A Phase 1b Study of LY2835219 in Combination With Multiple Single Agent Options for Patients With Stage IV NSCLC
Phase: PHASE1
Conditions: Carcinoma, Non-small Cell Lung
Sponsor: Eli Lilly and Company

Protocol I3Y-MC-JPBJ(h) 
 
 
A Phase 1b Study of Abemaciclib in Combination with Multiple Single-Agent Options for 
Patients with Stage IV NSCLC 
 
NCT02079636 
 
Approval Date: 8-Feb-2019 
 
 

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1. Protocol I3Y-MC-JPBJ(h)
A Phase 1b Study of Abemaciclib in Combination with 
Multiple Single-Agent Options for Patients with Stage IV 
NSCLC
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
abemaciclib unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.  This document and its associated attachments are subject to 
United States Freedom of Information Act (FOIA) Exemption 4.
Abemaciclib (LY2835219)
This Phase 1 study is a multicenter, nonrandomized, open-label, dose-escalation study 
followed by cohort expansion of oral abemaciclib in patients with metastatic non-small cell 
lung cancer.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Approved by Lilly:  18 November 2013
Amendment (a) Approved by Lilly:  03 March 2014
Amendment (b) Approved by Lilly:  23 December 2014
Amendment (c) Approved by Lilly:  17 February 2015
Amendment (d) Approved by Lilly:  07 December 2015
Amendment (e) Approved by Lilly:  06 October 2016
Amendment (f) Approved by Lilly:  20 December 2016
Amendment (g) Approved by Lilly:  06 November 2017
Amendment (h) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 08-Feb-2019 GMT

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2. Synopsis
Study I3Y-MC-JPBJ (JPBJ) is a Phase 1b trial for patients with non-small cell lung cancer 
(NSCLC) that will evaluate the safety and tolerability of abemaciclib in combination with 
multiple single-agent options in approximately 150 patients with metastatic NSCLC.

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Clinical Protocol Synopsis:  Study I3Y-MC-JPBJ
Name of Investigational Product: Abemaciclib  (LY2835219)
Title of Study:  A Phase 1b Study of Abemaciclib in Combination with Multiple Single-Agent Options for Patients 
with Stage IV NSCLC
Number of Planned Patients:
   Entered:  195
   Enrolled:  150
   Completed (approximate number of patients who will complete the 
endpoint):  150
Phase of Development:  Phase 1b
Length of Study:  46 months
Planned first patient visit:  March 2014
Planned last patient visit:  June 2018
Objectives:  
The primary objective of this study is to evaluate the safety and tolerability of abemaciclib when administered orally 
in combination with multiple single-agent options to patients with Stage IV non-small cell lung cancer (NSCLC) 
using Common Terminology Criteria for Adverse Events (CTCAE version 4.0, NCI 2009).
The secondary objectives of the study are to determine the pharmacokinetics (PK) of abemaciclib and 
pemetrexed, gemcitabine, ramucirumab, or LY3023414, when given in combination; and to document the 
antitumor activity of abemaciclib when given in combination with multiple single-agent options; and to 
characterize changes in patient-reported pain and disease-related symptoms collected via the MD Anderson 
Symptom Inventory-Lung Cancer (MDASI-LC).
Study Design:  
Multicenter, nonrandomized, open-label, dose-escalation Phase 1b study of abemaciclib in combination with 
1) pemetrexed, 2) gemcitabine, 3) ramucirumab, 4) LY3023414 (PI3K/mTOR dual inhibitor) (United States [US] 
only), and 5) pembrolizumab for approximately 150 patients with Stage IV NSCLC.
Diagnosis and Main Criteria for Inclusion and Exclusions:  
Inclusion Criteria
Patients may be included in the study if the following criteria are fulfilled:
[1]
For all parts:  The patient must have Stage IV NSCLC.  Eligibility is not restricted based on molecular 
features (for example, EGFR mutation or ALK translocation). However, all patients with 
nonsquamous NSCLC with EGFR activating mutations or ALK alterations should have received and 
progressed after appropriate tyrosine kinase inhibitor or ALK targeted therapy prior to enrollment.

For Part A (abemaciclib + pemetrexed):  Nonsquamous subtypes only.  The patient must have 
received at least 1 but not more than 3 prior therapies, including 1 platinum-based chemotherapy
for advanced/metastatic NSCLC.  Patients who have received pemetrexed as first-line or 
maintenance therapy must be >3 months after treatment for determining eligibility.

For Part B (abemaciclib + gemcitabine):  Any subtype.  The patient must have received at least 
1 but not more than 3 prior therapies for advanced/metastatic NSCLC.

For Part C (abemaciclib + ramucirumab):  Any subtype. The patient must have received at least 
2 but not more than 3 prior therapies for advanced/metastatic NSCLC.

For Part D (abemaciclib + LY3023414 [US only]):  Any subtype.  The patient must have 
received at least 2 but not more than 3 prior therapies for advanced/metastatic NSCLC. The 
patient must not have received prior treatment with any PI3K or mTOR inhibitor.

For Part E (abemaciclib+pembrolizumab): Any subtype. The patient must have received at least
1 but no more than 3 prior therapies for advanced/metastatic NSCLC.
[2]
Have the presence of either measureable or nonmeasurable disease as defined by the Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1).
[3]
Are 18 years of age.
[4]
Have given written informed consent prior to any study-specific procedures.
[5]
Have adequate organ function including:

Hematologic:  Absolute neutrophil count (ANC) 1.5 x 109/L, platelets 100 x 109/L, and 
hemoglobin 8 g/dL.  Patients may receive erythrocyte transfusions to achieve this hemoglobin 

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level at the discretion of the investigator.

Hepatic:  Bilirubin 1.5 times upper limits of normal (ULN), alanine aminotransferase (ALT) 
and aspartate transaminase (AST) 3.0 times ULN. For patients with tumor involvement of the 
liver, AST and ALT equaling ≤5.0 times ULN are acceptable.  Patients on Part A with tumor 
involvement of the liver and ALT or AST >3.0 to ≤5.0 times ULN must have Child-Pugh Class 
A using the Child-Turcotte scoring system.

Renal:  Serum creatinine 1.5 times ULN.  All patients must have a Creatinine Clearance (CrCl) 
>45 mL/min using the standard Cockcroft and Gault formula.

Part E: Thyroid: TSH within normal limits OR Total T3 or free T3 and free T4 within normal 
limits

Part E: Coagulation: PTT or aPTT <5 seconds above ULN and INR1.5 times ULN or PT 
<5 seconds above ULN. Patients receiving anticoagulant therapy are permitted if the PTT or 
aPTT and INR or PT are within therapeutic range of intended use of anticoagulants.
[6]
Have a performance status ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale.
[7]
Have discontinued all previous therapies for cancer (including chemotherapy, radiotherapy, 
immunotherapy, and investigational 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.
[8]
Are reliable and willing to make themselves available for the duration of the study and are willing to 
follow study procedures.
[9]
Males and females with reproductive potential must agree to use medically approved contraceptive 
precautions during the trial and for 3 months following the last dose of study drug.

Part E patients must agree to use medically approved contraceptive precautions during the trial 
and for 120 days (4 months) following last dose of study drug.
[10]
Females with childbearing potential must have a negative serum pregnancy test within 7 days of the 
first dose of study drug.

Part E female patients of childbearing potential must have a negative urine or serum pregnancy 
test within 72 hours prior to receiving the first dose of study medication. If urine test is positive 
or cannot be confirmed as negative, a serum pregnancy test will be required.
[11]
Have an estimated life expectancy of ≥12 weeks.
[12]
Are able to swallow oral medications.
Exclusion Criteria
Patients may not be included in the study if any of the following apply:
[13]
Have received treatment within 21 days of the initial dose of study drug with an investigational 
product or nonapproved use of a drug or device (other than the study drug/device used in this study) 
for noncancer indications or are concurrently enrolled in any other type of medical research judged not 
to be scientifically or medically compatible with this study.
[14]
Have a personal history of any of the following conditions: syncope of either unexplained or 
cardiovascular etiology, ventricular arrhythmia (including but not limited to ventricular tachycardia 
and ventricular fibrillation), or sudden cardiac arrest.  Exception: subjects with controlled atrial 
fibrillation for >30 days prior to study treatment are eligible.
[15]
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).
[16]
Patients on Parts A, B, D, and E only: Have central nervous system (CNS) metastasis with 
development of associated neurological changes 14 days prior to receiving study drug.  Patients may 
be receiving a stable low dose of corticosteroids. Screening of asymptomatic patients without history 
of CNS metastasis is not required.  Patients with untreated CNS metastases are ineligible.
[17]
Have a history of any other cancer (except nonmelanoma skin cancer or carcinoma in-situ of 
the cervix or breast), unless in complete remission with no therapy for a minimum of 3 years.
Patients with history of carcinoma in-situ of the breast must be off tamoxifen for at least 
21 days prior to first dose.
[18]
Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration 
of the trial, starting with the pre-screening or screening visit through 3 months after the last dose of 

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trial treatment

Part E patients: duration of the trial starts with the pre-screening or screening visit through 
120 days (4 months) after the last dose of trial treatment.
[19]
Have active bacterial, fungal, and/or known viral infection (for example, human 
immunodeficiency virus [HIV] antibodies, hepatitis B surface antigen [HBSAg], or hepatitis 
C antibodies [HCAb]).  Screening is not required for enrollment.
[20]
Parts A, B, C, and E have QTc interval of >470 msec on screening electrocardiogram (ECG).  Part D 
patients have a QTc interval of >450 msec on screening ECG at several consecutive days of 
assessment, if clinically indicated.
Additional Exclusion Criteria For Part C (Ramucirumab)
Patients may not be included to Part C if any of the following apply:
[21]
History or evidence of cardiovascular risk including any of the following

History of acute coronary syndromes (including myocardial infarction and angina), 
coronary angioplasty, or stenting within 6 months prior to enrollment.

History or evidence of current ≥Class II congestive heart failure as defined by New York 
Heart Association.

Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg 
and/or diastolic >90 mmHg which cannot be controlled by antihypertensive therapy.

Subjects with intracardiac defibrillators.
[27]
History or evidence of CNS metastases.  Radiographic screening of all patients without history of CNS 
metastasis is required.
[28]
Radiologically documented evidence of major blood vessel invasion or encasement by cancer.  The 
patient has radiographic evidence of intratumor cavitation, regardless of tumor histology.
[29]
Patients with uncontrolled thromboembolic or hemorrhagic disorders.
[30]
Patients receiving chronic daily treatment with aspirin ≥325 mg/day or other known inhibitors of 
platelet function including, but not limited to, clopidogrel.
[31]
Patients with a history of gross hemoptysis (defined as bright red blood of ≥½ teaspoon) within 
2 months of study entry.
[32]
Patients with nonhealing wounds, ulcers, or bone fractures within 28 days prior to study entry.
[33]
Patients who have undergone major surgery within 28 days prior to first dose of study medication or 
have subcutaneous venous access device placement within 7 days prior to first dose.
Additional Exclusion Criteria For Part D (LY3023414)
Patients may not be included to Part D if any of the following apply:
[22]
Have insulin-dependent diabetes mellitus or a history of gestational diabetes mellitus:  Patients with a 
type 2 diabetes mellitus are eligible if adequate control of blood glucose level is obtained by oral anti-
diabetics as documented by HbA1c <7%.
[23]
History or evidence of cardiovascular risk including any of the following:

History of acute coronary syndromes (including myocardial infarction and angina), 
coronary angioplasty, or stenting within 6 months prior to enrollment.
Additional Exclusion Criteria For Part E (Pembrolizumab)
[34]
Has had a prior anticancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 
or who has not recovered (for example, ≤ Grade 1 or at baseline) from adverse events due to 
agents administered more than 4 weeks earlier.
[35]
Active autoimmune disease that has required systemic treatment in past 2 years (for example, 
with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (such as thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.
[36]
Have received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu 
vaccines that do not contain a live virus are permitted.
[37]
Have hypersensitivity or allergic reactions attributed to compound of similar chemical or 
biological composition of pembrolizumab.
[38]
History of interstitial lung disease.
[39]
History of or current pneumonitis.

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Test Product, Dosage, and Mode of Administration:
Abemaciclib is administered orally at 100 mg, 150 mg, or 200 mg every 12 (±3) hours on Days 1 through 21 of a 
21-day cycle.
Planned Duration of Treatment:
Treatment period:  Patients will receive treatment until evidence of disease progression or other discontinuation 
criteria have been fulfilled.
Follow-up period (postdiscontinuation):  approximately 30 ± 7 days.
Criteria for Evaluation:
Safety:
Primary endpoint: Adverse events (AEs), clinical hematology and chemistry, National Cancer Institute (NCI)
CTCAE, version 4.0.
Statistical Methods:
Approximately 150 patients will be enrolled in this study.  The analyses for this study will be descriptive.  Data 
analyses will be provided by study part, dose group, and for all study patients combined wherever appropriate.  For 
continuous variables, summary statistics will include number of patients, mean, median, standard deviation, 
minimum, and maximum.  Categorical endpoints will be summarized using number of patients, frequency, and 
percentages.  Missing data will not be imputed.
All patient discontinuations will be documented, and the extent of each patient’s participation in the study will be 
reported.  If known, a reason for their discontinuation will be given.  Analysis of patient characteristics will include 
a summary of the following: patient demographics, baseline disease characteristics, prior disease-related therapies, 
concomitant medications.  Safety analyses will include summaries of the following: AEs, dose adjustments,
laboratory values, vital signs, DLTs, and ECGs.  Any antitumor activity will be listed and summarized as 
appropriate.
Health Outcomes: Change from baseline in MDASI-LC scores will be listed and summarized for each study part at 
each postbaseline time point specified in the study schedule.  Resource utilization will be described as appropriate.
Pharmacokinetic:  PK parameters will be summarized for abemaciclib and its metabolites and, whenever possible, 
for the other anticancer agents used in combination (pemetrexed, gemcitabine, ramucirumab, and LY3023414).

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3. Table of Contents
A Phase 1b Study of Abemaciclib in combination with 
multiple single-agent options for patients with Stage IV 
NSCLC
Section
Page
1.
Protocol I3Y-MC-JPBJ(h)  A Phase 1b Study of Abemaciclib in 
Combination with Multiple Single-Agent Options for Patients with 
Stage IV NSCLC ................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................7
4.
Abbreviations and Definitions...........................................................................................15
5.
Introduction ......................................................................................................................21
5.1.
Rationale and Justification for the Study ......................................................................23
5.1.1.
Rationale for Amendment (a)...............................................................................24
5.1.2.
Rationale for Amendment (b)...............................................................................24
5.1.3.
Rationale for Amendment (c)...............................................................................25
5.1.4.
Rationale for Amendment (d)...............................................................................25
5.1.5.
Rationale for Amendment (e)...............................................................................25
5.1.6.
Rationale for Amendment (f)................................................................................26
5.1.7.
Rationale for Amendment (g)...............................................................................26
5.1.8.
Rationale for Amendment (h)...............................................................................27
5.2.
Objectives ....................................................................................................................27
5.2.1.
Primary Objective ................................................................................................27
5.2.2.
Secondary Objectives...........................................................................................27
5.2.3.
Exploratory Objectives.........................................................................................27
5.3.
General Introduction to Abemaciclib............................................................................28
5.3.1.
Mechanism of Action and In Vitro/In Vivo Activity.............................................28
5.3.2.
Nonclinical Toxicology........................................................................................32
5.3.3.
Overview of Safety for Non-Small Cell Lung Cancer...........................................33
5.3.4.
Biomarkers...........................................................................................................33
5.4.
General Introduction to LY3023414.............................................................................34
5.4.1.
Mechanism of Action of LY3023414 ...................................................................34
5.4.2.
Clinical Summary of LY3023414.........................................................................34
5.5.
General Introduction to Pembrolizumab .......................................................................35
5.5.1.
Mechanism of Action of Pembrolizumab .............................................................35
5.5.2.
Clinical Summary of Pembrolizumab...................................................................36

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5.6.
Rationale for Selection of Dose of Abemaciclib ...........................................................37
5.6.1.
Rationale for Dose Selection of Abemaciclib and 
LY3023414 for Combination Therapy (Part D)....................................................38
5.6.2.
Rationale for Dose Selection of Abemaciclib and 
Pembrolizumab for Combination Therapy (Part E)...............................................38
6.
Investigational Plan...........................................................................................................39
6.1.
Study Population..........................................................................................................39
6.1.1.
Inclusion Criteria .................................................................................................39
6.1.2.
Exclusion Criteria ................................................................................................41
6.1.2.1.
Additional Exclusion Criteria for Part C (Ramucirumab)................................42
6.1.2.2.
Additional Exclusion Criteria for Part D (LY3023414)...................................43
6.1.2.3.
Additional Exclusion Criteria for Part E 
(Pembrolizumab)............................................................................................43
6.2.
Summary of Study Design............................................................................................43
6.2.1.
Study Completion and End of Trial......................................................................45
6.2.2.
Extension Period..................................................................................................45
6.3.
Discontinuations ..........................................................................................................45
6.3.1.
Discontinuation of Patients...................................................................................45
6.3.1.1.
Part C Discontinuations ..................................................................................47
6.3.2.
Discontinuation of Study Sites .............................................................................48
6.3.3.
Discontinuation of the Study................................................................................48
7.
Treatment..........................................................................................................................49
7.1.
Materials and Supplies .................................................................................................49
7.2.
Study Drug Administration ..........................................................................................49
7.2.1.
Dosing Schedule ..................................................................................................52
7.2.2.
Dose-Escalation Phase .........................................................................................52
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum 
Tolerated Dose Definition...............................................................................54
7.2.2.2.
Dose-Escalation Method.................................................................................54
7.2.3.
Dose-Confirmation Phase.....................................................................................55
7.2.4.
Dose Adjustments and Delays..............................................................................56
7.2.4.1.
Dose Adjustments...........................................................................................56
7.2.4.1.1.
Abemaciclib..............................................................................................56
7.2.4.1.1.1.
Hematologic Toxicity..........................................................................57
7.2.4.1.1.2.
Nonhematological Toxicity (except diarrhea and 
ALT increase) .....................................................................................58
7.2.4.1.1.3.
Diarrhea..............................................................................................58
7.2.4.1.1.4.
Hepatic Toxicity .................................................................................59
7.2.4.1.2.
Pemetrexed...............................................................................................59

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7.2.4.1.3.
Gemcitabine..............................................................................................60
7.2.4.1.4.
Ramucirumab ...........................................................................................60
7.2.4.1.4.1.
Infusion-Related Reactions .................................................................61
7.2.4.1.4.2.
Hypertension.......................................................................................63
7.2.4.1.4.3.
Thrombotic Events..............................................................................64
7.2.4.1.4.4.
Proteinuria ..........................................................................................64
7.2.4.1.5.
LY3023414...............................................................................................65
7.2.4.1.6.
Pembrolizumab.........................................................................................65
7.2.4.2.
Dose Delays ...................................................................................................65
7.2.4.2.1.
Abemaciclib..............................................................................................65
7.2.4.2.2.
Pemetrexed...............................................................................................66
7.2.4.2.3.
Gemcitabine..............................................................................................66
7.2.4.2.4.
Ramucirumab ...........................................................................................66
7.2.4.2.5.
LY3023414...............................................................................................67
7.2.4.2.6.
Pembrolizumab.........................................................................................67
7.2.4.3.
Special Treatment Considerations...................................................................71
7.2.4.3.1.
Immune Checkpoint Inhibitors..................................................................71
7.3.
Method of Assignment to Treatment ............................................................................71
7.4.
Blinding .......................................................................................................................71
7.5.
Concomitant Therapy...................................................................................................71
7.5.1.
Supportive Care ...................................................................................................72
7.5.1.1.
Supportive Management for Diarrhea .............................................................72
7.5.1.2.
Guidance for Monitoring of Renal Function in Patients 
on Abemaciclib ..............................................................................................73
7.5.1.3.
Supportive Care for Hyperglycemia – Part D Only .........................................73
7.5.1.4.
Supportive Care Guidelines for Pembrolizumab –Part E 
only................................................................................................................73
7.6.
Treatment Compliance .................................................................................................75
7.6.1.
Evaluable Patients................................................................................................75
8.
Safety, Pharmacokinetic, Pharmacodynamic, and Efficacy Data 
Collection .........................................................................................................................77
8.1.
Safety Evaluations........................................................................................................77
8.1.1.
Safety Data Collection and Review ......................................................................77
8.1.2.
Adverse Events ....................................................................................................78
8.1.2.1.
Serious Adverse Events ..................................................................................79
8.1.2.1.1.
Part E:  Events of Clinical Interest ............................................................81
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting .....................................81
8.1.2.2.1.
Prior to Administration of Study Drug(s) ..................................................81
8.1.2.2.2.
On Therapy...............................................................................................81

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8.1.2.2.3.
Follow-Up Visit........................................................................................81
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions..........................................82
8.1.2.4.
Summary of AE/SAE Reporting Guidelines ...................................................82
8.1.3.
Other Safety Measures .........................................................................................83
8.1.3.1.
Electrocardiograms.........................................................................................83
8.1.4.
Safety Monitoring ................................................................................................84
8.1.4.1.
Special Hepatic Safety Data Collection...........................................................84
8.1.4.2.
Venous Thromboembolic Events (VTEs)........................................................84
8.1.5.
Complaint Handling.............................................................................................85
8.2.
Sample Collection and Testing.....................................................................................85
8.2.1.
Samples for Study Qualification and Health Monitoring.......................................85
8.2.2.
Samples for Drug Concentration Measurements 
Pharmacokinetics/Pharmacodynamics..................................................................85
8.2.2.1.
Pharmacokinetic Samples...............................................................................86
8.2.3.
Samples for Tailoring Biomarkers........................................................................86
8.2.4.
Samples for Immunogenicity Research.................................................................87
8.3.
Efficacy Evaluations ....................................................................................................87
8.4.
Health Outcomes..........................................................................................................88
8.4.1.
Patient-Reported Outcomes..................................................................................88
8.4.2.
Resource Utilization.............................................................................................89
8.5.
Procedure/Sampling Compliance..................................................................................89
9.
Data Management Methods...............................................................................................90
9.1.
Data Quality Assurance................................................................................................90
9.2.
Data Capture Systems ..................................................................................................90
9.2.1.
Case Report Form ................................................................................................90
9.2.2.
Ancillary Data......................................................................................................91
10.
Data Analyses...................................................................................................................92
10.1. General Considerations ................................................................................................92
10.2. Patient Disposition .......................................................................................................92
10.3. Patient Characteristics ..................................................................................................92
10.4. Safety Analyses............................................................................................................92
10.5. Pharmacokinetic Analyses............................................................................................93
10.6. Efficacy........................................................................................................................93
10.7. Health Outcomes..........................................................................................................93
10.8. Interim Analyses ..........................................................................................................94
11.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................95
11.1. Informed Consent.........................................................................................................95
11.2. Ethical Review.............................................................................................................95

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11.3. Regulatory Considerations ...........................................................................................95
11.4. Investigator Information...............................................................................................96
11.5. Protocol Signatures ......................................................................................................96
11.6. Final Report Signature..................................................................................................96
12.
References ........................................................................................................................97

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List of Tables
Table
Page
Table JPBJ.7.1.
Treatment Combinations for Study I3Y-MC-JPBJ .........................................51
Table JPBJ.7.2.
Dose-Escalation Scheme for Study I3Y-MC-JPBJ .........................................53
Table JPBJ.7.3.
Dose-Escalation Scheme for Part C................................................................53
Table JPBJ.7.4.
Dose-Escalation Scheme for Part D ...............................................................53
Table JPBJ.7.5.
Dose-Escalation Scheme for Part E................................................................54
Table JPBJ.7.6.
Toxicity Dose Adjustments and Delays of Abemaciclib for Study I3Y-
MC-JPBJ.......................................................................................................56
Table JPBJ.7.7.
Dose Adjustments of Abemaciclib for Study I3Y-MC-JPBJ...........................57
Table JPBJ.7.8.
Hematologic Dose Reduction for Pemetrexed in Study I3Y-MC-JPBJ...........59
Table JPBJ.7.9.
Nonhematologic Dose Reduction for Pemetrexed in 
Study I3Y-MC-JPBJ......................................................................................59
Table JPBJ.7.10. Dose Adjustments of Gemcitabine for Study I3Y-MC-JPBJ...........................60
Table JPBJ.7.11. Dose Adjustments of Ramucirumab for Study I3Y-MC-JPBJ ........................61
Table JPBJ.7.12. Dose Adjustments of LY3023414 for Study I3Y-MC-JPBJ ...........................65
Table JPBJ.7.13. Dose Adjustments for Pembrolizumab in Study I3Y-MC-JPBJ......................68
Table JPBJ.7.14. Infusion Reaction Treatment Guidelines in Study I3Y-MC-JPBJ ...................74
Table JPBJ.8.1.
Adverse Event and Serious Adverse Reporting Guidelines for Study 
I3Y-MC-JPBJ................................................................................................83

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List of Figures
Figure
Page
Figure JPBJ.5.1. The extent of growth inhibition by abemaciclib mesylate in NSCLC 
xenografts correlates with KRAS status.........................................................30
Figure JPBJ.5.2. Combination efficacy studies with abemaciclib mesylate 
(AKA 2813524) in mouse xenograft models for human NSCLC....................31
Figure JPBJ.5.3. Abemaciclib mesylate antitumor effects in a rat orthotopic brain 
xenograft model.............................................................................................32
Figure JPBJ.6.1. Illustration of study design for clinical protocol I3Y-MC-JPBJ. .....................44

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List of Attachments
List of Protocol Attachments
Attachment
Page
Attachment 1.
Protocol JPBJ Study Schedule .....................................................................102
Attachment 2.
Protocol JPBJ Clinical Laboratory Tests......................................................108
Attachment 3.
Protocol JPBJ Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ................................................................................................109
Attachment 4.
Protocol JPBJ Pharmacokinetic Sampling Schedule.....................................110
Attachment 5.
Protocol JPBJ Recommendations for Reporting Serious Adverse Events .....115
Attachment 6.
Protocol JPBJ ECOG Performance Status....................................................116
Attachment 7.
Protocol JPBJ Creatinine Clearance Formula...............................................117
Attachment 8.
Protocol JPBJ Sampling Summary...............................................................118
Attachment 9.
Protocol JPBJ RECIST Criteria 1.1..............................................................120
Attachment 10.
Protocol JPBJ Inducers, Strong Inhibitors of CYP3A or Substrates of 
CYPs with Narrow Therapeutic Range ........................................................128
Attachment 11.
Protocol JPBJ Child-Pugh Score..................................................................130
Attachment 12.
Protocol JPBJ Protocol Amendment I3Y-MC-JPBJ(g) Summary A 
Phase 1b Study of Abemaciclib in Combination with Multiple 
Single-Agent Options for Patients with Stage IV NSCLC ............................131

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4. Abbreviations and Definitions
Term
Definition
ACS
American Cancer Society
AE
Adverse event:  Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not 
necessarily have a causal relationship with this treatment.  An adverse event 
(AE) can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with 
the use of medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC(0-tlast)
area under the plasma concentration-time curve from time zero to last 
measurable plasma concentration
AUC(0-∞)
area under the plasma concentration-time curve from time zero to infinity
audit
A systematic and independent examination of the study-related activities and 
documents to determine whether the evaluated study-related activities were 
conducted, and the data were recorded, analyzed, and accurately reported 
according to the protocol, applicable standard operating procedures (SOPs), 
good clinical practice (GCP), and the applicable regulatory requirement(s).
BP
blood pressure
BSC
best supportive care
BUN
blood urea nitrogen
Cmax
maximum plasma concentration
Cmin,ss
trough plasma levels
CBC
complete blood count
CDK
cyclin-dependent kinase
CL/F (or CL)
apparent systemic clearance
CNS
central nervous system

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collection database
A computer database where clinical trial data are entered and validated.
complaint
Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, purity, durability, reliability, safety, effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that Lilly is 
confident that results are accurate.  Confirmation will either occur immediately 
after initial testing or will require that samples be held to be retested at some 
defined time point, depending on the steps required to obtain confirmed results.
CR
complete response
CrCl
creatinine clearance
CRF/eCRF
case report form/electronic case report form: Sometimes referred to as clinical 
report form, a printed or electronic form for recording study participants’ data 
during a clinical study, as required by the protocol.
CRP
clinical research physician
CRS
clinical research scientist
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
dFdU
2’,2’-difluorodeoxyuridine
DLT
dose-limiting toxicity
DVT
deep vein thrombosis
ECG
electrocardiogram
ECHO
echocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eDC
electronic data capture
EGFR
epidermal growth factor receptor
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency

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EML4
echinoderm microtubule-associated protein-like 4
end of trial
End of trial is the date of the last visit or last scheduled procedure for the last 
patient.
enroll
Patients who are enrolled in the trial are those who have been assigned to a 
treatment and have received at least one dose of study treatment.
enter
Patients who are entered in the trial are those who have signed the informed 
consent form directly or through their legally acceptable representatives.
ERB/IRB
ethical review board/institutional review board:  /A board or committee 
(institutional, regional, or national) composed of medical and nonmedical 
members whose responsibility is to verify that the safety, welfare, and human 
rights of the patients participating in a clinical study are protected.
ERK
extracellular signal-regulated kinase
EU
European Union
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
GCP
good clinical practice
HBSAg
hepatitis B surface antigen
HCAb
hepatitis C antibodies
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
Informed consent
A process by which a patient voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the 
trial that are relevant to the patient’s decision to participate.  Informed consent 
is documented by means of a written, signed and dated informed consent form.
INR
International Normalized Ratio
interim analysis
An analysis of clinical study data that is conducted before the final reporting 
database is authorized for datalock.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used 
as a reference in a clinical trial.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a 
study is conducted by a team of individuals at a study site, the investigator is the 
responsible leader of the team and may be called the principal investigator.

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irRECIST
immune-related Response Evaluation Criteria In Solid Tumors
LC/MS/MS
liquid chromatography-mass spectrometry
legal representative
An individual, judicial, or other body authorized under applicable law to 
consent on behalf of a prospective patient, to the patient’s participation in the 
clinical study.
Lilly Safety System
Global safety database that tracks and reports serious adverse and spontaneous 
events occurring while using a drug/drug delivery system.
LLN
lower limit of normal
mAb
monoclonal antibody
MAPK
mitogen-activated protein kinase
MCV
Mean cell volume
MCHC
Mean cell hemoglobin concentration
MDASI-LC
MD Anderson Symptom Inventory- Lung Cancer
MedDRA
Medical Dictionary for Regulatory Activities
monitor
A person responsible for ensuring the investigator site complies with the 
monitoring plan, applicable local SOPs (if any), and global Medical SOPs.  
Monitors are trained on the investigational product(s), the protocol, informed 
consent document, any other written information provided to subjects, relevant 
SOPs, International Conference on Harmonisation Good Clinical Practice 
guidelines (ICH-GCP), and all applicable laws (for example, privacy and data 
protection) and regulations. 
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multi-gated acquisition
NCI
National Cancer Institute
NE
not evaluable 
NSAID
nonsteroidal anti-inflammatory drugs
NSCLC
Non-small cell lung cancer
open-label
A study in which there are no restrictions on knowledge of treatment allocation, 
therefore the investigator and the study participants are aware of the drug 
therapy received during the study.
ORR
overall response rate

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OS
overall survival
patient
A subject with a defined disease.
PD
progressive disease
PE
pulmonary embolism
PET
positron emission tomography
PFS
progression-free survival
PI3K/mTOR
phosphatidylinositol-3-kinase/ mammalian target of rapamycin
PK
pharmacokinetic
PK/PD
pharmacokinetics/pharmacodynamics
PR
partial response
pRb
Rb phosphorylation at serine 780
PS
performance status
PSA
prostate-specific antigen
PT
prothrombin time
Q2W
every 2 weeks
Q3W
every 3 weeks
Q12H
every 12 hours
Rb
retinoblastoma 
RECIST
Response Evaluation Criteria in Solid Tumors
rescreen
To screen a patient who was previously declared a screen failure for the same 
study
RPLS
reversible posterior leukoencephalopathy syndrome
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become 
part of a pool of potential candidates for participation in a clinical trial.  In this 
study, screening involves diagnostic procedures, exams, and blood tests.  
screen failure
A patient who does not meet one or more criteria required for participation in a 
trial
sponsor
The party who takes responsibility for the initiation, management and/or 
financing of a clinical study.

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study completion
This study will be considered complete 6 months after the last patient enters
treatment.  
SUSAR
suspected unexpected serious adverse reactions
t1/2
half-life
TBL
total bilirubin
TED70
threshold effective doses for 70% inhibition
TPO
third-party organization
ULN
upper limit of normal
US
United States
V/F
apparent volume of distribution
VEGF
vascular endothelial growth factor
VTE
venous thromboembolic event
WBC
white blood cell

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A Phase 1b Study of Abemaciclib in Combination with 
Multiple Single-Agent Options for Patients with Stage IV 
NSCLC
5. Introduction
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 incidence of lung cancer for both 
men and women is highest in North America and the third highest in Europe after breast and 
colorectal cancers (O’Conner 2011). The American Cancer Society (ACS) estimated in 2012, 
lung cancer accounted for 226,160 new cancer diagnoses and 160,340 deaths in the United States 
(US), which corresponded to almost 14% of all new cancer diagnoses and 28% of all 
cancer-related deaths (ACS 2012).
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. For 
the purposes of evaluation and treatment, disease stage is important to determine prognosis and
the primary consideration for treatment approach. The 1-and 5-year survival rates progressively 
decline as disease stage increases (Bülzebruck et al. 1992; Goldstraw et al. 2007; Pfannschmidt 
et al. 2007). The majority of patients with lung cancer are diagnosed with advanced or 
metastatic disease (ACS 2012). Many patients with locally advanced disease at diagnosis are 
treated with curative intent but later develop recurrence with advanced stage disease and no 
prospect of cure and survival outcomes remain poor (Benamore et al. 2007; Bonomi 2010).
Platinum-based chemotherapy has demonstrated significant improvement in overall survival 
(OS) compared to best supportive care (BSC) and is considered the standard first-line treatment 
for NSCLC in an unselected patient population (Marino et al. 1994; Non-small Cell Lung Cancer 
Collaborative Group 1995). Multiple randomized trials combined cisplatin or carboplatin with a 
“third-generation” drug (eg, gemcitabine, vinorelbine, paclitaxel, docetaxel) and demonstrated 
similar OS results (Kelly et al. 2001; Scagliotti et al. 2002; Schiller et al. 2002).
In addition, pemetrexed, a third-generation antifolate, has been investigated in the treatment of 
patients with advanced or metastatic NSCLC as part of a platinum doublet regimen in first-line 
therapy and was approved by the US Food and Drug Administration (FDA) and European 
Medicines Agency (EMA) in 2008 for patients with nonsquamous NSCLC (Scagliotti et al. 
2008, 2009).  To further enhance survival of patients with advanced and metastatic NSCLC, 
platinum-based doublet regimens have been combined with targeted agents such as bevacizumab 
(a humanized monoclonal antibody [mAb] against vascular endothelial growth factor [VEGF] 
ligand) and cetuximab (a chimeric mAb against epidermal growth factor receptor [EGFR])
(Sandler et al. 2006; Pirker et al. 2009; Reck et al. 2009).
A subset of NSCLC patients (17%) with EGFR mutations, mainly composed of adenocarcinoma 
histology, have significant improvement in progression-free survival (PFS) when treated with an 
EGFR targeted agent (eg, erlotinib) in the first-line setting (Reguart et al. 2010; Paz-Ares et al. 
2010). Similarly, a rarer subset of NSCLC patients (4%) with an echinoderm 

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microtubule-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) translocation, 
mainly adenocarcinoma histology and typically younger nonsmokers, have significant 
improvement in PFS when treated with the targeted agent, crizotinib, which acts as a protein 
kinase inhibitor (Shaw et al. 2013).
VEGF receptor-2 (VEGFR-2) is normally expressed exclusively on endothelial and 
hematopoietic cells and is overexpressed in patients with NSCLC (Sanmartin et al. 2009).  
Overexpression is most responsible for the mitogenic and angiogenic effects of VEGF.  The 
ligand/receptor interactions promote tumor angiogenesis, tumor growth, and metastasis.  
Targeting tumor-associated endothelial cells is a promising therapeutic approach because 
endothelial cells have genetic stability and are predisposed to develop less resistance compared 
to tumor cells.  VEGFR-2 signaling and VEGF-induced endothelial cell growth in vitro have 
produced antiangiogenic, antitumor, and antimetastatic activity in preclinical models (Skobe 
et al. 1997; Prewett et al. 1999). VEGFR-2 is a promising target for antibody-based inhibition 
and in combination with a targeted drug that induces inhibition of the cyclin-dependent kinases
(CDKs) CDK4 and CDK6, treatment outcomes for patients with advanced and/or metastatic
NSCLC may result in improved clinical benefit beyond what is observed with the current agents 
approved in second- and third-line therapy.
The expression of cyclin D1, a protein that preferentially binds to and activates CDK4 and 
CDK6, is induced by mitogenic growth factors, acting through various upstream signaling 
pathways.  These multiple signaling pathways, including mitogen-activated protein kinase 
(MAPK) and phosphatidylinositol 3-kinase (PI3K), converge downstream at the cyclin 
D1-CDK4 and CDK6 complex, leading to its activation.  Frequent activating aberrations of 
PI3K/mTOR signaling have been reported amongst others for breast cancer, mesothelioma, 
NSCLC, and endometrial cancers (Opitz et al. 2008; Courtney et al. 2010; Miller et al. 2011; 
Varghese et al. 2011).  The identification of molecular characteristics that promote greater 
likelihood for tumor response suggests a therapeutic opportunity to provide significant clinical 
benefit in patients with advanced and/or metastatic NSCLC.
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (Disis 2010). Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in 
various malignancies (Bremnes et al. 2011; Talmadge 2011; Mei et al. 2014).  In particular, the 
presence of CD8+ T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells 
correlates with improved prognosis and long-term survival (Liu et al. 2011). Cell–based studies
with abemaciclib, which evaluated the effect of abemaciclib on immune cell activity and 
metabolism, indicated moderate, not profound, inhibitory activity in T cells at clinical dose 
levels. Consequently, combining with a drug targeting the programmed death receptor-1 (PD-1) 
/ programmed death ligand 1 (PD-L1) pathway is attractive for therapeutic intervention in 
NSCLC.
Unfortunately, not all patients respond to first-line therapy and even patients who initially 
respond will likely relapse. Irrespective of response to first-line therapy, many patients continue 
to have a good performance status (PS) and are candidates for second-line therapy.  As 

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monotherapy, docetaxel, pemetrexed, and erlotinib are FDA and EMA approved for second-line 
therapy after progression of first-line chemotherapy (Gandara et al 2000; Hanna et al. 2004; 
Shepherd et al. 2005).  Most recently, Cyramza (ramucirumab) in combination with docetaxel 
was FDA approved for second-line metastatic NSCLC with disease progression on or after 
platinum-based chemotherapy (Garon et al. 2014). Third-line treatment options are limited for 
patients with advanced and/or metastatic NSCLC. Despite the numerous targeted agents that 
have been evaluated as third-line therapy or beyond, only erlotinib and crizotinib have received 
approval in the US (Langer et al. 2013) and European Union as third-line therapy.  Erlotinib is 
approved in all patients, but crizotinib only approved in specific tumors.  Available treatment 
options for second-line therapy and beyond are investigated to not only demonstrate safety and 
tolerability similar to the overall patient population, but to identify therapeutic options that yield 
improved clinical benefit for patients with advanced and/or metastatic NSCLC, as this area of 
investigation continues to represent an unmet medical need and warrants further prospective
study.
5.1.
Rationale and Justification for the Study
One of the hallmarks of cancer is cell cycle dysregulation, through either over activity of the 
proliferative machinery (by means of activating mutations in CDKs, gene amplification in 
regions of the genome that are responsible for encoding, and overexpression of individual 
proteins related to cell cycle proteins) or inactivation of the proteins that block the cell cycle (eg, 
p53 or p16, retinoblastoma complex).  These alterations render cells less dependent on mitogenic 
signaling for proliferation and result in tumor growth. Cell cycle dysregulation occurs in >90% 
of lung cancers, and therefore represents an attractive therapeutic target (Malumbres and 
Barbacid 2001).
During the cell cycle, the G1 restriction point controls entry into S phase and is essential for 
maintaining control of cell division (Ortega et al. 2002; Sherr 1996).  CDK4 and CDK6 
participates in a complex with D-type cyclins to initiate the transition through the G1 restriction 
point.  A broad spectrum of human cancers have alterations in the CDK4 and CDK6-cyclinD-
INK4-retinoblastoma (Rb) pathway through either increased CDK4 and CDK6-cyclinD activity 
or mutations that attenuate function of the INK4 or Rb proteins (Malumbres and Barbacid 2001).
The CDK4 and CDK6-cyclinD complex regulates the G1 restriction point through 
phosphorylation of the 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 (CDKI) by mutation or epigenetic silencing, 2) mutation/overexpression of either 
CDK4 and CDK6 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 CDK4 and CDK6-
cyclinD complex, all these cancers are potentially sensitive to pharmacologic inhibition of CDK4
and CDK6.  From a therapeutic standpoint, the goal of inhibiting CDK4and CDK6 with a small 
molecule inhibitor is to prevent cell cycle progression through the G1 restriction point, thus 
arresting tumor growth.

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Abemaciclib represents a potent and selective small molecule inhibitor of CDK4 and CDK6.  
Abemaciclib demonstrates antitumor activity in multiple mouse models of human cancer, 
physical and pharmacokinetic (PK) properties suitable for drug development, and an acceptable 
toxicity profile in nonclinical species. Abemaciclib administered orally demonstrates single-
agent activity and inhibits tumor growth in human xenograft models of NSCLC. In the Phase 1 
study, abemaciclib has shown acceptable safety/tolerability as well as evidence of clinical 
activity in multiple tumor types (additional information provided in Section 5.3.3).  Abemaciclib
demonstrated early single-agent clinical activity in NSCLC including 1 patient with confirmed 
partial response (PR) (Shapiro et al. 2013).
The sponsor, monitor, and investigators will perform this study in compliance with the protocol, 
good clinical practice (GCP) and International Conference on Harmonisation (ICH) guidelines, 
and applicable regulatory requirements.
5.1.1. Rationale for Amendment (a)
The protocol was amended prior to study initiation based on FDA feedback to adjust several 
eligibility criteria, enhance safety evaluation, and clarify monitoring of specific safety events.
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.
5.1.2. Rationale for Amendment (b)
The primary rationale for amendment (b) is to further evaluate safety and tolerability in an 
expansion cohort Part D of Study JPBJ, abemaciclib in combination with LY3023414 in patients 
with Stage IV NSCLC, as outlined in Section 8.1 of the initial protocol.
LY3023414 demonstrated clinical safety and tolerability benefit in NSCLC patients in Phase 1 
Study I6A-MC-CBBA (CBBA), and recent publications indicate that activating aberrations of 
the PI3K/mTOR pathway have been reported for NSCLC.  LY3023414 will replace trametinib as
the combination drug in Study Part D.
Ramucirumab exposure has been demonstrated to be related to response.  In order to increase the 
exposures of ramucirumab, a dose escalation has been added to the existing design where the 
ramucirumab dose was 10 mg/kg.  First, a dose of 8 mg/kg on Days 1 and 8 of a 21-day cycle 
will be evaluated in combination with abemaciclib.  If this is safe and tolerable, a dose of 
10 mg/kg on Days 1 and 8 of a 21-day cycle will be evaluated in combination with abemaciclib.
If any of the expansion cohorts indicate preliminary efficacy for the combination therapy, then 
approximately 12 more patients will be enrolled to obtain additional clinical evidence for 
efficacy.
Minor editorial changes have been made throughout the protocol to improve clarity and 
practicability of the protocol and secure alignment with the intended study design.

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5.1.3. Rationale for Amendment (c)
The rationale for amendment (c) is based on FDA recommendations to adjust the initial dose of 
abemaciclib for Part D.
Nonclinical murine xenograft models resulted in 15% to 20% body weight loss with the 
administration of abemaciclib 150-mg dose plus LY3023414 45-mg dose.  In addition,
abemaciclib is primarily metabolized in vitro by CYP3A4, and LY3023414 is a weak inhibitor of 
CYP3A4, therefore LY3023414 may lead to increased abemaciclib exposures.
In addition, modifications were performed for supportive management for diarrhea.  Minor 
typographical and formatting edits were made throughout the document for clarity and 
consistency.
5.1.4. Rationale for Amendment (d)
The primary rationale for amendment (d) is to further evaluate safety and tolerability in 
expansion cohort of Study JPBJ, abemaciclib in combination with pembrolizumab (Part E) in 
patients with Stage IV NSCLC.
Additional edits were made to update the dosing guidance for cases of hematologic toxicity and 
diarrhea and guidance on the use of blood cell growth factors. Lilly conducted a review across 
several clinical trials of abemaciclib and concluded that there were some inconsistencies in the 
guidance. This edit will harmonize the dosing guidance across all abemaciclib studies and 
clarify blood cell growth factors are only to be used in a manner consistent with American 
Society of Clinical Oncology (ASCO) guidelines.
Minor editorial changes have been made to reflect the new treatment arm, fix typographical and 
formatting errors, and to improve clarity and consistency throughout the document.
5.1.5. Rationale for Amendment (e)
The rationale for amendment (e) is to update the exclusion criteria regarding pneumonitis for 
patients participating in study Part E (abemaciclib in combination with pembrolizumab) and to 
harmonize them with the other clinical trials being conducted with pembrolizumab, as requested
by the manufacturer of pembrolizumab.
In addition, results from Study I3Y-MC-JPBA (JPBA) show that abemaciclib inhibited CDK4 
and CDK6 as indicated by inhibition of phosphoraylated retinoblastoma (pRb) and TopoII, 
which results in cell cycle inhibition upstream of the G1 restriction point at concentrations 
achieved by doses of 50 mg to 200 mg twice daily (BID). Sufficient abemaciclib exposures and 
cell cycle arrest were achieved by doses of 150 mg every 12 hours (Q12H). This inhibition was 
associated with clinical benefit. Further details on the inhibition of CDK4 and CDK6 by 
abemaciclib can be found in the Investigator’s Brochure (IB). Therefore, to avoid exposing
patients to unnecessary potential toxicity, the Study JPBJ protocol was amended to remove
escalation of abemaciclib to 200 mg BID in Part E of the study, such that the highest dose of 
abemaciclib to be evaluated in combination with pembrolizumab will be 150 mg Q12H. Parts A

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through D of the study were not modified, as the cohorts including abemaciclib 200 mg BID 
were ongoing or already completed at the time of this protocol amendment.
Additional updates were made to include information on guidance for renal function monitoring 
in patients on abemaciclib, supportive care for hyperglycemia for patients in Part D, and immune 
checkpoint inhibitors delayed toxicity.  Minor editorial changes have been made for clarity and 
consistency throughout the document.
5.1.6. Rationale for Amendment (f)
The primary rationale for amendment (f) is to incorporate additional hematology and chemistry
monitoring on Day 8 during cycles 2-8 of study Part E, abemaciclib in combination with 
pembrolizumab in patients with Stage IV NSCLC. The additional monitoring is based on the 
clinical data from neoMONARCH (I3Y-MC-JPBY). In the neoMONARCH study, resected 
breast cancer specimens after 14 weeks of abemaciclib monotherapy revealed increased 
infiltration with CD3 and CD8 lymphocytes compared to pre-treatment specimens. This 
observation suggests the theoretical possibility of additive or synergistic interaction between 
pembrolizumab and abemaciclib in terms of immune related side effects such as hepatitis.  More 
frequent laboratory monitoring allows for early detection should the side effect occur and earlier
intervention.  
Additionally, ongoing Part D Escalation Cohort 4a (abemaciclib 200mg Q12H in combination 
LY3023414 150mg Q12H) has been closed prior to completion of enrollment of this cohort.
Escalation Cohort 5 (abemaciclib 200mg Q12H in combination LY3023414 200mg Q12H) has 
been removed. The rationale of this change is the same as described in Section 5.1.5 for the 
removal of the Study JPBJ Part E escalation of abemaciclib to 200 mg BID.   
Furthermore, pembrolizumab background information has been updated to align with the 
approved label.  
Minor editorial changes have been made for clarity and consistency throughout the document.
5.1.7. Rationale for Amendment (g)
The primary rationale for amendment (g) is to incorporate Part D language for LY3023414 
dosing and dose adjustments (Section 7.2.4.1.5).  Modifications were included to update 
LY3023414 “capsule” to “capsules/tablets” due to potential formulation change, and to remove 
the food intake restrictions.  For LY3023414 in the relative bioavailability and food-effect Study 
I6A-EW-CBBB, decreases in exposure observed when a 200-mg dose was administered in a fed 
state, were not considered to be clinically relevant given the observed inter-subject variability.  
Therefore, the 1-hour LY3023414 dosing window after food intake has been removed from 
ongoing studies (Section 7.2).  
Additionally, the maximum tolerated dose (MTD) of abemaciclib + LY3023414 has been 
established, resulting in the revision in number of patients in the Confirmation Cohort D-4 from 
12 patients to 6 to 12 patients.  Therefore, a maximum of 12 patients will be enrolled to further 
examine the safety profile of the recommended combination dose of abemaciclib.  

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The extension period for Study JPBJ is clarified and a schedule of events have been added (see 
Attachment 1).
Dose modification Table JPBJ.7.13 for pembrolizumab was updated to include dose adjustments 
in case of myocarditis to be consistent with the current Investigator’s Brochure (IB) for 
pembrolizumab version 15. Formatting changes in the table were also made.
Minor editorial changes have been made for clarity and consistency throughout the document.
5.1.8. Rationale for Amendment (h)
Study JPBJ 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 metastatic setting.  The amendment updated the safety 
language regarding hepatic monitoring, assessment of renal function, and venous 
thromboembolic events (VTEs) for ongoing patients. Updates to Attachment 10 were completed 
to harmonize the list of CYP inhibitors and inducer, including those with narrow therapeutic 
range. Minor typographical and formatting edits were made throughout the document for clarity 
and consistency.
5.2.
Objectives
5.2.1. Primary Objective
The primary objective of this study is to evaluate the safety and tolerability of abemaciclib when 
administered orally in combination with multiple single-agent options to patients with Stage IV 
NSCLC using Common Terminology Criteria for Adverse Events (CTCAE version 4.0, 
NCI 2009).
5.2.2. Secondary Objectives
The secondary objectives of this study are:

To determine the PK of abemaciclib and pemetrexed, gemcitabine, ramucirumab, 
or LY3023414, when given in combination.

To document the antitumor activity of abemaciclib when given in combination 
with multiple single-agent options.

To characterize changes in patient-reported pain and disease-related symptoms 
collected via the MD Anderson Symptom Inventory-Lung Cancer (MDASI-LC).
5.2.3. Exploratory Objectives

To explore biomarkers relevant to abemaciclib and the disease state and to 
correlate these markers to clinical outcome and to abemaciclib.

To explore the relationship between pathways and signatures of sensitivity 
developed in preclinical models based on gene expression and response to therapy 
using archival tumor specimens (as samples are available).

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
To explore the relationship between genetic variants and the role in regulation of 
the cell cycle and association with observed clinical outcomes to abemaciclib.
5.3.
General Introduction to Abemaciclib
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) may be found in the IB.  Information on AEs expected to be related to the 
investigational product 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.
5.3.1. Mechanism of Action and In Vitro/In Vivo Activity
Abemaciclib mesylate is a potent inhibitor of CDK4 and CDK6 that is selective over other CDKs 
at the enzyme (3 orders of magnitude more selective for CDK4 compared to CDK1) and cellular 
level.  This is demonstrated in Colo 205 cells by potent cellular inhibition of Rb phosphorylation 
(pSer780, IC50 = 120 ± 36 nM) and by exclusive G1 cell cycle arrest (indicated by accumulation 
of cells with 2N DNA content) up to 6 M concentration.  Studies in other cancer cell models 
have confirmed and demonstrated that abemaciclib mesylate inhibits CDK4 and CDK6 to induce 
G1 arrest specifically in Rb+ cell lines versus lines which lack functional Rb (Rb-).  Using in 
vitro kinase panel screening, abemaciclib mesylate also demonstrates inhibition (IC50 <0.3 M) 
of the human protein kinases hCDK9, hPIM1, hPIM2, hHIPK2, hDYRK2, GSK3, hCDK5/P35, 
and CK2; however, the reversible G1 arrest seen in vitro and in vivo indicates that the CDK4 and 
CDK6 activity of abemaciclib mesylate predominates over these other activities.
The phenotypic selectivity for a G1 arrest is also demonstrated in animal studies.  In these 
studies, in vivo target inhibition was measured in human Colo 205 xenografts with an assay 
monitoring both biochemical and phenotypic inhibition of CDK4 and CDK6.  Rb 
phosphorylation at serine 780 (pRb) is a specific marker for CDK4 and CDK6 inhibition and 
also a phenotypic marker for G1 arrest, while TopoIIis a specific marker for cells in S phase 
and pHH3 is a marker for cells in M phase.  Inhibition of CDK4 and CDK6 associated with 
reduced pRb and a sustained G1 arrest is indicated by strong inhibition of all markers.  The 
capacity of abemaciclib mesylate to inhibit CDK4 and CDK6 in vivo is illustrated by the 
sustained pharmacodynamic response in mouse Colo 205 xenograft model, in which a 50 mg/kg 
oral dose resulted in ≥50% inhibition of Rb phosphorylation for 1 to 24 hours after dosing.  This 
effect also correlated with an inhibition of cell cycle progression as indicated by the potent 
suppression of pRb, TopoII, and pHH3 observed at 24 hours following dosing.  A dose 
response for inhibition was observed in these studies such that the threshold effective doses for 
70% inhibition (TED70) for pRb and TopoIIinhibition 24 hours after oral dosing were 14.1 and 
14.3 mg/kg, respectively.
The potential for broad antitumor efficacy by abemaciclib is indicated by the significant 
inhibition of tumor growth observed in multiple murine xenograft models for human cancer, 
including models for NSCLC cancer (NCI-H441, NCI-H2122, NCI-H358, NCI-H460); for 
colorectal cancer (Colo-205); for glioblastoma (U87 MG); for melanoma (A375); and for mantle 

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cell lymphoma (JeKo-1).  Although characterized by a different constellation of genomic 
mutations, each of these human xenograft models has an intact, functional Rb tumor suppressor 
protein.  Xenograft growth inhibition was, in general, dose dependent from 15 to 100 mg/kg 
following daily oral administration for 21 days.  Consistent with the mechanism of action of 
abemaciclib, the antitumor activity was correlated with a sustained inhibition of pRb, TopoII, 
and pHH3 in those studies where target inhibition data were collected as additional endpoints 
with efficacy.
Opportunities to tailor therapy with abemaciclib based on underlying genetic drivers may be 
possible for NSCLC, whereby genetically engineered mouse models have revealed a possible 
synthetic lethal relationship between mutational activation of KRAS and inactivation of CDK4
and CDK6 (Puyol et al. 2010).  Recent studies with abemaciclib mesylate done in murine models 
bearing human xenografts provide further support for this relationship for lung adenocarcinomas 
in that xenograft models such as NCI-H2122, NCI-H358, and NCI-H441, which all express an 
activated KRAS oncogene, were observed to be the most sensitive to monotherapy with 
abemaciclib mesylate.  Models which express a wild-type KRAS gene such as NCI-H1975 and 
NCI-H1650 were observed to be among the least sensitive of the lung adenocarcinoma models to 
growth inhibition by abemaciclib mesylate (Figure JPBJ.5.1).
Combination studies conducted in KRAS-mutant NSCLC models such as NCI-H441 or 
NCI-H2122 indicated the potential for additivity when agents such as gemcitabine, pemetrexed, 
DC101 (mouse surrogate of ramucirumab), and everolimus (mTOR inhibitor) were given in 
combination with abemaciclib mesylate.  In these studies the combination therapies as compared 
to the single-agent treatments resulted in either a greater inhibition of tumor growth during 
therapy or in a longer duration of growth inhibition following the cessation of treatment 
(Figure JPBJ.5.2).
As a result of its brain exposure, treatment with abemaciclib mesylate produces a statistically 
significant and dose-dependent improvement in survival when assessed in a rat orthotopic brain 
tumor model whereby tumor cells were implanted intracerebrally.  The Kaplan Meier survival 
analysis following 21 days of treatment at 20, 40, or 80 mg/kg showed a statistically significant 
improved survival in the 40- and 80-mg/kg groups such that median survival observed for these 
2 groups was 33.5 and 36.9 days, respectively, versus 25.1 days for the vehicle control group 
(Figure JPBJ.5.3).

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Athymic nude mice bearing NSCLC xenografts were treated with 25, 50, or 100 mg/kg of abemaciclib
mesylate daily for 21 days.  The percentage of tumor growth inhibition relative to the vehicle control 
groups was determined by setting the 21st day of dosing as the reference point for measuring inhibition, 
while the 100% tumor growth inhibition level was equal to the mean baseline tumor volume measured on 
the first day of dosing.  Values greater than 100% indicate tumor volumes that are less than the baseline on 
the first day of dosing (regression), whereas negative percent inhibition values indicate tumor volumes that 
are greater than vehicle controls on the 21st day.  The KRAS status of each xenografts model is also 
provided.
Abbreviations:  wt = wild-type KRAS, G12 = activating mutation that replaces the glycine at codon 12, 
Q61 = activating mutation that replaces the glutamine at codon 61; NSCLC = non-small cell lung cancer.
Figure JPBJ.5.1.
The extent of growth inhibition by abemaciclib mesylate in NSCLC 
xenografts correlates with KRAS status.

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5.3.3. Overview of Safety for Non-Small Cell Lung Cancer
A total of 51 patients with NSCLC have been treated with abemaciclib in Part B of Study JPBA 
as of 01 August 2013.  Fifty-one patients with NSCLC have experienced at least 1 AE.  
Treatment-emergent AEs (TEAEs) have been experienced by 48 patients with NSCLC.
A total of 46 patients with NSCLC in Part B experienced TEAEs that were considered possibly 
related to study drug.  The most common (≥10%) possibly drug-related TEAEs reported 
specifically for patients with NSCLC cancer included diarrhea (31 patients), nausea (23 patients), 
fatigue (18 patients), vomiting (13 patients), anemia (13 patients), white blood cell (WBC) count
decreased (10 patients), anorexia (9 patients), neutrophil count decreased (8 patients), weight 
loss (8 patients), creatinine increased (8 patients), platelet count decreased (7 patients), 
dehydration (6 patients), and hyponatremia (6 patients).
SAEs regardless of causality were experienced by 12 patients in Part B with NSCLC; no SAES
were possibly related to study drug.
The majority of laboratory AEs that were experienced by patients with NSCLC in Part B
postbaseline were Grade 1 or Grade 2 in severity, as determined by the investigator.  Grade 3+4 
laboratory AEs experienced by ≥5% of patients with NSCLC included WBC count decreased 
(6 patients), lymphocyte count decreased (5 patients), neutrophil count decreased (4 patients), 
and hyponatremia (3 patients).  Grade 3+4 laboratory AEs possibly related to study drug for 
patients with NSCLC included WBC count decreased (6 patients), lymphocyte count decreased 
(5 patients), neutrophil count decreased (4 patients), hyponatremia (2 patients), platelet count 
decreased (1 patient), and anemia (1 patient).
Among the 51 patients with NSCLC in Part B, 1 patient with NSCLC who received abemaciclib
150 mg Q12H had a dose-limiting toxicity (DLT)-equivalent toxicity of Grade 3 diarrhea that 
persisted more than 2 days despite maximal supportive intervention during Cycle 1.  Two 
patients with NSCLC who received abemaciclib 200 mg Q12H had DLT-equivalent toxicities, 
including 1 patient who experienced Grade 3 nausea during Cycle 1 that persisted more than 
2 days despite maximal supportive intervention, and 1 patient with Grade 3 fatigue during 
Cycles 1 and 2.
Three patients with NSCLC who were treated with abemaciclib 150 mg Q12H in Part B of the 
study died; 2 deaths were due to study disease (1 death during Cycle 1 and 1 death at follow up),
and 1 death was due to an overdose of narcotic, not associated with study drug.  Eight patients 
with NSCLC who were treated with abemaciclib 200 mg Q12H died during Part B of
Study JPBA due to study disease; 2 patients died during Cycle 1, and the remaining 6 patients 
died during follow up.
In general, the preliminary safety profile that has been observed for NSCLC patients is similar to 
the overall patient population analyzed in Study JPBA.
5.3.4. Biomarkers
A formalin-fixed paraffin-embedded (FFPE) archived tumor tissue sample, or precut, unstained 
slides if the FFPE tumor tissue blocks are not available, from any available archival specimen of 

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the patient’s tumor will be requested for biomarker related studies after study eligibility is 
confirmed.
Instructions and supplies required for the collection and shipment of the patients’ samples will be 
provided by the sponsor. Sample handling and shipment to the central laboratory will occur per 
instructions given to the study site. Bioanalytical samples collected to measure for specified 
biomarker tests will be stored in a sponsor designated facility and retained for a maximum of 
5 years following the last patient visit for the study.
Biomarkers will be used to explore the relationship between predictive biomarkers (such as 
tumor Rb status) and antineoplastic activity. Potential predictive biomarkers will be measured
throughout the study in archived tumor tissue (for example, from prior biopsy) for all patients 
(Parts A, B, C, D, and E).
5.4.
General Introduction to LY3023414
Detailed information about LY3023414 characteristics is provided in the IB. The following 
sections provide a brief summary most relevant to this Phase 1b study.
5.4.1. Mechanism of Action of LY3023414
LY3023414 is a potent selective inhibitor of the Class I PI3K isoforms, mTOR, and DNA-PK,
with selectivity in kinase enzyme assays as an ATP competitive inhibitor of PI3Kα (inhibition 
constant [Ki] 8.5 nM).  LY3023414 has inhibitory activity against PI3K/mTOR pathway targets 
in vitro and in vivo as measured by phosphoprotein levels from cultured cells and tumor 
xenografts.  LY3023414 has antiproliferative and cell-cycle arresting effects in cultured cancer 
cells, and anti-angiogenesis activity via inhibition of in vitro vascular cord formation.
5.4.2. Clinical Summary of LY3023414
LY3023414 is currently evaluated in the first human dose (FHD) Study CBBA.  In this study, a 
total of 48 patients were enrolled and 47 patients dosed with LY3023414 as of 26 September
2014.  There were 25 patients included in the once daily (QD) dosing Part A, ranging from 20 to 
450 mg QD and 13 patients in the subsequently opened BID dosing Part A2, ranging from 150 to 
250 mg BID.  Dose-limiting toxicities (DLTs) for QD were reported only at the 450-mg QD dose 
level and included 1 case each of hypotension, thrombocytopenia, and hyperkalemia (all Grade 3 
according to CTCAE).  For BID dosing, DLTs were observed at the 200-mg dose level (n=1 out 
of 6 patients; CTCAE Grade 2 nausea) and 250-mg BID dose level (n=3 out of 4 patients) and 
included 1 case each of fatigue, asthenia, mucositis, and hyponatremia (all Grade 3 according to 
CTCAE), and hypophosphatemia (CTCAE Grade 4).  Therefore, the MTD for LY3023414 QD 
and BID dosing was determined to be 325 mg QD and 200 mg BID.
In the Part B1 cohort, the impact of LY3023414 on the metabolic clearance of drugs that are
metabolized through CYP3A4, such as midazolam, was evaluated. As of the data cut-off date of
26 September 2014, Part B1 was completed with 10 patients enrolled, of whom 9 patients
received 1 or more doses of 200-mg BID LY3023414.

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The most common possibly LY3023414-related AEs reported across the 2 parts in at least 10% 
of patients include nausea (42.1%), vomiting (34.2%), fatigue (34.2%), diarrhea (15.8%), anemia 
(13.2%), asthenia (13.2%), and decreased appetite (13.2%).  Most of theseevents were graded as 
mild or moderate by the investigators.  There were only 4 possibly LY3023414-related AEs 
≥Grade 3 CTCAE reported in patients treated at a dose level up to the MTD for QD or BID 
LY3023414 dosing (n=31 patients),including 1 case each of fatigue, hypomagnesaemia, 
neutropenia, and anemia in a patient entering the study with CTCAE Grade 2 anemia (all 
CTCAE Grade 3).
Initialclinical pharmacokinetic/pharmacodynamic (PK/PD)data show, that LY3023414
maximum plasma concentration(C
max)and area under the plasma concentration-time curve 
(AUC∞)increased approximately dose-proportionally from 20 to 325 mg QD (within the QD 
dose range determined to be safe).  However, the Cmaxand AUC
∞increase was greater than dose 
proportional at 450 mg QD (i.e., exceeding the MTD).  PKdata following repeated BID 
LY3023414 (dose range of 150 to 250 mg BID) were consistent with PK data following 20 to 
325 mg QD.  The oral clearance (CL/F)ranged from approximately 77 to130 L/hour across the 
20-to-325-mg dose range associated with an oral volume of distribution (V/F)ranging from 
185to 315 L in that same dose range.  This clearance and volume lead to mean half-life (t
1/2)of 
2.07 hours (coefficient of variation [CV]=45%, n=35), consistent with the prediction.  Biomarker 
assessment demonstrated target inhibition as measured by p4EBP1 inhibition in peripheral 
mononuclear blood cells (PBMC) at LY3023414 dose levels ≥150 mg QD in a dose related 
manner.  With respect to anti-tumor activity, preliminary clinical benefit was observed in 
patients treated on both schedules of LY3023414, including 1 patient with a confirmed partial 
response.
Based on above outlined safety and tolerability, PK/PD,and preliminary activity data, and 
following discussions betweenthe sponsor and theinvestigators, the start of the tumor-specific 
expansion cohorts in StudyCBBAjustified a recommended dose of 200 mg BID.
5.5. General Introduction to Pembrolizumab
Detailed information about pembrolizumab characteristics is provided in the IB. The following 
sections provide a brief summary most relevant to this Phase 1bstudy.
5.5.1. Mechanism of Action of Pembrolizumab
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced 
malignancies. Keytruda®(pembrolizumab) is indicated for the treatment of patients across a 
number of indications.For more details on specific indications refer to the Investigator’s 
Brochure. 

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5.5.2. Clinical Summary of Pembrolizumab
An open-label Phase 1 trial (Keynote 001) is being conducted to evaluate the safety and clinical 
activity of single-agent pembrolizumab.  The dose-escalation portion of this trial evaluated 
3 dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) and the 
dose-expansion cohort evaluated 2 mg/kg every 3 weeks (Q3W) and 10 mg/kg Q3W in subjects 
with advanced solid tumors.  All dose levels were well tolerated and no DLTs were observed.  
This first-in-human study of pembrolizumab showed evidence of target engagement and 
objective evidence of tumor size reduction at all dose levels.  No MTD has been identified.
In Keynote 001, 2 randomized cohort evaluations (Cohorts B2 and D) of melanoma subjects 
receiving pembrolizumab at a dose of 2 mg/kg Q3W versus 10 mg/kg Q3W have been 
completed, and one randomized Cohort (Cohort B3) evaluating 10 mg/kg Q3W versus 10 mg/kg 
Q2W has also been completed.  The clinical efficacy and safety data demonstrate a lack of 
clinically important differences in efficacy or safety profile at these doses.  For example, in 
Cohort B2, advanced melanoma subjects who had received prior ipilimumab therapy were 
randomized to receive pembrolizumab at 2 mg/kg Q3W versus 10 mg/kg Q3W, and the overall 
response rate (ORR) was 28% (22/79) in the 2-mg/kg Q3W group and 28% (21/76) in the 
10-mg/kg Q3W group (per Response Evaluation Criteria In Solid Tumors Version 1.1 
[RECIST 1.1] by independent central review).  The proportion of subjects with drug-related AEs, 
Grade 3-5 drug-related AEs, serious drug-related AEs, or death or discontinuation due to an AE 
was comparable between groups.  Cohort D, which compared 2 mg/kg Q3W versus 10 mg/kg 
Q3W in advanced melanoma subjects naïve to ipilimumab, also demonstrated overall similarity 
in efficacy and safety profile between the 2 doses.  In Cohort B3, advanced melanoma subjects 
(irrespective of prior ipilimumab therapy) were randomized to receive pembrolizumab at 
10 mg/kg Q2W versus 10 mg/kg Q3W.  The results demonstrate that the ORR was 35.0% 
(41/117) in the 10-mg/kg Q2W group and 30.8% (33/107) in the 10-mg/kg Q3W group (per 
RECIST 1.1 by independent central review) (cut-off date of 18 April 2014).  The proportion of 
subjects with drug-related AEs, Grade 3-5 drug-related AEs, serious drug-related AEs, or death 
or discontinuation due to an AE was comparable between groups.
An integrated body of evidence suggests that 200 mg Q3W is expected to provide similar 
response to 2 mg/kg Q3W, 10 mg/kg Q3W, and 10 mg/kg Q2W.  Previously, a flat 
pembrolizumab exposure-response relationship for efficacy and safety has been found in subjects 
with melanoma in the range of doses between 2 mg/kg and 10 mg/kg.  Exposures for 200 mg 
Q3W are expected to lie within this range and will be close to those obtained with a 2-mg/kg 
Q3W dose.
A population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed using available data from 1139 subjects from 
PN001, of which the majority (94.6% [N=1077]) were patients with advanced melanoma. The 
distribution of exposures from the 200-mg fixed dose are predicted to considerably overlap those 
obtained with the 2-mg/kg dose and importantly will maintain individual patient exposures 
within the exposure range established in melanoma as associated with maximal clinical response. 
Additionally, this comparison also demonstrates that the 200-mg Q3W regimen provides no 

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substantive differences in PK variability (range of the distribution of individual exposures) as 
seen with weight-based dosing.
In translating to other solid tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in subjects with melanoma can be expected, as the antitumor 
effect of pembrolizumab is driven through immune system activation rather than through a direct 
interaction with tumor cells, rendering it independent of the specific tumor type.  In addition, 
available PK results in subjects with melanoma, NSCLC, and other solid tumor types support a 
lack of meaningful difference in PK exposures obtained at tested doses among tumor types.  
Thus, the 200-mg Q3W fixed-dose regimen is considered an appropriate fixed dose for other 
solid tumor indications as well.
Taken together, the choice of 200 mg Q3W as an appropriate dose is based on simulations 
performed using the population PK model of pembrolizumab showing that the fixed dose of 
200 mg Q3W will provide exposures that 1) are optimally consistent with those obtained with a 
2-mg/kg dose Q3W, 2) body weight-based dosing does not provide an advantage over fixed 
dosing and that both dosing strategies should provide adequate and similar control of PK 
variability, 3) will maintain individual patient exposures in the exposure range established in 
melanoma as associated with maximal efficacy response, 4) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe, and 
5) the dynamics of pembrolizumab target engagement would not vary meaningfully with tumor 
type.
Based on above outlined safety and tolerability, PK/PD, and preliminary activity data, the dose 
of pembrolizumab planned to be studied in Study JPBJ is 200 mg Q3W.
5.6.
Rationale for Selection of Dose of Abemaciclib
A dose range of 100 to 200 mg of abemaciclib administered orally twice daily was selected 
based on safety, clinical efficacy, and PK data from the first-in-human dose Study JPBA.
In Study JPBA, during the dose-escalation phase, preliminary analysis of PK data from the initial 
4 dose levels (50, 100, 150, and 225 mg every 24 hours) indicated less than dose-proportional 
increases in exposure. Based on these results, a twice-daily schedule was introduced for the 
following planned dose levels: 75, 100, 150, 200, 275, 350, and 450 mg Q12H. For the 
twice-daily schedule, the highest dose of abemaciclib evaluated was 275 mg Q12H. At this dose
level, 2 of the 3 patients experienced DLTs of Grade 3 fatigue. At the next lower dose level of
200 mg Q12H, 1 of the 7 patients also experienced a DLT of Grade 3 fatigue. Therefore, the 
maximum tolerated dose (MTD) was established at 200 mg Q12H and is hereunder referred to as 
the single-agent MTD.
During the tumor-specific expansion phases, patients initially received abemaciclib at the 
single-agent MTD of 200 mg Q12H. A preliminary interim safety review with data from 
56 patients indicated that 29 patients experienced diarrhea possibly related to study drug: 
17 Grade 1 events (30%), 9 Grade 2 events (16%), and 3 Grade 3 events (5%). Based on the
frequency of Grade 1/2 diarrhea and the observation of clinical activity at doses below the

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single-agent MTD, the initial starting dose was changed to 150 mg Q12H with JPBA 
amendment(f) to gain additional PK data and clinical experience around safety/tolerability.
An interim PK analysis was conducted on the steady-state PK data obtained in Study JPBA for 
abemaciclib and its 3 active metabolites from a total of 103 patients dosed repeatedly with 
abemaciclib at 150 and 200 mg Q12H.  This preliminary analysis suggested that the dose of 
200 mg dosed Q12H yields slightly higher steady-state plasma concentration levels for 
abemaciclib and its active metabolites.  Moreover, when examining patients’ plasma levels 
throughout the first cycle of treatment, the dose of 200 mg Q12H seems to maintain more 
consistent trough plasma levels (Cmin,ss) for all active entities in plasma.  In particular, the Cmin,ss
for abemaciclib was more consistently maintained at a value of approximately 200 ng/mL, which 
is associated with a more robust levels of pRb inhibition as measured in patients’ skin biopsies
and was previously related to cell cycle arrest and tumor growth inhibition in PK/PD analyses 
performed on mouse xenograft tumor models.  Based on the above and the observation that 
Grade 1/2 diarrhea is manageable with standard antidiarrheal agents (eg, loperamide), the initial 
starting dose returned to the single-agent MTD of 200 mg Q12H with JPBA amendment(g).  
Consistent with this approach, in Study JPBJ, the initial starting dose of abemaciclib during the 
dose-escalation phase is 150 mg Q12H (Parts A, B, and C) and 100 mg Q12H (Parts D and E) to 
gain PK data and clinical experience around the safety/tolerability when given in combination 
with another agent, before escalating to 200 mg Q12H in Parts A, B, C, and D or to 150 mg in 
Part E.
5.6.1. Rationale for Dose Selection of Abemaciclib and LY3023414 for
Combination Therapy (Part D)
Given the potential overlapping toxicities between abemaciclib and LY3023414, the starting 
dose of both compounds for combination therapy will be below the MTD determined for 
monotherapy for each compound (see Table JPBJ.7.4). If tolerated, both compounds will be 
escalated in combination as described in Section 7.2.2.
5.6.2. Rationale for Dose Selection of Abemaciclib and 
Pembrolizumab for Combination Therapy (Part E)
Given the risk for potential overlapping toxicities between abemaciclib and pembrolizumab, the 
starting dose of abemaciclib will be below the MTD determined for 
monotherapy.Pembrolizumab will be administered at the recommended Phase 2 dose determined 
in the Phase 1 study as described in Section 5.5.2.

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6. Investigational Plan
6.1.
Study Population
Individuals who do not meet the criteria for participation in this study (screen failure) may not be
rescreened.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.1. Inclusion Criteria
Patients may be included in the study if they meet all of the following criteria during screening 
prior to first dose of study drug.
[1] For all parts:  The patient must have Stage IV NSCLC.  Eligibility is not restricted 
based on molecular features (for example, EGFR mutation or ALK translocation).
However, all patients with nonsquamous NSCLC with EGFR activating mutations or 
ALK alterations should have received and progressed after appropriate tyrosine 
kinase inhibitor or ALK targeted therapy prior to enrollment.

For Part A (abemaciclib + pemetrexed):  Nonsquamous subtypes only.  The 
patient must have received at least 1 but not more than 3 prior therapies, including 
1 platinum-based chemotherapy for advanced/metastatic NSCLC. Patients who 
have received pemetrexed as first-line or maintenance therapy must be >3 months 
after treatment for determining eligibility.

For Part B (abemaciclib + gemcitabine):  Any subtype.  The patient must have 
received at least 1 but not more than 3 prior therapies for advanced/metastatic 
NSCLC.

For Part C (abemaciclib + ramucirumab):  Any subtype.  The patient must have 
received at least 2 but not more than 3 prior therapies for advanced/metastatic 
NSCLC.

For Part D (abemaciclib + LY3023414 [US only]):  Any subtype.  The patient 
must have received at least 2 but not more than 3 prior therapies for
advanced/metastatic NSCLC. The patient must not have received prior treatment 
with any PI3K or mTOR inhibitor.

For Part E (abemaciclib + pembrolizumab): Any subtype. The patient must have 
received at least 1 but no more than 3 prior therapies for advanced/metastatic 
NSCLC.
[2]
Have the presence of either measureable or nonmeasurable disease as 
defined by the Response Evaluation Criteria in Solid Tumors (RECIST 
1.1, Eisenhauer et al. 2009).
[3]
Are 18 years of age.

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[4]
Have given written informed consent prior to any study-specific 
procedures.
[5]
Have adequate organ function including:

Hematologic:  Absolute neutrophil count (ANC) 1.5 x 109/L, platelets 
100 x 109/L, and hemoglobin 8 g/dL.  Patients may receive erythrocyte 
transfusions to achieve this hemoglobin level at the discretion of the 
investigator.

Hepatic:  Bilirubin 1.5 times upper limits of normal (ULN), alanine 
aminotransferase (ALT) and aspartate transaminase (AST) 3.0 times 
ULN.  For patients with tumor involvement of the liver, AST and ALT 
equaling ≤5.0 times ULN are acceptable. Patients on Part A with tumor 
involvement of the liver and ALT or AST >3.0 to ≤5.0 times ULN must 
have Child-Pugh Class A using the Child-Turcotte scoring system (refer to 
Attachment 11).

Renal:  Serum creatinine 1.5 times ULN. All patients must have a 
Creatinine Clearance (CrCl) >45 mL/min using the standard Cockcroft 
and Gault formula (refer to Attachment 7).

For Part E: Thyroid: TSH within normal limits OR Total T3 or free T3 
and free T4 within normal limits (refer to Attachment 2).

For Part E: Coagulation : PTT or aPTT <5 seconds above ULN and 
INR1.5 times ULN or PT <5 seconds above ULN. Patients receiving 
anticoagulant therapy are permitted if the PTT or aPTT and INR or PT is
within therapeutic range of intended use of anticoagulants.
[6]
Have a PS ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale
(refer to Attachment 6).
[7]
Have discontinued all previous therapies for cancer (including 
chemotherapy, radiotherapy, immunotherapy, and investigational 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.
[8]
Are reliable and willing to make themselves available for the duration of 
the study and are willing to follow study procedures.
[9]
Males and females with reproductive potential must agree to use medically 
approved contraceptive precautions during the trial and for 3 months following 
the last dose of study drug (for example, intrauterine device (IUD), birth control 
pills, or barrier method). If condoms are used as a barrier contraceptive, a 
spermicidal agent should be added as double barrier protection.

Part E patients must agree to use medically approved contraceptive precautions 
during the trial and for 120 days (4 months) following last dose of study drug.

I3Y-MC-JPBJ(h) Phase 1 Oncology Protocol
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[10]
Females with childbearing potential must have a negative serum 
pregnancy test within 7 days of the first dose of study drug.

Part E female patients of childbearing potential must have a negative 
urine or serum pregnancy test within 72 hours prior to receiving the first 
dose of study medication. If urine test is positive or cannot be confirmed 
as negative, a serum pregnancy test will be required.
[11]
Have an estimated life expectancy of ≥12 weeks.
[12]
Are able to swallow oral medications.
6.1.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply during 
screening.
[13]
Have received treatment within 21 days of the initial dose of study drug 
with an investigational product or nonapproved use of a drug or device 
(other than the study drug/device used in this study) for noncancer 
indications or are concurrently enrolled in any other type of medical 
research judged not to be scientifically or medically compatible with this 
study.
[14]
Have a personal history of any of the following conditions: syncope of 
either unexplained or cardiovascular etiology, ventricular arrhythmia
(including but not limited to ventricular tachycardia and ventricular 
fibrillation), or sudden cardiac arrest.  Exception: subjects with controlled 
atrial fibrillation for >30 days prior to study treatment are eligible.
[15]
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).
[16]
Patients on Parts A, B, D and E only: Have central nervous system (CNS)
metastasis with development of associated neurological changes 14 days 
prior to receiving study drug.  Patients may be receiving a stable low dose 
of corticosteroids. Screening of asymptomatic patients without history of 
CNS metastasis is not required.  Patients with untreated CNS metastases 
are ineligible.
[17]
Have a history of any other cancer (except nonmelanoma skin cancer or 
carcinoma in-situ of the cervix or breast), unless in complete remission 
with no therapy for a minimum of 3 years. Patients with history of 
carcinoma in-situ of the breast must be off tamoxifen at least 21 days prior 
to first dose.
[18]
Is pregnant or breastfeeding, or expecting to conceive or father children 
within the projected duration of the trial, starting with the pre-screening or 
screening visit through 3 months after the last dose of trial treatment.

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
Part E patients: duration of the trial starts with the pre-screening or 
screening visit through 120 days (4 months) after the last dose of trial 
treatment.
[19]
Have active bacterial, fungal, and/or known viral infection (for example, 
human immunodeficiency virus [HIV] antibodies, hepatitis B surface 
antigen [HBSAg], or hepatitis C antibodies [HCAb]).  Screening is not 
required for enrollment.
[20]
Parts A, B, C, and E have QTc interval of >470 msec on screening 
electrocardiogram (ECG).

Part D patients have QTc interval of >450 msec on screening ECG at 
several consecutive days of assessment, if clinically indicated.
6.1.2.1.
Additional Exclusion Criteria for Part C (Ramucirumab)
Patients may not be included to Part C if any of the following apply:
[21]
History or evidence of cardiovascular risk including any of the following:

History of acute coronary syndromes (including myocardial infarction and 
angina), coronary angioplasty, or stenting within 6 months prior to enrollment.

History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association.

Treatment refractory hypertension defined as a blood pressure of systolic 
>140 mmHg and/or diastolic >90 mmHg which cannot be controlled by 
antihypertensive therapy.

Subjects with intracardiac defibrillators. 
[27]
History or evidence of CNS metastases. Radiographic screening of all patients 
without history of CNS metastasis is required.
[28]
Radiologically documented evidence of major blood vessel invasion or 
encasement by cancer.  The patient has radiographic evidence of intratumor 
cavitation, regardless of tumor histology.
[29]
Patients with uncontrolled thromboembolic or hemorrhagic disorders.
[30]
Patients receiving chronic daily treatment with aspirin ≥325 mg/day or other 
known inhibitors of platelet function including, but not limited to, clopidogrel.
[31]
Patients with a history of gross hemoptysis (defined as bright red blood of
≥½ teaspoon) within 2 months of study entry.
[32]
Patients with nonhealing wounds, ulcers, or bone fractures within 28 days prior to 
study entry.
[33]
Patients who have undergone major surgery within 28 days prior to first dose of 
study medication or have subcutaneous venous access device placement within 
7 days prior to first dose.

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6.1.2.2.
Additional Exclusion Criteria for Part D (LY3023414)
Patients may not be included to Part D if any of the following apply:
[22]
Have insulin-dependent diabetes mellitus or a history of gestational 
diabetes mellitus:

Patients with a type 2 diabetes mellitus are eligible if adequate control of 
blood glucose level is obtained by oral anti-diabetic agents as documented 
by HbA1c <7%.
[23]
History or evidence of cardiovascular risk including the following:

History of acute coronary syndromes (including myocardial infarction and 
angina), coronary angioplasty, or stenting within 6 months prior to 
enrollment.
6.1.2.3.
Additional Exclusion Criteria for Part E (Pembrolizumab)
Patients may not be included to Part E if any of the following apply:
[34]
Has had a prior anticancer monoclonal antibody (mAb) within 4 weeks 
prior to study Day 1 or who has not recovered (for example, ≤Grade 1 or 
at baseline) from adverse events due to agents administered more than 
4 weeks earlier.
[35]
Active autoimmune disease that has required systemic treatment in past 
2 years (for example, with use of disease-modifying agents, 
corticosteroids, or immunosuppressive drugs). Replacement therapy (such 
as thyroxine, insulin, or physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency, etc.) is not considered a form of 
systemic treatment.
[36]
Have received a live-virus vaccination within 30 days of planned 
treatment start. Seasonal flu vaccines that do not contain live virus are 
permitted.
[37]
Have hypersensitivity or allergic reactions attributed to compound of 
similar chemical or biological composition of pembrolizumab.
[38]
History of interstitial lung disease.
[39]
History of or current pneumonitis.
6.2.
Summary of Study Design
This study is a multicenter, nonrandomized, open-label, dose-escalation Phase 1b trial in 
approximately 150 patients with Stage IV NSCLC to receive abemaciclib in combination with 
1) pemetrexed (Part A), 2) gemcitabine (Part B), 3) ramucirumab (Part C), 4) LY3023414 
(Part D), and 5) pembrolizumab (Part E) as shown in Figure JPBJ.6.1. Patients will be enrolled 
into 1 of 5 study parts based on prior therapy or histology. During dose escalation, cohorts of at 
least 3 patients will be enrolled at each of the planned dose levels. Abemaciclib will be 

I3Y-MC-JPBJ(h) Phase 1 Oncology Protocol
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administered orally at 100 mg, 150 mg, or 200 mg every Q12H on Days 1 through 21 of a 
21-day cycle. Contingency for de-escalation to abemaciclib at 100 mg orally Q12H on Days 1
through 21 of a 21-day cycle will be permitted. In study Parts A, B, and E, at least 18 and up to 
24 patients; in study Part C, at least 30 and up to 42 patients; in study Part D, at least 27 and up 
to 42 patients will be enrolled. Patients will be treated with abemaciclib no greater than 200 mg 
Q12H (the established single-agent MTD) for Parts A, B, C, and D or 150 mg Q12H for Part E 
on Days 1 through 21 of a 21-day cycle.
All patients in the study will continue to receive abemaciclib unless 1 or more of the criteria for
discontinuation are fulfilled; the follow-up period for poststudy evaluation is 30 ± 7 days from 
the date of the last dose of study drug received.
Refer to Attachment 1 for the detailed Study Schedule.
To determine the recommended Phase 2 dose of abemaciclib in combination with pemetrexed, 
gemcitabine, ramucirumab, LY3023414, or pembrolizumab, an adequate sample size is required.  
A sufficient sample size will allow for an accurate evaluation of the relationship between 
exposure and toxicity, as well as an evaluation of the relationship between exposure and 
pharmacological effects using descriptive statistics and appropriate modeling techniques, if data 
warrant.  This sample size is estimated to be approximately 150 patients.
The planned duration of treatment is not fixed; patients will remain on study until progression or 
unacceptable toxicity, or they fulfill 1 of the criteria for study discontinuation (Section 6.3).  The 
follow-up period will be 30 ± 7 days after last dose of study drug.
Abbreviations:  MTD = maximum tolerated dose; NSCLC = non-small cell lung cancer.
Figure JPBJ.6.1.
Illustration of study design for clinical protocol I3Y-MC-JPBJ.
Refer to Attachment 1 for the Study Schedule.

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6.2.1. Study Completion and End of Trial
This study will be considered complete (that is, the scientific evaluation will be complete [study
completion]) 6 months after the last patient has entered treatment (received first dose).  “End of 
trial” refers to the date of the last visit or last scheduled procedure for the last patient.
6.2.2. Extension Period
Treatment may proceed for up to 3 years if the patient experiences a clinical benefit, as
determined by the investigator. Patients may continue to receive study treatment beyond 3 years 
if they continue to benefit from study drug and upon approval of the sponsor. Patients must be
discontinued from treatment at any time if they meet the criteria for discontinuation
(Section 6.3.1).
Patients who are in follow-up when the extension period begins will continue in follow-up until 
the final safety assessments are completed 30 days (±7) after last dose of study drug (see 
Attachment 1).
During the extension period, all AEs, SAEs, study drug dosing, and dose reduction of treatment 
will be collected on the electronic case report form (eCRF).
SAEs will also be reported to Lilly Global Patient Safety and collected in the pharmacovigilance 
system (see Section 8.1.2).  In the event that an SAE occurs, additional information (such as 
local laboratory results, concomitant medications, and hospitalizations) may be requested by 
Lilly in order to evaluate the reported SAE.  Lilly will notify investigators when the extension 
period begins.
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.
6.3.
Discontinuations
6.3.1. Discontinuation of Patients
The criteria for enrollment must be followed explicitly. If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified. A discussion must occur between 
the sponsor clinical research physician (CRP) and the investigator to determine whether the 
patient may continue in the study, with or without investigational product.  Inadvertently 
enrolled patients may be maintained in the study and on investigational product when the Lilly
CRP agrees with the investigator that it is medically appropriate for that patient. The patient 
may not continue in the study with or without investigational product if the Lilly CRP does not 
agree with the investigator’s determination that it is medically appropriate for the patient to 
continue. The investigator must obtain documented approval from the Lilly CRP to allow the 
inadvertently enrolled patient to continue in the study with or without investigational product.

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In addition, patients will be discontinued from all study treatment (Parts A, B, C, D, and E) 
and/or from the study in the following circumstances:

The patient has evidence of progressive disease.  In the case of a mixed response, patients 
who are receiving clinical benefit may remain on study treatment based on investigator 
discretion and discussion with Lilly CRP.
o
Part E patients may remain on study treatment with repeat imaging > 4 weeks to 
assess tumor response or confirmed progression per irRECIST to account for 
unique tumor response seen with immunotherapeutic drugs. 

The patient experiences unacceptable toxicity, including but not limited to the following 
circumstances (refer to Section 7.2.4).
o
The patient does not meet the criteria for recovery from toxicity within 14 days of 
the last day of the previous cycle.

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Investigator/Physician Decision
o
the investigator or attending physician decides that the patient should be 
discontinued from the study or study drug(s). If this decision is made because of 
an SAE or clinically significant laboratory value, then appropriate supportive 
measures are to be taken. Lilly or its designee is to be alerted immediately (refer 
to Section 8.1).
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study drug(s) occurs prior to introduction of the other 
agent

Patient Decision
o
the patient requests to be discontinued from the study or study drug

Sponsor Decision
o
Lilly stops the study or stops the patient’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and GCP

The patient is noncompliant with study procedures and/or treatment (Section 7.6).

For Part E, patients must discontinue pembrolizumab if the patient meets any 
discontinuation criteria or 24 months of pembrolizumab therapy, whichever occurs first. 
The reason for and date of discontinuation will be collected for all patients.  The date of 
discontinuation (for any of the above reasons) from study treatment is to be reported on the 

I3Y-MC-JPBJ(h) Phase 1 Oncology Protocol
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eCRF.  Patients who discontinue will have follow-up procedures performed as shown in the 
Study Schedule (Attachment 1).
For dose escalation, any patient who is discontinued from the study before receiving at least 75% 
of planned doses of abemaciclib in Cycle 1 will be deemed nonevaluable for assessment of that 
dose level and may be replaced unless they experience a DLT before withdrawal. Nonevaluable 
patients may be replaced to ensure that no fewer than 3 patients receive at least 75% of planned 
doses of abemaciclib in Cycle 1 at each dose level, unless enrollment to that cohort has stopped 
because more than 1 patient at that dose level has experienced a DLT.
6.3.1.1.
Part C Discontinuations
The investigator should withdraw a patient from abemaciclib and ramucirumab combination 
therapy for reasons including but not limited to the following:

the sponsor or designee or investigator terminates the study

an unacceptable AE/toxicity (for example, a persistent moderate toxicity that is 
intolerable to the patient) which in the opinion of the investigator, clearly 
attributed to ramucirumab
1. a Grade 3 or 4 infusion-related reaction which in the opinion of the investigator is 
clearly attributed to ramucirumab (for more information, see Section 7.2.4.1.4.1)

a Grade 3 or 4 arterial thrombotic event or a Grade 3 or 4 venous thrombotic 
event that is considered by the investigator to be life-threatening, or symptomatic 
and not adequately treated by anticoagulation therapy (for more information, see 
Section 7.2.4.1.4.3)

Grade 3 or 4 bleeding or hemorrhagic event
2. Grade 4 hypertension or persistent/recurrent hypertension (for more information, see 
Section 7.2.4.1.4.2)

Grade 4 proteinuria or persistent/recurrent proteinuria >3 g/24 hours (for more 
information, see Section 7.2.4.1.4.4)
3. any Grade 4 nonhematologic toxicity considered by the investigator to be related to 
ramucirumab. Any event which would warrant the dose of ramucirumab to be 
modified by >2 dose reductions, or if ramucirumab will be delayed for more than 
5 weeks from the last administered dose (delay of more than 14 days from start of 
the next cycle; for more information see Section 7.2.4.1.4).

hemoptysis that exceeds the severity grade present at baseline

any Grade 3-4 events consistent with congestive heart failure

new occurrence of hepatic encephalopathy and/or hepatorenal syndrome resulting 
from liver cirrhosis

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6.3.2. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges it necessary for any scientific, medical, safety, regulatory, ethical, 
or other reasons consistent with applicable laws, regulations, and GCP.
6.3.3. Discontinuation of the Study
The study will be discontinued if Lilly, while considering the rights, safety, and well-being of the 
patient(s), judges it necessary for any scientific, medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP.

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7. Treatment
7.1.
Materials and Supplies
Abemaciclib will be supplied as capsules or tablets for oral administration. The capsules/tablets
should be stored at room temperature according to the range provided on the product label and 
not opened, crushed, or dissolved. Investigators should instruct patients to store the 
capsules/tablets in the original package and in a location inaccessible to children. Clinical study 
materials will be labeled according to country regulatory requirements.
For Parts A and B (pemetrexed and gemcitabine, respectively), patients should receive standard 
of care agents as specified in the label.  All commercially available drugs should be stored and 
administered according to the label and will be supplied by the sponsor where required.
For Parts C, D, and E (ramucirumab, LY3023414, and pembrolizumab, respectively), patients 
should receive investigational agents as specified in the protocol. Ramucirumab (Part C) and 
pembrolizumab (Part E) should be stored and handled according to the product label and 
pharmacy manual and will be supplied by the sponsor.
Ramucirumab is a sterile, preservative-free solution for infusion of ramucirumab formulated in 
an aqueous solution at a concentration of 10 mg/mL (500 mg/50-mL vial).  The buffer contains 
10 mM histidine, 75 mM sodium chloride, 133 mM glycine, and 0.01% polysorbate 80, pH 6.0.  
Ramucirumab is supplied in single-use 50-mL nominal volume glass vials.
All excipients used for the manufacture of ramucirumab are of pharmacopeial grade.  No 
animal-derived components are used in the manufacture of ramucirumab excipients.
LY3023414 will be supplied in 25-mg, 100-mg or 200-mg capsules and as 50-, 100-, 150-, or 
200-mg tablets for oral administration. LY3023414 capsules/tablets should be stored within the 
temperature range stated on the label. Investigators should instruct patients to store the 
capsules/tablets at home in the provided container and to keep out of the reach of children.  
Capsules/tablets should not be opened, crushed, or dissolved.  LY3023414 will be labeled 
according to local regulatory requirements and supplied by the sponsor.
Pembrolizumab is a lyophilized powder solution for infusion, resconstitued with sterile water for 
injection prior to use. The buffer contains L-histidine, polysorbate 80 as surfactant, sucrose as 
stabilizer/tonicity modifier, and hydrochloric acid (HCl) and/or sodium hydroxide (NaOH) for 
pH adjustment if necessary.  Pembrolizumab is supplied in single-use 50-mg/vials.
Clinical study materials will be labeled according to the country’s regulatory requirements.
7.2.
Study Drug Administration
In Parts A, B, C, and D, patients will receive either 100 mg, 150 mg, or 200 mg of abemaciclib
orally Q12H in combination with: pemetrexed (Part A), gemcitabine (Part B), ramucirumab
(Part C), or LY3023414 (Part D). In Part E, patients will receive either 100 mg or 150 mg of 
abemaciclib orally Q12H in combination with pembrolizumab (Part E). In all study parts, de-
escalation of abemaciclib at 100 mg orally Q12H on Days 1 through 21 of a 21-day cycle will be 

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permitted. During Cycle 1 and Cycle 2, when abemaciclib is scheduled to be administered on 
the same day as the combination treatment and PK samples are drawn, abemaciclib should be 
given immediately after the combination treatment is administered.  Beyond Cycle 2 for Parts A, 
B, C, and E, abemaciclib may be administered at any time relative to the combination treatment.  
For Part D, abemaciclib and LY3023414 should be taken at approximately the same time 
irrespective of cycle time or PK sampling.
Pemetrexed (500 mg/m2) will be administered as an approximate 10-minute IV infusion on 
Day 1 of a 21-day cycle.  No dose reduction is necessary unless the patient experiences toxicity 
(see Section 7.2.4.1.2).  No dose escalations are permitted. Prior to initiating pemetrexed, 
initiate supplementation with oral folic acid (folic acid 400 g to 1000 g orally once daily 
beginning 7 days before the first dose) and intramuscular vitamin B12. Continue folic acid 
during the full course of therapy and for 21 days after the last dose and continue vitamin B12 
supplementation throughout treatment. Administer corticosteroids (e.g., dexamethasone 4 mg 
orally twice daily) the day before, the day of, and the day after pemetrexed administration.
Gemcitabine (1250 mg/m2) will be administered as an approximate 30-minute IV infusion on 
Days 1 and 8 of a 21-day cycle. No dose reduction is necessary unless the patient experiences 
toxicity (see Section 7.2.4.1.3).  No dose escalations are permitted.
Ramucirumab (8 mg/kg or 10 mg/kg) will be administered as an approximate 60-minute IV 
infusion followed by a 1-hour observation period during Cycles 1 and 2.  If there is no evidence 
of an infusion-related reaction during the initial 2 cycles of ramucirumab, then no observation 
period is required for subsequent treatment cycles.  In the event an infusion-related reaction 
occurs thereafter, then the 1-hour observation should be reinstituted. Premedication is 
recommended prior to infusion of ramucirumab.  Recommended premedication agents include 
histamine H1 antagonists such as diphenhydramine hydrochloride (or equivalent).  Additional 
premedication may be provided at the investigator’s discretion.  Premedication must be provided 
in the setting of a prior Grade 1-2 infusion-related reaction, as detailed in Section 7.2.4.1.4.1.  
All premedication administered must be adequately documented in the electronic data capture
(eDC).
The first dose of ramucirumab is dependent upon the patient’s baseline body weight in 
kilograms. Subsequent doses of ramucirumab must be recalculated if there is a ≥10% change 
(increase or decrease) in body weight from last dose calculation; subsequent doses may be 
recalculated if there is a <10% change (increase or decrease) in body weight from last dose 
calculation.
For Patients in Part D, LY3023414 will be administered orally, Q12H on a 21-day cycle. 
LY3023414 should be taken approximately at the same time each dosing day with a full glass of 
water concomitantly with abemaciclib.  LY3023414 may be taken with or without food. Patients 
should swallow the capsules/tablets as a whole, and should not chew or crush them. 
If the patient misses a dose of LY3023414, the patient should take the dose as soon as possible, 
but not less than 6 hours before the next dose is due for BID dosing.  If the next dose is due in 
less than 6 hours, the patient should skip the missed dose and take the next dose as scheduled.

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If vomiting occurs after taking LY3023414, the patient should be instructed not to retake the 
dose.  Patients should take the next scheduled dose of LY3023414.  If vomiting persists, the 
patient should contact the investigator.
On clinic days with postdose PK sampling associated with blood glucose monitoring (Day 1 of 
Cycles 1 and 2), patients are permitted to eat a light snack at least 2.5 hours prior to the study 
drug dosing, but are then asked to fast until after the 4 hour postdose samples are collected.  High
sugar foods (for example, sugary breakfast cereals, fruit juices, coffee with sugar, etc.) should be 
avoided as part of this light snack. Missed doses should not be taken within 12 hours (± 2 hours) 
of the next dose. No dose reduction is necessary unless the patient experiences toxicity (see 
Section 7.2.4.1.5).
Pembrolizumab 200 mg (fixed dose) will be administered as an approximate 30-minute IV 
infusion on Day 1 of a 21-day cycle followed by a 1-hour observation period during Cycles 1 
and 2. Signs and symptoms of infusion-related reactions usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. All 
cycles thereafter, no observation period will be required. Sites should make every effort to target 
infusion timing to be as close to 30 minutes as possible. However, given the variability of 
infusion pumps from site to site, a window between -5 minutes and +10 minutes is permitted 
(that is, infusion time can be 25 to 40 minutes).
The treatment combinations that will be administered with the assigned dose of abemaciclib in 
Parts A, B, C, D, and E in this study are listed in Table JPBJ.7.1.
Table JPBJ.7.1.
Treatment Combinations for Study I3Y-MC-JPBJ
Study 
Part
Combination 
Drug
Dose
Route of 
Administration
Dose Frequency
Abemaciclib
Dose Range
A
pemetrexed
500 mg/m2
IV
Day 1
100 to 200 mg
B
gemcitabine
1250 mg/m2
IV
Days 1 and 8
100 to 200 mg
C
ramucirumab
8 mg/kg, 10 mg/kg
IV
Days 1 and 8 or Day 1
100 to 200 mg
D
LY3023414
100 mg, 150 mg, 200 mg
oral
Q12H
100 to 150 mg
E
pembrolizumab
200 mg
IV
Day 1
100 to 150 mg
Abbreviations:  IV = intravenous; Q12H = every 12 hours.
Note:  Dose frequency is described for each 21-day cycle.
The investigator or designee is responsible for:

explaining the correct use of the investigational agent(s) and planned duration of each 
individual’s treatment to the patient and, if appropriate, to the patient’s designated legal 
representative,

verifying that instructions are followed properly, 

maintaining accurate records of study drug dispensation, destruction, and collection, and

returning or destroying all unused medication to Lilly or its designee at the end of the 
study.

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Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug(s) so that the situation can be assessed.
7.2.1. Dosing Schedule
Abemaciclib dosing is administered on a twice-daily schedule.  Patients will receive abemaciclib
orally Q12H (±3 hours) for Days 1 through 21 of a 21-day cycle. Patients should not consume 
food beginning 1 hour before and ending 1 hour after taking study drug.
Study drug should be taken at approximately the same time(s) each day. If a patient misses or 
vomits a dose, that dose should be omitted. Patients must record the time and amount of each 
dose taken (or alternatively, the time and amount of the dose missed or vomited) in a daily diary.
Patients should receive pemetrexed (Part A), gemcitabine (Part B), ramucirumab (Part C),
LY3023414 (Part D), or pembrolizumab (Part E) according to the Study Schedule
(Attachment 1).
Patients will receive abemaciclib until progression or unacceptable toxicity, unless 1 or more of 
the criteria for discontinuation (refer to Section 6.3.1) are fulfilled; the follow-up period for 
poststudy evaluation will be 30 ± 7 days from the date of the last dose of study drug received
(when the final safety assessments are completed).
For Cycle 2 and beyond, a delay of ≤7 days in the start of a cycle (Day 1) for justifiable reasons
(for example, inclement weather, holidays, or weekends) other than toxicity will be permitted
and does not constitute a protocol violation.
For Cycle 2 and beyond, a delay of ≤14 days in the start of a cycle (Day 1) to allow for recovery
from toxicity will be permitted and does not constitute a protocol violation (refer to
Section 7.2.4).
7.2.2. Dose-Escalation Phase
Dose escalation follows safety assessments using the standard scoring system, CTCAE version 
4.0, established by the National Cancer Institute (NCI). Any AEs possibly related to abemaciclib
were considered as toxicities.
For the dose-escalation phase, Table JPBJ.7.2 and Table JPBJ.7.3 summarize the abemaciclib
proposed starting dose levels of 150 mg, and 200 mg Q12H on a 21-day cycle for Parts A, B, and 
C. During the dose-escalation phase, the abemaciclib proposed start dose levels of 100 mg and
150 mg Q12H on a 21-day cycle are summarized for Parts D (Table JPBJ.7.4) and E 
(Table JPBJ.7.5). Three patients are planned for treatment at each dose level; however, the exact 
number of patients treated at a specific dose level depends on the number of patients within the 
cohort who experience a DLT. If a patient in a given cohort experiences a DLT during Cycle 1, 
then subsequent patients are enrolled sequentially.  For Part D, the first patient enrolled in this 
part will be observed for a DLT (as defined in Section 7.2.2.1) during the first 14 days of Cycle 1 
before subsequent patients are treated at that dose level.  If the first patient does not experience a 
DLT during this period, subsequent patients may be concurrently enrolled in the initial cohort.  
In subsequent cohorts, patients may be enrolled concurrently.

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In all cohorts, every patient will be assessed for toxicity (based on CTCAE version 4.0 grading) 
on Day 21 of Cycle 1.
Table JPBJ.7.2.
Dose-Escalation Scheme for Study I3Y-MC-JPBJ
Cohort/Study Part
Patients/Cohort
Abemaciclib Dose
1
3-6
150 mg Q12H
2
3-6
200 mg Q12H
3
12
200 mg or MTD Q12H
Abbreviations: Q12H = every 12 hours; MTD = maximum tolerated dose under the combination treatment.
The scheme is repeated for study Parts A and B (abemaciclib in combination with pemetrexed [Part A], gemcitabine 
[Part B]).
Note:  During dose escalation, de-escalation to 100 mg of abemaciclib Q12H is allowed for study parts.
Table JPBJ.7.3.
Dose-Escalation Scheme for Part C
Cohort/Study Part
Patients/Cohort
Abemaciclib Dose
Ramucirumab Dose
C-1 Escalation Cohort 1
3-6
150 mg Q12H
10 mg/kg Day 1 
C-2 Escalation Cohort 2
3-6
200 mg Q12H
10 mg/kg Day 1
C-3 Confirmation Cohort
12
200 mg or MTD Q12H
10 mg/kg Day 1
C-4 Escalation Cohort 3
3-6
150 mg Q12H
8 mg/kg Days 1 and 8
C-5 Escalation Cohort 4
3-6
150 mg Q12H
10 mg/kg Days 1 and 8
C-6 Confirmation Cohort 5
6
150 mg Q12H
MTD Days 1 and 8
Abbreviations: Q12H = every 12 hours; MTD = maximum tolerated dose under the combination treatment.
Note:  During dose escalation, de-escalation to 100 mg Q12H of abemaciclib is permitted.
Table JPBJ.7.4.
Dose-Escalation Scheme for Part D
Cohort/Study Part
Patients/Cohort
Abemaciclib Dose
LY3023414 Dose
D-1    Escalation Cohort 1
3-6
100 mg Q12H
100 mg Q12H
D-2    Escalation Cohort 2
3-6
150 mg Q12H
100 mg Q12H
D-3    Escalation Cohort 3
3-6
150 mg Q12H
150 mg Q12H
D-5* Escalation Cohort 4a
3-6
200 mg Q12H
150 mg Q12H
D-6  Escalation Cohort 4b
3-6
150 mg Q12H
200 mg Q12H
D-4
Confirmation Cohort
6-12
MTD Q12H
MTD Q12H
Abbreviations: MTD = maximum tolerated dose under the combination treatment; Q12H = every 12 hours.
Note:  During dose escalation, de-escalation to 100 mg Q12H of abemaciclib is permitted.
* D-5 Cohort 4a enrollment closed before completion of cohort. Reference Section 5.1.6.  
The dose-escalation phase is guided by safety assessments from Days 1 through 21 of Cycle 1
for all patients in the cohort and also by the emerging PK data from previous cohorts. If none of
the patients in a cohort experienced a DLT, dose escalation could occur to the next prespecified
dose level. For all cohorts, if safety assessments and/or the emerging PK data indicate either that 
dose escalation should occur to a dose level lower than the next prespecified dose level or that 
dose de-escalation should occur to a dose level lower than the current dose level, then safety
assessments and/or the emerging PK data could be used to select an alternate dose level within

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these constraints. In Study JPBA, the single-agent MTD was established at 200 mg Q12H for 
the twice-daily schedule (as discussed in Section 5.6).
Table JPBJ.7.5.
Dose-Escalation Scheme for Part E
Cohort/Study Part
Patients/Cohort
Abemaciclib Dose
Pembrolizumab Dose
E-1   Escalation Cohort 1
3-6
100 mg Q12H
200 mg Day 1
E-2   Escalation Cohort 2
3-6
150 mg Q12H
200 mg Day 1
E-4  Confirmation Cohort
12
MTD Q12H
200 mg Day 1
Abbreviations: MTD = maximum tolerated dose under the combination treatment; Q12H = every 12 hours.
7.2.2.1.
Dose-Limiting Toxicity Determination and Maximum Tolerated Dose 
Definition
A DLT is defined as an AE occurring between Day 1 and Day 21 of Cycle 1 for a patient 
enrolled in the dose-escalation phase that is possibly related to either abemaciclib or the 
combination therapy and fulfills any 1 of the following criteria:

Grade 3 or 4 nonhematological toxicity according to the NCI CTCAE version 4.0 (except 
for nausea, vomiting, diarrhea, or electrolyte disturbance),

Grade 3 or 4 nausea, vomiting, diarrhea, or electrolyte disturbance that persists more than 
2 days despite maximal supportive intervention.

Grade 4 hematological toxicity that persists more than 5 days.

Grade 3 or 4 thrombocytopenia with bleeding.

Grade 3 or 4 neutropenia with fever.

For patients in Part D only, the following additional exceptions apply:
o
transient (≤5 days) Grade 3 hyperglycemia (fasting) 
o
Grade 3 hypertriglyceridemia or hyperlipidemia without optimal treatment.
Investigators, together with the Lilly CRP, can declare a DLT if a patient is experiencing
increasing toxicity during treatment, and it becomes clear that it is not going to be possible to
complete the treatment without exposing the patient to excessive risk.
A DLT-equivalent is defined as an AE that would have met the criteria for DLT if it had
occurred during Cycle 1 for a patient enrolled in the dose-escalation phase, but that occurs 
between 1) Day 1 and Day 21 of Cycle 2 and beyond for a patient enrolled in the dose-escalation
phase and 2) at any time for a patient in the dose-expansion phase.  The MTD will be assessed 
for each study part and is defined as the highest dose level at which less than 33% of patients 
experience a DLT during Cycle 1.
7.2.2.2.
Dose-Escalation Method
If 1 of 3 patients at any dose level in any study part experiences a DLT, then up to 3 additional 
patients will be enrolled at that dose level.  If a DLT is observed in ≥2 out of a maximum of 
6 patients at any given dose, dose escalation will cease and either the previous dose level will be 
declared the MTD for the combination therapy or, following discussions between the 

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investigators and the sponsor, additional patients may be treated at intermediate doses between 
the previous dose level and the level above the MTD for the combination therapy.
For study Parts A, B, and C, if >2 of 6 patients experience a DLT at 150 mg Q12H, then the dose 
of abemaciclib should be de-escalated to 100 mg Q12H and enrollment to the cohort should 
proceed as noted above.  For Parts D and E, if >2 of 6 patients experience a DLT at abemaciclib 
100 mg Q12H in combination with Part D LY3023414 or Part E pembrolizumab, then 
enrollment to the cohort should cease and no additional patients will be accrued until this safety 
review is completed and a decision is made how to proceed. The safety review and decision will 
be documented in writing.
7.2.3. Dose-Confirmation Phase
After the MTD for each combination therapy has been identified in each study part in the 
dose-escalation phase, up to approximately 12 patients will be enrolled in each of the 5
confirmation groups:  patients receiving pemetrexed (Part A), gemcitabine (Part B), 
ramucirumab (Part C), LY3023414 (Part D), or pembrolizumab (Part E). In addition, Part C will 
include a second dose-escalation and confirmation cohort of approximately 12 patients to 
evaluate alternate dosing schedules for ramucirumab with 8 mg/kg on Days 1 and 8 and if 
tolerable, dose escalate to 10 mg/kg on Days 1 and 8 of a 21-day cycle.  For Part D, enrollment 
into the dose-confirmation phase will include a minimum of 6 patients and a maximum of 12 
patients. The establishment and confirmation of the combination therapy dose for the program 
will determine the actual number of patients enrolled into the dose-confirmation cohort.  For 
Parts A, B, C,  and E following the dose-confirmation phase, if clinical data indicate preliminary
efficacy for the combination therapy, then approximately 12 more patients, a total of 
approximately 24 patients, will be enrolled to the confirmation cohort to obtain clinical evidence 
for efficacy.
During the dose-confirmation phase, patients may enroll concurrently and will be treated at a 
dose no greater than the MTD for the specific study part.  During the dose-escalation phase, 
abemaciclib may, at the discretion of the investigator, be de-escalated to 100 mg Q12H.  For all 
patients, dose adjustments are permitted as outlined in Section 7.2.4.
If DLT-equivalents occur in 33% or more of patients within a specific dose-expansion group, 
then investigators and the Lilly CRP will assess the nature and severity of these toxicities.  No 
additional patients will be accrued until this safety review is completed and a decision is made 
either to continue at the current dose or to de-escalate the dose and define a new dose for the 
expansion phase. A decision will be made to explore an intermittent dosing schedule at the 
current MTD, or a lower dose for each combination therapy. The safety review and decision will 
be documented in writing.

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7.2.4. Dose Adjustments and Delays
7.2.4.1.
Dose Adjustments
7.2.4.1.1. Abemaciclib
Table JPBJ.7.6 presents dose adjustments to occur if the event is possibly related to abemaciclib.
Table JPBJ.7.6.
Toxicity Dose Adjustments and Delays of Abemaciclib for Study
I3Y-MC-JPBJ
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Hematologic Toxicity
Section 7.2.4.1.1.1
Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MAY be reduced 
by 1 dose level -
investigator’s discretion.
Hematologic Toxicity
Section 7.2.4.1.1.1
Recurrent Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced 
by 1 dose level.
Hematologic Toxicity
Section 7.2.4.1.1.1
Grade 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced 
by 1 dose level.
Hematologic toxicity: If 
patient requires administration 
of blood cell growth factors
Section 7.2.4.1.1.1
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 1 dose level unless 
already performed for 
incidence of toxicity that 
lead to the use of growth 
factor.
Nonhematologic Toxicitya
(except diarrhea and ALT 
increased)
Section 7.2.4.1.1.2
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 1 dose level.
Nonhematologic Toxicity
Section 7.2.4.1.1.2
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MUST be reduced 
by 1 dose level.
Diarrhea
Sections 7.2.4.1.1.3 and 
7.5.1.1
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.
Diarrhea
Sections 7.2.4.1.1.3 and 
7.5.1.1
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 1 dose level.
Diarrhea
Sections 7.2.4.1.1.3 and 
7.5.1.1
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced 
by 1 dose level.

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Toxicity Dose Adjustments and Delays of Abemaciclib for Study I3Y-MC-JPBJ
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
ALT Increased 
Sections 7.2.4.1.1.4 and 
8.1.4.1
Persistent or recurrent
b 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 7.2.4.1.1.4 and 
8.1.4.1
Grade 4 (>20.0×ULN) d
Abemaciclib MUST be 
discontinued.
Abemaciclib MUST be 
discontinued.
ALT Increased with increased 
total bilirubin, in the absence 
of cholestasis
Sections 7.2.4.1.1.4 and 
8.1.4.1
Grade 3 increased ALT (˃5.0 x 
ULN) with total bilirubin >2 x 
ULN d
Abemaciclib MUST be 
discontinued
Abemaciclib MUST be 
discontinued
Abbreviations:  ALT = alanine transaminase; ASCO = American Society of Clinical Oncology; 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 8.1.4.1 and 7.5.1.2.
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).  
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
8.1.4.1 for additional guidance for hepatic monitoring
Dose adjustments are allowed both within a cycle and between cycles.
If a patient who, in the judgment of the investigator, is receiving clinical benefit from study
therapy requires further dose reduction than is outlined in Table JPBJ.7.7, then the investigator
must discuss with the Lilly CRP prior to any further dose reduction.  For patients requiring dose 
reduction(s), re-escalation to a prior dose level is permitted only after consultation with the Lilly 
CRP.
Dose omissions are allowed within a cycle. If a patient requires omission of more than 25% of
doses during a cycle for tolerability, then treatment may continue if the investigator determines
the patient is receiving clinical benefit.
Table JPBJ.7.7.
Dose Adjustments of Abemaciclib for Study I3Y-MC-JPBJ
Dose Adjustment
Oral Dose
Frequency
0
200 mg
Every 12 hours
1
150 mg
Every 12 hours
2
100 mg
Every 12 hours
7.2.4.1.1.1.
Hematologic Toxicity
If a patient experiences a Grade 3 hematologic toxicity possibly related to abemaciclib, then 
dosing must be suspended (until toxicity resolves to either baseline or at least Grade 2) and the 
dose of abemaciclib may be reduced at the investigator’s discretion as outlined in 
Table JPBJ.7.6.

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If a patient experiences a recurrent Grade 3 or a 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 JPBJ.7.6.
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 (regardless of severity), then 
dosing 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. The dose of abemaciclib must
be reduced by 1 dose level (unless already performed for incidence of toxicity that lead to the use 
of growth factor) as outlined in Table JPBJ.7.6.
7.2.4.1.1.2.
Nonhematological Toxicity (except diarrhea and ALT increase)
If a patient experiences >Grade 3 nonhematologic toxicity 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 JPBJ.7.6.
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
refer to Section 7.2.4.1.1.3 or ALT increased, refer to Section 8.1.4.1) 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 JPBJ.7.6.
7.2.4.1.1.3.
Diarrhea
If a patient experiences Grade 2 diarrhea that does not resolve with maximal supportive measures 
(refer to Section 7.5.1.1) 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 or any Grade diarrhea that requires hospitalization (refer to 
Section 7.5.1.1) study drug must be suspended (until the toxicity resolves to either baseline or at 
least Grade 1); and a dose reduction is required. For Grade 3 or Grade 4 diarrhea, the dose must 
be suspended and a dose reduction is required Table JPBJ.7.6.

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7.2.4.1.1.4.
Hepatic Toxicity
Dose modifications and management for increased ALT are provided in Table JPBJ.7.6. 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 8.1.4.1 for additional hepatic 
monitoring guidance.
7.2.4.1.2. Pemetrexed
Pemetrexed dose adjustments at the start of a subsequent cycle should be based on nadir 
hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. 
Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should 
be re-treated using the guidelines in Table JPBJ.7.8, which are suitable for using pemetrexed as a 
single-agent or in combination.
Table JPBJ.7.8.
Hematologic Dose Reduction for Pemetrexed in 
Study I3Y-MC-JPBJ
Dose of Pemetrexed (mg/m2)
Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3
75% of previous dose
Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC
75% of previous dose
Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC
50% of previous dose
Abbreviations:  ANC = absolute neutrophil count; CTCAE = common terminology criteria for adverse events.
a
These criteria meet the CTCAE version 4.0 definition of ≥CTC Grade 2 bleeding.
If patients develop nonhematologic toxicities (excluding neurotoxicity) >Grade 3, treatment 
should be withheld until resolution to less or equal to the patent’s baseline value. Treatment 
should be resumed according to Table JPBJ.7.9.
Table JPBJ.7.9.
Nonhematologic Dose Reduction for Pemetrexed in 
Study I3Y-MC-JPBJ
Dose of Pemetrexed (mg/m2)
Any Grade 3 or 4 toxicities except mucositis
75% of previous dose
Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 
4 diarrhea
75% of previous dose
Grade 3 or 4 mucositis
50% of previous dose
Pemetrexed therapy should be discontinued if a patient experiences any hematologic or
nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 
neurotoxicity is observed. Pemetrexed should not be administered to patients whose creatinine
clearance is <45 mL/min using the standard Cockcroft and Gault formula (refer to Attachment 7).

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Caution should be exercised when administering pemetrexed concurrently with nonsteroidal 
anti-inflammatory drugs (NSAIDs) to patients whose creatinine clearance is <80 mL/min. 
7.2.4.1.3. Gemcitabine
Patients receiving gemcitabine should be monitored prior to each dose (Day 1 and Day 8 of each 
cycle) with a complete blood count (CBC), including differential and platelet count. If marrow 
suppression is detected, therapy should be modified or suspended according to guidelines in 
Table JPBJ.7.10.
Table JPBJ.7.10.
Dose Adjustments of Gemcitabine for Study I3Y-MC-JPBJ
Absolute Granulocyte Count
(x 106/L)
Platelet Count
(x 106/L)
% of Full Dose
>1000
AND
>100,000
100%
500-999
OR
50,000-99,000
75%
<500
OR
<50,000
HOLD
Dose Modifications for Nonhematologic Adverse Reactions
Permanently discontinue gemcitabine for any of the following:

Unexplained dyspnea or other evidence of severe pulmonary toxicity

Severe hepatic toxicity

Hemolytic-Uremic Syndrome

Capillary Leak Syndrome
Withhold gemcitabine or reduce dose by 50% for other severe (Grade 3 or 4) nonhematological 
toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or 
vomiting.
7.2.4.1.4. Ramucirumab
Dose modifications are permitted for investigational product in the setting of non-life-threatening 
and reversible Grade 3 clinical AEs (for example, fever) considered to be at least possibly related 
to investigational product and that resolve to Grade ≤1 or pretreatment baseline within 
1 treatment cycle (approximately 3 weeks). If a Grade 4 AE occurs and is deemed at least 
possibly related to ramucirumab, then treatment should be discontinued except in the specific 
case of Grade 4 fever or Grade 4 laboratory abnormalities.  If Grade 4 fever or laboratory 
abnormalities resolve to Grade ≤1 or baseline within 1 treatment cycle (approximately 3 weeks), 
treatment with ramucirumab may be continued at the discretion of the investigator.  In these 
settings, ramucirumab may be readministered.  If a second instance of such an event occurs, 
ramucirumab should be subsequently readministered at a reduced dose level.  A second dose 
reduction is permitted for this level of event (Grade 3 or 4) (refer to Table JPBJ.7.11).  If the 
dose of ramucirumab is reduced because of potentially related AEs, subsequent dose increases 
are not permitted. Specific guidelines for ramucirumab dose modifications related to infusion 
reactions and thrombotic events are provided in Section 7.2.4.1.4.1 and Section 7.2.4.1.4.3, 

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respectively.  Criteria for dose reduction in the setting of hypertension and proteinuria are 
detailed in Section 7.2.4.1.4.2 and Section 7.2.4.1.4.4, respectively.
Table JPBJ.7.11.
Dose Adjustments of Ramucirumab for Study I3Y-MC-JPBJ
Dose Adjustment
IV Dose
Dose Frequency
0
10 mg/kg
Days 1 and 8 or Day 1
1
8 mg/kg
Days 1 and 8 or Day 1
2
6 mg/kg
Days 1 and 8 or Day 1
3*
5 mg/kg
Days 1 and 8
Abbreviation:  IV = intravenous.
* Ramucirumab 5 mg/kg is only permitted on the alternate dosing schedule on Days 1 and 8 administration.  
Patients who require >2 dose reductions should be discontinued from ramucirumab.
Patients who enter the study with symptoms or laboratory values equivalent to NCI-CTCAE 
v. 4.0 Grade 1 or 2 AEs should not have dose reductions related to the persistence or mild 
worsening of those symptoms or laboratory values; dose reductions may be warranted if 
worsening of symptoms or laboratory values is clinically significant in the opinion of the 
investigator.
If the start of the next cycle is delayed due to ramucirumab-related toxicity, abemaciclib should 
continue as scheduled.  If clinically appropriate, both treatments can be delayed up to a 
maximum of 7 days to maintain synchronized administration.  However, if either abemaciclib or 
ramucirumab dosing is permanently discontinued, dosing should be continued with the 
remaining compound according to the schedule, if clinically indicated.
Patients receiving ramucirumab should be monitored prior to each dose (Day 1 only or Day 1 
and Day 8 of each cycle).  In the case of ramucirumab-related toxicity, ramucirumab will be 
delayed for 1 week and administered on Day 8 of the treatment cycle provided toxicities have 
resolved to Grade <2 or baseline.  If toxicities have not resolved on Day 8, omit ramucirumab for 
that cycle.
If toxicity related to ramucirumab does not resolve in the same treatment cycle, ramucirumab can 
be delayed up to 42 days.  If the toxicity does not resolve within 42 days, ramucirumab should be 
discontinued unless the patient is receiving clinical benefit and agreement occurs between the 
treating investigator and Lilly CRP.
AEs of concern, which may or may not be associated with ramucirumab therapy, may include 
infusion-related reactions, hypertension, arterial or venous thrombotic events, bleeding 
(hemorrhagic) events, proteinuria, gastrointestinal perforation, congestive heart failure, surgery 
and impaired wound healing, liver injury/liver failure, and reversible posterior 
leukoencephalopathy syndrome (RPLS).
7.2.4.1.4.1.
Infusion-Related Reactions
Any treatment-related infusion-related reactions are defined according to the NCI-CTCAE v 4.0 
definition (NCI-CTCAE v 4.0 section “General disorders and administration site conditions”).  

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Symptoms occurring during or following infusion of ramucirumab may also be defined 
according to AE categories such as allergic reaction, anaphylaxis, or cytokine release syndrome 
(NCI-CTCAE v 4.0 section “Immune system disorders”).  In the setting of symptoms occurring 
during or following infusion of ramucirumab, investigators are encouraged to use the AE term 
“infusion-related reaction” and any additional terms (including those not listed here) that best 
describe the event.
Consistent with usual medical practice, selected parenteral medications may be utilized for 
Grade 2 allergic/hypersensitivity reaction as detailed below.  The Lilly CRP should be contacted 
immediately if questions arise concerning the grade of the reaction.
The following are treatment guidelines for infusion-related reactions:
Grade 1:

Slow the infusion rate by 50%.

Monitor the patient for worsening of condition.

For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg IV 
(or equivalent); additional premedication may be administered at the investigator’s 
discretion.
Grade 2:

Stop the infusion.

Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), acetaminophen 
650 mg orally for fever, and oxygen.

Resume the infusion at 50% of the prior rate once the infusion-related reaction has 
resolved or decreased to Grade 1; the infusion duration should not exceed 2 hours.

Monitor for worsening of condition.

For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg IV 
(or equivalent); additional premedication may be administered at the investigator’s 
discretion.
For a second Grade 1 or 2 infusion-related reaction, administer dexamethasone 8 to 10 mg IV (or 
equivalent); then, for subsequent infusions, premedicate with diphenhydramine hydrochloride 
50 mg IV (or equivalent), acetaminophen 650 mg orally, and dexamethasone 8 to 10 mg IV (or 
equivalent).
Grade 3:

Stop the infusion and disconnect the infusion tubing from the patient.

Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), dexamethasone 
8 to 10 mg IV (or equivalent), bronchodilators for bronchospasm, and other 
medications/treatment as medically indicated.

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
Patients who have a Grade 3 infusion-related reaction will not receive further 
investigational product but will continue to be followed on the protocol.
Grade 4:

Stop the infusion and disconnect the infusion tubing from the patient.

Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), dexamethasone 
8 to 10 mg IV (or equivalent), and other medications/treatment as medically indicated.

Give epinephrine or bronchodilators as indicated.

Hospital admission for observation may be indicated.

Patients who have a Grade 4 infusion-related reaction will not receive further 
investigational product, but will continue to be followed on the protocol.
If a patient should have an infusion-related reaction to ramucirumab, all attempts should be made 
to obtain blood samples for both immunogenicity and PK analysis as close to the onset of the 
event as possible, at the resolution of the event, and 30 days following the event (see 
Attachment 1).
7.2.4.1.4.2.
Hypertension
The following are treatment guidelines for hypertension (an expected AE in patients receiving 
ramucirumab) that develops during the study.
Grade <3:

If the hypertension is not associated with symptoms, continue ramucirumab and initiate 
antihypertensive therapy.

If the hypertension is associated with symptoms, hold ramucirumab until symptoms 
resolve and initiate antihypertensive therapy.

If ramucirumab is held more than once for hypertension (ie, symptomatic hypertension, 
markedly elevated blood pressure unresponsive to antihypertensive therapy), the dose of 
ramucirumab should resume at a reduced dose level.  A second dose reduction should be 
undertaken if an additional postponement of ramucirumab is required.
Grade 3:  (systolic blood pressure [BP] ≥160 mm Hg or diastolic BP ≥100 mm Hg; medical 
intervention indicated; more than 1 drug or more intensive therapy than previously used 
indicated)

For Grade 3 hypertension not associated with symptoms, continue investigational product 
with more intensive antihypertensive therapy.  If systolic BP remains ≥160 mm Hg or 
diastolic BP ≥100 mm Hg >3 weeks after initiation of additional antihypertensive 
therapy, hold investigational product while continuing appropriate antihypertensive 
therapy.

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
If the hypertension is associated with symptoms, hold ramucirumab until symptoms 
resolve and initiate antihypertensive therapy.

If ramucirumab is held more than once for hypertension (that is, symptomatic 
hypertension, markedly elevated blood pressure unresponsive to antihypertensive 
therapy), the dose of ramucirumab should resume at a reduced dose level.  A second dose 
reduction should be undertaken if an additional postponement of ramucirumab is 
required.
Grade 4 or Refractory:
Patients with Grade 4 hypertension (life-threatening consequences; eg, malignant hypertension, 
transient or permanent neurologic deficit, hypertensive crisis; or urgent intervention indicated) or 
patients whose hypertension is poorly controlled (>160 mm Hg systolic or >100 mm Hg diastolic 
for >4 weeks) despite appropriate oral medication (>2 oral agents at MTD) will be discontinued 
from ramucirumab.  Treatment with abemaciclib may be continued, if appropriate in the opinion 
of the investigator.
7.2.4.1.4.3.
Thrombotic Events
Investigators should perform all testing required to fully characterize arterial or venous 
thrombotic/vascular events.  The incidence and type of thrombotic/vascular events will be 
collected and reported.
Patients who develop ≤Grade 3 venous thrombotic events (deep vein thrombosis [DVT] or 
pulmonary embolism [PE]) may continue study therapy, with the consent of the Lilly CRP, if the 
event is not considered to be life-threatening in the opinion of the investigator, the patient is 
asymptomatic, and/or the event can be adequately treated with low molecular weight 
heparin-based therapy.  The treatment combination (abemaciclib + ramucirumab) should be 
discontinued in the setting of a DVT or PE that occurs or intensifies while the patient is receiving 
therapeutic anticoagulation therapy.
7.2.4.1.4.4.
Proteinuria
If, while receiving ramucirumab, a patient has proteinuria ≥2+ per a dipstick or routine urinalysis 
test, ramucirumab will continue as scheduled, and a 24-hour urine collection will be conducted 
prior to the subsequent scheduled treatment cycle.  If the protein level is <2 g/24 hours, the 
patient will continue on ramucirumab at the same dose without interruption.  If the protein level 
is 2 to 3 g/24 hours, ramucirumab for the subsequent cycle will be held for 3 weeks and a 
24-hour urine collection will be repeated.  Treatment with ramucirumab will resume at a reduced 
dose level once the protein level returns to <2 g/24 hours.  A second dose reduction is permitted 
if proteinuria >2 g/24 hours recurs.  Ramucirumab will be discontinued if the protein level is >3 
g/24 hours, if there is a third occurrence of proteinuria >2 g/24 hours, or if the protein level does 
not return to <2 g/24 hours within 3 weeks.

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7.2.4.1.5. LY3023414
For patients receiving combination treatment with abemaciclib and LY3023414 in Part D, the 
same guidelines for dose adjustments due to toxicities possibly related to LY3023414 apply as 
outlined for abemaciclib in Section 7.2.4.1.1.
Dose adjustments of LY3023414 are described in Table JPBJ.7.12.
Table JPBJ.7.12.
Dose Adjustments of LY3023414 for Study I3Y-MC-JPBJ
Dose Adjustment
Oral Dose
Frequency
0
200 mg
Every 12 hours
1
150 mg
Every 12 hours
2
100 mg
Every 12 hours
For patients in Part D (LY3023414 + abemaciclib), the investigator will interpret and document 
whether or not an AE has a reasonable possibility of being related to each of the study drugs, 
taking into account the disease, concomitant treatments, or pathologies, in order to individually 
adjust study drug(s) doses. For a toxicity that due to its nature is possibly related to LY3023414 
only, dose adjustments for abemaciclib should be considered only after dose adjustment of 
LY3023414 (and vice versa for possibly only abemaciclib-related toxicities; see Section 
7.2.4.1.1).  LY3023414 should be dose-reduced to the next lower dose level (Table JPBJ.7.12)
following discussion between the investigator and the sponsor.  
Following discussion between the investigator and the sponsor, reductions to intermediate dose 
levels and splitting the total daily dose of LY3023414 in uneven morning and evening doses 
(e.g., 100 mg in the morning/200 mg in the evening instead of 150 mg BID) will be allowed, as 
long as none of the doses (morning/evening) exceed the MTD for QD dosing of 325-mg/d 
LY3023414 monotherapy.  Dosing of either abemaciclib or LY3023414 or both may be dose 
adjusted due to possibly study drug-related toxicities, as deemed clinically appropriate at the 
investigator discretion.
7.2.4.1.6. Pembrolizumab
Pembrolizumab must be withheld (dose reductions are not permitted) for drug-related toxicities 
and severe or life-threatening AEs. See Section 7.2.4.2.6 for pembrolizumab dose adjustment 
and corticosteroid usage and Section 7.5.1.4 for supportive care guidelines for pembrolizumab.
7.2.4.2.
Dose Delays
7.2.4.2.1. Abemaciclib
Before the start of each cycle, hematologic toxicity possibly related to abemaciclib must resolve
to either baseline or at least Grade 2.
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 7.5.1
for guidance and supportive measures of diarrhea toxicity possibly related to abemaciclib or 
Section 8.1.4.1 for additional hepatic monitoring guidance.

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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 should be considered for discontinuation from the study.
7.2.4.2.2. Pemetrexed
To start the next cycle, the following criteria must be fulfilled:

ANC ≥1.5 x 103/L (≥1.5 x 109/L), platelets ≥100 x 103/L (≥100 x 109/L)

Creatinine clearance is ≥45 mL/min
The start of next cycle should be delayed for up to 2 weeks (14 days) to allow for recovery.  If a 
delay of more than 2 weeks (14 days) due to unresolved toxicity is necessary, 1 or both of the 
drugs should be discontinued (depending on the causality of the drug).  The other agent should 
be continued, with the patient remaining on study, if clinically indicated.
7.2.4.2.3. Gemcitabine
To start the next cycle, the following criteria must be fulfilled:

ANC ≥1.5 x 103/L (≥1.5 x 109/L), platelets ≥100 x 103/L (≥100 x 109/L)
The start of next cycle should be delayed for up to 2 weeks (14 days) to allow for recovery.  If a 
delay of more than 2 weeks (14 days) due to unresolved toxicity is necessary, 1 or both of the 
drugs should be discontinued (depending on the causality of the drug).  The other agent should 
be continued, with the patient remaining on study, if clinically indicated.
7.2.4.2.4. Ramucirumab
To start the next cycle, the following criteria must be fulfilled:

Total bilirubin less than or equal to ULN

AST and ALT ≤2.5 x ULN, or ≤5 x ULN if the transaminase elevation is due to 
liver metastases

ANC ≥1.5 x 103/L (≥1.5 x 10
9/L), platelets ≥100 x 103/L (≥100 x 109/L)

NCI-CTCAE v 4.0 Grade <2 (except for alopecia; for hypertension, see 
Section 7.2.4.1.4.2, and for proteinuria, see Section 7.2.4.1.4.4)
When ramucirumab is administered on Day 1 of a 21-day cycle, the start of next cycle should be 
delayed for up to 2 weeks (14 days) to allow for recovery.  If a delay of more than 2 weeks due 
to unresolved toxicity is necessary, 1 or both of the drugs should be discontinued (depending on 
the causality of the drug).  The other agent should be continued, with the patient remaining on 
study, if clinically indicated.  When ramucirumab is administered on Day 1 and Day 8 of a 
21-day cycle, the start of the next cycle can be delayed up to 3 weeks to allow for recover.  If a 
delay of more than 3 weeks due to unresolved toxicity is necessary, 1 or both of the drugs should 
be discontinued.
Patient should be weighed at the beginning of each cycle and may be dosed based on actual body 
weight.  Applied dosages should be no more than 10% above or below calculated ones.  The first 
dose of ramucirumab is dependent upon the patient’s baseline body weight in kilograms.  This 

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dose must be recalculated if there is a ≥10% change (increase or decrease) in body weight from 
the last dose calculation.
Ramucirumab infusion can be administered on Day 1 (±3 days) of each cycle due to 
administrative reasons only (for example, weekend) will be considered acceptable and is at the 
discretion of the treating investigator.
7.2.4.2.5. LY3023414
For patients receiving combination treatment with abemaciclib and LY3023414 in Part D, the 
same guidelines for dose delays and supportive measures for possibly LY3023414-related 
toxicities apply as outlined for abemaciclib in Section 7.2.4.2.1.
Dosing of either abemaciclib or LY3023414 or both may be delayed due to possibly study drug-
related toxicities as deemed clinically appropriate at the investigator discretion.
7.2.4.2.6. Pembrolizumab
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Therefore, early recognition and initiation of 
treatment are critical to reduce complications. Based on existing clinical study data, more AEs 
were reversible and could be managed with interruptions of study treatment, administration of 
corticosteroids, and/or other supportive care. Dose modification and toxicity management 
guidelines for AEs associated with pembrolizumab are provided in Table JPBJ.7.13 below.  

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Table JPBJ.7.13.
Dose Adjustments for Pembrolizumab in Study I3Y-MC-JPBJ
General instructions:
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been 
tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg 
prednisone or equivalent per day within 12 weeks. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be initiated 
if irAEs cannot be controlled by corticosteroids.
Immune-related AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 
Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper
Monitor participants for signs and 
symptoms of pneumonitis
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment
Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently discontinue
Diarrhea /Colitis 
Grade 2 or 3
Withhold
Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper
Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus).
Participants with ≥ Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis. 
Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids.  If 
Grade 4
Permanently discontinue

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sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion.
AST / ALT elevation or Increased 
bilirubin
Grade 2
Withhold
Administer 
corticosteroids (initial 
dose of 0.5-1 mg/kg 
prednisone or 
equivalent) followed by 
taper
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme value 
returned to baseline or is stable
Grade 3 or 4 
Permanently discontinue
Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper
Type 1 diabetes mellitus (T1DM) 
or Hyperglycemia
Newly onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold
Initiate insulin 
replacement therapy for 
participants with T1DM 
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes.
Hypophysitis
Grade 2
Withhold
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated. 
Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4 
Withhold or permanently 
discontinuea
Hyperthyroidism 
Grade 2
Continue 
Treat with non-selective 
beta-blockers (e.g., 
propranolol) or 
thionamides as 
appropriate 
Monitor for signs and symptoms of 
thyroid disorders. 
Grade 3 or 4 
Withhold or 
permanently discontinuea
Hypothyroidism
Grade 2-4
Continue 
Initiate thyroid 
replacement hormones 
Monitor for signs and symptoms of 
thyroid disorders. 

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(eg, levothyroxine or 
liothyroinine) per 
standard of care
Nephritis and Renal dysfunction
Grade 2
Withhold 
Administer 
corticosteroids 
(prednisone 1-2 mg/kg 
or equivalent) followed 
by taper.
Monitor changes of renal function
Grade 3 or 4 
Permanently discontinue
Myocarditis
Grade 1 or 2
Withhold
Based on severity of AE 
administer 
corticosteroids
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes
Grade 3 or 4
Permanently discontinue
All other immune-related AEs
Intolerable/ 
persistent Grade 2
Withhold
Based on type and 
severity of AE 
administer 
corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes
Grade 3
Withhold or discontinue based 
on the type of event.  Events that 
require discontinuation include 
and not limited to:  Gullain-
Barre Syndrome, encephalitis
Grade 4 or recurrent 
Grade 3 
Permanently discontinue
a  Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 
and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  

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7.2.4.3.
Special Treatment Considerations
7.2.4.3.1. Immune Checkpoint Inhibitors 
Immune therapies are potentially associated with delayed toxicity.  Patients who have received 
prior immune checkpoint inhibitors or other immunotherapy should be monitored for potential 
signs of a delayed toxicity after discontinuation of immunotherapy.  Treatment of a suspected 
toxicity should be according to the immune checkpoint inhibitor’s label and may include 
immediate use of corticosteroids, an immune-suppressive therapy, and increased laboratory 
monitoring and physical assessments.  Current recommendations for monitoring for delayed 
toxicity range between 90 days and 1 year after treatment discontinuation (Champiat et al. 2016).
7.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be assigned to receive abemaciclib in this study.  
Before each patient’s enrollment into the study, an eligibility check must be conducted between 
the investigational site and the Lilly clinical research personnel to confirm that each patient 
meets all enrollment criteria.  Upon confirmation of eligibility, the sponsor will confirm the dose 
and identification number assignment for each patient.  No dose escalations (that is, to the next 
cohort) can occur without prior discussion and agreement with the responsible Lilly CRP.
7.4.
Blinding
This is an open-label study.
7.5.
Concomitant Therapy
Pemetrexed, gemcitabine, ramucirumab, LY3023414, and pembrolizumab are permitted in 
Parts A, B, C, D, and E, respectively.
No other chemotherapy, radiotherapy, immunotherapy, cancer-related hormone therapy, or 
experimental drugs will be permitted while the patients are on this study. Palliative radiotherapy, 
unless required due to progressive disease, is permitted during the study.  Disease progression 
requiring specific antitumor therapy will necessitate early discontinuation from the study.  
Appropriate documentation for all forms of premedications, supportive care, and concomitant 
medications must be captured on the case report form.
For Part E, systemic glucocorticoids for any purpose other than to modulate symptoms from an 
adverse event of suspected immunologic etiology are not permitted while patients are on study 
therapy.  The use of physiologic doses of corticosteroids may be approved after consultation with 
the Lilly CRP. Inhaled steroids are allowed for management of asthma.
In vivo, abemaciclib is extensively metabolized through oxidation.  The results from an in vitro 
human recombinant cytochrome P450 (CYP) phenotyping study indicate that oxidative 
metabolism of abemaciclib is primarily catalyzed by CYP3A.  Based on these findings, 
grapefruit juice as well as inducers (for example, phenytoin and carbamazepine) and strong 
inhibitors of CYP3A should be substituted or avoided if possible (Attachment 10).

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In vitro studies in primary cultures of human hepatocytes indicate that abemaciclib and its 
metabolites LSN2839567 and LSN3106726 down regulate mRNA of CYPs including CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A at clinically relevant concentrations.  The 
mechanism of mRNA down regulation and its clinical relevance are not yet understood.  
Therefore, caution should be exercised when coadministering substrate drugs of the above CYPs 
with narrow therapeutic margin.  For LY3023414, preclinical data suggested potential inhibition 
of CYP3A4-mediated metabolism and potential secondary QTc interval prolongation by 
LY3023414.  The clinical data from Study CBBA indicates LY3023414 is a weak inhibitor of 
CYP3A4 as concomitant administration of LY3023414 and midazolam leads to an increased 
exposure of midazolam (fold increase:  mean 1.459 (CV 30.5 %) (90% CI 1.21 – 1.76).  
LY3023414 may lead to increase in exposure of abemaciclib and other CYP3A4 substrates.  
Therefore, caution should be exercised when coadministering substrate drugs of CYP3A4 with 
narrow therapeutic margin.
Patients should receive full supportive care during this study.
WBC growth factors may be used in accordance with the ASCO guideline (Smith et al. 2006) if 
clinically indicated. However, these agents must be discontinued at least 24 hours before 
beginning the next cycle of treatment.
Erythropoiesis-stimulating agents (ESAs, including erythropoietin and darbepoetin) may be used 
in accordance with the ASCO/ASH guideline (Rizzo et al. 2010) if clinically indicated.  
Transfusion therapy is permitted during this study.
7.5.1. Supportive Care
7.5.1.1.
Supportive Management for Diarrhea
At enrollment, patients should receive instructions for diarrhea management.  In the event of 
diarrhea, supportive measures should be initiated as early as possible.  These include the 
following:

At the first sign of loose stools, the patient should initiate antidiarrheal therapy (for 
example, loperamide) and notify the investigator 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 antidiarrheal therapy within 24 hours to either baseline 
or Grade 1, then dosing should be suspended until diarrhea is resolved to baseline or 
Grade 1.
When study drug recommences, dosing should be adjusted as outlined in Table JPBJ.7.6
In severe cases of diarrhea, the measuring of neutrophil counts and body temperature and 
proactive management of diarrhea with antidiarrheal agents should be considered.

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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 diarrhea associated with severe nausea or vomiting should 
be carefully monitored and given fluid (IV hydration) and electrolyte replacement.
7.5.1.2.
Guidance for Monitoring of Renal Function in Patients on Abemaciclib
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 alterations (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 JPBJ.7.6).
7.5.1.3.
Supportive Care for Hyperglycemia – Part D Only
Hyperglycemia has been observed in patients treated with LY3023414.  Patients who develop 
hyperglycemia during the study should be treated according to the American Diabetes 
Association and European Association for the Study of Diabetes consensus guidelines.  It is 
recommended to start treatment with an oral antidiabetic medication, preferably sitagliptin.  
Additional options may include repaglinide or low-dose sulfonylureas (with due precautions, 
including standard education of patients regarding the signs of hypoglycemia).
7.5.1.4.
Supportive Care Guidelines for Pembrolizumab –Part E only
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 7.2.4.2.6.  Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids. Note that several courses of steroid tapering may 
be necessary, as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are intended 
to be applied when the investigator determines the events to be related to pembrolizumab.
Note:  If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table JPBJ.7.13 for 
guidelines regarding dose modification.
Management of Infusion Reactions:

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Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion reaction 
are provided in Table JPBJ.7.14.
Table JPBJ.7.14.
Infusion Reaction Treatment Guidelines in Study I3Y-MC-JPBJ
NCI CTCAE Grade
Treatment
Premedication at subsequent dosing
Grade 1
Mild reaction; infusion interruption not 
indicated; intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion interruption 
but responds promptly to symptomatic 
treatment (e.g., antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤24 hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may include
but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 50% 
of the original infusion rate (e.g., from 100 mL/hr to 
50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further trial treatment 
administration.
Subject may be premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with:
Diphenhydramine 50 mg po (or equivalent 
dose of antihistamine).
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization indicated 
for other clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may include 
but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from further 
trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug administration.
Abbrevations:  IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events; NSAIDS = non-steroidal anti-inflammatory drugs.

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7.6.
Treatment Compliance
Patient compliance with study drug(s) will be assessed at each visit by review of the patient 
diary, direct questioning, and counting of returned capsules/tablets.  Deviation(s) from the 
prescribed dosage regimen should be recorded on the eCRF.
The patient must take 75% of the intended dose to be deemed compliant with study drug 
administration.  Similarly, a patient may be considered noncompliant if he or she is judged by the 
investigator to have intentionally or repeatedly taken more than 125% of the prescribed amount 
of medication in a cycle. Dose suspensions or delays may occur and will not result in a patient 
being considered as noncompliant. Any missed doses during a cycle will be omitted and not 
replaced.  In the event of a missed dose, a patient should resume and continue dosing beginning 
with the next scheduled dose. Potential discontinuation of a patient due to study drug 
noncompliance will be discussed between the investigator and the Lilly CRP before making the 
final determination for discontinuation. If a patient is discontinued due to study drug 
noncompliance, the patient may be replaced.
Pemetrexed, gemcitabine, ramucirumab, and pembrolizumab will be administered intravenously 
at the investigational site, under the direction of the investigator.  As a result, a patient’s 
compliance with study drug administration is ensured.  Patients should attend scheduled clinic 
visits and must comply with study criteria under their control.  Deviation(s) from the prescribed 
dosage regimen should be recorded on the eCRF.
For Part E, an overdose will be defined as ≥1000 mg (5 times the dose) of pembrolizumab.  No 
specific information is available on the treatment of overdose of pembrolizumab. In the event of 
overdose, the subject should be observed closely for signs of toxicity.  Appropriate supportive 
treatment should be provided if clinically indicated.
7.6.1. Evaluable Patients
Patients who withdraw from the study before receiving study drug(s) will be replaced and will 
not be included in the safety or efficacy assessments.  Safety analyses will be conducted on all 
patients who have received at least 1 dose of study drug, regardless of whether they are deemed 
evaluable for the assessment of a dose level.
For dose escalation, any patient who is discontinued from the study before receiving at least 75% 
of planned doses of abemaciclib (and LY3023414 in Part D) in Cycle 1 will be deemed 
nonevaluable for assessment of that dose level and may be replaced unless they experience a 
DLT before withdrawal.  Nonevaluable patients may be replaced to ensure that no fewer than
3 patients receive at least 75% of planned doses of abemaciclib in Cycle 1 at each dose level, 
unless enrollment to that cohort has stopped because more than 1 patient at that dose level has 
experienced a DLT.
Patients evaluable for PK will have received at least 1 dose of the study drug and have sufficient 
samples collected to allow the estimation of abemaciclib PK parameters.  Patients who complete 
Cycle 1 of therapy but are not evaluable for PK may be replaced upon consultation with the 

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investigator(s) and the Lilly CRP to ensure adequate PK data collection, unless enrollment to that 
cohort has stopped because more than 1 patient at that dose level has experienced a DLT.

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8. Safety, Pharmacokinetic, Pharmacodynamic, and 
Efficacy Data Collection
8.1.
Safety Evaluations
The safety and tolerability of abemaciclib have been assessed in nonclinical toxicology studies,
and the results from these studies are detailed in the IB.  This Phase 1 study contains detailed 
safety monitoring that will permit initial characterization of the safety profile of abemaciclib in 
patients.  Study procedures and their timing, including the collection of blood samples, are 
described in the Study Schedule (Attachment 1).
Blood samples and ECGs will be collected at the times specified in the Study Schedule 
(Attachment 1).  Standard laboratory tests, including chemistry and hematology panels, will be 
performed.  A serum pregnancy test will be administered if applicable.  Attachment 2 lists the 
specific laboratory tests that will be performed for this study. 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. When both a local and central 
laboratory result are obtained and there is a discrepancy in these laboratory values, the local 
laboratory values will be used for determining a DLT, after discussion with the study 
investigator(s).
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of
confirmed test results. Certain samples may be retained for a longer period, if necessary, to
comply with applicable laws, regulations, or laboratory certification standards.
If a patient’s dosage is reduced or treatment 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.
All concomitant medications should be recorded throughout the patient’s participation in the
study, until conclusion of the study follow-up period.
8.1.1. Safety Data Collection and Review
Investigators are responsible for monitoring the safety of patients who have entered into this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of the patient during the study.
The investigator remains responsible for following, through an appropriate health care option,
AEs that are serious, considered related to study treatment or the study, or that caused the patient 
to discontinue before completing the study.  The patient should be followed until the event is 
resolved, the event is no longer considered to be drug-related, the event becomes stable or 
returns to baseline, a new treatment is initiated for the patient, or the patient dies or is lost to 

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follow up.  Frequency of AE and SAE follow-up evaluation is left to the discretion of the 
investigator.
The timing of all safety evaluations is shown in the Study Schedule (Attachment 1).  
Table JPBJ.8.1 presents a summary of AE and SAE reporting guidelines.  Table JPBJ.8.1 also 
shows which database or system is used to store AE and SAE data.
8.1.2. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  A clinical study AE is any untoward medical occurrence 
in a patient or clinical investigation subject administered a pharmaceutical product and which 
does not necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  Any clinically significant findings from labs, 
vital sign measurements, and so on, that occur should also be reported to Lilly or its designee as 
an AE.  Lack of drug effect is not an AE in clinical studies because the purpose of the clinical 
study is to establish drug effect. Progression of the cancer under study is not considered an 
adverse event unless it is considered to be drug-related by the investigator and sponsor.
The investigator, monitor, and sponsor will review the collected data regularly for evidence of 
AEs.  All patients will be assessed routinely for AEs as outlined in the Study Schedule 
(Attachment 1).  All AEs observed will be graded using CTCAE v 4.0.
The NCI-CTCAE v 4.0 will serve as the reference document for choosing appropriate 
terminology for, and grading the severity of, all AEs and other symptoms. All AEs observed 
will be graded using CTCAE v 4.0.  Any minor version of CTCAE v 4.0 may be used for this 
study.  Minor CTCAE v 4.0 updates from the NCI will not necessitate a protocol amendment.  
For AEs without matching terminology within the NCI-CTCAE v 4.0 criteria, the investigator
will be responsible for selecting the appropriate system organ class and assessing severity grade 
based on the intensity of the event.  Note that both CTCAE term (actual or coded) and severity 
grade must be selected by study site personnel and collected on the eCRF.  This collection is in 
addition to verbatim text used to describe the AE.
In addition to collecting the AE verbatim, the CTCAE term, and the CTCAE severity grade, AE 
verbatim text will also be mapped by the sponsor or designee to corresponding terminology 
within the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.
Cases of pregnancy that occur during maternal or paternal exposures to study drug should be 
reported. Upon documentation of pregnancy, the patient must be removed from the study and
treatment with study drug must be stopped immediately.  Data on fetal outcome and 
breastfeeding should be collected, if feasible, for regulatory reporting and drug safety evaluation.
For patients in Part E, any pregnancy should be reported from the time of treatment allocation 
through 120 days following cessation of treatment, or 30 days following cessation of treatment if 
patient initiates new anticancer therapy, whichever is earlier. 

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For all enrolled patients, study site personnel will record the occurrence and nature of each 
patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  While the patient is on study, site personnel will record any 
change in these preexisting condition(s) and the occurrence and nature of any AEs.  In addition 
all AEs related to protocol procedures are reported to Lilly or designee.
After the informed consent form (ICF) is signed, all AEs possibly related to protocol procedures 
are reported to Lilly or designee via eCRF. Regardless of relatedness to study drug(s), all AEs 
occurring while the patient is receiving study drug must be reported to Lilly or its designee via 
eCRF.
Lilly or its designee will be alerted to AEs occurring from the time of treatment allocation 
through 30 ± 7 days after a patient is discontinued from the study only if the investigator believes 
that the event may have been caused by the study drug or protocol procedures.
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 eDC the circumstances and data leading 
to any such dosage reduction or discontinuation of treatment. 
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to study medication, study procedure, or other concomitant treatment or 
pathologies via eDC.
The investigator decides whether he or she interprets the observed AEs as either related to 
disease, to the study medication, study procedure, or other concomitant treatment or pathologies.  
To assess the relationship of the AE to the study drug, the following terminologies are defined:

Related:  a direct cause and effect relationship between the study treatment and 
the AE is likely.

Possibly related:  a cause and effect relationship between the study treatment and 
the AE has not been demonstrated at this time and is not probable, but is also not 
impossible.

Unrelated:  without question, the AE is definitely not associated with the study 
treatment.
As per Lilly’s standard operating procedures all “related” and “possibly related” AEs and SAEs 
will be defined as related to study drug.
8.1.2.1.
Serious Adverse Events
SAE collection begins after the patient has signed the informed consent document. During 
therapy with study drug and for 30 ± 7 days after the last dose of study drug, all SAEs will be 
collected regardless of relatedness to study drug or protocol procedures. Beyond 30 ± 7 days 
from the last dose of study drug, only ongoing or new SAEs possibly related to study drug or 
protocol procedures should be reported.  SAE collection prior to administration of study drug(s), 
see Section 8.1.2.2.1.

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Previously planned surgeries (prior to signing the ICF) should not be reported as SAEs unless the 
underlying medical condition has worsened during the course of the study.
Preplanned 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 therapy or other protocol-required procedure) should not 
be considered SAEs.
An SAE is any AE during this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization (except for study drug 
administration)

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the
outcomes listed in this definition. 
SAEs due to disease progression, including death, should not be reported unless the investigator 
deems them to be possibly related to the study drug.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  Drug- or procedure-related SAEs should be followed until they resolve, are no 
longer considered to be drug related, become stable or return to baseline, the patient starts a new 
therapy, the patient dies, or the patient becomes lost to follow up.
For Part E, SAE collection begins after the patient has signed the informed consent document, 
during therapy, and for 90 days following cessation of treatment, or 30 days following cessation 
of treatment if the subject initiates new anticancer therapy, whichever is earlier.
If an investigator becomes aware of SAEs occurring after the patient’s participation in the trial 
has ended, and the investigator believes that the SAE is related to a protocol procedure or study 
drug, the investigator should report the SAEs to the sponsor, and the SAEs will be entered in the 
Lilly Safety System.

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Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.  
8.1.2.1.1. Part E: Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow-up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is 
the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, or procedure.
For the time period beginning at treatment/randomization through 30 days following cessation of 
treatment, any ECI, or follow-up to an ECI, whether or not related to the Sponsor’s product, must 
be reported within 24 hours to the Sponsor.
An event of clinical interest is defined as: 1) an overdose of pembrolizumab (see Section 7.6) 
that is not associated with clinical symptoms or abnormal laboratory values or 2) an elevated 
AST or ALT laboratory value that is great than or equal to 3X the ULN and an elevated total 
bilirubin laboratory value that is greater than or equal to 2X the ULN, and at the same time, an 
alkaline phosphatase laboratory value that is less than 2X the ULN, as determined by way of 
protocol-specific laboratory testing or unscheduled laboratory testing.
8.1.2.2.
Adverse Event and Serious Adverse Event Reporting
Data on SAEs that occur before the end of trial will be stored in the collection database and the 
Lilly Safety System.
8.1.2.2.1. Prior to Administration of Study Drug(s)
During screening, all AEs and SAEs (regardless of relatedness to protocol procedures) are 
collected after the patient has signed the ICF.  For patients who do not enroll in the trial (that is, 
have not received at least 1 dose of abemaciclib), only AEs and SAEs related to protocol 
procedures are required to be collected. 
8.1.2.2.2. On Therapy
All AEs and SAEs, regardless of relatedness to study drug(s) or protocol procedures, occurring 
while the patient is receiving study drug must be reported to Lilly or its designee.  A patient is 
considered to be receiving study drug from the time he/she receives the first dose of study drug 
to when he/she receives the last dose of study drug.
8.1.2.2.3. Follow-Up Visit
All AEs and SAEs, regardless of relatedness to study drug(s) or protocol procedures, occurring 
during the follow-up visit must be reported to Lilly or its designee.  The follow-up visit starts 
following the last dose of study drug.  At the end of the follow-up visit, the patient will be 
required to have specific safety assessments (Attachment 1).  The timing of these safety 
assessments is 30 ± 7 days from the date of the last dose of study drug received.

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Following the safety assessments, which mark the end of the follow-up visit, the patient will be 
discontinued from the study, unless there is an ongoing AE or SAE that is possibly related to 
study drug.  In this instance, the patient should be followed in subsequent follow-up visits until 
the event is resolved, the event is no longer considered to be drug-related, the event becomes 
stable or returns to baseline, a new treatment is initiated for the patient, or the patient dies or is 
lost to follow-up.
If it is deemed to be in the best interest of the patient to start a new anticancer treatment prior to 
the scheduled end of the follow-up visit, the follow-up visit duration may be shortened. In this 
case, the follow-up assessments should be completed prior to the initiation of the new therapy.
After the follow-up visit, AEs are not required to be reported unless the investigator feels the 
AEs were related to either study drug, drug delivery system, or a protocol procedure. If an 
investigator becomes aware of SAEs believed to be related to protocol procedures or study drug, 
the investigator should report the SAE to the sponsor, and the SAE will be entered in the Lilly 
Safety System.
8.1.2.3.
Suspected Unexpected Serious Adverse Reactions
The US 21 CFR 312.32, the European Union (EU) Clinical Trial Directive 2001/20/EC, and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of suspected unexpected serious adverse reactions (SUSARs).  SUSARs are 
SAEs that are not listed in the Development Core Safety Information in the IB and that the 
investigator identifies as related to study drug or procedure.  The US 21 CFR 312.32, the EU
Clinical Trial Directive 2001/20/EC, and the associated detailed guidances or national regulatory 
requirements in participating countries require the reporting of SUSARs.  Lilly has procedures 
that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulatory regulations and the associated detailed guidances.
8.1.2.4.
Summary of AE/SAE Reporting Guidelines
The AE and SAE reporting guidelines are summarized in Table JPBJ.8.1.

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Table JPBJ.8.1.
Adverse Event and Serious Adverse Reporting Guidelines for 
Study I3Y-MC-JPBJ
Timing
Types of AEs/SAEs Reported
Collection 
Database
Lilly Safety 
System
Prestudy (baseline assessments)
(starts at the signing of informed 
consent and ends just before the 
first dose of study drug)
Preexisting conditions
All AEs
All SAEs regardless of relatedness
x
x
x
x
On therapy
(starts at first dose of study drug[s]
and ends at last dose of study 
drug[s])
All AEs
All SAEs regardless of relatedness
x
x
x
Follow-up visit 
(starts following the last dose of 
study drugs[s] and ends when end 
of study safety assessments are 
completed [30 days (±7)a after last 
dose of study drugs(s)]).
All AEs
All SAEs regardless of relatedness
x
x
x
Extension period
All AEs 
All SAEs regardless of relatedness
x
x
x
Extension period follow up
All AEs 
All SAEs regardless of relatedness
x
x
x
Subsequent follow-up visits, if 
necessary for patient monitoring
Ongoing AEs possibly related to 
study drug(s) or protocol procedures
All SAEs related to protocol 
procedures or study drug
x
x
x
Patient no longer on study
All SAEs related to protocol 
procedures or study drug that the 
investigator becomes aware of
x
a Part E requires SAE collection through 90 days following cessation of treatment or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier
Abbreviations:  AEs = adverse events; SAEs = serious adverse events.
8.1.3. Other Safety Measures
8.1.3.1.
Electrocardiograms
This study requires ECG monitoring at both baseline and Cycle 1 Day 15 (see Attachment 1).  
For each subject 12-lead digital ECGs will be obtained as single ECGs according to the Study 
Schedule (Attachment 1). Patients must be supine for approximately 5 to 10 minutes before 
ECG collection and remain supine during ECG collection. ECGs may be obtained at additional 
times, when deemed clinically necessary.  Collection of more ECGs than expected at a particular 
time point is allowed when needed to ensure high quality records.
ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at the
site as soon after the time of ECG collection as possible, and ideally while the patient is still
present, to determine whether any clinically relevant findings are present. The investigator (or 
qualified designee) must document his/her review of the ECG printed at the time of evaluation.  

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After enrollment, if a clinically significant increase in the QTcB 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.
8.1.4. Safety Monitoring
The Lilly CRP or CRS will monitor safety data throughout the course of the study. Lilly will 
review SAEs within time frames mandated by standard operating procedures and will review 
trends, laboratory analytes, and AEs at periodic intervals. Attachment 5 provides 
recommendations for reporting SAEs.
To ensure patient safety and comply with regulatory guidance, the investigator is to consult with 
the Lilly CRP/CRS regarding collection of specific recommended clinical information and 
follow-up laboratory tests (see Attachment 3).
8.1.4.1.
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 

discontinuation from study treatment due to a hepatic event or an abnormality of 
liver tests
8.1.4.2.
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 

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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.  
8.1.5. Complaint Handling
Lilly collects complaints on study drugs used in clinical studies in order to ensure the safety of 
study participants, monitor quality, and facilitate process and product improvements.
Complaints related to concomitant drugs are reported directly to the manufacturers of those 
drugs in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
complaint process in accordance with the instructions provided for this study:

recording a complete description of the complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
8.2.
Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study.
Attachment 8 provides a summary of the estimated maximum number and volume of invasive 
samples, for all sampling, during the study
8.2.1. Samples for Study Qualification and Health Monitoring
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
8.2.2. Samples for Drug Concentration Measurements 
Pharmacokinetics/Pharmacodynamics 
PK samples will be collected as specified in the Pharmacokinetic Sampling Schedule 
(Attachment 4).

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8.2.2.1. PharmacokineticSamples
Venous blood samples from all patients will becollectedto measure concentrations of
abemacicliband its metabolites (LSN2839567 [M2], LSN3106729 [M18], and LSN3106726
[M20]).Separatevenous blood samples from patients willalsobecollectedto measure
concentrations of pemetrexed (PartA), gemcitabine plus its metabolite 
2’,2’-difluorodeoxyuridine (dFdU)(PartB), ramucirumab (PartC), and LY3023414(PartD).
Instructions for the collection and handling of blood samples will be provided by thesponsor.  A 
maximum of 5additional PK (blood) samples may be added or removed during the study if
warranted and agreed upon by both the investigator and sponsor. For instance, if during Cycle1
or 2, the patient is in the clinic for management of his/her disease or study-related events,
additional PK (blood) samples, not to exceed 5 per patient, may be collected following
documented discussions between the investigator and sponsor.The actual date and time 
(24-hour clock time) of eachsampling will be recorded.
PK plasmaor serumsamples will be analyzed at a laboratory designated by the sponsor.  Plasma 
concentrations of abemacicliband its metabolites (LSN2839567 [M2], LSN3106729[M18], and 
LSN3106726 [M20])in all study parts will be assayed using a validated liquid chromatography 
coupled withtandem mass spectrometry (LC/MS/MS) method. For study PartsA, B,and 
D,concentrations of the combination agents(pemetrexed, gemcitabine plus its metabolite dFdU, 
and LY3023414)will be assayed using a validated LC/MS/MS method.For studyPart C, 
concentrations of ramucirumab will be assayed using a validated enzyme-linked immunosorbent 
assay (ELISA)method.Bioanalytical samples collected to measureinvestigational product and
each combination agentconcentration and metabolism, and/or protein binding,will be retained 
for amaximum of 2years following last patient visit for the study.Thesamples will be stored 
at a facility designated by the sponsor.Supplies required for the collection and shipment of the 
samples will be provided by the sponsor.  Sample handling and shipment to the central 
laboratory will occur per instructions given to thestudy site.
8.2.3. Samples for Tailoring Biomarkers
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations and ERBs allow, a bloodsample will be collectedfor pharmacogenetic analysis.
In the event of an unexpected AE or the observation of unusual response, the pharmacogenetic 
biomarker samples may be genotyped and analysis may be performed to evaluate a genetic 
association with response to study medication.  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.

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A FFPE archived tumor tissue sample or 15 unstained slides, cut at 5 microns, and 1 H&E slide 
containing tumor specimen will be requested if available and used for exploratory analysis. Due 
diligence should be used to make sure that tumor specimen (not normal adjacent or tumor 
margins) is provided.  Pathology notes accompanying archival tissue may also be requested.
Tumor blocks or partial blocks will be sectioned and returned to the investigator after completion 
of analysis.
For Part E, submission of FFPE tumor tissue sample blocks are preferred. If submitting 
unstained slides, the slides should be freshly cut and submitted to the testing laboratory within 
14 days from site slide sectioning date otherwise a new specimen will be requested.
The samples will be coded with the patient number and stored for up to a maximum 15 years 
after the last patient visit for the study at a facility selected by the sponsor.  The samples and any 
data generated from them can only be linked back to the patient by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the study drug.
Samples will be destroyed according to a process consistent with local regulation.
8.2.4. Samples for Immunogenicity Research
Blood samples for the determination of anti-ramucirumab antibodies are to be collected at the
specified time points, including at baseline (-14 days), prior to the ramucirumab infusion on 
Day 1 in Cycle 3 and Cycle 5, and at the 30-day (±7 days) follow-up visit (Attachment 1).
Additionally, blood samples for the determination of ramucirumab concentration are to be 
collected at the 30-day (±7 days) follow-up visit (Attachment 1).
In the event of an investigational product-related infusion reaction, every effort should be made 
to collect a blood sample for an anti-ramucirumab antibody determination, as well as a blood 
sample for ramucirumab serum concentration, as close to the onset of the reaction as possible, at 
the resolution of the event, and 30 days following the event. 
Anti-ramucirumab antibodies will be determined using a validated immunoassay at a laboratory 
designated by the sponsor or designee. Bioanalytical samples collected to measure 
immunogenicity will be retained for a maximum of 5 years following last patient visit for the 
study.
Samples may be stored for a maximum of 15 years following last patient visit for the trial at a 
facility selected by the sponsor to enable further analysis of immune responses to ramucirumab.  
The duration allows the sponsor to respond to regulatory requests related to ramucirumab.
8.3.
Efficacy Evaluations
A secondary objective of the study is to document the antitumor activity of abemaciclib when 
given in combination with multiple therapies.  Refer to Attachment 1 for details regarding the 
timing of specific efficacy measures.
Each patient will be assessed by 1 or more of the following radiologic tests for tumor 
measurement:

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
Computed tomography (CT) scan

Magnetic resonance imaging (MRI)

Chest x-ray
Each patient’s full extent of disease will also be assessed with:

Tumor measurement by RECIST 1.1 or irRECIST, refer to Attachment 9
(Eisenhauer et al. 2009)

Evaluation of tumor markers, if indicated.

Evaluation of PS (refer to the ECOG scale, Attachment 6).
All lesion assessments, whether by physical exam or radiological methods, should be repeated by
the same method at least 4 weeks following the initial observation of an objective response to
ensure response confirmation. If a patient is discontinued from the study, repeat radiology may
be omitted if there are clear clinical signs of progressive disease.
8.4.
Health Outcomes
8.4.1. Patient-Reported Outcomes
The health outcomes research goal is to explore and characterize patient-reported pain (“worst 
pain”), disease-related symptoms, and interference items as measured by the MDASI-LC.  The 
patient-reported questionnaire should be completed by patients when a language translation is 
available in which the patient is fluent or literate.
At each time point identified in the Study Schedule (Attachment 1), the MDASI-LC should be 
administered to the patient prior to extensive interaction with site staff and study drug 
administration.
Item responses 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 interfered 
completely). The MDASI–LC is a self-reported lung cancer instrument (Mendoza et al. 2011)
that consists of 22 items covered by one of the following dimensions:

Pain scale (1 item)

Fatigue scale (1 item)

Core symptom scale (11 total items addressing nausea, disturbed sleep, distress, shortness 
of breath, remembering things, lack of appetite, drowsy, dry mouth, sad, vomiting, 
numbness/tingling)

Lung cancer symptoms (3 items: coughing, constipation, sore throat)

Interference with mood or functional status (6 items: general activity, mood, work, 
relations with other people, walking, enjoyment of life)

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The MDASI-LC recall period is 24 hours, and typical completion time for this instrument is 5 to 
10 minutes.
8.4.2. Resource Utilization
Investigators will be asked to report the use of concomitant medications (in particular, 
analgesics), radiation therapy, surgery, and hospitalization days. This information should be 
collected during the study and through the 30-day (±7 days) follow-up visit.
8.5.
Procedure/Sampling Compliance
Every attempt will be made to enroll patients who have the ability to understand and comply 
with instructions.  Noncompliant patients may be discontinued from the study.
The collection times of safety assessments, PK samples, and efficacy measurements are given as 
targets, to be achieved within reasonable limits.  The scheduled time points may be subject to 
minor alterations; however, the actual collection time must be correctly recorded on the eDC.
The scheduled collection times may be modified by the sponsor based on analysis of the safety 
and PK information obtained during the study.  Any major modifications that might affect the 
conduct of the study, patient safety, and/or data integrity will be detailed in a protocol 
amendment.

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9. Data Management Methods
9.1.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This session 
will give instruction on the protocol, the completion of the eCRFs, 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 eCRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database. 
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable institutional 
review boards (IRB)/ERBs with direct access to the original source documents.
9.2.
Data Capture Systems
9.2.1. Case Report Form
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect 
patient-reported outcome measures (for example, a rating scale), a daily dosing schedule or an 
event diary. 
For data handled by a data management third-party organization (TPO), eCRF data and some or 
all data that are related will be managed and stored electronically in the TPO system.  
Subsequent to the final database lock, validated data will be transferred to Lilly’s data 
warehouse, using standard Lilly file transfer processes.
For data handled by the sponsor internally, eCRF data and some or all data that are related will 
be managed by the sponsor and stored electronically in the sponsor’s system.

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9.2.2. Ancillary Data
Data managed by a central vendor will be stored electronically in the central laboratory’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
system and TPO system.
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly system and TPO 
system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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10.
Data Analyses
10.1. General Considerations
Approximately 150 patients may be enrolled in this multicenter, open-label, dose-escalation,
5-part, Phase 1b study with dose escalation followed by dose confirmation.  Patients will be 
enrolled into 1 of 5 study parts based on prior therapy or histology.  During the dose-escalation
portion of study Parts A, B, and C, 6 to 12 patients will be enrolled; Part D, 18 to 36 patients will 
be enrolled; and Part E, 9 to 18 patients will be enrolled. During the dose-confirmation portion 
of study Parts A, B, C, D, and E, up to 12 patients will be enrolled. Part C expansion cohort will
evaluate alternate dosing schedules in approximately 12 to 18 patients.  Additionally, for study 
Parts A, B, C, and E, following the confirmation phase, if clinical data indicate preliminary 
efficacy, approximately 12 more patients will be enrolled to obtain clinical evidence for efficacy.
Statistical analysis of this study will be the responsibility of the sponsor. The analyses for this 
study will be descriptive, except for possible exploratory analysis as deemed appropriate.  Data 
analyses will be provided by study part, dose group, and for all study patients combined 
wherever appropriate. For continuous variables, summary statistics will include number of 
patients, mean, median, standard deviation, minimum, and maximum.  Categorical endpoints 
will be summarized using number of patients, frequency, and percentages.  Missing data will not 
be imputed.  Refer to the statistical analysis plan for this study for further detail.
The interpretation of the study results will be the responsibility of the investigator with the Lilly
CRP, pharmacokineticist, and statistician.  The CRP and statistician will also be responsible for 
the appropriate conduct of an internal review for both the final study report and any study-related 
material to be authorized by Lilly for publication.
Exploratory analyses of the data not described below will be conducted as deemed appropriate.
10.2. Patient Disposition
All patient discontinuations will be documented, and the extent of each patient’s participation in 
the study will be reported.  If known, a reason for their discontinuation will be given.
10.3. Patient Characteristics
Patient characteristics will include a summary of the following:

Patient demographics will be reported

Baseline disease characteristics

Prior disease-related therapies 

Concomitant medications
Other patient characteristics will be summarized as deemed appropriate.
10.4. Safety Analyses
All patients who receive at least 1 dose of abemaciclib will be evaluated for safety and toxicity.  
AE terms and severity grades will be assigned by the investigator using CTCAE, version 4.0.

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Safety analyses will include summaries of the following:

AEs, including severity and possible relationship to study drug

dose adjustments

vital signs 

weight

DLTs 

laboratory values and ECGs
10.5. Pharmacokinetic Analyses
PK analyses will be conducted on patients who have received at least 1 dose of the study drug 
and have had samples collected.  
PK parameter estimates will be computed for abemaciclib, its metabolites, and whenever 
possible, for other anticancer agents used in the combination (pemetrexed, gemcitabine, 
ramucirumab, and LY3023414). These PK parameters will be computed by standard 
noncompartmental methods of analysis using WinNonlin Professional Edition on a computer that
meets or exceeds the minimum requirements for this program.
The primary parameters for analysis will be maximum concentration (Cmax) and area under the 
concentration-time curve (AUC0-tlast, AUC0-∞).  Other noncompartmental parameters, such as 
time of half-life (t1/2), apparent clearance (CL/F), and apparent volume of distribution (V/F) may 
be reported.  
In addition to a standard noncompartmental assessment, the plasma concentration data of
abemaciclib will also be analyzed by means of a compartmental approach using NONMEM.  
Plasma data from all patients will be pooled for analyses to determine the compartmental PK
parameters and between- and within-patient variability. Covariate analysis will be also
performed. Once a structural and statistical model has been established, the effect of patient
factors will be assessed. Covariate data distributions will be assessed.
Additional exploratory analyses will be performed if warranted by data, and other validated PK 
software programs (for example, NONMEM) may be used if appropriate and approved by 
Global Pharmacokinetic management.  The version of any software used for the analysis will be 
documented, and the program will meet the Lilly requirements of software validation.
10.6. Efficacy
The study was not designed to make an efficacy assessment.  However, any tumor response data 
will be tabulated and summarized where appropriate.
10.7. Health Outcomes
Change from baseline in MDASI-LC scores will be listed and summarized for each study part at 
each postbaseline time point specified in the Study Schedule (Attachment 1). Resource 
utilization will be described as appropriate.

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10.8. Interim Analyses
Since this is a dose-finding study, data will be reviewed on a cohort-by-cohort basis during the 
study, until the MTDs are determined for each combination therapy.  The purpose of these 
cohort-by-cohort reviews is to evaluate the safety data at each dose level and determine if a DLT 
has been observed that would suggest MTD for each combination therapy has been met or 
exceeded.  The investigators and the Lilly study team will make the determination regarding 
dose escalation based upon their review of the safety and tolerability data as described in this 
protocol.  
During the dose-confirmation portion of each study part, interim analyses may be conducted to 
review available safety, PK, PD, and efficacy data once enrollment to that particular part (A, B, 
C, D, or E ) has completed and all patients in that part have either completed 2 cycles of therapy 
or discontinued from the treatment.  

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11.
Informed Consent, Ethical Review, and 
Regulatory Considerations
11.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the study in a timely manner.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study and to document that the 
patient is satisfied with his or her understanding of the potential risks and benefits of 
participating in the study and desires to participate in the study.
The investigator is ultimately responsible for ensuring that informed consent is given by each 
patient or legal representative before the study is started.  This includes obtaining the appropriate 
signatures and dates on the ICF prior to the performance of any protocol procedures and prior to 
the administration of study drug.
11.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites(s).  
All ICFs must be compliant with the ICH guideline on GCP.  
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  The ERB(s) will review the protocol as required.
The study site’s ERB(s) should be provided with the following:

the current IB or package labeling (for example, Patient Information Leaflet, Package 
Insert, or Summary of Product Characteristics) and updates during the course of the study

ICF

relevant curricula vitae
11.3. Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines 
2) the International Conference on Harmonisation (ICH) Good Clinical Practices (GCP) 
Guideline [E6]
3) applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).

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An identification code assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting AEs and/or other study-related data.
11.4. Investigator Information
Site-specific contact information may be provided in a separate document.
11.5. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
11.6. Final Report Signature
The final report coordinating investigator or designee will sign the clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
The investigator with the most enrolled patients will serve as the final report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the final report coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.

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epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. 2010;28(33):4996-5010.
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Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl 
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Rosell R, Camps C. Soluble vascular endothelial growth factor receptor 2 (VEGFR2): New 
biomarker in advanced non-small cell lung cancer (NSCLC)? J Clin Oncol. 2009;27(suppl). 
Abstract e22108.
Scagliotti GV, De Marinis F, Rinaldi M, Crinò L, Gridelli C, Ricci S, Matano E, Boni C, 
Marangolo M, Failla G, Altavilla G, Adamo V, Ceribelli A, Clerici M, Di Costanzo F, 
Frontini L, Tonato M; Italian Lung Cancer Project. Phase III randomized trial comparing three 
platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol. 
2002;20(21):4285–4291.
Scagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, Simms L, Shepherd FA.
The differential efficacy of pemetrexed according to NSCLC histology: a review of two 
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Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, 
Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing 
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advanced-stage non-small cell lung cancer. J Clin Oncol. 2008;26(21):3543–3551.
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Attachment 1.
Protocol JPBJ Study Schedule

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Relative Day Prior to 
Day 1 of Cycle 1
28
14
7
Comments
Immunogenicity
X
For Part C only:  Immunogenicity samples are to be drawn at 
baseline (Day -14).
Urinalysis 
X
Part C and D only. Performed locally.  If urine dipstick or routine 
analysis indicates proteinuria ≥2+, a 24-hour urine collection (to 
assess protein) must be obtained.
Brain MRI/CT
X
Part C only: Patients will have a baseline brain MRI or CT to rule 
out evidence of CNS metastases.
MDASI-LC
X
MDASI-LC should be administered at baseline (Day -14 to 
Day -1).  Patients should complete before interaction with site staff.
Abbreviations:  CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
ECG = electrocardiogram; FFPE = formalin-fixed paraffin-embedded; LLN = lower limit of normal; LVEF = left 
ventricular ejection fraction; Meds = medications; MDASI-LC = MD Anderson Symptom Inventory- Lung 
Cancer; MRI = magnetic resonance imaging; PK = pharmacokinetic; PD = pharmacodynamic.

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During and Poststudy Assessments
Cycle/Visit
Cycle 1
Cycle 2 and Beyond
a
(if Applicable)
Follow-Up
b
Relative Day within a Cycle
1
8 ± 2
15 ± 2
1
8 ± 2
Medical history
X
X
X
Physical exam
X
X
X
X
Vital signs and weight (temperature, pulse rate, blood
pressure, respiratoryrate)
X
X
X
X
Performance status
X
X
X
CTCAE version 4.0 grading (see Section 8.1.2)
X
X
X
c
Concomitant medications
X
X
X
Tumor measurement (palpable and visible) (see Section 8.3)
X
X
X
ECG
d
X
Abemaciclib therapy
e
Daily every 12 hours
Pemetrexed therapy
f
X
X
Gemcitabine therapy
g
X
X
X
X
Ramucirumab therapy
h
X
X
X
X
LY3023414 therapy
i
Daily every 12 hours
Pembrolizumab therapy 
j
X
X
Radiological tumor assessment
k
X
X
l
Urinalysis
m
X
Hematology
n
X
X
X
X
X
Serum chemistry
n
X
X
X
X
X
Thyroid Functiono
X
X
X
Coagulation Parametersp
X
X
Blood PK sampling
q
X
X
X
X
Immunogenicity
r
X
X
DNA genotyping blood
sample (stored)
X
s
MDASI-LC
t
X
X
Abbreviations:  AE = adverse event; aPTT = activated partial thromboplastin time; CTCAE = Common Terminology Criteria for Adverse Events;
ECG = electrocardiogram; LLN = lower limit of normal; PK = pharmacokinetic; PD = pharmacodynamic; PT/INR = prothrombin time / International 
Normalized Ratio; SAE = serious adverse event.

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During and Poststudy Assessments (continued)
a
Study procedures are to be completed on Day 1 of every cycle starting with Cycle 2 Day 1 (±2 days). Patients may continue to receive study treatment 
beyond 3 years if they are benefiting from abemaciclib or until they meet the criteria for discontinuation as cited in Section 6.3.  Data collected will include: 
AEs, SAEs, study drug dosing and dose reductions as cited in Section 6.2.2.
b
Follow-up starts the day after the patient and the investigator agree that the patient will no longer continue study treatment and ends when final safety 
assessments are completed 30 days (±7) after last dose of study drug.
c
All drug- or procedure-related AEs and SAEs should be followed until they resolve, are no longer considered to be drug- or procedure-related, become stable 
or return to baseline, the patient starts a new therapy, the patient dies, or the patient becomes lost to follow up.  Frequency of evaluation is left to the judgment
of the investigator.  Data on SAEs that occur before the end of trial will be stored in the collection database and the Lilly safety system.
d
Local ECGs (no replicates required) should be obtained at baseline (Day -14 to Day -1) and at Cycle 1 Day 15.
e
Abemaciclib is to be administered every 12 hours on Days 1 through 21 of each cycle.  Patients should not consume food beginning 1 hour before and ending 
1 hour after taking study drug.
f
For Part A, pemetrexed is to be administered on Day 1 of a 21-day cycle.
g For Part B, gemcitabine is to be administered on Days 1 and 8 of a 21-day cycle.
h For Part C, ramucirumab is to be administered on Day 1 of a 21-day cycle.  Following dose confirmation, the expansion cohorts will evaluate alternate dosing 
schedule on Days 1 and 8 of a 21-day cycle.
i
For Part D, LY3023414 is to be administered every 12 hours on Days 1 through 21 of each cycle. LY3023414 may be taken with or without food. On clinic 
days with postdose PK sampling (Day 1 of Cycle 1 and 2), patients are permitted to eat a light snack at least 2.5 hours prior to the study drug dosing, but are 
then asked to fast until after the 4 hour postdose samples are collected.  Glucose testing will be done via Accu-Chek or equivalent (see Attachment 2 and
Attachment 4).
j
For Part E, pembrolizumab is to be administered on Day 1 of a 21-day cycle.
k
Imaging studies are performed locally.  Radiological assessment is performed at baseline (Day -28 to Day -1), then on Day 1 (or up to 7 days before Day 1) of 
every other cycle beginning with Cycle 3.
l
If a patient is discontinued from the study, repeat radiology may be omitted if progressive disease can be documented quantitatively with clinical 
measurements (see Section 8.3).
m Part C and D only.  Performed locally.  Routine dipstick measurements within 72 hours prior to treatment on Day 1 of every second cycle (screening period, 
before Cycle 3, Cycle 5, and every 2 cycles thereafter) and, if clinically indicated, microscopic analysis.  If urine dipstick or routine analysis indicates 
proteinuria ≥2+, a 24-hour urine collection (to assess protein) must be obtained.
n
For central versus local labs, refer to the Clinical Laboratory Tests (see Attachment 2).  For Part D only, HbA1c, triglycerides, and cholesterol will be drawn 
on Day 1 of every third cycle beginning with Cycle 3. For Part E only, Days 1 chemistry and hematology labs will be drawn for all cycles and Day 8 
chemistry and hematology will be drawn for the first 8 treatment cycles. 
o Thyroid studies will performed every other cycle following Cycle 2 (see Attachment 2).
p PT/INR and aPTT should be collected at Screening and at the mandatory Safety Follow-up Visit after discontinuation of study therapy.  Coagulation 
parameters should be determined throughout the study when clinically indicated.  PT/INR and aPTT will be analyzed by the local study site laboratory (see 
Attachment 2).
q
PK sampling should be performed during Cycle 1 and Cycle 2.  For complete details, see PK schedule attachment (Attachment 4).

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Attachment 2.
Protocol JPBJ Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya (except as indicated)
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume (MCV)
Chloride
Mean cell hemoglobin concentration (MCHC)
Calcium
Leukocytes (WBC)
Albumin
Neutrophils (segmented + bands)
Total protein
Lymphocytes
Blood urea nitrogen (BUN)
Monocytes
Creatininea, b, d
Eosinophils
Alkaline phosphatase
Basophils
Alanine aminotransferase (ALT)
Platelets
Aspartate aminotransferase (AST)
Total bilirubin and direct bilirubin
Urinalysis (Part C and D only)b, c
Color
Glucose, fasting (Part D only)b, e
pH
HBA1c (Part D only)a
Specific gravity
Cholesterol (Part D only)a
Protein
Triglyceride (Part D only)a
Glucose
Ketones
Serum pregnancy test (females of child bearing
Blood
potential only)b (local only)
Urobilinogen
Bilirubin
Triidothyronine (T3) or Free Triidothyronine (FT3) 
(Part E only) a,f
Nitrites
Free thyroxine (FT4) (Part E only) a,f
Leukocyte esterase
Thyroid stimulating hormone (TSH) (Part E only) a,f
Microscopic evaluation of urine sediment (for 
casts and crystals)
PT/INR (Part E only) b
aPTT (Part E only) b
Abbreviations:  RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated (central) laboratory.
b
Assayed by investigator-designated (local) laboratory.
c
Urine dipstick or routine analysis indicate proteinuria ≥2+ at baseline and/or while receiving study drug a 
24 hour urine collection (to assess protein) must be obtained.
d
Creatinine clearance (CrCl) requires the use of local creatinine result (see Attachment 7).  Creatinine will be 
assayed by both central and local laboratories when used to calculate CrCl, otherwise only to be drawn centrally.
e
Glucose testing will be performed locally via Accu-Chek or equivalent.
f
If TSH is not within normal limits at baseline, the subject may still be eligible if total T3 or free T3 and free T4 
are within normal limits.

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Attachment 3.
Protocol JPBJ 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
(CRP).
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils, segmented + 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
Anti-smooth muscle antibodya
CPK 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = International Normalised Ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Attachment 4.
Protocol JPBJ Pharmacokinetic Sampling 
Schedule
Pharmacokinetic Sampling Schedule
Part A – Abemaciclib with Pemetrexed
PK Sample 
Number
Cycle and 
Day
Dosing of Study Drugs
Sampling Time for PK from Blood
(Study Drugs)a
1
C1D1
Abemaciclib
Pemetrexed
Predose (0 h)
2
C1D1
Immediately after abemaciclib dose
3
C1D1
1 h ± 10 min after abemaciclib dose
4
C1D1
2 h ± 10 min after abemaciclib dose
5
C1D1
4h ± 20 min after abemaciclib dose
6
C1D1
6 h ± 20 min after abemaciclib dose
7
C1D1
8 h ± 20 min after abemaciclib dose
8
C1D1
10 h ± 20 min after abemaciclib doseb
9
C1D8
Abemaciclib
Predose (0 h)
10
C1D15
Abemaciclib
Predose (0 h)
11
C2D1
Abemaciclib
Pemetrexed
Predose (0 h)
12
C2D1
1 h ± 10 min after abemaciclib dose
13
C2D1
2 h ± 10 min after abemaciclib dose
14
C2D1
4 h  ± 20 min after abemaciclib dose
15
C2D1
6 h ± 20 min after abemaciclib dose
16
C2D1
8 h ± 20 min after abemaciclib dose
17
C2D1
10 h ± 20 min after abemaciclib doseb
Abbreviations: C = cycle; D = day; h = hour; min = minute; PK = pharmacokinetic.
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites concentrations. Separate samples of approximately 2 mL of whole blood will be drawn for 
measurement of pemetrexed concentrations.
b
To omit the collection of the 10 hour “postdose” PK sample for that day does not constitute a protocol violation.

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Part B – Abemaciclib with Gemcitabine
PK Sample 
Number
Cycle and 
Day
Dosing of Study Drugs
Sampling Time for PK from Blood
(Study Drugs)a
1
C1D1
Abemaciclib
Gemcitabine
Predose (0 h)
2
C1D1
Immediately after abemaciclib dose
3
C1D1
1 h ± 10 min after abemaciclib dose
4
C1D1
2 h ± 10 min after abemaciclib dose
5
C1D1
4h ± 20 min after abemaciclib dose
6
C1D1
6 h ± 20 min after abemaciclib dose
7
C1D1
8 h ± 20 min after abemaciclib dose
8
C1D1
10 h ± 20 min after abemaciclib doseb
9
C1D8
Abemaciclib
Gemcitabine
Predose (0 h)
10
C1D15
Abemaciclib
Predose (0 h)
11
C2D1
Abemaciclib
Gemcitabine
Predose (0 h)
12
C2D1
1 h ± 10 min after abemaciclib dose
13
C2D1
2 h ± 10 min after abemaciclib dose
14
C2D1
4 h  ± 20 min after abemaciclib dose
15
C2D1
6 h ± 20 min after abemaciclib dose
16
C2D1
8 h ± 20 min after abemaciclib dose
17
C2D1
10 h ± 20 min after abemaciclib doseb
Abbreviations: C = cycle; D = day; h = hour; min = minute; PK = pharmacokinetic.
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites concentrations.  Separate samples of approximately 2 mL of whole blood will be drawn for 
measurement of gemcitabine and its metabolite concentrations.
b To omit the collection of the 10 hour “postdose” PK sample for that day does not constitute a protocol violation.

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Part C – Abemaciclib with Ramucirumab
PK Sample 
Number
Cycle and 
Day
Dosing of Study Drugs
Sampling Time for PK from Blood
(Study Drugs)a
1
C1D1
Abemaciclib
Ramucirumabc
Predose (0 h)
2
C1D1
Immediately after abemaciclib dose
3
C1D1
1 h ± 10 min after abemaciclib dose
4
C1D1
2 h ± 10 min after abemaciclib dose
5
C1D1
4h ± 20 min after abemaciclib dose
6
C1D1
6 h ± 20 min after abemaciclib dose
7
C1D1
8 h ± 20 min after abemaciclib dose
8
C1D1
10 h ± 20 min after abemaciclib doseb
9
C1D8
Abemaciclib
Ramucirumabc
Predose (0 h)
10
C1D15
Abemaciclib
Predose (0 h)
11
C2D1
Abemaciclib
Ramucirumabc
Predose (0 h)
12
C2D1
1 h ± 10 min after abemaciclib dose
13
C2D1
2 h ± 10 min after abemaciclib dose
14
C2D1
4 h  ± 20 min after abemaciclib dose
15
C2D1
6 h ± 20 min after abemaciclib dose
16
C2D1
8 h ± 20 min after abemaciclib dose
17
C2D1
10 h ± 20 min after abemaciclib doseb
Abbreviations: C = cycle; D = day; h = hour; min = minute; PK = pharmacokinetic.
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites concentrations.  Separate samples of approximately 2 mL of whole blood will be drawn for 
measurement of ramucirumab concentrations.
b
To omit the collection of the 10 hour “postdose” PK sample for that day does not constitute a protocol violation.
c
For Part C dose escalation (C1, C2) and dose confirmation (C3), ramucirumab should only be administered on 
Day 1 of the 21-day cycle. For Part C expansion cohort (C4, C5, and C6), ramucirumab should be administered 
on Days 1 and 8 of a 21-day cycle.  See Table JPBJ.7.3.

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Part D – Abemaciclib with LY3023414
PK Sample 
Number
Cycle and 
Day
Dosing of Study Drugs
Blood 
Glucosec
Sampling Time for PK from 
blood
(Study Drugs)
a
1
C1D1
Abemaciclib
LY3023414
X
Predose (0 h)
c
2
C1D1
X
Immediately after  combination
c
3
C1D1
X
1 h ± 10 min after combination
c
4
C1D1
X
2 h ± 10 min after combination
c
5
C1D1
X
4h ± 20 min after combination
c
6
C1D1
X
6 h ± 20 min after combination
c
7
C1D1
X
8 h ± 20 min after combination
c
8
C1D1
10 h ± 20 min after combination
b
9
C1D8
c
Abemaciclib
LY3023414
X
Predose (0 h)
10
C1D15
c
Abemaciclib
LY3023414
X
Predose (0 h)
11
C2D1
c
Abemaciclib
LY3023414
X
Predose (0 h)
12
C2D1
X
1 h ± 10 min after combination
c
13
C2D1
X
2 h ± 10 min after combination
c
14
C2D1
X
4 h  ± 20 min after combination
c
15
C2D1
X
6 h ± 20 min after combination
c
16
C2D1
X
8 h ± 20 min after combination
c
17
C2D1
10 h ± 20 min after combination
b
Abbreviations: C = cycle; D = day; h = hour; min = minute; PK = pharmacokinetic.
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its 
metabolites concentrations.  Separate samples of approximately 2 mL of whole blood will be drawn for 
measurement of LY3023414 concentrations.  Abemaciclib and LY3023414 will be administered together, 
approximately at the same time.
b
To omit the collection of the 10 hour “postdose” PK sample for that day does not constitute a protocol violation.
c
Additional local blood glucose measurements to be performed. Patients are permitted to eat a light snack at least 
2.5 hours prior to the morning study drug dosing on these days, but are then asked to fast until after the 4 hour 
postdose samples are collected. High-sugar foods (for example, sugary breakfast cereals, fruit juices, coffee with 
sugar, etc.) should be avoided for this light snack until after predose collection.

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Part E – Abemaciclib with Pembrolizumab
PK Sample 
Number
Cycle and 
Day
Dosing of Study Drugs
Sampling Time for PK from blood
(Abemaciclib)
a
1
C1D1
Abemaciclib
Pembrolizumab
Predose (0 h)b
2
C1D1
Immediately after abemaciclib dose
3
C1D1
1 h ± 10 min after abemaciclib dose
4
C1D1
2 h ± 10 min after abemaciclib dose
5
C1D1
4h ± 20 min after abemaciclib dose
6
C1D1
6 h ± 20 min after abemaciclib dose
7
C1D1
8 h ± 20 min after abemaciclib dose
8
C1D1
10 h ± 20 min after abemaciclib dose
c
9
C1D8
Abemaciclib
Predose (0 h)
10
C1D15
Abemaciclib
Predose (0 h)
11
C2D1
Abemaciclib
Pembrolizumab
Predose (0 h)
12
C2D1
1 h ± 10 min after abemaciclib dose
13
C2D1
2 h ± 10 min after abemaciclib dose
14
C2D1
4 h  ± 20 min after abemaciclib dose
15
C2D1
6 h ± 20 min after abemaciclib dose
16
C2D1
8 h ± 20 min after abemaciclib dose
17
C2D1
10 h ± 20 min after abemaciclib dose
c
Abbreviations: C = cycle; D = day; h = hour; min = minute; PK = pharmacokinetic.
a
Samples of approximately 2 mL of whole blood will be drawn for measurement of abemaciclib and its
metabolites concentrations.
b
The predose samples should be taken prior to abemaciclib and pembrolizumab dosing. The date and time of 
abemaciclib dose and pembrolizumab infusion start and stop time should be recorded on the appropriate forms. 
The date and time of all PK samples should be recorded on the appropriate forms.
c
To omit the collection of the 10 hour “postdose” PK sample for that day does not constitute a protocol violation.

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

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Attachment 6.
Protocol JPBJ ECOG Performance Status
ECOG Performance Status
Activity Status
Description
0
Fully active, able to carry on all predisease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able 
to carry out performance of a light or sedentary nature, for example,
light housework, office work
2
Ambulatory and capable of all 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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Attachment 7.
Protocol JPBJ Creatinine Clearance 
Formula
Note:  This formula is to be used for calculating CrCl from local laboratory results only.
For serum creatinine 
concentration in mg/dL:
CrCl =
(140 – agea) (wt)    0.85 (if female), or 1.0 (if male)
(mL/min) 
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl  =
(140 – agea) (wt)  0.85 (if female), or 1.0 (if male)
(mL/min)
0.81 serum creatinine 
(mol/L)
Abbreviation:  CrCl = creatinine clearance
a age in years, weight (wt) in kilograms.
Source:  Cockcroft and Gault 1976.

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Attachment 8.
Protocol JPBJ Sampling Summary
This table summarizes the maximum number of samples (venipunctures), volumes for all 
sampling, and tests (study qualification, health monitoring/safety monitoring, drug concentration, 
tailoring biomarkers, immunogenicity, and exploratory) 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-JPBJ Sampling Summary
Purpose
Sample 
Type
Maximum Amount per 
Sample
Maximum 
Number 
Samples
Maximum 
Total Amount
Study qualificationa
Blood
6 mL
3
18 mL
Health monitoring/Safety 
monitoring (may be more 
than 1 tube)b
Blood
24 mL/Cycle 1
12mL/Cycle 2-n
5.5mL/ Cycles 2-8, Day 8
12mL/Follow up
6
3
7
3
182.5 mL
Archived formalin-fixed, 
paraffin-embedded tumor 
tissue 
Tissue
5 micron
15 slides
75 micron
Drug concentration of 
abemaciclib for all patients 
in trial
Blood
2 mL
17
34 mL
Drug concentration of 
pemetrexed for all patients 
in Part A
Blood
2 mL
17
34 mL
Drug concentration of 
gemcitabine for all patients 
in Part B
Blood
2 mL
17
34 mL
Drug concentration of 
ramucirumab for all patients 
in Part C
Blood
2 mL
17
34 mL
Drug concentration of 
LY3023414 for all patients 
in Part D
Blood
2 mL
17
34 mL
Tailoring biomarkers
Blood
9 mL
1
9 mL
Immunogenicity (Part C 
patients on ramucirumab 
only)
Blood
5 mL
4
20 mL
Hepatic monitoringb
Blood
3 - 30 mL
-

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

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

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

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

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

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

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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for objective progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, that is the reference for calculation of 
progressive disease).
Independent Review of Response and Progression
When objective response (CR + PR) is the primary end point, and when key drug development 
decisions are based on the observation of a minimum number of responders, it is recommended 
that all claimed responses be reviewed by an expert(s) independent of the study.  If the study is a 
randomized trial, ideally reviewers should be blinded to treatment assignment.
irRECIST Assessment of Disease (Part E only)
As noted above, if tumor imaging shows initial disease progression, the study site may elect to 
continue treatment, repeat imaging ≥ 4 weeks later and assess tumor response or confirmed 
progression per irRECIST.
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor response 
seen with immunotherapeutic drugs. irRECIST will be used by site investigator/local radiology 
review to assess tumor response and progression, and make treatment decisions. These data will 
be collected in the clinical database.
Table 3. Imaging and Treatment after First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD by 
RECIST 1.1 
Repeat imaging 
at > 4 weeks at 
site to confirm 
PD
May continue study 
treatment at the local site 
Investigator’s discretion 
while awaiting 
confirmatory tumor 
imaging by site by 
irRECIST.
Repeat imaging at >
4 weeks to confirm 
PD per physician 
discretion only
Discontinue treatment
Repeat tumor 
imaging confirms
PD by irRECIST 
at the local site
No additional 
imaging 
required
Discontinue treatment 
(exception is possible 
upon consultation with 
sponsor)
No additional 
imaging required
N/A

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Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
Repeat tumor 
imaging shows 
SD, PR or CR by 
irRECIST by the 
local site
Continue
regularly 
scheduled 
imaging 
assessments
Continue study treatment 
at the local site 
Investigator’s discretion
Continue regularly 
scheduled imaging 
assessments
May restart study treatment if 
condition has improved and/or 
clinically stable per 
Investigator’s discretion. 
Next tumor image should 
occur according to the every 
X week (XX ± 7 days) 
imaging schedule for the first 
year and Y weeks (XX ± 7 
days) after the first year.

In determining whether or not the tumor burden has increased or decreased, local study 
site investigators should consider all target lesions as well as non-target lesions (please 
refer to irRECIST TIP Sheet). Subjects that are deemed clinically unstable are not 
required to have repeat tumor imaging for confirmation.

For a clinically stable subject with first radiologic evidence of progressive disease by 
RECIST 1.1 (i.e., unconfirmed progression of disease), it is at the discretion of the
site investigator to continue treating the subject with the assigned treatment per protocol 
until progression of disease is confirmed at least 28 days from the date of the scan first 
suggesting PD. If radiologic progression is confirmed by subsequent scan then the 
subject will be discontinued from trial treatment. If radiologic progression is not 
confirmed by irRECIST per the site, then the subjects may continue on treatment and 
follow the regular imaging schedule intervals until progression is confirmed at a later 
time point by the site.
o
NOTE: If a subject has confirmed radiographic progression (i.e. 2 scans at least 
4 weeks apart demonstrating progressive disease) per irRECIST, but the subject is 
achieving a clinically meaningful benefit, and there is no further increase in the 
tumor burden at the confirmatory tumor imaging, an exception to continue 
treatment may be considered following consultation with the Sponsor. In this 
case, if treatment is continued, tumor imaging should continue to be performed 
following the intervals as outlined in Table 3.

Any subject deemed clinically unstable should be discontinued from trial treatment at 1st
radiologic evidence of PD and is not required to have repeat imaging for PD 
confirmation.

In subjects who discontinue study therapy without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
using the same imaging schedule used while on treatment (every Y weeks (XX days ± 7 
days), until (1) the start of new anti-cancer treatment, (2) disease progression (3) death, or 
(4) the end of the study, whichever occurs first.
irRECIST data will be collected in the clinical database.

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Attachment 10.
Protocol JPBJ Inducers, Strong Inhibitors 
of CYP3A or Substrates of CYPs with Narrow Therapeutic 
Range
The information in this attachment is provided for guidance to investigators and 
does not preclude the use of these medications if clinically indicated.
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.
Strong inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Verapamil

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Cytochrome P450 Substrates with Narrow Therapeutic Range
Cytochrome P450
Substrate
CYP1A2
Theophylline
Tizanidine
CYP2C9
Warfarina
Phenytoin
CYP2D6
Thioridazine
Pimozide
CYP3A
Alfentanil
Astemizole
Cisapride
Cyclosporine
Dihydroergotamine
Ergotamine
Fentanyl
Pimozide
Quinidine
Sirolimus
Tacrolimus
Terfenidine
a
Important note:  For patients who receive concomitant warfarin, appropriate monitoring of the International Normalized 
Ratio (INR) must be performed.

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Attachment 11.
Protocol JPBJ Child-Pugh Score
Child-Pugh Score
The Child-Pugh score employs 5 clinical measures of liver disease.  Each measure is scored 
1 through 3, with 3 indicating most severe derangement.
Measure
1 Point
2 Points
3 Points
Total bilirubin, mol/L (mg/dL)
<34 (<2)
34-50 (2-3)
>50 (>3)
Serum albumin (g/dL)
>3.5
2.8-3.5
<2.8
PT INR
<1.7
1.71-2.30
>2.30
Ascites
None
Mild
Moderate to Severe
Hepatic encephalopathy
None
Grade I-II (or suppressed with 
medication)
Grade III-IV (or 
refractory
Abbreviations:  INR = International Normalized Ratio; PT = prothrombin time.
Source: Pugh et al. 1973.

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Attachment 12.
Protocol JPBJ Protocol Amendment 
I3Y-MC-JPBJ(g) Summary A Phase 1b Study of 
Abemaciclib in Combination with Multiple Single-Agent 
Options for Patients with Stage IV NSCLC
Overview
Protocol I3Y-MC-JPBJ, A Phase 1b Study of Abemaciclib in Combination with Multiple 
Single-Agent Options for Patients with Stage IV NSCLC, has been amended.  The new protocol 
is indicated by Amendment (h) and will be used to conduct the study in place of any preceding 
version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Included TBL and VTE in abbreviations (Section 4).

Section 5.1.8 incorporated rationale for Amendment (h) to update safety monitoring 
information for hepatic conditions, renal function, and VTEs.

Included tablets as a formulation that will be supplied (Section 7.1)

Section 7.2.4.1.1 modified, including addition of Table JPBJ.7.6 along with Sections 
7.2.4.1.1.1, 7.2.4.1.1.2, 7.2.4.1.1.3, and 7.2.4.1.1.4 for alignment with safety updates.

Sections 7.5.1.2, 8.1.4.1, and 8.1.4.2 incorporated additional safety monitoring language for 
renal function, hepatic conditions, and VTEs. 

CYPs text updated to align with abemaciclib program information (Attachment 10).
Minor typographical and formatting edits were made throughout the document for clarity and 
consistency.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Section 4. Abbreviations and Definitions
Term
Definition
…
…
TBL
total bilirubin
…
…
VTE
venous thromboembolic event
…
…
Section 5.1.7. Rationale for Amendment (g)
…
Dose modification Table JPBJ.7.12Table JPBJ.13 for pembrolizumab was updated to include 
dose adjustments in case of myocarditis to be consistent with the current Investigator’s Brochure 
(IB) for pembrolizumab version 15. Formatting changes in the table were also made.
…
Section 5.1.8. Rationale for Amendment (h)
Study JPBJ 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 metastatic setting.  The amendment updated the safety 
language regarding hepatic monitoring, assessment of renal function, and venous 
thromboembolic events (VTEs) for ongoing patients. Updates to Attachment 10 were completed 
to harmonize the list of CYP inhibitors and inducer, including those with narrow therapeutic 
range. Minor typographical and formatting edits were made throughout the document for clarity 
and consistency.
Section 7.1. Materials and Supplies
Abemaciclib will be supplied as capsules or tablets for oral administration.  The capsules/tablets 
should be stored at room temperature according to the range provided on the product label and 
not opened, crushed, or dissolved.  Investigators should instruct patients to store the 

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capsules/tablets in the original package and in a location inaccessible to children.  Clinical study 
materials will be labeled according to country regulatory requirements.
…
Section 7.2.4.1.1. Abemaciclib
Table JPBJ.7.6 presents dose adjustments to occur if the event is possibly related to abemaciclib.
Table JPBJ.7.6.
Toxicity Dose Adjustments and Delays of Abemaciclib for Study
I3Y-MC-JPBJ
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Hematologic Toxicity
Section 7.2.4.1.1.1
Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MAY be reduced 
by 1 dose level -
investigator’s discretion.
Hematologic Toxicity
Section 7.2.4.1.1.1
Recurrent Grade 3
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced 
by 1 dose level.
Hematologic Toxicity
Section 7.2.4.1.1.1
Grade 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 2.
Dose MUST be reduced 
by 1 dose level.
Hematologic toxicity: If 
patient requires administration 
of blood cell growth factors
Section 7.2.4.1.1.1
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 1 dose level unless 
already performed for 
incidence of toxicity that 
lead to the use of growth 
factor.
Nonhematologic Toxicitya
(except diarrhea and ALT 
increased)
Section 7.2.4.1.1.2
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 1 dose level.
Nonhematologic Toxicity
Section 7.2.4.1.1.2
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to 
either baseline or Grade 1.
Dose MUST be reduced 
by 1 dose level.
Diarrhea
Sections 7.2.4.1.1.3 and 
7.5.1.1 
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.
Diarrhea
Sections 7.2.4.1.1.3 and 
7.5.1.1
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 1 dose level.

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Toxicity Dose Adjustments and Delays of Abemaciclib for Study I3Y-MC-JPBJ
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Diarrhea
Sections 7.2.4.1.1.3 and 
7.5.1.1
Grade 3 or 4
Dose MUST be suspended 
until toxicity resolves to at 
least Grade 1.
Dose MUST be reduced 
by 1 dose level.
ALT Increased 
Sections 7.2.4.1.1.4 and 
8.1.4.1
Persistent or recurrent
b 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 7.2.4.1.1.4 and 
8.1.4.1
Grade 4 (>20.0×ULN) d
Abemaciclib MUST be 
discontinued.
Abemaciclib MUST be 
discontinued.
ALT Increased with increased 
total bilirubin, in the absence 
of cholestasis
Sections 7.2.4.1.1.4 and 
8.1.4.1
Grade 3 increased ALT (˃5.0 x 
ULN) with total bilirubin >2 x 
ULN d
Abemaciclib MUST be 
discontinued
Abemaciclib MUST be 
discontinued
Abbreviations:  ALT = alanine transaminase; ASCO = American Society of Clinical Oncology; 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 8.1.4.1 and 7.5.1.2.
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).  
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 
8.1.4.1 for additional guidance for hepatic monitoring
Dose adjustments are allowed both within a cycle and between cycles. 
If a patient experiences a recurrent Grade 3 or a 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 JPBJ.7.6.
If a patient experiences a Grade 3 hematologic toxicity possibly related to abemaciclib, then 
dosing must be suspended (until toxicity resolves to either baseline or at least Grade 2) and the 
dose of abemaciclib may be reduced at the investigator’s discretion as outlined in Table 
JPBJ.7.6.
If a patient requires administration of blood cell growth factors (regardless of severity), then 
dosing 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.  The dose of abemaciclib must
be reduced by 1 dose level (unless already performed for incidence of toxicity that lead to the use 
of growth factor) as outlined in Table JPBJ.7.6.
If a patient experiences >Grade 3 nonhematologic toxicity 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 JPBJ.7.6.

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If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
refer to Section 7.5.1) possibly related to abemaciclib that does not resolve with maximal 
supportive measures within 7 days to either baseline or Grade 1, then dosing may be suspended 
(until the toxicity resolves to either baseline or at least Grade 1) and the dose of abemaciclib may
be reduced as outlined in Table JPBJ.7.6.
If a patient who, in the judgment of the investigator, is receiving clinical benefit from study 
therapy requires further dose reduction than is outlined in Table JPBJ.7.67, then the investigator 
must discuss with the Lilly CRP prior to any further dose reduction.  For patients requiring dose 
reduction(s), re-escalation to a prior dose level is permitted only after consultation with the Lilly 
CRP.
…
Table JPBJ.7.67.
Dose Adjustments of Abemaciclib for Study I3Y-MC-JPBJ
…
Section 7.2.4.1.1.1. Hematologic Toxicity
If a patient experiences a Grade 3 hematologic toxicity possibly related to abemaciclib, then 
dosing must be suspended (until toxicity resolves to either baseline or at least Grade 2) and the 
dose of abemaciclib may be reduced at the investigator’s discretion as outlined in Table 
JPBJ.7.6.
If a patient experiences a recurrent Grade 3 or a 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 JPBJ.7.6.
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 (regardless of severity), then 
dosing 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.  The dose of abemaciclib must

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be reduced by 1 dose level (unless already performed for incidence of toxicity that lead to the use 
of growth factor) as outlined in Table JPBJ.7.6.
Section 7.2.4.1.1.1. Nonhematological Toxicity (except diarrhea and ALT increase)
If a patient experiences >Grade 3 nonhematologic toxicity 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 JPBJ.7.6.
If a patient experiences persistent or recurrent Grade 2 nonhematologic toxicity (except diarrhea; 
refer to Section 7.2.4.1.1.3 or ALT increased, refer to Section 8.1.4.1) 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 JPBJ.7.6.
Section 7.2.4.1.1.3. Diarrhea
If a patient experiences Grade 2 diarrhea that does not resolve with maximal supportive measures 
(refer to Section 7.5.1.1) 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 or any grade diarrhea that requires hospitalization (refer to 
Section 7.5.1.1) study drug must be suspended (until the toxicity resolves to either baseline or at 
least Grade 1); and a dose reduction is required. For Grade 3 or Grade 4 diarrhea, the dose must 
be suspended and a dose reduction is required Table JPBJ.7.6.
Section 7.2.4.1.1.4. Hepatic Toxicity
Dose modifications and management for increased ALT are provided in Table JPBJ.7.6. 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 8.1.4.1 for additional hepatic 
monitoring guidance.
Section 7.2.4.1.2. Pemetrexed
Pemetrexed dose adjustments at the start of a subsequent cycle should be based on nadir 
hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy.  

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Treatment may be delayed to allow sufficient time for recovery.  Upon recovery, patients should 
be re-treated using the guidelines in Table JPBJ7.7Table JPBJ.7.8, which are suitable for using 
pemetrexed as a single-agent or in combination.
Table JPBJ.7.78.
Hematologic Dose Reduction for Pemetrexed in 
Study I3Y-MC-JPBJ
…
If patients develop nonhematologic toxicities (excluding neurotoxicity) >Grade 3, treatment 
should be withheld until resolution to less or equal to the patent’s baseline value.  Treatment 
should be resumed according to Table JPBJ.7.8Table JPBJ.7.9.
Table JPBJ.7.89.
Nonhematologic Dose Reduction for Pemetrexed in 
Study I3Y-MC-JPBJ
…
Section 7.2.4.1.3. Gemcitabine
Patients receiving gemcitabine should be monitored prior to each dose (Day 1 and Day 8 of each 
cycle) with a complete blood count (CBC), including differential and platelet count.  If marrow 
suppression is detected, therapy should be modified or suspended according to guidelines in 
Table JPBJ.7.9Table JPBJ.7.10.
Table JPBJ.7.910.
Dose Adjustments of Gemcitabine for Study I3Y-MC-JPBJ
…
Section 7.2.4.1.4. Ramucirumab
Dose modifications are permitted for investigational product in the setting of non-life-threatening 
and reversible Grade 3 clinical AEs (for example, fever) considered to be at least possibly related 
to investigational product and that resolve to Grade ≤1 or pretreatment baseline within 
1 treatment cycle (approximately 3 weeks). If a Grade 4 AE occurs and is deemed at least 
possibly related to ramucirumab, then treatment should be discontinued except in the specific 
case of Grade 4 fever or Grade 4 laboratory abnormalities.  If Grade 4 fever or laboratory 
abnormalities resolve to Grade ≤1 or baseline within 1 treatment cycle (approximately 3 weeks), 
treatment with ramucirumab may be continued at the discretion of the investigator.  In these 
settings, ramucirumab may be readministered.  If a second instance of such an event occurs, 
ramucirumab should be subsequently readministered at a reduced dose level.  A second dose 
reduction is permitted for this level of event (Grade 3 or 4) (refer to Table JPBJ.7.10Table 
JPBJ.7.11).  If the dose of ramucirumab is reduced because of potentially related AEs, 
subsequent dose increases are not permitted.  Specific guidelines for ramucirumab dose 
modifications related to infusion reactions and thrombotic events are provided in Section 

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7.2.4.1.4.1 and Section 7.2.4.1.4.3, respectively.  Criteria for dose reduction in the setting of 
hypertension and proteinuria are detailed in Section 7.2.4.1.4.2 and Section 7.2.4.1.4.14 
respectively.
Table JPBJ.7.1011.
Dose Adjustments of Ramucirumab for Study I3Y-MC-JPBJ
…
Section 7.2.4.1.5. LY3023414
For patients receiving combination treatment with abemaciclib and LY3023414 in Part D, the 
same guidelines for dose adjustments due to toxicities possibly related to LY3023414 apply as 
outlined for abemaciclib in Section 7.2.4.1.1.
Dose adjustments of LY3023414 are described in Table JPBJ.7.11Table JPBJ.7.12.
Table JPBJ.7.1112.
Dose Adjustments of LY3023414 for Study I3Y-MC-JPBJ
…
For patients in Part D (LY3023414 + abemaciclib), the investigator will interpret and document 
whether or not an AE has a reasonable possibility of being related to each of the study drugs, 
taking into account the disease, concomitant treatments, or pathologies, in order to individually 
adjust study drug(s) doses.  For a toxicity that due to its nature is possibly related to LY3023414 
only, dose adjustments for abemaciclib should be considered only after dose adjustment of 
LY3023414 (and vice versa for possibly only abemaciclib-related toxicities; see Section 
7.2.4.1.1).  LY3023414 should be dose-reduced to the next lower dose level (Table 
JPBJ.7.11Table JPBJ.7.12) following discussion between the investigator and the sponsor.
…
Section 7.2.4.2.1. Abemaciclib
…
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 7.5.1 
for guidance and supportive measures of diarrhea toxicity possibly related to abemaciclib or  
Section 8.1.4.1 for additional hepatic monitoring guidance.
…
Section 7.2.4.2.1.1. Diarrhea
A patient with diarrhea requiring hospitalization (irrespective of grade) or severe diarrhea 
(Grade 3 or 4) must have study drug suspended (until the toxicity resolves to either baseline or at 

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least Grade 1) and must have the study drug dose reduced by 1 dose level as outlined in Table 
JPBJ.7.6.
If a patient experiences persistent or recurrent Grade 2 diarrhea that does not resolve with 
maximal supportive measures (refer to Section 7.5.1) within 24 hours to either baseline or at 
least Grade 1, then study drug should be suspended (until the toxicity resolves to either baseline 
or at least Grade 1) and the dose of study drug may be reduced by 1 dose level as outlined in 
Table JPBJ.7.6 at the discretion of the investigator.
Section 7.2.4.2.6. Pembrolizumab
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Therefore, early recognition and initiation of 
treatment are critical to reduce complications. Based on existing clinical study data, more AEs 
were reversible and could be managed with interruptions of study treatment, administration of 
corticosteroids, and/or other supportive care. Dose modification and toxicity management 
guidelines for AEs associated with pembrolizumab are provided in Table JPBJ.7.12Table 
JPBJ.7.13 below. 
Table JPBJ.7.1213.
Dose Adjustments for Pembrolizumab in Study I3Y-MC-JPBJ
…
Section 7.5.1.2. Guidance for Monitoring of Renal Function in Patients on Abemaciclib
…
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 alterations (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 JPBJ.7.6).
Section 7.5.1.4. Supportive Care Guidelines for Pembrolizumab—Part E only
…
Note:  If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table JPBJ.7.12Table 
JPBJ.7.13 for guidelines regarding dose modification.
Management of Infusion Reactions:

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Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion.  Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion reaction 
are provided in Table JPBJ.7.13Table JPBJ.7.14.
Table JPBJ.7.1314.
Infusion Reaction Treatment Guidelines in Study I3Y-MC-JPBJ
…
Section 8.1.4. Safety Monitoring
The Lilly CRP or CRS will monitor safety data throughout the course of the study.  Lilly will 
review SAEs within time frames mandated by standard operating procedures and will review 
trends, laboratory analytes, and AEs at periodic intervals.  Attachment 5 provides 
recommendations for reporting SAEs.

If a study patient experiences elevated ALT >5X ULN and elevated total bilirubin 
>2X ULN, clinical and laboratory monitoring should be initiated by the investigator.

For patients entering the study with ALT >3X ULN, monitoring should be triggered 
at ALT >2X baseline.
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP/CRS regarding collection of specific recommended 
clinical information and follow-up laboratory tests (see Attachment 3).
Section 8.1.4.1. 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

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
ALT>8x ULN for patients 

discontinuation from study treatment due to a hepatic event or an abnormality of 
liver tests
Section 8.1.4.2. 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.
Attachment 10. Protocol JPBJ Inducers, Strong Inhibitors of CYP3A or Substrates of VYPs with Narrow 
Therapeutic Range
…
Strong inhibitors of CYP3A
All HIV protease inhibitors
Aprepitant
Ciprofloxacin
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Verapamil
Cytochrome P450 Substrates with Narrow Therapeutic Range
Cytochrome P450
Substrate
CYP1A2
Theophylline
Tizanidine
CYP2C8
Paclitaxel
…
…

Leo Document ID = 475f9892-9d0f-4b44-a370-1fe324bd1e45
Approver: 
Approval Date & Time: 08-Feb-2019 16:09:06 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 08-Feb-2019 21:06:03 GMT
Signature meaning: Approved
PPD
PPD