o wi n g occ urre d base d o n t he c h ose n 
st u d y desi g n.
Hist oric al C o ntr ols
I n t he R E V E L st u d y ( Gar o n et al. 2 0 1 4), N S C L C patie nts were ra n d o mize d t o eit her d oceta xel 
pl us ra m uci r u ma b or d oceta xel mo n ot h era p y after recei vi n g first-li ne plati n u m base d t hera p y . A 
t otal of 1 2 5 3 patie nts were ra n d o mize d wit h 6 2 8 assi g ne d t o ra m ucir u ma b pl us d oceta xel a n d 
6 2 5 pati e nts assi g ne d t o place b o pl us d oceta xel, wit h t he s q ua m o us p o p ulati on bei n g 1 5 7 a n d 
1 7 1 res pecti vel y. We use data fr o m all s q ua m o us patie nt ra n d o mize d t o d oceta xel
m o n ot hera p y  
ar m. 
 
 
O per ati n g C h ar acteristics
I n t his st u d y, t he e x peri me ntal t hera p y will be c o nsi dere d s u peri or t o c o ntr ol if t he p osteri or 
pr o ba bilit y t hat t he H R f or P F S of e x peri me ntal vers us c o ntr ol is < 1 is > 9 5 % or, f or m all y, if 
Pr( Treat m e nt H R < 1) >9 5 %.  Ta ble 1 s h o ws t he o perati n g c haracterist ics t hat c orres p o n d t o t his 
decisi o n r ul e.  T hese res ults are base d o n 1 , 0 0 0 si m ulate d trials per sce nari o, a n d N = 15 0 pati e nts 
ra n d omize d 2: 1 fa v ori n g t he e x peri me ntal ar m f or eac h trial.  F or p ur p oses of si m ulati o n, t he 
accr ual rate is ass u me d t o be 2 patie nts per wee k, a n d t he fi nal efficac y a nal ysis will be 
perf or m e d 1 2 m o nt hs after t he last pati e nt is e nr olle d.
We s h o w o perati n g c haracteristics u n der 2 differe nt ass u m pt i ons of t he tr ue hazar d rate i n t he 
c urre nt c o ntr ol ar m i n Ta ble 1.  T he pr o ba bilit y of s uccess is calc ulate d f or st u d y  desi g ns wit h 
B A C a n d wit h o ut B A C. U n der t he ass u m pt i on t hat t he c urre nt c o ntr ol ar m has t he sa me P F S 
hazar d rate a s t he hist orical c o ntr ols 
 t he B A C desi g n will ha ve a b o ut 
9 0. 5 % p o wer t o detect a n H R of 0. 6 4 wit h a T y pe I err or rate of 5. 5 %.
Wit h o ut B A C desi g n , 
t his st u d y w o uld ha ve o n l y 7 6. 1 % p o wer. He nce, t he B A C desi g n s u bsta nt iall y i m pr o ves 
o perati n g c haracterist ics c om pare d t o sta n dar d desi g ns.
C CI
C CI


I 3 Y-M C -J P B X ( b) Cli ni c al Pr ot o c ol
P a g e 9 1
L Y 2 8 3 5 2 1 9
C CI


I 3 Y-M C -J P B X ( b) Cli ni c al Pr ot o c ol
P a g e 9 2
L Y 2 8 3 5 2 1 9
Pr ot o c ol J P B X R E CI S T Crit eri a 1. 1
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
C CI
C CI


I 3 Y-M C -J P B X ( b) Cli ni c al Pr ot o c ol
P a g e 9 3
L Y 2 8 3 5 2 1 9
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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C CI


I 3 Y-M C -J P B X ( b) Cli ni c al Pr ot o c ol
P a g e 9 4
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.
 
 
 
 
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I 3 Y-M C -J P B X ( b) Cli ni c al Pr ot o c ol
P a g e 9 5
L Y 2 8 3 5 2 1 9
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
C CI
C CI


I 3 Y-M C -J P B X ( b) Cli ni c al Pr ot o c ol
P a g e 9 6
L Y 2 8 3 5 2 1 9
 
 
 
 
 
 
 
 
 
 
 
 
C CI


I 3 Y-M C -J P B X ( b) Cli ni c al Pr ot o c ol
P a g e 9 7
L Y 2 8 3 5 2 1 9
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI


I 3 Y-M C -J P B X ( b) Cli ni c al Pr ot o c ol
P a g e 9 8
L Y 2 8 3 5 2 1 9
 
 
 
 
 
 
  
 
 
C CI


I3Y-MC-JPBX(b) Clinical Protocol
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Protocol JPBX Pharmacokinetic and ECG 
Sampling Schedule
It is essential that the exact time of abemaciclib dose on the day of PK sampling and the 3 days 
prior to the PK sample is recorded on the appropriate form according to the instructions
provided.  The exact time of collection of each venous blood sample must also be recorded on 
the appropriate form. Aberrations to specified ECG and sampling times will not be considered 
protocol deviations as long as the ECG and samples are taken and the actual ECG and sampling 
time is recorded.
Pharmacokinetic and ECG Sampling Schedule for Abemaciclib Patients Only
Cycle (C) and 
Day (D)
ECG 
Collection
PK Sample 
Number
Dosing of 
Abemaciclib
Sampling Time for ECG and PK from Blooda
Baseline (Day 
-14 to Day -1)
X
C1D1
X
1
X
Pre-dose (0 h)c
C1D8
X
2
Xb
At least 4 hrs after taking abemaciclib dose at 
home (that is, upon arrival at site)d
C1D8
X
3
3 ± 0.5 h after PK Sample Number 2 (that is, at 
least 7 ± 0.5 h after taking abemaciclib dose at 
home)
C2D1
X
4
X
Pre-dose (0 h)c
C2D1
5
3 + 0.5 h after abemaciclib dose
C3D1
6
X
Pre-dose (0 h)c
C4D1
7
X
Pre-dose (0 h)c
30-Day 
Follow- up
X
Abbreviations: C = Cycle; D = Day; h = hour(s); ECG = electrocardiogram; PK = pharmacokinetic.
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites.
b
On Cycle 1 Day 8 only, patient should take abemaciclib dose at home at least 4 h before arrival at site.  The time 
of abemaciclib dose intake must be recorded that day.
c
Patient is administered abemaciclib in the clinic after required pre-dose ECG and/or PK sample is obtained 


I3Y-MC-JPBX(b) Clinical Protocol
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Protocol JPBX Sampling Summary
This table summarizes the maximum number of samples (venipunctures, biopsies), volumes for 
all sampling, and tests (study qualification, health monitoring, drug concentration,
pharmacodynamics/tailoring biomarkers) during the study. The summary below provides
estimates. More samples could be required in the case of retests, additional health monitoring (if
needed), or for patients continuing treatment beyond the protocol-specified number of cycles in
the study. Fewer samples may actually be taken (for example, patients who discontinue from the
study).
Protocol I3Y-MC-JPBX Sampling Summarya
Purpose
Sample Type
Maximum 
Amount per 
Sample
Maximum 
Number 
Samples
Maximum 
Total 
Amount
Health monitoringa
Blood for 
Chemistry
2.5 mL
14
35 mL
Blood for 
Hematology
2.0 mL
14
28 mL
Drug concentration
Plasma
2 mL
7
14 mL
Pharmacodynamic and/or other 
biomarkers
Plasma
6 mL
3
18 mL
Stored sample for 
pharmacogenetic evaluations
Whole Blood
10 mL
1
10 mL
Hepatic monitoringb
Blood
3 - 30 mL
-
-
Biomarkers, tissue
FFPE tumor tissue 
slides or block
FFPE tumor tissue 
slides OR
FFPE tumor block 
10-15
unstained 
slides or a 
tissue block
FFPE tumor 
tissue slides 
or block
Total blood volume
105 mL
Abbreviation:  FFPE = formalin-fixed, paraffin embedded.
a
Covers baseline, Cycles 1 through 6, plus V801.
b
Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with the designated medical monitor.


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Protocol JPBX Inducers and Strong 
Inhibitors of CYP3A
The information in this table is provided for guidance to investigators and does not preclude the 
use of these medications if clinically indicated.
Strong Inducers of CYP3A
Carbamazepine
Dexamethasonea
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St John’s wort
Moderate Inducers of CYP3A
Bosentan
Lenisurad
Modafinil
Primidone
Telotristat ethyl
Strong Inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin
Conivaptan
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Posaconazole
Troleandomycin
Verapamil
a
Important note:  All patients may receive supportive therapy with dexamethasone, preferably 7 days, if 
clinically indicated.


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Protocol JPBX CTCAE 4.03 Definitions for Diarrhea and Interstitial 
Lung Disease
Diarrhea will be evaluated in this study using the criteria proposed by Common Terminology Criteria for Adverse Events (CTCAE) 
v4.0 revised:  CTCAE 4.03-June 14, 2010:  Gastrointestinal disorders. 
Gastrointestinal Disorders
Grade
Adverse Event
1
2
3
4
5
Diarrhea
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy 
output compared to 
baseline.
Increase of 4-6 stools per 
day over baseline; 
moderate increase in 
ostomy output compared 
to baseline
Increase 7 stools per day 
over baseline; incontinence; 
hospitalization indicated; 
severe increase in ostomy 
output compared to baseline; 
limiting self-care ADL
Life-threatening 
consequences; urgent 
intervention indicated
Death
Definition:  a disorder characterized by frequent and watery bowel movements
Abbreviation:  ADL = Activities of Daily Living.


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Interstitial lung disease/pneumonitis will be evaluated in this study using the criteria proposed by CTCAE v4.0 revised:  CTCAE 
4.03–June 14, 2010:  Respiratory, thoracic, and mediastinal disorders.
Respiratory, Thoracic, and Mediastinal Disorders
Grade
Adverse Event
1
2
3
4
5
Pneumonitis
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL
Severe symptoms; limiting 
self-care ADL; oxygen 
indicated
Life-threatening respiratory 
compromise; urgent 
intervention indicated (e.g., 
tracheotomy or intubation)
Death
Definition: a disorder characterized by inflammation focally or diffusely affecting the lung parenchyma
Abbreviation:  ADL = Activities of Daily Living.


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Protocol JPBX Amendment(b) Summary A 
Randomized Phase 2 Study of Abemaciclib (LY2835219) 
versus Docetaxel in Patients with Stage IV Squamous 
Non-Small Cell Lung Cancer Previously Treated with 
Platinum-Based Chemotherapy
Overview
Study I3Y-MC-JPBX, a Randomized Phase 2 Study of Abemaciclib (LY2835219) versus 
Docetaxel in Patients with Stage IV Squamous Non-Small Cell Lung Cancer Previously Treated 
with Platinum-Based Chemotherapy, has been amended.  The new protocol is indicated by 
Amendment (b) and will be used to conduct the study in place of any preceding version.
The overall changes and rationale for the changes made to this protocol are as follows:

Interstitial lung disease (ILD) and multidrug and toxin extrusion protein (MATE) were 
added to the list of abbreviations (Section 4).

Rationale for Amendment (b) was added (Section 5.4).

References to study drug were modified in Sections 9.2, 9.7, and 12.2.5.

Table JPBX.9.2 was updated with dose adjustment criteria for ILD/pneumonitis.

Section 9.4.2.1.2.2 was updated to reflect the addition of ILD/pneumonitis dose 
modifications.

ILD/pneumonitis dose modifications (Section 9.4.2.1.2.5) and safety monitoring 
guidance were added (Section 10.3.3.4).

Section 9.6 was modified to align with updates to the Investigator’s Brochure.

Attachment 10 was updated to include additional CYP3A inducers and inhibitors.

CTCAE 4.03 Grade definitions for ILD/pneumonitis were added in Attachment 11.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
4.  Abbreviations and Definitions
Term
Definition
…
ILD
interstitial lung disease
…
MATE
multidrug and toxin extrusion protein
…
5.4.
Rationale for Amendment (b)
Study JPBX protocol was amended to update the safety monitoring and guidance for interstitial 
lung disease (ILD)/pneumonitis. Changes to the dose adjustment and delay section and Table 
JPBX.9.2 were done to specify dose modifications in response to ILD/pneumonitis events.  
These updates are in alignment with changes made in the development core safety information of 
the IB.
The protocol was updated to bring references to abemaciclib into alignment with the sponsor’s 
standard language.
Section 9.6 (Concomitant Therapy) was updated to align with the current IB.  Additional 
language was added cautioning against concomitant use of abemaciclib and substrates of the 
following:

P-glycoprotein

breast cancer resistance protein

organic cation transporter 2

multidrug and toxin extrusion protein 1 (MATE1), and

MATE2-K
Substrates of these transporters, including metformin, digoxin, and dofetilide, should be 
substituted or avoided.
The Concomitant Therapy (Section 9.6) was also updated to remove cautionary language 
regarding coadministration of narrow therapeutic index CYP substrate drugs. This is based on a 
clinical study (Study I3Y-MC-JPCB) which found no meaningful effect of abemaciclib on the 
pharmacokinetics of CYP substrates, namely caffeine [CYP1A2], S-warfarin [CYP2C9], 
midazolam [CYP3A], and dextromethorphan [CYP2D6].  
The list of Inducers and Strong Inhibitors of CYP3A (Attachment 10) was also modified to 
reflect updated guidance.


I3Y-MC-JPBX(b) Clinical Protocol
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Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.
9.2.
Materials and Supplies
Abemaciclib will be supplied by Lilly as capsules for oral administration.  Abemaciclib capsules
should be stored according to the temperature range listed on the product label, and should not be 
opened, crushed, or chewed.
9.4.2.1.
Dose Adjustments and Delays
Table JPBX.9.2.
Toxicity Dose Adjustments and Delays of Abemaciclib for 
Study JPBX
Toxicity Type
Dose Adjustment Guidelines
Dose Action
Dose Change
…
Nonhematologic Toxicitya
(except diarrhea, and ALT 
increased, and 
ILD/Pneumonitis)
Section 9.4.2.1.2.2
Persistent or recurrentb
Grade 2 that does not resolve 
with maximal supportive 
measures within 7 days to 
baseline or Grade 1
Dose MUST be 
suspended until toxicity 
resolves to either 
baseline or Grade 1.
Dose MUST be 
reduced by one dose 
level.
Nonhematologic Toxicity
(except diarrhea, ALT 
increased, and 
ILD/Pneumonitis)
Section 9.4.2.1.2.2
Grade 3 or 4
Dose MUST be 
suspended until toxicity 
resolves to either 
baseline or Grade 1.
Dose MUST be 
reduced by one dose 
level.
...
ALT Increased with 
increased total bilirubin, in 
the absence of cholestasis
Sections 9.4.2.1.2.4 and 
10.3.3.1
Grade 3 increased ALT (˃5.0×
x ULN) with total bilirubin 
>2× x ULN
Abemaciclib MUST be 
discontinued
Abemaciclib MUST
be discontinued.
ILD/Pneumonitis
Sections 9.4.2.1.2.5 and 
10.3.3.4
Grade 2 that persists or recurs 
despite maximal supportive 
measures and does not return 
to baseline or Grade 1 within 7 
days
Dose MUST be 
suspended until toxicity 
resolves to baseline or 
Grade ≤1.
Dose MUST be 
reduced by 1 dose 
level.
ILD/Pneumonitis
Sections 9.4.2.1.2.5 and 
10.3.3.4
Grade 3 or 4
Abemaciclib MUST be 
discontinued.
Abemaciclib MUST
be discontinued.
Abbreviations:  ALT = alanine transaminase; ASCO = American Society of Clinical Oncology; ILD = interstitial lung 
disease; ULN = upper limit of normal.
Note:  MAY = per the investigator’s clinical judgment; MUST = mandatory.
a
Additional guidance for hepatic and renal monitoring is in Sections 10.3.3.1 and 10.3.3.2.


I3Y-MC-JPBX(b) Clinical Protocol
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b
Determination of persistent events will be at the discretion of the investigator.  Recurrent toxicity refers to the 
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).  As a 
general guidance, based on the risk/benefit balance assessment per the investigator, for a patient who experiences 
a new episode of Grade 3 hematological toxicity after more than 8 weeks following the last episode of same 
Grade 3 hematological toxicity, the investigator may consider resuming the patient on the same drug dose should 
the patient satisfy the following conditions:

shows stable hematological counts (Grade ≤2) during that timeframe

has absence of any signs or risk of infection 

is benefiting from study treatment
c
Note: the patient who presents with no liver metastases at baseline.
d
Grade 3 ALT increased is a trigger for additional assessments and possibly hepatic monitoring.  See Section 
10.3.3.1 for additional guidance for hepatic monitoring
9.4.2.1.2.2.
Nonhematologic Toxicity (except diarrhea)
Refer to Section 9.4.2.1.2.3 for guidance and supportive measures of diarrhea toxicity possibly 
related to abemaciclib, or Sections 9.4.2.1.2.4 and 10.3.3.1 for additional hepatic monitoring 
safety and monitoring guidance, and Sections 9.4.2.1.2.5 and 10.3.3.4 for ILD/pneumonitis 
guidance.  If a patient experiences ≥Grade 3 nonhematologic toxicity (except diarrhea, refer to 
Section 9.4.2.1.2.3; or ALT increased, refer to Sections 9.4.2.1.2.4 and 10.3.3.1to Section 
10.3.3.1; ILD/pneumonitis, refer to Sections 9.4.2.1.2.5 and 10.3.3.4) possibly related to 
abemaciclib, then dosing must be suspended (until the toxicity resolves to either baseline or at 
least Grade 1) and the dose of abemaciclib must be reduced as outlined in Table JPBX.9.3.
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea, 
refer to Section 9.4.2.1.2.3; ALT increased, refer to Sections 9.4.2.1.2.4 and 10.3.3.1; 
ILD/pneumonitis, refer to Sections 9.4.2.1.2.5 and 10.3.3.4)(except diarrhea, refer to 
Section 9.4.2.1.2.3 or ALT increased, refer to Section 10.3.3.1) possibly related to abemaciclib 
that does not resolve with maximal supportive measures within 7 days to either baseline or 
Grade 1, then dosing must be suspended (until the toxicity resolves to either baseline or at least 
Grade 1) and the dose of abemaciclib must be reduced as outlined in Table JPBX.9.3.
9.4.2.1.2.5.
Interstitial Lung Disease/Pneumonitis
Dose modifications and management for ILD/pneumonitis are provided in Table JPBX.9.2. For 
persistent or recurrent Grade 2 ILD/pneumonitis that does not resolve with maximal supportive 
measures within 7 days to baseline or Grade 1, treatment with abemaciclib must be suspended 
until the toxicity resolves to baseline or Grade 1 and the dose must be reduced by 1 dose level.  
For Grade 3 or 4 ILD/pneumonitis, the patient must be discontinued from abemaciclib.  Refer to 
Section 10.3.3.4 for additional ILD/pneumonitis monitoring guidance.
9.6.
Concomitant Therapy
…
Abemaciclib is extensively metabolized through oxidation by cytochrome P450 (CYP) 3A.  In 
clinical drug interaction studies, coadministration of clarithromycin, a strong CYP3A inhibitor, 
increased exposure (area under the concentration-time curve) to abemaciclib by 3.4-fold (Study 


I3Y-MC-JPBX(b) Clinical Protocol
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I3Y-MC-JPBE) and coadministration of rifampin, a strong CYP3A inducer, decreased exposure 
to abemaciclib by 95% (Study I3Y-MC-JPBF).  Therefore, grapefruit or grapefruit juice as well 
as inducers and inhibitors of CYP3A should be substituted or avoided if possible (Attachment 
10). Although dexamethasone is a CYP3A4 inducer, use during the study is allowed.  The dose 
of corticosteroids, including dexamethasone, will be captured throughout the study.
In vivo in humans, abemaciclib is extensively metabolized through oxidation.  Additionally, the 
results from an in vitro human recombinant cytochrome P450 (CYP) phenotyping study indicate 
that oxidative metabolism of abemaciclib is primarily catalyzed by CYP3A4.  Based on these
findings, grapefruit juice as well as inducers and strong inhibitors of CYP3A4 should be 
substituted or avoided if possible (Attachment 10). Although dexamethasone is a CYP3A4 
inducer, use during the study is allowed.  The dose of corticosteroids, including dexamethasone, 
will be captured throughout the study.
Abemaciclib can be coadministered with drugs that are substrates of CYP enzymes.
Abemaciclib and/or its major metabolites inhibit the efflux transporters P-glycoprotein and 
breast cancer resistance protein and renal transporters organic cation transporter 2, MATE1, and 
MATE2-K at clinically relevant concentrations.  Therefore, substrates of these transporters such 
as metformin and those with a narrow therapeutic index such as digoxin and dofetilide should be 
substituted or avoided if possible.
In addition, in vitro studies in cultured human hepatocytes indicate that abemaciclib and its 
major metabolites LSN2839567 and LSN3106726 down regulate mRNA of 1 or more CYPs, 
including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A, at clinically relevant 
concentrations.  The mechanism of down regulation and its clinical relevance are presently not 
understood.  Therefore, care should be taken when coadministering substrate drugs of the above 
CYPs with narrow therapeutic margin (Attachment 10).
Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel 
may be modified by the concomitant administration of compounds that induce, inhibit, or are 
metabolized by cytochrome P450 3A4.  In vivo studies showed that the exposure of docetaxel 
increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4.  
Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel.  Concomitant 
use of docetaxel injection and drugs that inhibit CYP3A4 may increase exposure to docetaxel 
and should be avoided.  Grapefruit juice as well as inducers and strong inhibitors of CYP3A4 
should be substituted or avoided if possible (Attachment 10).  If systemic administration of a 
CYP3A4 inhibitor cannot be avoided Iin patients receiving treatment with docetaxel injection, 
consider close monitoring for toxicity and/or a docetaxel injection dose reduction. could be 
considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided.  
Grapefruit juice as well as inducers (for example, phenytoin and carbamazepine) and strong 
inhibitors of CYP3A4 should be substituted or avoided if possible (Attachment 10).  The dose of 
corticosteroids, including dexamethasone, will be captured throughout the study.
…


I 3 Y-M C -J P B X ( b) Cli ni c al Pr ot o c ol
P a g e 1 0 9
L Y 2 8 3 5 2 1 9
9. 7 .
Tr e at m e nt C o m pli a n c e
…
A be macicli b c o m plia nce will  be assesse d b y c o u nti n g ret ur ne d ca ps uless oli d oral d osa ge u nits.  
St u d y  me dicatio n a d mi nistrati o n data will be rec or de d i n t he patie nt’s me dical rec or d a n d e C R F .
1 0. 3. 3. 4  I nt er stiti al L u n g Di s e a s e/ P n e u m o niti s
I nterstiti al lu n g disease/ p ne u m o nit is has bee n i de ntifie d as a n a d verse dr u g reacti o n f or 
a be macicli b. T he m ajori t y of e ve nts o bser ve d i n cli nical trials were Gra de 1 or Gra de 2 wit h 
serio us cases a n d fatal  e ve nts re p orte d. A d dit i onal i nf or mat i on is a vaila ble i n t he I B.
As k y o ur pati e nts t o re p ort a n y ne w or w orse ni n g p ul m o nar y  s ym pt o ms s uc h as d ys p nea, c o u g h, 
a n d fe ver, a n d i n vesti gate a n d treat as per yo ur l o c al  cli nical practice (i ncl u di n g c ortic oster oi ds 
as a p pr o priate). If I L D/ p ne u m onit is is s us pecte d, i n vesti gati o ns ma y i ncl u de i ma gi n g, s uc h as 
hi g h -res ol uti on c o m p ute d t o m o gra p h y, br o nc he oal ve o lar lava ge, a n d bi o ps y  as cli nicall y 
i n dicate d.
Refer t o Ta ble J P B X. 9. 2 f or g uida nce o n d ose a dj ust m e nts of a be macicli b f or patie nts wit h 
I L D/ p ne u m onit is (see At tac h me nt 1 1 f or I L D/ p ne u m onit is C T C A E gra des). Disc o nt i n ue
a be macicli b i n cases of se vere I L D/ p ne u m o nit is.
1 2. 2. 5 .
Tr e at m e nt C o m pli a n c e
…
Treat me nt c o m plia nce i nf or mat i on f or a be macicli b will be c ollecte d t hr o u g h ca ps ule s oli d oral 
d osa ge u nit c o u nts at eac h t u m or assess me nt visit.  T he esti mate of perce n t c o mplia nce will be 
gi ve n b y :
Perce nt C o m plia nce =
Act ual  c u m ulati ve d ose ta ke n
E x pecte d c u m ulati ve d ose t o be ta ke n x 1 0 0
T he act ual  c u mulat i ve d ose ta ke n will be deter mi ne d base d o n c o u nti n g t he n u m ber of  ca ps ules 
d osa ge u nits ret ur ne d at eac h visit a n d s u btracti n g t hat n u m ber fr om t he n u m ber of ca ps ules 
d osa ge u nits di s pe nse d.  …


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Attachment 10.
Protocol JPBX Inducers and Strong Inhibitors of CYP3A or 
Substrates of CYPs with Narrow Therapeutic Range
The information in this table is provided for guidance to investigators and does not preclude the 
use of these medications if clinically indicated.
Strong Inducers of CYP3A
Carbamazepine
Dexamethasonea
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St John’s wort
a
Important note:  All patients may receive supportive therapy with dexamethasone, preferably 7 days, if 
clinically indicated.
Moderate Inducers of CYP3A
Bosentan
Lenisurad
Modafinil
Primidone
Telotristat ethyl
Strong Inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin
Conivaptan
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Posaconazole
Troleandomycin
Verapamil
a
Important note:  All patients may receive supportive therapy with dexamethasone, preferably 7 days, if 
clinically indicated.


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Cytochrome P450 Substrates with NarrowTherapeutic Range
CYP1A2
Theophylline
Tizanidine
CYP2C9
Warfarin
Phenytoin
CYP2D6
Thioridazine
Pimozide
CYP3A
Alfentanil
Astemizole
Cisapride
Cyclosporine
Dihydroergotamine
Ergotamine
Fentanyl
Pimozide
Quinidine
Sirolimus
Tacrolimus
Terfenidine
Attchment 11.
Protocol JPBX CTCAE 4.03 Diarrhea Definitions for Diarrhea and 
Interstitial Lung Disease
Interstitial lung disease/pneumonitis will be evaluated in this study using the criteria proposed by 
CTCAE v4.0 revised:  CTCAE 4.03–June 14, 2010:  Respiratory, thoracic, and mediastinal 
disorders.


I3Y-MC-JPBX(b) Clinical Protocol
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Respiratory, Thoracic, and Mediastinal Disorders
Grade
Adverse Event
1
2
3
4
5
Pneumonitis
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated
Symptomatic; 
medical 
intervention 
indicated; 
limiting 
instrumental 
ADL
Severe 
symptoms; 
limiting 
self-care ADL; 
oxygen 
indicated
Life-threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated (e.g., 
tracheotomy or 
intubation)
Death
Definition: a disorder characterized by inflammation focally or diffusely affecting the lung parenchyma
Abbreviation:  ADL = Activities of Daily Living.


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

SAP_001.pdf: 
I3Y-MC-JPBX Statistical Analysis Plan Version 1
A Randomized Phase 2 Study of Abemaciclib (LY2835219) versus Docetaxel in Patients with 
Stage IV Squamous Non-Small Cell Lung Cancer Previously Treated with Platinum-Based 
Chemotherapy
NCT02450539 
Approval Date: 09-Jun-2015 


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1.
Statistical Analysis Plan:
I3Y-MC-JPBX:  A Randomized Phase 2 Study of 
Abemaciclib (LY2835219) versus Docetaxel in Patients 
with Stage IV Squamous Non-Small Cell Lung Cancer 
Previously Treated with Platinum-Based Chemotherapy
Confidential Information
The information contained in this  Statistical Analysis Plan 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.
Abemaciclib (LY2835219)
Study JPBX is a multicenter, randomized, open-label, parallel, comparator-controlled, 
Phase 2 trial in Stage IV squamous non-small cell lung cancer patients who have 
progressed after platinum-based chemotherapy, evaluating second-line treatment with
abemaciclib versus docetaxel.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Statistical Analysis Plan electronically signed and approved by Lilly on date provided
below.
Approval Date: 09-Jun-2015 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I3Y-MC-JPBX:  A Randomized Phase 2 
Study of Abemaciclib (LY2835219) versus Docetaxel in Patients 
with Stage IV Squamous Non-Small Cell Lung Cancer Previously 
Treated with Platinum-Based Chemotherapy.......................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................7
4.1.
Primary Objective ..........................................................................................................7
4.2.
Secondary Objectives.....................................................................................................7
4.3.
Exploratory Objectives...................................................................................................7
5.
Study Design.......................................................................................................................8
5.1.
Summary of Study Design..............................................................................................8
5.2.
Determination of Sample Size ........................................................................................8
6.
A Priori Statistical Methods ..............................................................................................10
6.1.
General Consideration..................................................................................................10
6.1.1.
Populations ..........................................................................................................10
6.1.2.
Definitions and Conventions ................................................................................10
6.2.
Handling of Dropouts or Missing Data.........................................................................11
6.3.
Patient Disposition .......................................................................................................11
6.4.
Patient Characteristics ..................................................................................................11
6.4.1.
Baseline Demographics and Patient......................................................................11
6.4.2.
Historical Illnesses ...............................................................................................11
6.4.3.
Prior Therapies.....................................................................................................11
6.4.4.
Post Study Treatment Discontinuation Therapies .................................................11
6.5.
Treatment Compliance .................................................................................................11
6.6.
Concomitant Therapy...................................................................................................12
6.7.
Efficacy Analyses ........................................................................................................12
6.7.1.
Stratification Factors............................................................................................12
6.7.2.
Primary Outcome and Methodology.....................................................................12
6.7.3.
Secondary Outcome and Methodology.................................................................13
6.7.4.
Sensitivity Analyses.............................................................................................13
6.8.
Health Outcomes/Quality-of-Life Analyses..................................................................14
6.9.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................15
6.10. Tailoring Biomarker Analyses......................................................................................15
6.11. Safety Analyses............................................................................................................15


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6.11.1.
Extent of Exposure...............................................................................................15
6.11.2.
Adverse Events ....................................................................................................15
6.11.3.
Deaths..................................................................................................................16
6.11.4.
Clinical Laboratory Evaluation.............................................................................16
6.11.5.
Vital Signs and Other Physical Findings...............................................................16
6.11.6.
Electrocardiograms ..............................................................................................16
6.11.7.
Hospitalizations and Transfusions ........................................................................17
6.12. Subgroup Analysis .......................................................................................................17
6.13. Interim Analysis...........................................................................................................17
6.14. Protocol Violation........................................................................................................17
6.15. Annual Report Analysis ...............................................................................................18
6.16. Clinical Trial Registry Analyses...................................................................................18
7.
Unblinding Plan................................................................................................................19
8.
References ........................................................................................................................20


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Table of Contents
Table
Page
Table JPBX.6.1.
Progression-Free Survival Sensitivity Analysis 1 ......................................14


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Table of Contents
Figure
Page
Figure JPBX.5.1.
Illustration of study design..........................................................................8


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior to the first patient visit.


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4.
Study Objectives
4.1.
Primary Objective
The primary objective of this study is to compare treatment with abemaciclib versus docetaxel
therapy with respect to investigator-assessed PFS in patients with Stage IV squamous cell
carcinoma NSCLC who have relapsed after prior platinum-based therapy for advanced disease.
4.2.
Secondary Objectives
The secondary objectives of the study are as follows:

To evaluate the pharmacokinetic (PK) parameters including abemaciclib and its active 
metabolites

To compare treatment of abemaciclib versus docetaxel with respect to the following:
o
Overall survival (OS)
o
Overall response rate (ORR) [complete response (CR) + partial response (PR)]
o
Disease control rate (DCR) [CR + PR + stable disease (SD)]
o
Time to worsening of Performance Status (PS)
o
The safety and tolerability using the National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE version 4.0)
o
Change from baseline in patient-reported outcomes (PROs), including: 1) the MD 
Anderson Symptom Inventory Lung Cancer (MDASI-LC) questionnaire pain and 
disease-related symptoms scores; and 2) the EuroQol Group’s EQ-5D-5L 
questionnaire index score, derived from the 5-item descriptive system, and visual 
analog scale (VAS) self-rated health score.
4.3.
Exploratory Objectives 

To explore potential biomarkers related to the cell cycle pathway components,
abemaciclib, and/or the pathogenesis of lung cancer, and their associations with clinical 
outcomes

To explore the relationship between abemaciclib exposure and response

To explore if change in tumor size is associated with PFS and OS


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5.
Study Design
5.1.
Summary of Study Design
Study I3Y-MC-JPBX (JPBX) is a multicenter, randomized, open-label, parallel, comparator-
controlled, Phase 2 trial in Stage IV squamous NSCLC patients who have progressed after
platinum-based chemotherapy for advanced disease, evaluating treatment with abemaciclib
versus docetaxel.
Patients will be stratified at randomization according to the following: ECOG PS (0 vs. 1);
number of prior therapies (received only platinum-based therapy vs. platinum-based therapy plus
immune checkpoint inhibitor); and time since the initiation of first-line therapy (≤9 vs. >9
months).
Figure JPBX.5.1. illustrates the study design.
Abbreviations: IV = intravenous; N = number; NSCLC = non-small cell lung cancer; PD = progressive 
disease; PO = orally; Q12H = every 12 hours; R = randomized.
Figure JPBX.5.1.
Illustration of study design.
5.2.
Determination of Sample Size
The primary objective of this study is to compare abemaciclib versus docetaxel in terms of PFS 
in patients with Stage IV squamous cell carcinoma NSCLC after progression with a 
platinum-based therapy for advanced disease.  The study will enroll approximately 150 patients 
in 2:1 randomization (100 patients in abemaciclib and 50 patients in docetaxel).  The primary 
PFS analysis will be performed after 120 PFS events are observed.  Historical information will 
be incorporated into control arm during the primary analysis by using a Bayesian approach.
Assuming a hazard ratio (HR) of 0.64, with 150 patients and the proposed Bayesian design, 
power of 90.5% was estimated by simulation.  Under a frequentist design, this sample size yields 
roughly 75% power with 1-sided type I error of 0.05.


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If the true median PFS for the docetaxel arm is 3 months, the HR of 0.64 amounts to an 
approximately 1.7-month improvement in median PFS for the abemaciclib arm under an 
additional assumption of exponential survival distribution.
Refer to Protocol Attachment 6 for more detail on the statistical model and simulations.


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6.
A Priori Statistical Methods
6.1.
General Consideration
Statistical analysis of this study will be the responsibility of Lilly.
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.
Any other change to the data analysis methods described in the protocol, and the justification for
making the change, will be described in the clinical study report.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
6.1.1. Populations
The entered population includes all patients who sign the informed consent document.
The enrolled or intent-to-treat (ITT) population includes all randomized patients.
The randomized and treated (RT) population includes all randomized patients who received at
least 1 dose of abemaciclib or Docetaxel.
All efficacy analyses will be based on the intent-to-treat population, unless otherwise stated.
Safety analyses will be based on the randomized and treated population.
Pharmacokinetic analyses will be conducted on all patients who have received at least 1 dose of
abemaciclib and have had samples collected.
Pharmacodynamic 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.
6.1.2. Definitions and Conventions
Study drug refers to LY2835219 (abemaciclib).
The date of first dose is the date of the first dose of study drug.
The baseline value of an assessment is the last value observed prior to the first dose of study
drug.
The study day of an event or assessment will be calculated as the difference between the day of
the event or assessment and the date of first dose plus 1.  For example, if an event occurs on
08JUN2014 and the date of first dose was 06JUN2014, the study day of the event is 3.
One month is defined as 365/12 days.


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6.2.
Handling of Dropouts or Missing Data
With the exception of dates, missing data will not be imputed.  The method of imputation for any
dates that are imputed is described in the relevant section.
6.3.
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, treated in the study, reasons for
discontinuation from study treatment and reasons for discontinuation from study.  Reason for
discontinuation from both study treatment and the study will be summarized by pre-determined
categories.  If the reason for discontinuation is adverse event (AE), the associated AE term will
be reported.
A summary of all important protocol deviations will be provided.
6.4.
Patient Characteristics
6.4.1. Baseline Demographics and Patient 
Patient demographics and baseline disease characteristics will be listed for all patients on therapy
and summarized by study part.  Patient demographics will include sex, race, age, height, weight, 
and body mass index (BMI).  Baseline disease characteristics will include basis for diagnosis, 
initial pathological diagnosis (histological or cytological), disease stage and Eastern Cooperative 
Oncology Group (ECOG) performance status.
6.4.2. Historical Illnesses
Historical illnesses are clinically relevant events in the past that ended before the screening visit.  
Historical illnesses (using Preferred Term(s) [PTs] from the most current version of the Medical
Dictionary for Regulatory Activities [MedDRA]) will be summarized by treatment arm.
6.4.3. Prior Therapies
Prior systemic therapies will be summarized by drug name and treatment arm.
6.4.4. Post Study Treatment Discontinuation Therapies
The numbers and percentages of patients reporting postdiscontinuation therapies will be
provided overall, by type of therapy (surgery, radiotherapy, or systemic therapy), and by drug
name.
6.5.
Treatment Compliance
The number of dose omissions, reductions, and delays, cycles received, and dose intensity will
be summarized for all treated patients per treatment arm.
Treatment compliance of abemaciclib will be measured by pill counts and summarized by cycle.
Within each cycle, compliance will be calculated as the ratio of total dose taken to the total
assigned dose (minus any dose adjustments and doses omitted/withheld for medical reasons).  


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The total assigned dose for a patient with no adjustments or omissions is 200 mg per dose × 2
doses per day × 21 days = 8400 mg.
Docetaxel will be administered only by trained medical personnel at the investigational sites and
under the direction of the investigator.  As a result, monitoring of patient compliance is ensured.  
Patients who require a delay of more than 14 days in starting a new cycle of docetaxel (>35-day
interval between consecutive cycles) should be considered as protocol violation.
6.6.
Concomitant Therapy
All medications will be coded to the generic preferred name according to the current World 
Health Organization (WHO) drug dictionary. All concomitant medications will be summarized 
by treatment arm using the preferred name.
6.7.
Efficacy Analyses
6.7.1. Stratification Factors
The stratification factors for the analysis are: ECOG PS (0 vs 1); number of prior therapies
(received only platinum-based therapy vs. platinum-based therapy plus immune checkpoint 
inhibitor); and time since the initiation of first-line therapy (≤9 vs. >9 months)
The stratification factors are captured in the IWRS and on electronic clinical (case) report forms
(eCRFs).  Unless otherwise stated, all stratification analyses will be based on the stratification
factors per CRF.
6.7.2. Primary Outcome and Methodology
The primary efficacy measure is investigator-assessed progression-free survival (PFS) as defined 
as the time from randomization until the first evidence of objective progression as defined by 
RECIST 1.1 (Eisenhauer et al. 2009) or death from any cause, whichever is earlier.  Patients who 
have neither progressed nor died will be censored at the day of their last radiographic tumor 
assessment, if available, or the date of randomization if no postbaseline radiographic assessment 
is available.  The detailed censoring rules are described in Protocol Table JPBX.10.1.
The primary analysis of PFS will be performed after at least 120 investigator-assessed PFS
events have occurred.  PFS will be compared between treatment arms by using a Bayesian
exponential-likelihood model with a hierarchical random effects distribution on treatment
effects.  The final model will incorporate historical data from a completed study (Garon et al.
2014) to augment the prospective control-arm data.  If the Bayesian posterior probability of 
superiority of abemaciclib arm to docetaxel arm (that is, HR <1) exceeds 0.95, then it will be 
concluded that the experimental arm is superior.  See Protocol Attachment 6 for more details.
In addition to the primary analysis of PFS, following analysis will also be conducted:

Log-rank test will be used to compare the PFS distribution between treatment groups 
with and without adjustment using the same factors as the randomization scheme.  The p-
value will be compared with the traditional threshold of 0.05. 


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
Kaplan-Meier method (Kaplan and Meier 1958) will be used to estimate the PFS curve 
for each treatment group.

The Cox proportional hazard model (Cox 1972) will be used to estimate the HR and 
corresponding 95% CI with and without stratified by randomization factors.
6.7.3. Secondary Outcome and Methodology
Secondary efficacy objective for this study include comparison of OS, ORR, DCR, and time to
worsening of PS.  The definition of secondary efficacy measures are listed in Protocol Section 
10.1.4.
Kaplan-Meier analysis will be performed on the observed distribution of OS.  Parameter
estimates of the OS median and quartiles will be reported for each treatment group.  All
parameter estimates will be quoted together with their 95% confidence limits.  Overall survival
will be compared between treatment arms using the log-rank test adjusted by randomization 
factors.  The adjusted Cox proportional hazard model (Cox 1972) will be used to estimate the 
HR and corresponding 95% CI. 
The ORR and DCR of each treatment arm will be calculated as defined by RECIST v1.1.  All
rates will be compared between treatment arms based on a normal approximation for the
difference between the rates.
Exploratory analysis may be performed to investigate associations between change in tumor size
data and PFS and OS data.
6.7.4. Sensitivity Analyses
Sensitivity analyses will be undertaken for calculation of the primary endpoint in order to
evaluate the robustness of the analysis by changing one or more of the censoring rules stated in
the primary analysis.  The following sensitivity analyses will be performed for PFS:
Progression-Free Survival Sensitivity Analysis 1 (forward-dating progressions at unscheduled
assessments): if a patient has objective progression at an unscheduled disease assessment, then
the PFS time for that patient will be forward-dated to the next scheduled disease assessment.  
The definition of PFS for this sensitivity analyses is presented in Table JPBX.6.1.  Those items
that differ from Protocol Table JPBK.12.1. are underlined.


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Table JPBX.6.1.
Progression-Free Survival Sensitivity Analysis 1
Situation
Date of Progression or Censor
Outcome
1
No baseline tumor assessments
Date of Randomization
Censored
2
No post baseline assessments and no death
Date of Randomization
Censored
3
No documented progression and no death (with a 
post-baseline tumor assessment)
Date of last adequate tumor assessment
Censored
4
Patient lost to follow-up (or withdrew consent from 
study participation) before documented progression 
or death
Date of last adequate tumor assessment
Censored
5
Documented progression
Date of documented progression.
If a tumor assessment was done on 
multiple days, use the earliest date for 
that visit.
Progressed
6
Death without documented progression
Date of death
Progressed
7
Death or documented progression after missed ≥2 
consecutively post-baseline tumor assessment visits
Date of last adequate tumor assessment 
before missed assessments or date of 
randomization, whichever is later
Censored
8
Objective progression at an unscheduled disease 
assessment
Date of next scheduled disease
assessment
Progressed
6.8.
Health Outcomes/Quality-of-Life Analyses
Patient-reported outcomes are measured through paper versions of the following:

MD Anderson Symptom Inventory- Lung Cancer (with 11 exploratory items for brain
metastases (9) and potential toxicities (2))

EuroQol 5-Dimension 5 Level (EQ-5D 5L).
Percentage of compliance and reasons for non-compliance will be summarized by treatment arm 
and time point.  Percentage of compliance will be calculated as the number of completed 
assessments divided by the number of expected assessments (that is, patients still on study and 
alive).
Data from the MDASI-LC instrument will be scored as described by Mendoza and colleagues
(Mendoza et al. 2011).  Descriptive statistics will be used to describe several subscales and 
individual items by treatment arm: symptom severity (13 core items plus lung-cancer items), 
core severity (13 core items only), interference (6 interference items), brain symptoms 
(weakness, understanding, speaking, seizures, concentrating, appearance, irritability) as well as 
individual items headache, diarrhea and rash.  Additionally, a composite score based on the 5 
most severe baseline symptoms from items 1 through 16 will be described using descriptive 
statistics by treatment arm and cycle.
If a patient does not complete all items on the MDASI-LC, the mean score for a subscale will be
calculated when at least 50% of the items for that subscale were answered.


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The EQ-5D 5L data will be scored as described in literature (van Hout et al. 2012).  The index
score is calculated from a set of item weights to derive a score of 0 to 1, with 1 representing the
best health status.  United Kingdom (UK) weights will be applied for the base case.
The EQ-5D 5L responses for each item will be summarized by frequency and corresponding
percentages by treatment arm and best response category.  Descriptive statistics for the index and
VAS will be calculated by arm and best response category. 
Additional exploratary analysis will be described in a separate health outcome analysis plan.
6.9.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods
Pharmacokinetic (PK) analyses will be performed according to a separate PK analysis plan.
6.10. Tailoring Biomarker Analyses
Analysis of biomarkers will be described in a separate biomarker analysis plan
6.11. Safety Analyses
Safety analyses will be based on the RT Population as defined in Section 6.1.1.  Patients will be
grouped according to treatment received in Cycle 1.
6.11.1. Extent of Exposure
Extent of exposure will be measured by dose intensity and relative dose intensity and summarize 
by treatment arm.  For abemaciclib, dose intensity is defined as actual cumulative amount of 
drug taken (pill dispensed – pill returned) in treatment divided by duration of treatment in days.  
Relative dose intensity will be calculated as ratio of actual cumulative amount of drug taken in 
treatment to the assigned cumulative drug in treatment.The assigned cumulative dose for each 
patient during each cycle is 200 mg per dose × 2 doses per day × 21 days = 8400 mg.  The 
assigned cumulative dose while on study is 8400 mg × number of cycles started.
For docetaxel, exposure will be measured in a similar approach.  Daily dose intensity and 
relative dose intensity in treatment will be calculated based on the planned dosage and actually 
administrated dosage that captured in CRF page. 
Dose adjustments and omissions, along with the reason for adjustment or omission, will be
summarized.
6.11.2. Adverse Events
Verbatim text for the adverse events will be entered by the investigator , as well as the adverse
event (AE) terms and severity grades per CTCAE Version 4.0.
Since all the terms in CTCAE Version 4.0 are themselves LLTs of MedDRA, adverse events will
be handled in the following manner:

The CTCAE Version 4 term reported by the investigator will be mapped to the 
corresponding MedDRA PT and system organ class (SOC), unless the reported 
CTCAE term is ‘Other – specify’.


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
If the reported CTCAE term is ‘Other – specify’ the MedDRA LLT, PT and SOC
mapped from the verbatim AE term will be used.

All listings and summaries will use the PT resulting from this process.
Serious adverse event (SAE) and relationship of AE to the study drug are defined in Protocol 
Section 10.3.1.1.  The derivation of treatment emergent adverse event (TEAE) is described in 
Protocol Section 12.2.11.
Overview of adverse event will be summarized for abemaciclib.  The following TEAE/SAE 
listings and summaries will be produced:

Summary of TEAEs by PT (all grade and grade ≥3)

Summary of TEAEs by SOC and PT (all grade and grade ≥3)

Summary of TEAEs by PT and maximum grade (1-5)

List of SAEs

Summary of SAEs by SOC and PT (all grade and grade ≥3)
The four summaries will be produced for all TEAEs/SAEs and repeated for TEAEs/SAEs related
to study treatment.
6.11.3. Deaths
All deaths on study not attributed to study disease by the investigator will be listed along with
the reason for death, if known.  For those deaths attributed to an AE, the listing will include the
PT of the AE.  A summary of deaths including reasons for death will be produced.
6.11.4. Clinical Laboratory Evaluation
All relevant hematology and chemistry laboratory values will be graded according to CTCAE
Version 4.  These calculated grades will be summarized by cycle and maximum post-baseline
grade over the entire study.
6.11.5. Vital Signs and Other Physical Findings
Temperature, blood pressure, pulse rate, respiration rate, weight and ECOG PS will be
summarized by cycle.
6.11.6. Electrocardiograms
Local electrocardiograms (ECGs) will be summarized by cycle and overall.  The summary by
cycle will classify patients as having normal or abnormal ECG and summarize AEs identified by
ECG within each cycle.  The overall summary will classify patients as having an abnormal ECG
at any point and summarize all AEs identified by ECG.


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6.11.7. Hospitalizations and Transfusions
The frequency and percentage of patients with any hospitalizations and Transfusions experienced 
during the study treatment period or 30-day post discontinuation follow-up period will be 
summarized by treatment arm.
6.12. Subgroup Analysis
Subgroup analyses of PFS and OS will be performed for each of following potential prognostic
subgroup variables:

All baseline stratification factors

Age (<65 years vs. ≥65 years)

Region (North America vs. Europe vs. Other)

Race (Caucasian vs. Asian vs. Other)
If a level of a factor consists of fewer than 10% of randomized patients, analysis within that level
will be omitted.
Analyses will be done within subgroup and, separately, across subgroups with a test of
interactions of subgroups with treatment performed.  Estimated HRs and CIs for the within
subgroup analyses will be presented as a forest plot along with p-values for tests of interactions
between subgroup variables and treatment.
Other subgroup analyses may be performed as deemed appropriate.  If any safety analyses
identify important imbalances between arms, subgroup analyses of these endpoints may be
performed.
6.13. Interim Analysis
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed
necessary for reasons other than a safety concern, the protocol must be amended.
6.14. Protocol Violation
Protocol violations that can be derived from the data and are related to inclusion/exclusion
criteria or treatment will be summarized.  These violations will include those defined by:

Inclusion/Exclusion Criteria
o
Diagnosis
o
Prior treatments received
o
Age
o
Performance Status

Treatment
o
Dose delays


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o
Dose reductions
6.15. Annual Report Analysis
Annual report analyses, including Developmental Safety Update Report (DSUR) and
Investigational Brochure (IB) analyses, are described in the abemaciclib Program Safety
Analysis Plan.
6.16. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry
(CTR) requirements.  Analyses provided for the CTR requirements include the following:
Summary of AEs, provided as a dataset which will be converted to an XML file.  Both SAEs and
‘Other’ AEs will be summarized by MedDRA PT.

An AE is considered ‘Serious’ whether or not it is a treatment emergent adverse event 
(TEAE).

An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each SAE and ‘Other’ AE, for each term and treatment group, the following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

Adverse event (AE) reporting is consistent with other document disclosures for example, 
the clinical study report (CSR), manuscripts, and so forth.
In addition, a participant flow will be created that will describe how many enrolled patients
completed the study, and for those who did not, the frequency of each reason for not completing.  
This analysis will be based on study discontinuation, not treatment discontinuation.  A patient
will be identified as having completed the study if the patient dies while on the study or the
patient had discontinued study treatment and is in follow up at the time of the final OS analysis.  
Patients who withdraw consent before the final OS analysis or who are still on treatment at the
time of the final OS analysis will be identified as not completing the study.


I3Y-MC-JPBX Statistical Analysis Plan Version 1
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LY2835219
7.
Unblinding Plan
JPBX is an open-label study.


I3Y-MC-JPBX Statistical Analysis Plan Version 1
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LY2835219
8.
References
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Leo Document ID = 3d7a0e22-5ff7-47f2-8e16-2addc6081ca8
Approver: 
Approval Date & Time: 09-Jun-2015 16:58:37 GMT
Signature meaning: Approved